Full Report - Malaria Centre - London School of Hygiene & Tropical ...

Malaria Centre Report 2006 – 07

Malaria Centre 

London School of Hygiene & Tropical Medicine 

Keppel Street 

London 

WC1E 7HT 

www.lshtm.ac.uk/malaria 

Tel: +44 (0) 20 7 636 2295 

Director: Prof. Christopher Whitty 

Deputy Director: Dr David Baker 

Manager: 

Dr Becky Wright 

Copies of this report may be obtained from the above website or address

Contents 

Foreword.............................................................. 2 

Introduction......................................................... 2 

Policy Relevance.................................................. 3 

Research Summaries: 

Parasite Biology.............................................. 4 

Immunology & Vaccination......................... 10 

Drug Development & Drug Resistance..... 18 

Epidemiology.................................................. 26 

Clinical Trials & Clinical Studies............... 35 

Vector Control................................................ 49 

Social & Economic Sudies............................ 57 

Facilities: 

The Malaria Repository...................................... 74 

Malaria Reference Laboratory (MRL)................ 75 

Hospital for Tropical Diseases (HTD)................ 75 

Executive Summaries: 

Research Capacity, Development & Training.... 76 

Translational Research....................................... 77 

Publications 2006-07............................................ 78 

Staff & Students................................................... 90 

Contact information............................................ 92 

Abbreviations....................................................... 93

2 

Foreword 

Introduction 

Malaria remains one of the major diseases of poverty 

in Africa, Asia and South America. The London 

School of Hygiene & Tropical Medicine (LSHTM) has a 

long tradition of conducting malaria research to support the 

fight against this major but avoidable and treatable disease 

of the most vulnerable. LSHTM remains committed to this 

fight and there is clear evidence of success in many areas of 

the world, with falling incidence of malaria in many areas 

and introduction of new prevention and treatment strategies, 

many of which are underpinned by research done at the 

School. 

This report highlights the broad range of research 

undertaken here from fundamental research in parasite 

and vector biology, and immunology through to social and 

economic studies with the majority of studies having clear 

and direct implications for public health. One of the unique 

strengths of LSHTM malaria research is its multi-disciplinary 

nature. The Malaria Centre brings together those researching 

in malaria from all disciplines to ensure an integrated 

approach. The success of this approach is acknowledged both 

in the conventional academic measures of major high-profile 

publications and grants, and also in the many members of 

the Malaria Centre who advise the WHO, governments and 

major institutions. The LSHTM is committed to continuing 

to build on the strength of the integrated approach of the 

Malaria Centre. 

Professor Sir Andrew Haines 

Director of LSHTM 

The two years covered by this report have been very 

positive for malaria research and control and the work 

of the Malaria Centre. There has been evidence from several 

countries including Rwanda, The Gambia, Zanzibar and 

Zambia of significant declines in malaria. This demonstrates 

that systematic application of control and treatment measures 

such as those highlighted in this report, can have a substantial 

impact on health. 

Political and financial commitment to malaria continued, 

boosted by the commitment of the Director General of 

WHO and Bill and Melinda Gates, to the eventual eradication 

of malaria. In the UK, there has been sustained commitment to 

malaria research from DFID and the All-Party Parliamentary 

Malaria Group. 

Scientifically, the two years covered by this report have 

been very successful for the Malaria Centre across the 

wide range of scientific disciplines represented within it. 

The pages of the Report should give some indication of the 

breadth and depth of the research undertaken. 

The success of the cross-diciplinary model of the 

Malaria Centre in research and capacity building 

has been recognized by the recent award of several major 

grants including a grant for US$39.7 million from the Bill 

and Melinda Gates Foundation for the ACT Consortium, a 

grant of £7.3 million from the Wellcome Trust for training 

and research capacity development and major grants from 

the Medical Research Council, Wellcome Trust, Gates 

Foundation, DFID, European Union and others. 

Malaria remains one of the most important yet most 

defeatable diseases of poverty and the Malaria 

Centre aims to continue to play a leading role in all aspects 

of the attack on malaria, from the initial basic science to 

development of new tools through to final field-testing, 

operational and economic evaluations of interventions 

and assisting policymakers and those involved in tackling 

malaria on the ground. 

Christopher Whitty 

Director, Malaria Centre 

London School of Hygiene & Tropical Medicine

3 

Policy Relevance 

The Malaria Centre conducts research across the range from 

basic science through to applied and translational research. 

The ultimate aim of this research is to provide best evidence for 

policy and practice in the prevention, diagnosis and treatment of 

malaria throughout the world. Members of the Malaria Centre 

from all disciplines provide technical support for the policy 

process for WHO, DFID and the Department of Health in the UK 

and for major philanthropic foundations, as well as providing 

technical assistance to malaria control programs in the countries 

in which the Malaria Centre works. 

In this report, earlier sections concentrate on the basic science 

through to the early trial stages of interventions. We hope the 

majority of these studies will eventually lead to interventions 

which can have an impact on malaria. The second half covering 

Clinical Trials & Clinical Studies, Vector Control and Social & 

Economic studies have direct policy relevance as they are testing 

interventions which have been developed through basic science 

from many disciplines in the field. This report includes studies 

across a range of geographical and policy settings. 

Examples of studies with direct policy relevance in the case 

management and prevention of malaria are: 

• Studies on the new intervention on the intermittent 

preventive treatment in infancy (IPTi) and intermittent 

preventive treatment in children (IPTc) across a range of 

geographical and social settings, particularly in Africa. 

• The often overlooked problems in the management of 

vivax malaria, particularly in areas where health services 

are fractured. This includes trials in the North-West Frontier 

Province of Pakistan and Afghanistan. 

• Diagnostic strategies for malaria and associated anaemia, 

including rapid diagnostic tests, laboratory studies testing 

sensitivity and specificity of tests, through to operational 

studies determining how diagnostic tools are used in practice 

(often not as anticipated) and the potential economic impact 

of deploying these tests in Africa. 

• Mapping the extent of drug resistance and then testing new 

drugs where drug resistance is a problem. 

• Studies on severe malaria and malaria in pregnancy. 

• The spread of insecticide-resistance and the development 

of long-lasting net technology, along with renewed interest 

in the elimination of malaria in some settings, means that 

vector control is going through a very exciting period and 

a wide-range of studies in this report have policy relevance 

for vector control. These range from tests for detection of 

synthetic pyrethroids on bed-nets and walls, through to 

the effects of long-lasting nets in practice and their costeffectiveness. 

There is a major program for the development 

of new insecticides and investigation of innovative methods 

such as use of fungi for adult malaria mosquito control. 

• A particular strength of the LSHTM Malaria Centre is the 

combination of practical field and laboratory studies with 

an internationally recognized group of scientists working 

in economic and social issues. Cost effectiveness and cost 

benefit studies of drugs, diagnostic tests and vector control 

measures are combined with real life studies in health 

systems research in Africa and Asia. This includes studies 

in countries which are highly endemic for malaria, such as 

Tanzania, and those where malaria can be underestimated, 

such as Yemen and the Philippines. 

• An effective malaria vaccine is still some way off 

deployment but in addition to immunological studies 

helping to develop vaccines and clinical studies assessing 

current vaccine candidates, social and economic studies of 

how they could be deployed once they are developed are 

already underway. 

• Surveillance of malaria is vital for malaria reduction 

programmes. Centre projects are monitoring changes in 

transmission with sensitive molecular and serological 

techniques suitable for scale-up to regional and national 

level. 

• The Malaria Centre has engaged strongly with the scientific 

questions that would need to be answered in any attempt 

to eliminate malaria, which would need a multi-speciality 

approach. 

The Malaria Centre members aim to package and present data 

in ways which are most useful to policy makers where it 

is policy-relevant. This includes authoring reports on behalf of 

bodies such as DFID and the All-Party Parliamentary Malaria 

Group, which pull together data both produced by the Malaria 

Centre itself and from other sources. Individual members of the 

Malaria Centre working in malaria endemic countries maintain 

very close relationships with national malaria control programs 

to ensure that all research conducted is policy-relevant in the 

local environment and that the results are fed back as quickly as 

possible to assist policy makers in their decisions. 


4 Parasite Biology 

Adetailed understanding of parasite biology at the molecular level is essential to maximize the chance of 

developing new drug classes and has implications for our understanding of how the parasite can survive 

and spread. Conventionally effective antimicrobials target particular cell structures, or biochemical pathways, 

and especially the dividing stage of parasites and bacteria. There is increasing interest in the sexual stages of 

the parasite, which are essential to the spread of malaria; if drugs or vaccines developed on the basis of an 

understanding of gametocyte function can be used to target these stages, this has important implications for 

control. Animal models of malaria can give insights into how malaria parasites interact with their host. There 

are examples of research in all these areas in this section. 

The life cycle of the malaria parasite 

Erythrocytic 

cycle in liver 

merozoite penetrates 

red blood cell 

Erythrocytic 

cycle in blood 

sporozoites 

injected 

into human 

with saliva 

of mosquito 

sporozoite 

penetrates 

liver cell 

merozoites 

reinvade 

red cells 

macro-gametocyte 

micro-gametocyte 

HUMAN 

sporozoites in 

salivary gland 

fertilisation 

gametocytes taken 

into mosquito 

stomach with 

blood meal 

microgamete 

MOSQUITO 

(Anopheles) 

ookinete 

gametogenesis 

oocyst ruptures 

to liberate sporozoites 

which penetrate 

salivary 

gland 

sporogeny 

ookinete penetrate 

midgut 

wall of mosquito 

to develop into 

oocyst 

A 

B 

Fluorescence analysis of P. falciparum parasites stably transfected with 

episomes expressing green fluorescent protein (GFP) under the control 

of a sexual stage specific promoter. 

GFP expression was visualized with UV light and appears green in the micrographs. 

Nuclear staining with DAPI appears blue. 

Panel A shows stage IV gametocytes and panel B stage V. 


Targeting malaria transmission through interference with 

signalling in Plasmodium falciparum gametocytogenesis 

(SIGMAL) 

LSHTM investigators: Spencer Polley, Quinton Fivelman and David Baker 

External investigators/collaborators: Christian Doerig (Wellcome Centre for Molecular 

Parasitology, Glasgow/Inserm U609); Amit Sharma (Intl Centre for Genetic Engineering & 

Biotechnology, New Delhi); Laurent Meijer (CNRS, Paris); Pietro Alano (Istituto Superiore di 

Sanita, Rome), Francis Mulaa (Uni. of Nairobi, Kenya) 

Funding body: European Commission 

Inhibiting transmission of the malaria parasite from infected humans to the 

mosquito vector would be of considerable interest in the context of malaria 

control, especially in order to prevent the dissemination of drug-resistant 

genotypes. Since only sexual forms of the parasite (the gametocytes) are 

infective to the mosquito, blocking gametocytogenesis would prevent

SUMMARY 

Targeting malaria transmission through interference with 

signalling in Plasmodium falciparum gametocytogenesis 

Sex ratio studies in P. falciparum 

Identifying the determinants of centromere function in 

the human malaria parasite Plasmodium falciparum 

Functional analysis of Plasmodium falciparum genes 

expressed during sexual stage development using microarrays 

and gene transfection techniques 

Genome-wide patterns of copy number variation in the 

malaria parasite Plasmodium falciparum 

Evolutionary, population genetic and functional 

analyses of a malaria gamete surface protein 

gene family 

Gene-specific signatures of elevated non-synonymous 

substitution rates correlate poorly across the 

Plasmodium Genus 

Characterisation of a family of Plasmodium membrane 

skeleton proteins 

Parasite Biology 

Characterization of Plasmodium LCCL proteins 

The role of metacaspases in Plasmodium development 

and apoptosis 

5 

transmission. The molecular control of gametocytogenesis is not understood. 

Our laboratories have independently brought significant contributions to the 

characterisation of (i) components of signalling pathways, some of which 

are likely to be involved in differentiation, and (ii) proteins expressed at the 

onset of gametocytogenesis, such as Pfg27 and Pfs16. We have merged these 

lines of investigation to generate an integrated picture of the early events of 

sexual development at the molecular level. Furthermore, we have undertaken 

screening assays for enzymes suspected to be involved in gametocytogenesis 

to identify compounds able to interfere with malaria transmission. This 

programme has therefore been an important interface between our biological 

research and identification of potential drugs that can inhibit transmission of 

malaria. 

Sex ratio studies in P. falciparum 

LSHTM investigators: Samana Schwank, Colin 

Sutherland, Chris Drakeley 

Funding Body: Europaeischer Lasndersverein der 

Industrie 

Gametocytes, the sexual blood stages of 

the malaria parasite, are responsible for the 

transmission from the vertebrate host to 

the mosquito vector. Inside the mosquito, 

gametocytes release their male and female 

gametes, of which some will undergo 

fertilization leading to the continuation of the 

life cycle. Malaria parasites, like many other 

eukaryotes, are thought to be able to alter the 

sex ratio of their gametes to maximize the Day 3 

reproductive output and thereby inevitably Male Ab +ve 96 

Female Ab +ve 3 

influence the epidemiology of this disease. Apparent Sex Ratio 0.97 

The standard method for quantifying sex 

ratios in P. falciparum is based on the visual 

identification of male and female gametocytes by light microscopy. Limitation 

of gametocyte’s availability from field samples and difficulty of sexing 

gametocytes have hampered sex ratio studies so far, despite their important 

role in transmitting this disease. Sex ratios in the malaria parasite have been 

reported to change corresponding to a variety of factors such as in the presence 

of chemotherapy, certain immunological factors, host hormones and the 

presence of polyclonal infections. Our project focuses on the establishment 

of an assay that will allow the quantification of sex specific proteins via 

quantitative RT-PCR which will enable us to establish more precise sex ratios 

data from field samples, whether for examining the effect of treatment on 

sex ratio or for longitudinal monitoring of changes in sex ratio over extended 

periods of gametocyte carriage. We are using the IFAT technique to provide 

validated sex ratios in vitro and to elucidate the timing of the expression of sex 

specific proteins during gametocyte development. 

Day 5 

Male Ab +ve 14 

Female Ab +ve 19 

Apparent Sex Ratio 0.42 

Immunofluorescent antibody test (IFAT) showing immature gametocyte 

stages II and III (Day3) and mature stages IV and V gametocytes (Day 

5) visualised using antibodies to a-tubulin II (red fluorescence), and 

Pfs377 (green fluorescence). 

a-tubulin II is expressed by all gametocytes early in development, and is 

therefore not a truly male-specific marker. 

Pfs377 comes on late in only a proportion of gametocytes, and its prevalence 

is consistent with the known frequency of female gametocytes. Therefore, this 

can be used as a gender-specific marker, but only in mature gametocytes. 

Gametocytes labelled with Pfs377 antibodies are generally also labelled with 

a-tubulin II antibodies. 



Identifying the determinants of 

centromere function in the human 

malaria parasite Plasmodium 

falciparum 

LSHTM investigators: John Kelly, David Baker, 

Jenny Spence and Marta Staff 

External investigators/collaborators: Judit Nagy 

(Imperial College London) and Brendan Crabb (The 

Walter and Eliza Hall Institute of Medical Research, 

Australia) 

Funding body: Wellcome Trust 

Fine-mapping of the etoposide-mediated topoisomerase II cleavage 

sites. 

Genomic DNA from etoposide-treated and non-treated parasites was digested 

with restriction enzymes (Kpn I and Nco I) and analyzed by Southern 

blotting using a chromosome 5-specific probe (C5-A). 

Above: the % GC content is shown across this region of the chromosome 

determined using the ARTEMIS 4 program. 

Middle: the position of the coding regions in the schematic are indicated by 

blue boxes and the black box shows the position of the AT-rich domain. The 

location of the C5-A probe is shown in pink. Red arrow heads (a-d) highlight 

the major cleavage products on the autoradiograph and their corresponding 

positions on the schematic of the genomic DNA map. 

The vertical black bar (lower left) corresponds to the position of the AT-rich 

domain. 

Lower right boxed: an autoradiograph of a Southern blot hybridized with a 

probe (C5-C) located 150 kb from the putative centromere that indicates no 

etoposide-mediated topisomerase II cleavage. 


The aims of this project are to determine 

the mechanisms by which P. falciparum 

chromosomes are faithfully dispersed to 

daughter nuclei (segregation) prior to cell 

division and to identify how the proteins 

that carry out this process differ from those 

in human cells. The project builds on our 

recent study that provided biochemical 

evidence for the location of P. falciparum 

centromeres. We used a specific inhibitor 

(etoposide) of the topoisomerase II enzyme 

to fine-map the centromeres. Specifically, 

we wish to understand how chromosome 

segregation occurs in the bloodstream form 

of the parasite, which is responsible for disease pathology. Resolution of this 

question will have implications for our understanding of basic parasite biology 

and, in a more general context, the process of cell division. In addition, the 

work may lead to the identification of parasite-specific molecules that could 

serve as targets for chemotherapeutic intervention. 

Functional analysis of Plasmodium falciparum genes expressed 

during sexual stage development using microarrays and gene 

transfection techniques 

LSHTM investigators: Quinton Fivelman, Louisa McRobert, David Baker 

External investigators/collaborators: A. Cowman (WEHI, Australia); A. Craig, (LSTM, 

Liverpool); A. Holder (NIMR, London); A. Ivens (The Sanger Centre); C. Newbold (WIMM, 

Oxford); A. Waters (Leiden University, Netherlands); A. Wilkinson (University of York) 


The sexual stages of malarial parasites are responsible for transmission 

of the disease. In order to better understand genes important to the sexual 

development process, highly synchronised gametocytes were cultured in 

vitro using a newly developed method allowing magnetic separation of 

early stages. Transcriptome profiling of developing gametocytes was carried 

out using Affymetrix microarray technology and the data interpreted using 

a novel knowledge-based data-mining algorithm termed ontology-based 

pattern identification (OPI). This analysis resulted in the identification of a 

sexual development cluster containing 246 genes of which approximately 

75% were hypothetical, exhibiting highly-correlated, gametocyte-specific 

expression patterns. Inspection of the upstream promoter regions of these 

246 genes revealed putative cis-regulatory elements for sexual development 

transcriptional control mechanisms. Transfection has now been established at 

LSHTM as a standard technique to investigate gene function. Genes encoding 

enzymes of the cyclic nucleotide signalling pathways have been studied in


7 

detail and a role for the second messenger cGMP (and its downstream protein 

kinase, PKG) in sexual differentiation has been demonstrated. The work has 

provided genetic validation of PKG as a transmission-blocking drug target. 

Genome-wide patterns of copy number variation 

in the malaria parasite Plasmodium falciparum 

LSHTM investigators: Ian Cheeseman, Kevin Tetteh, Lindsay Stewart, 

David Conway 

External investigators/collaborators: Natalia Gomez-Escobar, 

Michael Walther (MRC, The Gambia); Celine Carret, Alasdair Ivens, 

Dominic Kwiatkowski (Sanger Institute, Cambridgeshire) 

Funding body: MRC 

Gene copy number variation (CNV) represents one of the 

major forms of genome sequence variation responsible 

for several major phenotypes of the malaria parasite, 

Plasmodium falciparum, including drug resistance, loss 

of cytoadherence and alteration of erythrocyte invasion 

pathways. Despite this appreciation of the importance 

of CNV genes in P. falciparum biology, little is known 

about the extent of their genome-wide diversity. We have 

conducted a whole-genome survey of CNV genes in P. 

falciparum using comparative genomic hybridisation 

(CGH) of a panel of 16 cultured isolates to a customdesigned 

high density Affymetrix GeneChip, PFSanger. 

We find strong associations of CNV genes with genomic 

location (sub-telomeric), length (shorter) and orthology 

to genes in other sequenced Plasmodium species (less). 

We identify previously undescribed CNV genes, with 

potential phenotypic implications. These results suggest 

that the generation of CNVs in the malaria parasite is a 

highly non-random process due to both mutational and 

selective processes. Studies to investigate the potential 

role of CNV changes during culture adaptation are 

underway with Gambian isolates. 

Log2 ratio 

hybridisation 

intensity 

Log2 ratio 

hybridisation 

intensity 

Evolutionary, population genetic and functional 

analyses of a malaria gamete surface protein 

gene family 

LSHTM investigators: David Conway, David Baker, Kevin Tetteh, Spencer Polley, Tom 

Anthony 

External investigators/collaborators: Andy Waters (Leiden University Medical Centre, 

Netherlands) 


Male and female malaria parasites must mate with one another in the bloodmeal 

inside the midgut of a female mosquito before the parasite life-cycle can 

proceed. The aim of this project is to study the molecular interactions between 

male and female Plasmodium falciparum gametes using both evolutionary 

and functional analysis of four members of the P48/45 gene family thought 

to be expressed on the gamete surface. Because loci involved in mating 

interaction in many other taxa species have been shown to evolve rapidly 

and often under positive selection, we examined sequence variation in these 

genes. Analysis of sequence variation in 11 laboratory isolates and a single 

isolate of Plasmodium reichenowi, the sister species of P. falciparum, gave 

almost significant McDonald-Krietman results for both Pf47 and Pf48/45, 

2 

1 

0 

-1 

-2 

2 

1 

0 

-1 

-2 

Chromosome 9 - T996 

0 100 200 

300 

PF11710w 

PF11715w 

PF11720w 

PF11725w 

PF11730w 

PF11735w 

PF11740w 

PF11745w 

PF11750w 

PF11755w 

PF11760w 

PF11765w 

PF11770w 

PF11775w 

PF11780w 

PF11785w 

PF11790w 

Chromosome 5 - Dd2 (blue), W2 (red) 

0 100 200 

300 

PFE1085w 

PFE1090w 

PFE1095w 

PFE1100w 

PFE1105w 

PFE1110w 

PFE1115w 

PFE1120w 

PFE1125w 

PFE1130w 

PFE1135w 

PFE1140w 

PFE1145w 

PFE1150w 

PFE1155w 

PFE1160w 

PFE1165w 

PFE1170w 

Hb3 

Palo Alto 

3D7 

Fcc-2 

7G8 

Wellcome 

T994 

W2 

Dd2 

D8 

RO33 

T1902 

T998 

K1 

MAD20 

D10 

W2me 

Dd2 

T994 

D6 

D10 

Count 

60 

T996 

Fcc-2 

K1 

3D7 

Wellcome 

Hb3 

7G8 

MAD20 

T9102 

Palo Alto 

RO33 

Count 

20 

colour key and 

histogram 

-2 0 2 

colour key and 

histogram 

-2 0 2 

Copy number variable regions of the P. falciparum genome. 

Genomic plots of chromosomes 9 and 5, each point represents hybridisation 

signal of a single gene. Value of 1/-1 correspond to gene amplifications and 

deletions respectively. Heatmaps show the CNV regions in detail across all 

examined strains; green represents positive values, red represents negative 

values of hybridisation signals. 

Deletion of chromosome 9 has been shown to mediate a loss of cytoadherance 

to erythrocyte cell surface receptors such as CD36. This is mediated 

through loss of the cytoadherance linked asexual gene 9 (clag9, PFI1703w). 

We showed that this sub-telomeric deletion is common in laboratory-derived 

strains of P. falciparum (present in 7 of 16 tested isolates, top panel). 

Resistance to mefloquine is propogated through expansion of a multigenic 

region of chromosome 5 containing the pfmdr1 gene (PFE1150w). This is 

seen amplified along with 13 other consecutive genes in the resistant strains 

Dd2 and W2mef. 

0 

0 



but clearly non-significant results for both Pf36 and Pf38. Further analysis 

of Pf47 alleles using global blood stage isolates of P. falciparum gave both 

significant McDonald-Krietman results and significant Fst results between 

three populations from different continents similar to results seen previously 

for Pfs48/45. We further analysed these two genes Pf47 and Pfs48/45 by 

sequencing 5 gene fragments from diploid oocysts of P. falciparum oocysts 

collected in Tanzania. Compared to a suite of microsatellite markers, both these 

genes displayed higher inbreeding coefficients (Fis) at several polymorphic 

loci sites. Taken together these results suggest that these sites are under 

positive selection and may therefore be functionally important in affecting 

mating interactions. Work is now proceeding to test these hypotheses using 

allelic replacement experiments in P. falciparum. 

Gene-specific signatures of elevated non-synonymous substitution 

rates correlate poorly across the Plasmodium Genus 

LSHTM investigators: Gareth D. Weedall, Spencer D. Polley, David J. Conway 

Funding body: MRC, Wellcome Trust 

Gene-specific signatures of elevated non-synonymous substitution 

rates correlate poorly across the Plasmodium Genus 

Scatterplots of dN/dS estimates for orthologous loci in phylogenetically independent 

Plasmodium species pairs: A. vivax-knowlesi vs. falciparum-reichenowi, 

B. yoelii-berghei vs. falciparum-reichenowi and C. yoelii-berghei 

vs. vivax-knowlesi. A line of identity representing equal selective constraint 

/ positive selection in orthologous genes in different species is shown on 

each plot (dotted line). Open squares represent a set of genes encoding 

surface-accessible candidate ligands, closed squares a set of control genes 

not predicted to be under selection. 

0’ 10’’ 20’ 

30’ 

Characterization of a family of Plasmodium membrane skeleton proteins 

Time-lapse microscopy showing that PbIMC1a-deficient (KO) sporozoites 

have abnormal cell shape and reduced circular gliding motility, compared to 

wild-type (WT) sporozoites. 


WT 

KO 

Comparative genome analyses of parasites allow large scale investigation 

of selective pressures shaping their evolution. An acute limitation to such 

analysis of Plasmodium falciparum is that there is only very partial lowcoverage 

genome sequence of the most closely related species, the chimpanzee 

parasite P. reichenowi. However, if orthologous genes have been under similar 

selective pressures throughout the Plasmodium genus, then positive selection 

on the P. falciparum lineage might be predicted to some extent by analysis of 

other lineages. 

Three independent pairs of closely-related species in different sub-generic 

clades (P. falciparum and P. reichenowi; P. vivax and P. knowlesi; P. yoelii and 

P. berghei) were compared for a set of 43 candidate ligand genes considered 

likely to be under positive directional selection and a set of 102 control genes 

for which there was no selective hypothesis. The ratios of non-synonymous to 

synonymous substitutions (dN/dS) were significantly elevated in the candidate 

ligand genes compared with control genes in each of the three clades. However, 

the rank order correlation of dN/dS ratios for individual candidate genes was 

very low, less than the correlation for the control genes. 

The inability to predict positive selection on a gene in one lineage by 

identifying elevated dN/dS ratios in the orthologue within another lineage 

needs to be noted as it reflects that adaptive mutations are generally rare events 

that lead to fixation in individual lineages. Thus, it is essential to complete the 

genome sequences of particular species of phylogenetic importance, such as 

P. reichenowi. 

Characterisation of a family of Plasmodium membrane skeleton 

proteins 

LSHTM investigators: Annie Tremp, Johannes Dessens 

External investigators/collaborators: Dr Emad Khater (Ain Shams University, Cairo, Egypt) 


Membrane skeletons have key roles in development, cell shape and structural 

integrity. We have identified a conserved family of putative membrane skeleton 

proteins in Plasmodium that are structurally related to articulins. One of these 

proteins, PbIMC1a, was functionally characterised using gene disruption 

in P. berghei. The results show that PbIMC1a is exclusively expressed in 

sporozoites, localizes to the pellicle structure and is essential for maintaining 

normal cell shape, structural integrity, gliding motility and infectivity. We are


9 

currently investigating other members of the family by fluorescent protein 

tagging and gene disruption. 

Characterization of Plasmodium LCCL proteins 

LSHTM investigators: Victoria Carter, Johannes Dessens 

External investigators/collaborators: Dr Meiji Arai (University of Occupational and 

Environmental Health, Japan) 


The rodent malaria Plasmodium berghei scavenger receptor-like protein 

PbSR is a predicted extracellular protein that contains several distinct 

protein modules implicated in lipid, protein and carbohydrate binding, 

indicating that its function involves interaction with the vertebrate host 

or insect vector. It was shown previously that PbSR-deficient parasites 

form normal numbers of oocysts in vector mosquitoes but fail to produce 

infectious sporozoites, pointing to the role of this protein in the oocyst 

during sporogony. We have generated a genetically modified parasite line 

that expresses, instead of the native PbSR protein, a recombinant version of 

PbSR that is double-tagged with red fluorescent protein at the N-terminus 

and green fluorescent protein at the C-terminus. Confocal microscopy 

shows that PbSR is synthesized in blood stage macrogametocytes and, after 

macrogamete ferilization, gets targeted to the crystalloids. Malaria crystalloids 

are transient organelles that form in developing 

ookinetes and disappear after oocyst transition. 

Since their description in the 1960s little research 

has been done on the crystalloids and hence their 

origins and functions have remained elusive for 

more than four decades. PbSR is a member of 

a conserved protein family containing LCCL 

domains and we are applying similar strategies to 

characterize the other LCCL protein family members. 

The role of metacaspases in Plasmodium development and 

apoptosis 

LSHTM investigators: Ludovic Le Chat, Johannes Dessens 

Funding body: Leverhulme Trust 

The malaria parasite encodes a wide range of proteases necessary to facilitate its 

many developmental transitions in vertebrate and insect hosts. Amongst these 

are three predicted cysteine proteases structurally related to metacaspases. We 

have generated Plasmodium berghei parasites in which the coding sequence 

of one of these metacaspases, PbMC1, is removed and replaced with a 

green fluorescent reporter gene, to investigate the expression of PbMC1, its 

contribution to parasite development as well as its involvement in previously 

reported high level apoptosis-like cell death of P. berghei ookinetes. Our 

results show that the pbmc1 gene is expressed in female gametocytes and 

all downstream mosquito stages including sporozoites. We failed to detect an 

apparent loss-of-function phenotype, suggesting that PbMC1 is a functionally 

redundant gene. We also observed much lower levels of apoptosis-like parasite 

death than previously reported. We are now investigating the role of the other 

two Pb metacaspases by gene disruption. 

Electron micrograph of a Plasmodium berghei ookinete showing a typical 

crystalloid organelle, highlighted in green. 

An ookinete of a parasite line that expresses double fluorescent protein-tagged 

PbSR. 

Red and green fluorescence localizes to the crystalloid organelle (arrow). 

PbMC1-deficient sporozoites expressing 

green fluorescent protein. 


10 Immunology & Vaccination 

There is now a broad consensus that if there is to be an effective vaccine against malaria it is more likely 

to come from combinations of different vaccine candidates which target different components of the 

parasite or different stages of the life cycle, rather than a single candidate. It is therefore essential to identify 

a wide range of vaccine targets. A variety of different immune responses to potential vaccine targets needs 

to be assessed in the laboratory before the vaccine can be deployed in Man and this section contains several 

examples of these. The pathophysiology of severe malaria is incompletely understood and this stands in the 

way both of developing vaccines against severe malaria and the development of drug interventions for use in 

those with severe malaria. There is also an increasing interest in the impact of malaria control measures on 

the development of immunity; this may well have implications for attempts at high-level control and, eventually, 

elimination of malaria from areas where it is currently common. Researchers at the Malaria Centre 

use a combination of molecular, immunological, epidemiological and mathematical modelling approaches to 

investigate these questions. 

Pf12 

Pf92 

Pf38 

Pf113 

MSP10 

MSP6_3D7 

MSP7 

MRSP1 

MRSP2 

MRSP3 

MRSP4 

MRSP5 

PF13_0192 

PF13_0194 

PF10_0347 

PF10_0348 

PF10_0352 

MSP9 

SERA 5 

RAMA 

Rhop148 

Prohibitin 

RAP1 

RAP2 

RAP3 

Pf34 

0 

100 bp 1000 bp 

Coding sequence 

6-cys region 

GPI-anchor 

Repeats 

EGF/Lamin domain 

SPAM domain 

DBL domain 

4-cys region 

Scheme of the 26 genes studied showing positions of individual nucleotide 

polymorphisms among 14 P. falciparum isolates as vertical lines 

above each gene. 

Fixed differences between P. falciparum and P. reichenowi are shown as vertical 

lines below each gene. Positions of insertions and deletions are also 

indicated on each gene repeat sequences and defi ned domains. Horizontal 

lines indicate regions on each gene that could not be generated with the 

PCR strategy used. 

Cysteine proteinase region 

Band 7 family region 

Detecting exceptional signatures 

of balancing selection in malaria 

parasites 

LSHTM investigators: Kevin K.A. Tetteh, Lindsay 

Stewart, David J. Conway (currently based at MRC 

The Gambia) 

External investigators/collaborators: Gareth Weedall 

(Instituto Gulbenkian de Ciencia, Portugal), Isabella 

Ochola, Kevin Marsh (Wellcome-KEMRI, Kilifi), Alfred 

A. Ngwa (MRC The Gambia) 

Funding body: Wellcome Trust Programme grant 

Signal peptide 

Several Plasmodium falciparum merozoite 

Intron 

antigens have been shown to be under 

Insertion / deletions 

SNP 

diversifying natural selection and are targets 

of allele-specific immunity, signalling 

their vaccine candidacy for either multiple 

allele or conserved domain formulation. To 

investigate whether there are many additional 

P .falciparum merozoite proteins that are 

polymorphic and show such molecular 

signatures of selection, 24 genes were 

identified as a prioritised set that had not 

been intensively studied previously, encoding 

proteins on the merozoite surface or associated 

with the rhotpries or micronemes. Each of 

the genes was sequenced from 14 distinct 

cultured isolates from diverse geographical 

origins and from the closely related species 

P. reichenowi. No gene showed significant 

non-neutrality under a McDonald-Kreitman 

test (for skew of within- and betweenspecies 

coding and non-coding changes), but 5 genes with an adequately 

high within-species nucleotide diversity were chosen for an allele frequencybased 

analysis in an endemic population in The Gambia. Of these genes only 

one showed significant evidence of diversifying (balancing) selection with 

Tajima’s D test. The study shows that only a very small proportion of surfaceexposed 

merozoite protein genes have significant signatures predicting them 

to be targets of protective acquired immunity, encouraging intensive analysis 

of the few that do and sensitive genome-wide approaches to identifying the 

remainder. 


SUMMARY 

Detecting exceptional signatures of balancing selection in 

malaria parasites 

A Phase I/IIb randomised, double-blind, controlled study 

of the safety, immunogenicity and proof of concept 

of RTS,S/AS02D, a candidate malaria vaccine, when 

incorporated into an Expanded Program on Immunization 

(EPI) regimen that includes DTPw/Hib in infants living in 

a malaria-endemic region 

Phase I trial of MSP3-LSP vaccine 

A Phase IIb RCT of the efficacy of the malaria vaccine 

candidate RTS,S/AS01E 

Malaria Vaccine Trials in Kintampo, Ghana 

Immunology & Vaccination 

Use of Antigen Arrays to profile immune 

responses against Malaria 

Anti-toxic immunity in malaria: neutralizing 

anti-toxin antibodies in acute and immune P. 

falciparum sera 

Accessory-cell-dependent activation of NK 

cells by Plasmodium falciparum 

Haemoglobin C and S role in acquired immunity against 

Plasmodium falciparum malaria 

Determinants of the longevity of naturally acquired 

antibody responses to blood stage Plasmodium falciparum 

antigens 

11 

Understanding the impact of malaria control interventions 

on the development of immunity in naturally exposed 

populations 

Estimating trends in malaria transmission using serological 

markers of malaria exposure 

The role of Foxp3+ regulatory T cells in Plasmodium 

yoelii malaria-infected mice 

Microparticles in cerebral malaria 

A Phase I/IIb randomised, double-blind, controlled study of the 

safety, immunogenicity and proof of concept of RTS,S/AS02D, a 

candidate malaria vaccine, when incorporated into an Expanded 

Program on Immunization (EPI) regimen that includes DTPw/ 

Hib in infants living in a malaria-endemic region 

LSHTM investigators: David Schellenberg, Joanna Schellenberg 

External investigators/collaborators: Salim Abdulla, Richard Budundu, Ajuza Jumanne, 

Honorati Masanja, Clemens Masesa, Christopher Membi, Hassan Mshinda, Oscar Mukasa, 

Rolf Oberholzer, Honorati Urassa, John Wigayi (IHRDC, Tanzania), Conor Cahill, W Ripley 

Ballou, Ozzie Berger, Joe Cohen, Marie-Ange Demoitié, Marie Claude Dubois, Amanda Leach, 

Marc Lievens, Isabelle Ramboer, Joelle Thonnard, Marie Chantal Uwamwezi, Johan Vekemans 

(GSK Biologicals), Marcel Tanner (STI), Ali Hamisi (Tanzanian Ministry of Health), Filip 

Dubovsky, Aric Gregson, Marla Sillman (MVI) 

The RTS,S/AS02 candidate malaria and hepatitis B vaccine is being developed 

for the routine immunization of infants and children living in malaria-endemic 

areas. RTS,S/AS02D is being developed to be integrated into the EPI in 

malaria-endemic regions. This is the first trial in which RTS,S/AS02D will 

be co-administered with DTPw/Hib vaccine (i.e. a vaccine protecting against 

diphtheria, tetanus, pertussis and hemophilus influenza type b) to infants. The 

trial is designed to evaluate the safety and immunogenicity of RTS,S/AS02D 

when co-administered with a multi-valent DTPw/Hib vaccine, in comparison 

with a regimen of 3 doses of Engerix-B + TETRActHib at the same ages. 

340 infants will be recruited to this phase I/IIb, single centre, double blind, 

randomised controlled trial. The study, which is led in Tanzania by Dr Salim 

Abdulla, started in July 2006 and will be completed mid 2008. 

Field workers in Tanzania doing their weekly active case detection 

visits, including finger pricks when a child is found to have fever. 

Children in Burkina Faso. 

Phase I trial of MSP3-LSP vaccine 

LSHTM Investigators: Simon Cousens 

External Investigators/Collaborators: CNRFP, Burkina Faso 

Funding body: AMANET 

A single-blind, Phase I trial of the long synthetic peptide of MSP3 (MSP3- 

LSP) versus tetanus toxoid vaccine was carried out in 30 adult males living 

in an area of stable and seasonal malaria transmission. Three doses of each 

vaccine were administered and participants were followed for a year. Humoral 

and cell-mediated immune responses were assessed. There were no serious 

adverse events in either vaccine group and only one systemic adverse event 

(tachycardia), which occurred in an individual receiving MSP3-LSP. In 

both groups participants reported local reactions at the site of injection. No 

clinically significant biological abnormalities following vaccination were 

observed. Humoral immune responses (IgG, IgG subclasses, IgM) to MSP3- 

LSP peptide were similar in the two groups following vaccination. Some cellmediated 

immune responses appeared to differ between the two vaccine groups. After the second dose of MSP3-LSP, there appeared 

to be a marked increase in the lymphocyte proliferation index and IFN-g in response to stimulation with MSP3-LSP. MSP3-LSP 

appears to be well-tolerated by adult males previously exposed to natural P. falciparum infection and may be able to stimulate an 

enhanced cell-mediated immune response in individuals with some degree of pre-existing immunity. 



A Phase IIb RCT of the efficacy of the malaria vaccine candidate 

RTS,S/AS01E 

LSHTM investigators: Chris Drakeley, Roly Gosling, Brian Greenwood, Paul Milligan, Hugh 

Reyburn, Eleanor Riley, Lorenz von Seidlein 

External Investigators /collaborators: John Lusingu, Martha Lemnge, Raimos Olomi, Thor 

Theander 

Funding body: MVI 

The objective of this ongoing study is the primary immunization of healthy 

male and female children aged 5 months to 17 months with the RTS,S/AS01E 

candidate malaria vaccine. This vaccine is being developed for the routine 

immunization of infants and children living in malaria-endemic areas as part 

of the EPI. The RTS,S/AS01E vaccine candidate consists of sequences of the 

circumsporozoite (CS) protein and hepatitis B surface antigen (HBsAg) with 

the adjuvant system AS01. The vaccine specifically targets the pre-erythrocytic 

stage of Plasmodium falciparum. In Mozambique, the RTS,S/AS02A vaccine 

has demonstrated 30% efficacy against clinical malaria and 58% efficacy 

against severe malaria in children aged 1 to 4 years. The RTS,S/AS01 vaccines 

have been developed in parallel with the RTS,S/AS02 vaccines with the aim 

of improving the immune response and increasing vaccine efficacy. The trial 

is conducted in two sites: Kilifi, Kenya and Korogwe, Tanzania. By June 

2008 all 445 children required by protocol had been vaccinated either with 

the candidate vaccine RTS,S or a control. Follow up of study participants will 

end in September 2008. The funders of the trial are providing capacity for 

future vaccine trials in Korogwe including project offices and laboratories in 

Korogwe (see pictures left). 

Building of new laboratories and offices in Korogwe, Tanzania. 

This is part of capacity development undertaken during trials of the malaria 

vaccine candidate RTS,S/AS01E in the local area. 

Sensitization of community members at durbars prior to initiation of 

the RTS,S malaria vaccine trials in Kintampo, Ghana. 

Malaria Vaccine Trials in Kintampo, Ghana 

LSHTM Investigators: Seth Owusu-Agyei, Daniel Chandramohan, Paul Miligan, Brian 

Greenwood 

External investigators/collaborators: Seth Owusu-Agyei, Kwaku Poku Asante, Ruth Owusu, 

Kingsley Osei-Kwakye (KHRC) 

Funding body: GSK Biologicals, MVI, MCTA, INDEPTH Network. 

The RTS,S malaria vaccine has been shown to be safe in trials using healthy 

adults in the United States of America, Belgium and then in Kenya, followed 

by trials among children in Mozambique and The Gambia where they were 

again found to be safe. The vaccine was shown to cause minor symptoms like 

fever and drowsiness for some children and these symptoms disappeared after 

a few days. 

In September 2006, Kintampo Health Research Centre (KHRC) in 

collaboration with LSHTM joined efforts in developing the RTS,S vaccine 

in the middle belt of Ghana. It embarked on a malaria vaccine trial among 

children 5 – 17months of age in the Kintampo North and South Districts of 

Ghana. The objective of this trial was to assess the safety of the vaccine in 

this age group. The trial is particularly significant as it compares the impact 

of three potential immunization schedules (0,1; 0,1,2; 0,1,7 months) on the 

immune response. This will enable the partners to identify the most effective 

immunization schedule prior to the commencement of Phase III studies. 

A total of 540 children have been recruited and are participating in this trial. 

270 children have been recruited by KHRC while the rest have been recruited 

by Kumasi Centre for Collaborative Research in Agogo. All children have 

received vaccinations and are being followed up passively until April 2008. 



13 

Use of Antigen Arrays to profile immune 

responses against Malaria 

LSHTM investigators: Patrick Corran, Kevin Tetteh, Spencer 

Polley, David Conway, Eleanor Riley 

External Investigators /collaborators: Julian Gray, Elena 

Mangia, Tito Bacarese-Hamilton Qiuxiang Li, Andrea Crisanti 

(Imperial College, London), Anthony A. Holder (NIMR) 

Funding body: EU FP6; DTI; Ministry Of Education Italy; MRC 

Antigenic responses of a host to a complex pathogen, 

such as P. falciparum, are themselves complex and 

natural antibody-mediated immunity to malaria 

probably operates through the cooperative effect of 

responses to many antigens. The ability to visualise 

patterns of antigenic responses against the range of 

antigens presented by the malaria parasite, and to 

recognise associations between responses to particular 

subsets of antigens, may give a better understanding 

of the nature of protection and help to explain immune 

protection more fully than the study of single antigens. 

In addition, it may offer valuable insights into the way 

in which partially protective candidate antigens should 

be combined in order to provide significant levels of 

protection. 

We have developed a microarray assay using 18 

recombinant antigens from 4 major blood-stage 

vaccine candidates (MSP-1, MSP-2, MSP-3 and AMA- 

1). The results have been compared to ELISA assays 

in which a number of the same antigens were assayed 

Serum A 

European 

serum 

individually, and the arrays have been used to analyse total IgG responses 

in a set of sera from malaria-exposed children who differ in the extent of 

their clinical immunity. Clinical immunity was not significantly associated 

with the response to any single antigen. However, the combined response to 

AMA-1 plus representatives of both the major allelic families of MSP-2 was 

significantly associated with protection from clinical malaria when evaluated 

by two independent methods. 

These results appear to justify the extension of this approach to larger arrays 

representing a significant proportion of the P. falciparum proteome, and we 

will be continuing this collaboration and seeking ways to extend the use of 

these arrays with Prof. Andrea Crisanti under a further EU FP7 grant. 

Anti-toxic immunity in malaria: neutralizing anti-toxin 

antibodies in acute and immune P. falciparum sera 

LSHTM investigators: J. Brian de Souza, Patrick Corran, Tom Doherty, Eleanor Riley 

External Investigators /collaborators: D. Channe Gowda (Penn State University, USA) G. 

Pasvol (Northwick Park Hospital & Imperial College, London) 

Funding body: MSc student project costs 

It is generally thought that the soluble mediators induced by malaria 

toxins contribute not only to fever but also to the end-organ, metabolic 

and haematological consequences of disease. TNF-α and LT-α have been 

shown to increase expression of parasitized erythrocyte receptors such as 

ICAM-1 on endothelial cells, thus potentially initiating a vicious cycle 

(that may lead to severe malaria) by sequestering more parasitized cells and 

further increasing local cytokine production. Parasite exoantigens such as 

glycosylphosphatidylinositol (GPI) are strongly implicated in this response 

Serum B 

No serum 

min 

1 

2 

3 

4 

5 

6 

7 

8 

9 

Serum C 

1 

2 

3 

4 

5 

6 

7 

8 

9 

10 

11 

12 

13 

14 

15 

16 

17 

18 

Immune response profiles against Malaria using antigen arrays 

Colour-coded array responses for 18 different antigens (listed at the right) 

for fi ve different sera : four sera (A-D) from adults living in a malaria-endemic 

area (Brefet in The Gambia), one European non-immune and a no serum 

control (Gray et al. (2007) Clinical Chemistry 53: 1244-1253). 

% TNF-a neutralisation 

90 

80 

70 

60 

50 

40 

30 

20 

10 

0 

10 

11 

12 

13 

14 

15 

16 

17 

18 

Serum D 

1. MSP1 block 2 PA Repeats Only 

2. MSP1 block 2 Wellcome Repeats Only 

3. MSP1 block 2 3D7 Full Length 

4. MSP1 block 2 Wellcome Full Length 

5. MSP1 block 2 MAD20 Full Length 

6. MSP1 block 2PA Full Length 

7. MSP1 block 2 RO33 Full Length 

8. MSP1 block 2 K1 Super Retreat 

9. MSP1 block 2 K1 Flanking Only 

10. MSP1 block 2 MAD20 Repeats Only 

11. MSP1 block 2 3D7 Repeats Only 

12. MSP1 block 2 MAD20 Flanking Only 

13. MSP3 3D7 

14. MSP1-19 

15. MSP3 K1 

16. MSP2 3D7 

17. MSP2 FC27 

18. AMA-1 

max 

Neutralisation of GPI-induced TNF-a 

release by macrophages 

0.0001 0.001 0.01 0.1 1 

mg/ml IgG 

Non-immune 

Non-immune 

Immune 

Immune 

Immune 

Immune 

Acute 

Neutralization of GPI-induced TNF-a release by macrophages. 

Reduced TNF-α production by macrophages after pre-incubation of glycosylphosphatidylinositol 

(GPI) with varying concentrations of IgG purifi ed from 

plasma of non-immune (dark blue lines), immune (orange lines) and acutely 

infected (dark green line) donors. 



intact iRBC 

logama 

1.5 2 2.5 3 3.5 

logmsp2 

1.5 2 2.5 3 3.5 

GPI 

Monocyte or 

myeloid DC 

Unknown 

receptor 

TLR2 

TLR4 

NK cell activation in response to Plasmodium falciparum-infected 

red blood cells (iRBC) is strictly dependent on multiple signals from 

myeloid accessory cells. 

AA AC AS C C S C S S 


logeba175 

1.5 2 2.5 3 3.5 

logmsp3 

1.5 2 2.5 3 3.5 

contactdependent 

signal 



IFN-g 

secretion 


logmsp1 

1.5 2 2.5 3 3.5 

logpse 

1.5 2 2.5 3 3.5 

IL-2 

rec 

IL-12 

rec 



Means levels of total IgG against several blood stage antigens of Plasmodium 

falciparum (AMA1, EBA-175, MSP-1 19, MSP-2, MSP-3, schizont 

extract (pse)- see y axis) and parasite schizont extract in urban samples 

of Mossi from Ouagadougou, Burkina Faso according to the different 

haemoglobin genotypes (AA, AC, AS, CC, SC, SS). 

The horizontal lines in each box correspond to the median values, the lower 

edge of each box is the 25% ile and the upper edge is the 75% ile. The 

whiskers represent the range of the data beyond these percentiles, excluding 

outliers represented by dots. 

and it has been proposed that GPI may be a suitable target for anti-disease 

vaccines. However, there is as yet little firm evidence that anti-GPI antibodies 

protect against severe malarial disease in humans, although these antibodies 

do develop following natural infection with Plasmodium falciparum. 

In preliminary “toxin”-neutralization studies in vitro we have established that 

only serum with high titres of anti-GPI IgG, from immune or acute infection, 

can neutralise the induction of TNF-a by P. falciparum GPI, suggesting that 

NK cell anti-GPI antibodies may have neutralising ability. 

Type I 

IFN rec 

Accessory-cell-dependent cytotoxicity 

activation of NK cells by Plasmodium 

falciparum 

LSHTM direct investigators: recognition 

of iRBC 

Kirsty Newman, Daniel Korbel, Julius Hafalla, Eleanor Riley 

Unknown 

External receptor Investigators /collaborators: Daniel M. Davis (Imperial College London), Peter 

Parham (Stanford University, USA) 

Funding body: MRC, Boehringer Ingelheim Fonds 

IL-18 

rec 

IL-12, IL-2, IL-18 and Type-I 

IFN secretion 

Natural killer (NK) cells have a crucial role in combating infections and cancers 

and their surface receptors can directly recognize and respond to damaged, 

transformed or non-self cells. Whereas some virus-infected cells are recognized 

by this same route, NK-cell responses to many pathogens are triggered by 

a quite different mechanism. Activation of NK cells by these pathogens 

requires the presence of accessory cells such as monocytes, macrophages and 

dendritic cells. Recent studies have identified numerous pathogen-recognition 

receptors that enable accessory cells to recognise different pathogens and 

subsequently transmit signals – both contact-dependent and soluble – to NK 

cells which respond by upregulating their cytotoxic potential and production 

of inflammatory cytokines. 

We have found that the ability of human NK cells to produce IFN-g in response 

to stimulation by Plasmodium falciparum-infected red blood cells (iRBC) is 

strictly dependent upon multiple, contact-dependent and cytokine-mediated 

signals derived from both monocytes and myeloid dendritic cells (mDC). 

We find that both monocytes and mDC express an activated phenotype 

following incubation with iRBC and secrete pro-inflammatory cytokines. The 

magnitude of the NK cell response (and of the KIR-CD56 bright NK cell 

population in particular) is tightly correlated with resting levels of accessory 

cell maturation, indicating that heterogeneity of the NK response to malaria is 

a reflection of deep-rooted heterogeneity in the human innate immune system. 

These findings have far-reaching implications for the study of immunity to 

infection in human populations. 

Haemoglobin C and S role in acquired immunity against 

Plasmodium falciparum malaria 

LSHTM investigators: Federica Verra, David Conway and Kevin Tetteh 

External investigators/collaborators: David Modiano (university of Rome “La Sapienza”), 

Kevin Marsh, Tom Williams, Pete Bull, Faith Osier, George Warimwe, Greg Fegan (KEMRI), 

Jacques Simporé (Burkina Faso) 

Funding body: Wellcome Trust (FV), Biomalpar (DM) 

Conclusive evidence exists of the protective role of Haemoglobin C (HbC; 

β6Glu→Lys) against clinical Plasmodium falciparum malaria as well as of 

HbS (β6Glu→Val), both occurring in Burkina Faso, West Africa. However, the 

mechanism(s) of the protection exerted remain(s) debated for both haemoglobin 

variants, HbC and HbS. Recently, an abnormal display of PfEMP1, an antigen 

involved in malaria pathogenesis, was reported on HbAC and HbCC infected 

erythrocytes that showed reduced cytoadhesion and impaired rosetting in vitro. 

On this basis it has been proposed that HbC protection might be attributed


15 

to the reduced PfEMP1-mediated adherence of parasitized erythrocytes in 

the microvasculature. We investigated the impact of this hypothesis on the 

development of acquired immunity against Plasmodium falciparum variant 

surface antigens (VSA) encoding PfEMP1 in HbC in comparison with HbA 

and HbS carriers of Burkina Faso. Results showed that the reported abnormal 

cell-surface display of PfEMP1 on HbC infected erythrocytes observed in 

vitro is not associated to lower anti- PfEMP1 response in vivo. Higher immune 

response against the VSA panel and malaria antigens were observed in all 

adaptive genotypes containing at least one allelic variant HbC or HbS in the 

low transmission urban area whereas no differences were detected in the high 

transmission rural area. In both contexts the response against tetanus toxoid 

was not influenced by the β-globin genotype. Thus, these findings suggest 

that both HbC and HbS affect the early development of naturally acquired 

immunity against malaria. 

Determinants of the longevity of naturally acquired antibody 

responses to blood stage Plasmodium falciparum antigens 

LSHTM investigators: Onome J. Akpogheneta, Nancy O. Duah, Kevin K.A. Tetteh, David J. 

Conway 

External Investigators/collaborators: Samuel Dunyo, Margaret Pinder (MRC Laboratories, 

The Gambia); David E. Lanar (Walter Reed Army Institute of Research, USA) 


To investigate the determinants of longevity of naturally acquired antibody 

responses to malaria, serum IgG to blood stage P. falciparum vaccine candidate 

antigens was examined in cohorts of children aged up to 6 years during the 

dry seasons of 2003 and 2004 in The Gambia. Antibody responses in this 

cohort were influenced by persistent malaria infection so analysis focused 

particularly on children who did not have parasites detected after the first 

time point. Antibodies to most antigens declined more slowly in the oldest 

age group of children (> 5 years old) and more rapidly in the youngest (< 3 

years old). However, antibodies to merozoite surface protein 2 (MSP2) were 

shorter-lived and were not more persistent in older children. The age-specific 

and antigen-specific differences were not explained by different IgG subclass 

response profiles, indicating the probable importance of differential longevity 

of plasma cell populations rather than antibody molecules. It is likely that 

young children mostly have short-lived plasma cells and thus experience rapid 

decline in antibody levels while older children have longer lasting antibody 

responses that depend on long-lived plasma cells. 

Understanding the impact of malaria control interventions on the 

development of immunity in naturally exposed populations 

LSHTM Investigators: Colin Sutherland, David Schellenberg, Chris Drakeley, Roly Gosling, 

Eleanor Riley 

External Investigators/collaborators: Azra Ghani (Imperial College, London) 

Funding body: HPAUK 

We have considered the development of acquired protective immunity to 

Plasmodium falciparum infection in young African children in the context of 

three current strategies for malaria prevention: insecticide-impregnated bed 

nets or curtains, anti-sporozoite vaccines and intermittent preventive therapy. 

We found evidence that each of these measures may permit attenuated P. 

falciparum blood-stage infections, which do not cause clinical malaria but can 

act as an effective blood-stage “vaccine”. We hypothesised that the extended 

serum half-life and rarely considered liver-stage prophylaxis provided by 

the anti-folate combination sulphadoxine-pyrimethamine, frequently lead to 

A millet grinder in a village in Burkina Faso. 

Lowest Ab conc (%) 

100 

80 

60 

40 

20 

0 

* 

5yrs 

MSP1 

Schizont 

extract 

Importance of age as a determinant of antibody response longevity 

among children without parasites after day 0. 

Lowest ratio of antibody levels compared to starting values. Medians and 

inter-quartile ranges are shown in the boxes, bars represent upper and lower 

adjacent values ( , p


such attenuated infections in high transmission areas, and thus contribute to 

the sustained protection from malaria observed among children receiving the 

combination as intermittent preventative therapy or for parasite clearance in 

vaccine trials. 

Taking a modelling approach, we then looked forward to any possible longterm 

(10-50 years) harm or benefit of reducing exposure to malaria in endemic 

areas, as it has been widely hypothesised that interventions which lower 

community exposure to malaria may delay the acquisition of immunity. The 

trade-off between reduction in exposure and the development of immunity 

was explored using a two-component model of immunity. Our model predicts 

that the benefits of reduced morbidity in the first 5-10 years may be offset by 

a greater burden of disease decades later. However, the negative impact of 

having fewer immune individuals in the population can be counterbalanced 

by the simultaneous implementation of multiple highly effective interventions 

for an indefinite period. Thus a dynamic, evolving intervention programme 

may secure substantial, stable reductions in malaria transmission. 

OD 492m 

2.5 

2.0 

1.5 

1.0 

0.5 

0 

2.5 

2.0 

1.5 

1.0 

0.5 

0 

2.5 

2.0 

1.5 

1.0 

0.5 

0 

2.5 

2.0 

1.5 

1.0 

0.5 

0 

MSP-1 19 

-GST fusion P. falciparum 

MSP-1 19 

-GST fusion P. vivax 

AMA-1 P. falciparum 

CSP P. falciparum 

Skyline plot showing individual serum responses (OD) to 4 malaria antigens. 

Skyline plot showing individual serum responses (OD) to 4 malaria antigens 

(P . falciparum MSP-1, P. vivax MSP-1, P. falciparum AMA-1 & P. falciparum 

CSP) in an age cross-sectional study from Cambodia, highlighting differential 

binding of antibodies to MSP-1 from different species of Plasmodium and 

the range of immunogenicity of the different P. falciparum antigens MSP-1, 

AMA-1 and CSP. 

Estimating trends in malaria transmission using serological 

markers of malaria exposure 

LSHTM Investigators : Patrick Corran, Jackie Cook, Lucy Okell, Jon Cox, Jayne 

Bruce, Eleanor Riley, Chris Drakeley 

External Investigators /collaborators: Azra Ghani, Jamie Griffin (Imperial 

College, London), David Modiano (University of Rome), Duong Socheat (Cambodia 

National Malaria Control Programme), Sylvia Meek (Malaria Consortium) 

Funding : Wellcome Trust 

Estimation of malaria transmission intensity is key for the successful 

deployment and assessment of malaria control methods. Current 

entomological and parasitological methods are subject to constraints, 

particularly in areas of low transmission. Anti-malarial antibodies 

constitute a record of infection history and the age-specific prevalences 

of malaria-specific antibodies reflect cumulative exposure to malaria 

over increasing periods of time. We have previously used sera 

collected from individuals resident at different malaria transmission 

intensities in Tanzania to show that age specific sero-prevelance 

rates correlate well with existing measures of transmission intensity 

entomological inoculation rate (EIR). We have now shown that antibodies 

to Plasmodium vivax MSP-1 do not cross-react with those to P. falciparum 

MSP-1, allowing separate sero-conversion rates (and therefore transmission 

intensities) to be calculated for P. vivax and P. facliparum. In efforts to develop 

a simple field assay, we have shown that antibodies can be reliably extracted 

from filter paper, a matrix very suitable for field studies in remote areas, and 

that sampling individuals attending health facilities, irrespective of health 

status, can provide a rapid assessment of malaria transmission intensity. 

The role of Foxp3+ regulatory T cells in Plasmodium yoelii 

malaria-infected mice 

LSHTM investigators: Kevin N. Couper, Daniel G. Blount, Julius C.R. Hafalla, J. Brian de 

Souza, Eleanor M. Riley 

External Investigators /collaborators: Mark Wilson, Isabelle Suffia, Yasmine Belkaid (National 

Institute of Allergy and Infectious Disease, NIH, USA); Nico van Rooijen (Vrije Universiteit, The 

Netherlands); Richard A Flavell (Yale University School of Medicine, USA) 



CD4 + CD25 + Foxp3 + regulatory T cells (Treg) mediate potent anti-inflammatory 

responses and are known to both down-regulate parasite clearance mechanisms 

and prevent immunopathology in various protozoal infections. Analysis of T 

reg function in model systems is facilitated by their depletion using anti-CD25 

antibodies but there has been considerable debate about the effectiveness of this 

strategy. Using 7D4 and/or PC61 anti-CD25 antibodies we found that numbers

and percentages of CD25 hi cells, but not Foxp3 + cells, were transiently reduced 

after 7D4 treatment whereas treatment with PC61 - alone or in combination 

with 7D4 (7D4+PC61) - reduced but did not eliminate Foxp3 + cells for up to 

two weeks. Importantly, all protocols failed to eliminate significant populations 

of CD25 - Foxp3 + or CD25 low Foxp3 + cells, which retained potent regulatory 

capacity. We showed that repopulation of the spleen by CD25 hi Foxp3 + 

cells results from re-expression of CD25 on peripheral populations of 

CD25 - Foxp3 + . In 7D4+PC61-treated mice undergoing acute malaria 

infection, repopulation of the spleen by CD25 + Foxp3 + cells occurs 

extremely rapidly with malaria infection driving proliferation and CD25 

expression in peripheral CD4 + CD25 - Foxp3 + cells and/or conversion of 

CD4 + CD25 - Foxp3 - cells. 

Importantly, however, we could find no role for classical CD4+CD25 hi 

Foxp3+ regulatory T cells in mice infected by either the lethal (17XL) 

or non-lethal (17X) strain of Plasmodium yoelii. Rather, we found that 

adaptive IL-10-producing, CD4+ T cells (which are CD25-, Foxp3-, and 

CD127-) down-regulate pro-inflammatory responses and impede parasite 

clearance. Moreover, we found that neither NK cells, T cells or B cells, 

nor IFN-g play any significant role in control of the primary peak of P. 

yoelii parasitaemia. By contrast, depletion of monocytes/macrophages 

exacerbated parasite growth and anaemia during both lethal and nonlethal 

acute P. yoelii infections, indicating that there is an IFN-g, NK cell 

and T cell independent pathway for induction of effector macrophages 

during acute malaria infection. 

Microparticles in cerebral malaria 

LSHTM investigators: J. Brian de Souza, Kevin Couper, Julius Hafalla, Rachel Greig, Eleanor 

Riley 

External Investigators /collaborators: GE Grau, N. Hunt (University of Sydney); G. Chimini 

(University of Marseille); L. Renia (University of Singapore); B. Ryffel (University of Orleans 

and CNRS, France); M. Molyneux (University of Malawi); D. Burger (University of Geneva); I. 

Gouado (University of Douala, Cameroon) 

Funding body: EU-FP6 Programme 

Induction of pro-inflammatory cytokines by parasite-derived 

toxins has been implicated in the pathogenesis of cerebral 

malaria (CM). This may promote parasite sequestration within 

the microvasculature or, as recent data suggest, may lead to 

the release of endothelial microparticles (MP) with consequent 

neuropathology. Grau and colleagues have shown that 

microparticles were present at increased levels in the peripheral 

blood of Malawian children with CM and this was backed up 

by similar findings in experimental murine CM. Microparticles 

are formed from a process known as vesiculation, which is the 

shedding of plasma membrane vesicles from the cell surface, 

resulting from a loss of phospholipid asymmetry and exposure 

of negatively charged phospholipids at the outer leaflet of the 

plasma membrane. MPs are thus submicron elements carrying 

antigens and functional properties of their cell of origin. 

They are found in a number of inflammatory conditions and 

their production can be enhanced in vitro by several inducers, 

including pro-inflammatory cytokines. We are currently studying the role of 

microparticles in the initiation and effector phases respectively, of experimental 

and human cerebral malaria. 


Side scatter 

Foxp3 

Forward scatter 

10 4 

10 3 

10 2 

10 1 

CD4 

PBS 

7D4 

17 

10 0 10 0 

10 0 10 1 10 2 10 3 10 4 10 0 10 1 10 2 10 3 10 4 

10 0 10 0 

10 0 10 1 10 2 10 3 10 4 10 0 10 1 10 2 10 3 10 4 

PC61 

7D4+PC61 

10 4 

10 4 

10 3 

10 3 

10 2 

10 2 

10 1 

10 1 

10 4 

10 3 

10 2 

10 1 

Flow cytometric assay of CD3+ splenic lymphocytes cells collected 3 

days after treatment with anti-CD25 antibodies. 

Treatment of mice with anti-CD25 antibodies 7D4, PC61 or 7D4+PC61 leads 

to only a modest decrease in the percentage of splenic Foxp3+ CD4+ T cells 

from 11.6% control levels to 10.9, 7.9 and 8.2% (7D4, PC61 and 7D4+PC61, 

respectively. 

1µm beads 

(internal 

controls) 

Region containing 

Microparticles (MPs) 

PBS 

controls 

(diluent) 

Minor 

symptoms 

Severe 

malaria 

0.39% 

Circulating microparticle (MP) levels during malaria infection. 

0.04% 

0.03% 

Annexin V (stains MPs) 

Left panel shows an example FACS plot of platelet-free plasma. MPs (relative 

to 1μm bead setting) in plasma from infected individual appear in the red 

circle. 1µm beads (top right, green circle) are used in setting up the machine 

to ensure reproducible data acquisition and analysis. 

Right panels show Annexin V positive events (indicative of the presence of 

MPs) in plasma from uninfected controls and from mild and severe malaria 

cases. 

Side scatter 


18 Drug Development & Drug Resistance 

Even to stand still against malaria, we need constantly to develop new drugs; the parasite is highly effective 

at evolving resistance to drug classes, which then spread, so gradually we will lose old drug classes. 

To advance we need new drug classes against new targets. Members of the Malaria Centre are involved in 

mapping the spread of drug resistance in Africa and Asia, understanding the reasons for it and the development 

of new drugs against P falciparum and P vivax malaria. Whilst most of this work is undertaken in support of 

malaria-endemic countries, members of the Malaria Centre also collaborate with colleagues in the NHS to 

understand drug resistance in travellers from the UK returning with malaria. 

(antibiotic) 

ACT 

AL 

AP 

AQ 

AS (ART) 

AS+CD 

CD 

CQ 

DHA 

DP 

MQ 

MQ-AS 

P 

PQ 

Q 

SP 

Common anti-malarial drugs 

& their abbreviations 

azithromycin 

Artemisinin Combination Therapy 

artemether-lumefantrine (coartem) 

atovaquone / proguanil 

(4-aminoquinoline) amodiaquine 

artesunate 

Artesunate + chlorproguanil-dapsone 

(currently withdrawn from use) 

chlorproguanil-dapsone (lapdap) 

(4-aminoquinoline) chloroquine 

dihydroartemisinin 

dihydroartemisinin-piperaquine 

mefl oquine 

mefl oquine plus artesunate 

(bis 4-aminoquinoline) piperaquine 

primaquine 

quinine 

sulphadoxine-pyrimethamine 

P. falciparum genes implicated in drug resistance 

pfcrt 

pfmdr1 

pfcyt 

pfdhfr 

pfdhps 

pfatp6 

chloroquine resistance transporter 

multi-drug resistance 

cytochrome b 

dihydrofolate reductase (DHFR) 

dihydropteroate synthase (DHPS) 

ATPase6 adenosine triphosphate enzyme 

Mapping drug resistance genes in Africa 

LSHTM investigators: Cally Roper, Richard Pearce, Hirva Pota, Rosalynn Ord, Daniel 

Chandramohan, Margaret Kweku, Wilfred Mbacham, Caroline Lynch, Badara Cissé, Diadier A. 

Diallo, Sian Clarke , James Tibenderana 

External investigators/collaborators: Partnerships with Research Institutions in Burkina Faso, Cameroon, 

The Gambia, Gabon, Ghana, Senegal, South Africa and Sudan; M.B. Evehe, W. Mbacham (University of 

Yaounde I, Cameroon), Bâ. El Hadj (Institut de Recherche pour le Développement, Senegal), G. Mombo- 

Ngoma. (Albert Schweitzer Hospital, Gabon), A. Malisa (Sokoine University of Agriculture & IHRDC, 

Tanzania), W. Inojosa (CUAMM Angola), A. Matondo (Uige Provincial Hospital, Uige Angola), D.A.Diallo 

(Centre National de Recherche et de Formation Sur Le Paludisme, Burkina Faso), I.V. van den Broek, T. D. 

Swarthout (Manson Unit, MSF-UK), A. Assefa (Tigray Bureau of Health, Ethiopia), S. Dejene (Médecins Sans 

Frontières Ethiopia), M.P. Grobusch (University of the Witwatersrand, South Africa), F. Njie, S. Dunyo (MRC, 

The Gambia), S. Owusu-Ageyi (Kintampo Health Research Centre, Ghana), J. P. Guthmann (Epicentre & 

Institut de Veille Sanitaire, France), M. Bonnet (Epicentre, France), K. I. Barnes (University of Cape Town, 

South Africa), E. Streat (Ministry of Health, Mozambique), S. T. Katokele, P. Uusiku (Ministry of Health and 

Social Services, Namibia), C. O. Agboghoroma, O. Y. Elegba (National Hospital 

Abuja, Nigeria), B. Cissé (Université Cheikh Anta Diop de Dakar, Senegal), I. E. 

A-Elbasit (University of Khartoum, Sudan), H. A. Giha (Arabian Gulf University, 

Kingdom of Bahrain), S. P. Kachur (CDC, USA), J. Rwakimari (National Malaria 

Control Programme, Uganda), P. Chanda, M. Hawela (National Malaria Control 

Centre, Zambia), I. Naidoo, B. Sharp (MRC, South Africa) 

Funding: GMP 

Investigators from a large number of organisations are 

collaborating to summarise the contemporary distribution 

of resistance genes in African P. falciparum malaria. 

The genetic data being mapped comes from a mixture of 

published data gathered from scientific literature and a large 

body of original data. Resistance lineages can be identified 

by analysis of flanking microsatellite polymorphisms 

and we are mapping their dispersal among contemporary 

P. falciparum populations in 20 African countries (see 

map left). The dispersal of resistance genes can explain 

geographical differences in drug efficacy and, importantly, 

it gives us insight into malaria migration in Africa today. 

Mapping drug resistance genes in Africa. 

Figure shows the spatial coverage of sites in Africa where sulphadoxine 

resistant dhps mutant lineages of P. falciparum malaria have been mapped. 

Molecular surveillance of mefloquine-artesunate 

(MQ-ART) resistance in the Upper Orinoco, 

Amazonas State, Venezuela 

LSHTM investigators: Emily Bongard, Caterina Fanello, Livia Vivas 

External investigators/collaborators: Magda Magris, Johanna 

Goncalves, Irma Rodríguez (Centro Amazonico para la Investigacion y el 

Control de la Enfermedades Tropicales, CAICET), Sarai Vivas-Martinez (Universidad Central 

de Venezuela), Wolfram Metzger (Max-Planck-Institute for Infection Biology, Berlin/ Institute 

for Tropical Medicine Tübingen) 

Funding body: WHO-TDR Roll Back Malaria Program, Ministry of Science and Technology 

and Ministry of Health, Venezuela 


Drug Development & Drug Resistance 

19 

SUMMARY 

Mapping drug resistance genes in Africa 

Molecular surveillance of mefloquine-artesunate (MQ- 

ART) resistance in the Upper Orinoco, Amazonas State, 

Venezuela 

The geography of highly resistant dhfr in East Africa 

Markers of evolving resistance to Artemisinin Combination 

Therapy (ACT) and their association with enhanced 

transmission of Plasmodium falciparum to Anopheline 

mosquitoes 

Antimalarial drug resistance among imported cases of P. 

falciparum in London hospitals 

Identification of potential molecular markers of amodiaquine 

(AQ) resistance in Plasmodium falciparum isolates 

from different endemic settings 

AntiMal integrated project: development of 

new drugs and drug combinations for the treatment 

of malaria 

REdox Antimalarial Drug discovery (READ- 

UP) 

New inhibitors of P. falciparum dihydrofolate reductase 

(DHFR) 

Evaluating the effects of combination therapy on transmission 

and the selection of drug resistant Plasmodium 

falciparum, and the implications for public health 

In vitro sensitivity of fresh Venezuelan P. falciparum and 

P. vivax isolates to anti-malarial drugs currently under 

development by Medicines for Malaria Venture (MMV) 

Interdisciplinary Monitoring Project for Antimalarial 

Combination Therapy in Tanzania (IMPACT-Tz) 

Modulation of CD36 expression, PPARү activation 

and P. falciparum phagocytosis by different families of 

antimalarial drugs 

Further studies on the mode of action of the bis 4-aminoquinoline 

piperaquine (PQ) 

Due to the high rate of therapeutic failures after chloroquine (CQ) and 

sulphadoxine/pyrimethamine (SP) treatment, MQ-ART was introduced as 

first line treatment for uncomplicated P. falciparum malaria at the end of 2004. 

Given the difficulties in implementation of in vivo/in vitro sensitivity studies 

to monitor drug resistance in remote areas such as the Upper Orinoco (e.g. 

adequate period of patient follow up and lack of infrastructure for parasite 

culture), the use of molecular genotyping represents an extremely important 

tool. Molecular markers associated with therapeutic failure to SP and CQ 

have been used to detect resistance to these drugs. More recently, Pfmdr gene 

mutations and increase in gene copy numbers are being considered important 

determinants of in vitro and in vivo resistance to MQ and decreased in vitro 

sensitivity to ART. Field studies in 4 sites of the Amazonas state have been 

completed and molecular analysis of samples is ongoing. Data obtained in this 

study will provide the baseline for further drug resistance monitoring following 

the introduction of the combination therapy and will guide decisions on drug 

policies by the Venezuelan Ministry of Health. 

The geography of highly resistant dhfr in East Africa 

LSHTM investigators: Richard Pearce, Caroline Lynch, Inbarani Naidoo, Jon Cox, Hirva Pota, 

Cally Roper 

External investigators/collaborators: John Rwakimari (National Malaria Control Programme, 

Ministry of Health of Uganda), James Tibenderana, (Malaria Consortium Africa Offi ce, Uganda), 

Tom Egwang, Constance Awang (Molecular Biology Laboratories (MBL), Uganda) 

Funding body: GMP 

Pyrimethamine-resistance mutations in the dhfr gene: S108N, C59R and N51I, 

are common in Africa, but the highly resistant I164L is rarely seen. Although 

I164L was established in South East Asia twenty years ago, its long anticipated 

emergence in Africa appears not to have occurred. The isolated reports of 

mutant infections (often following treatment) seem to indicate that some 

important precondition for the successful transmission of mutant parasites 

was not being met. In a review of the published literature, we identified 94 

surveys in 70 unique geographical localities in Africa where P. falciparum 

isolates have been tested for the I164L mutation. The 52 references which 

describe them are available as embedded links within a map which is available 

online at www.drugresistancemaps.org (see figure). Of the 6753 isolates tested 

99.8% were non-mutant. 

We have sequence-confirmed 10 P. falciparum infections carrying a 164 

mutation at dhfr, all sampled from malaria patients in southwest Uganda in 

2005. We have investigated this focus of highly resistant dhfr in southwest 

Uganda by carrying out community prevalence surveys during March-April 

2007. Our aim is to establish whether or not the mutant parasites are being 

locally transmitted. 

Aerial view of a Yanomami ‘shabono’ surrounded by rainforest, Upper 

Orinoco, Venezuela. 

A shabono is a hut, used as temporary dwellings, built in clearings in the 

jungle, using the wood cleared. 

The geography of highly resistant dhfr in East Africa. 

In a review of the published literature, 94 surveys were identifi ed in 70 

unique geographical localities in Africa, where P. falciparum isolates have 

been tested for the I164L mutation. The 52 references which describe them 

are available as embedded links within a map which is available online at 

www.drugresistancemaps.org as shown above. 



Norm. fluoro 

wild-type alleles 

CVMNK 

Norm. fluoro 

chloroquineresistant 

alleles 

CVIERT 

Markers of evolving resistance to Artemisinin Combination 

Therapy (ACT) and their association with enhanced transmission 

of Plasmodium falciparum to Anopheline mosquitoes 

LSHTM investigators: Colin Sutherland, Nahla Gadalla, Rachel Hallett 

External investigators/collaborators: Badria El Sayed (Tropical Medicine 

Research Institute, Khartoum); Badara Cisse (Université Cheikh Anta 

Diop de Dakar, Senegal); Teun Bousema (KCMC, Tanzania; University of 

Nijmegen; The Netherlands) 

Funding body: EU FP7 MALACTRES consortium; WHO-TDR; IAEA; Bill 

& Melinda Gates Foundation 

0.05 

0 

threshold 

0.05 

threshold 

0 5 10 15 20 25 30 35 40 cycle 0 5 10 15 20 25 30 35 40 cycle 

Fluorescent probe-based assay of pfcrt alleles in 21 isolates from 

Sudan 

Real-time qPCR experiment discriminating between wild-type alleles at codons 

72 – 76 of the pfcrt gene (left panel) and chloroquine-resistant alleles 

(right panel) in malaria patients prior to treatment with chloroquine (method 

described in Sutherland et al., 2007). The majority of isolates were resistant, 

and this was reflected in the large proportion of treatment failures which 

occurred in this study carried out near Gedaref, Sudan in 2004 (Gadalla, El 

Sayed & Sutherland, in preparation). 

0 

This newly funded 5-year project will employ principles 

developed in earlier GMP-funded studies where we 

demonstrated that genetic changes in the malaria parasite 

genome are strongly associated with differences in the 

infectiousness of treated individuals. In association with 

established research partners in Sudan, Tanzania, Senegal 

and elsewhere, we will examine parasite isolates from ACTtreated 

malaria patients for molecular markers in a number of candidate genes 

of interest (pfmdr1, pfcrt, pfatp6, and others) and test for association with 

enhanced prevalence of gametocyte carriage and increased transmissibility 

to mosquitoes in membrane-feeding experiments. A variety of techniques 

will be employed to identify markers, including fluorescent probe-based realtime 

qPCR (see figure) and direct sequencing of PCR-amplified sequences of 

interest. We are also pioneering quantitative measurements of gene expression 

in RNA samples taken directly from malaria patients. 

DHFR 51-59-108 

haplotypes 

Triple mutant IRN 

Double mutant ICN 

Wild-type NCS (sensitive) 

Total 

PfCRT 72-76 

haplotypes 

CVMNK (sensitive) 

CVIET 

CVMNK / CVIET 

Total 

Number of 

patients 

38 

44 

Number of 

patients 

29 

45 

16% 

100% 

Detection of SP and CQ resistance alleles in the pfdhfr (top table) 

and pfcrt (bottom table) loci in 45 patients presenting to HTD with P. 

falciparum malaria. 

2 

7 

9 

7 

86.4% 

4.5% 

15.9% 

106.8% 

20% 

64% 

Antimalarial drug resistance among imported cases of P. 

falciparum in London hospitals 

LSHTM Investigators: Colin Sutherland, Martina Burke & Peter Chiodini 

External investigators/collaborators: John Klein (St Thomas’ Hospital), Geoff Pasvol 

(Northwick Park) 

Funding: HPAUK 

Based in the Malaria Reference Laboratory and the Department of Clinical 

Parasitology at the Hospital for Tropical Diseases, this project is performing 

surveillance for drug-resistant malaria parasites among imported cases of 

malaria in the UK. We have found that markers of chloroquine (CQ) and 

sulphadoxine-pyrimethamine (SP) resistance among our patients, in the pfcrt, 

pfdhfr and pfdhps loci, including some rare alleles, are common. This is not 

surprising, as the majority of our cases originate in people travelling in sub- 

Saharan Africa.We have tested a number of malaria isolates from acute P. 

falciparum patients failing therapy with atovaquone / proguanil for mutations 

in the pfcyt-b locus. We have been able to show an association between the 

presence of mutations at codon 268 of this gene and the occurrence of delayed 

recrudescence (>=20 days after treatment) among these patients. Failure to 

clear parasitaemia in the first 4 days after treatment was not associated with 

pfcyt-b mutations in any of our case series of 10 patients. We are currently 

testing P. falciparum isolates of interest for amplification in the copy number 

of the pfmdr1 locus, and for point mutations in this locus, as these are markers 

associated with reduced sensitivity to mefloquine, amodiaquine and artemetherlumefantrine. 

In future work, we hope to establish assays for, and to monitor, 

markers of resistance in P. vivax and other human malaria parasites. 



21 

Identification of potential molecular markers of amodiaquine 

(AQ) resistance in Plasmodium falciparum isolates from different 

endemic settings 

LSHTM investigators: Colin Sutherland, Rachel Hallett, Georgina Humphreys, Khalid Beshir, 

Mark Rowland 

External investigators/collaborators: Theonest Mutabingwa (NIMR) 

Funding body: GMP; EU MALACTRES Consortium 

In Africa, AQ is now playing a significant role in combination treatment 

of malaria. It is imperative that AQ-resistance is described, its prevalence 

determined and its spread monitored. This would be facilitated if molecular 

markers for AQ resistance were identified, permitting deployment of AQcontaining 

combinations where resistance-associated alleles were rare. 

This project began with genotyping experiments to investigate the association 

of known polymorphisms in 2 Plasmodium falciparum genes, pfcrt and pfmdr1, 

with the outcome of AQ treatment in clinical trials from different settings. A 

pfcrt haplotype ‘SVMNT’(amino acids at codons 72-76) was found to be fixed 

in trial samples from Jalalabad, which showed a high degree of AQ resistance. 

This haplotype has also been associated with high AQ resistance in in vitro 

tests. A clinical trial carried out in Muheza, Tanzania, also demonstrated high 

in vivo resistance to AQ, but the parasites carried the pfcrt haplotype ‘CVIET’. 

A pfmdr1 polymorphism, codon 1246Y, was found to be selected after AQ 

treatment failure in Muheza, but not in Jalalabad, where all parasites carried 

the wild-type pfmdr1-1246D (Humphreys et al., 2007). 

It is therefore postulated that the pfcrt-SVMNT haplotype may be sufficient to 

produce high levels of chloroquine (CQ) and AQ resistance in Asian parasites, 

without further mutation in pfmdr1, but that the CQ selected African pfcrt 

haplotype of CVIET requires one or more additional mutations, possibly 

including pfmdr1-D1246Y, to become fully AQ resistant. We are currently 

further testing this hypothesis with full-length sequencing of the pfmdr1 locus 

in isolates from Jalalabad. 

An electrophoresis gel containing DNA digested with restriction 

enzymes. 

Photo: James E. Blankenship, Ph.D., jeblanke@utmb.edu 

AntiMal integrated project: development of new drugs and drug 

combinations for the treatment of malaria 

LSHTM investigators: Sarah Charnaud, Patrice Mimche, Livia Vivas 

External investigators/collaborators: S.A. Ward, P. Bray (LSTM), P. 

O’Neill, (UoL, UK), H. Vial, B. Meunier (CNRS, France), S. Krishna 

(SGUL,UK), C. Doerig (INSERM, France/UK), D. Taramelli (UNIMI, 

Italy), M. Lanzer (UoH, Germany), D. Monti (ISTM, Italy), A. Thomas 

(BPRC, Netherlands), I. Gilbert (UoD, UK), D. Gonzales (CSIC, Spain), R. 

Brun (STI, Switzerland), K. Wilson (UoY, UK), G. Campiani (UoS, Italy), S. 

Issifou (MRU, Gabon), F. Mulaa (UoN, Kenya), L. Meijer (CNER, France), 

R. Aman (ACCT, Kenya), A. Kharazmi (LICA, Denmark), S. Pegoraro (4SC, Germany), P. Patel 

(COSMOS, India), F. Cosledan (Palumed, France), D. Leroy (Merck-Serono, Switzerland), D. 

Jabes (NeED, Italy), H. Jomaa (J-LU, Giessen), S. Van Calenberg (UGENT, NTUU, Ukraine), 

F. Jehl, (Pasteur Institute, Strasbourg), M. Schlitzer (PU, Marburg), A. Nzila (KEMRI, Kenya), 

M. Ngotho (IPR, Kenya), C. Parkinson (CSIS, South Africa) 

Funding body: EU FP6 Malaria Drugs Initiative 

The AntiMal Integrated Project (IP) comprises complementary clusters of 

basic and applied scientific investigation to provide candidate molecules 

for future clinical evaluation. Through AntiMal’s programme, 29 European 

research groups support the network’s goals to generate viable lead drug 

molecules in collaboration with 8 Small-Medium Enterprises (SMEs) and 4 

partners from malaria-endemic countries (including two SMEs). The goal is 

to establish a portfolio of new antimalarial drugs and to manage this portfolio 

through an industry standard, pre-clinical evaluation and select candidates 

from within the portfolio for progression to ‘first into man’ studies. Ultimately 

Participants of the AntiMal “kick off” meeting 31st May 2006, Liverpool 

School of Tropical Medicine. 



this initiative will produce antimalarial drugs registered to internationally 

recognised standards of excellence which have potential utility in the affordable 

treatment of malaria within malaria-endemic countries and Europe. Work at 

LSHTM provides a platform for efficacy evaluation across the consortium and 

also focuses on the investigation of pharmacodynamic and pharmacokinetics 

of new anti-malarial drugs and drug combinations (for more information see 

www.antimal.eu). 

Platanal Health Post, Upper Orinoco, Venezuela December 2005. 

READUP Workshop at OCEAC, Yaounde, Cameroon, 28-29 April 2008. 

REdox Antimalarial Drug discovery (READ-UP) 

LSHTM investigators: Eloise Thompson, Livia Vivas 

External investigators/collaborators: Serge Petit Idéalp (Pharma/IDEALP, France); Françoise 

Nepveu (Université Paul Sabatier and Institut de Recherche pour le Développement, France), 

Paolo Arese (Universita Di Torino, Italy), Leonardo Basco (OCEAC-IRD, Cameroon) ; 

Laurence Touchard-Nicod (ACIES, France) 

Funding body: EU- FP6-Strep Initiative 

The READ-UP project aims at identifying antimalarial drug candidates with 

the capacity to generate radical transient species within the parasitised red 

blood cell without the need for cleavage of the endoperoxide bridge which 

is typical of artemisinins. The project brings together 4 public and 2 industry 

organisations in Europe and Africa to drive the research through the different 

steps of drug discovery and hit-to-lead optimisation from the pilot scale 

production towards pre-clinical studies. The project involves hit-to-lead 

optimisation through molecular modelling, testing of new chemical entities 

in vitro and in vivo and pharmacological, pharmacokinetics, toxicological and 

mechanisms studies. The goal is to identify one antimalarial drug candidate 

with two back-ups for further pre-clinical studies. Work at LSHTM focuses on 

the biological characterization of selected compounds (for more information 

see http://www.ird.fr/read-up/). 

New inhibitors of P. falciparum dihydrofolate reductase (DHFR) 

LSHTM investigators: Emily Bongard, Simon Croft, Livia Vivas 

External investigators/collaborators: Yongyuth Yuthavong, Sumalee Kamchonwongpaisan 

(BIOTEC, Thailand National Science and Technology Development Agency), William N. 

Charman, Susan Charman, Danielle McLennan, Karen White (Victoria College of Pharmacy, 

Monash University, Australia) 

Funding body: MMV 

The DHFR Project Team. 

Photo: Pascal Fantauzzi, MMV. 


Drugs which inhibit the folate pathway have been widely used for the treatment 

of Plasmodium falciparum malaria, but their efficacy has gradually declined due 

to the emergence of drug resistance. Resistance to pyrimethamine, an inhibitor 

of the dihydrofolate reductase (DHFR) enzyme, develops through single point 

mutations within the active site of the plasmodial DHFR. This project aims to 

design, synthesize and develop new low cost DHFR inhibitors with activity 

against DHFR resistant plasmodium and identification of activity and ADME 

(Absorption, Distribution, Metabolism, Excretion) limitations of inhibitor 

scaffolds to optimize leads for oral delivery and pre-clinical development. 

Highly efficacious enzyme inhibitors have been designed and synthesized, 

which bind with high affinity to the wild-type and resistant DHFR enzymes. 

Research during the last 2 years has focused on resolving bioavailability and 

metabolism issues with the aim of selecting a drug candidate by the end of 

2008. Work at BIOTEC focuses on the molecular biology, biochemistry, X-ray 

crystallography, chemistry and molecular modelling studies. The Monash 

University group focuses on lead optimization and LSHTM on efficacy and 

biological characterization of inhibitors (for more information see www.mmv. 

org).


23 

Evaluating the effects of combination therapy on transmission 

and the selection of drug resistant Plasmodium falciparum, and 

the implications for public health 

LSHTM investigators: Neal Alexander, Rachel Hallett, Rosalynn Ord, Anna 

Randall, Mark Rowland, Colin Sutherland, Geoffrey Targett, Chris Drakeley, 

Christopher Whitty, Diadier Diallo, Badara Cisse, Seth Owusu-Agyei, Paul 

Milligan 

External investigators/collaborators: Sam Dunyo (MRC Laboratories, The 

Gambia) 

Funding body: GMP, Wellcome Trust; WHO-TDR 

This long-running project continues to shed light on the 

development of anti-malaria drug resistance. We recently used 

a modelling approach to assess the likely impact of Intermittent 

Preventive Treatment (IPT) on drug resistance, in terms of 

the genetic coefficient of selection. The results suggest a risk 

of shortening the useful life of anti-malaria drugs if IPT is 

implemented over a wide childhood age range. On the other 

hand, IPT delivered only to infants seems unlikely to appreciably 

shorten the drugs’ useful life. 

We also found evidence that resistance to chloroquine (CQ) has costs to the 

parasite as well as benefits. Genotypes of parasites sampled over five years 

in The Gambia showed a seasonal cycle of the prevalence of drug resistanceassociated 

genotypes, with resistance increasing throughout each rainy season, 

when drug pressure is high, then decreasing over the dry season when most 

infections are asymptomatic and thus not treated (see figure right). 

Prevalence 

100 

90 

80 

70 

60 

50 

40 

30 

20 

10 

0 

54 69 79 88 97 105 113 121 129 137 145 153 161 169 177 187 

Start of 

transmission 

season: 

Aug/Sep 

Number of days since 200mm cumulative rainfall 

End of 

transmission 

season: 

Nov/Dec 

Resistant allele of 

pfcrt (76T) 

Sensitive allele of 

pfcrt (76K) 

10 day rolling mean of prevalence of crt76K, crt76T against seasonality 

index. 

Tracking CQ-resistant and CQ-sensitive pfcrt alleles in Gambian children 

presenting with clinical malaria: summarised across 5 seasons, 1998-2002 

(N=425). 

Children with both alleles contribute to both curves, as these are prevalence 

data. 

In vitro sensitivity of fresh Venezuelan P. falciparum and P. vivax 

isolates to anti-malarial drugs currently under development by 

Medicines for Malaria Venture (MMV) 

LSHTM investigators: Emily Bongard, Livia Vivas 

External investigators/collaborators: Magda Magris, Irma Rodríguez (Centro Amazonico para 

la Investigacion y el Control de la Enfermedades Tropicales, CAICET) 

Funding body: MMV 

The in vitro sensitivity profile against circulating Plasmodium isolates from 

different parts of the world is an important element in the evaluation of new 

drugs as a complement to observations made with laboratory strains. To 

support the preclinical evaluation of new drugs currently under development 

by Medicines for Malaria Venture (MMV), the main objective of this study 

is to determine the in vitro susceptibility of P. falciparum and P. 

0.3 

vivax fresh clinical isolates from the Venezuelan Amazon region 

with distinct drug-resistance patterns and to rule out the possibility of 

cross-resistance. 

Interdisciplinary Monitoring Project for Antimalarial 

Combination Therapy in Tanzania (IMPACT-Tz) 

LSHTM investigators: Richard Pearce and Cally Roper 

External investigators/collaborators: S. Patrick Kachur , Peter Bloland ( Malaria 

Branch, CDC, USA), Salim Abdulla, Hassan Mshinda (IHRDC, Tanzania), Allen 

Malisa (Sokoine University of Agriculture, Tanzania) 

Funding: USAID, CDC, Wellcome Trust 

It is argued that we can prolong the efficacy of antimalarial drugs 

through policy-mediated reductions in drug pressure, but so far supporting 

evidence from the field has been lacking. In this study parasite populations 

were sampled by random, cross sectional community-based surveys which 

were carried out annually before, during and after treatment policy switches 

Frequency 

0.2 

0.1 

0 

Centro Amazonico para la Investigacion y Control de las Enfermedades 

Tropicales (CAICET), Puerto Ayacucho, Amazonas State, 

Venezuela. 

Policy change 

Kilombero Ulanga 

Rufi ji 

2000 2001 2002 

Year 

Frequency of the Sulphadoxine Pyrimethamine (SP) resistant genotype 

before, during and after a national switch to first line SP treatment in 

two rural settings in southeast Tanzania (Kilombero Ulanga and Rufiji). 



in two rural settings in southeast Tanzania. A genetic analysis of resistance 

genes among the P. falciparum infections surveyed showed that the influence 

of treatment policy on the genetic composition of the parasite reservoir was 

profound. We concluded that national policy change had a substantial impact on 

drug pressure in these rural areas, showing that even where access to treatment 

is imperfect and treatment coverage is 

relatively low, selection through first line 

treatment can rapidly change the genetic 

composition of the parasite population. 

Modulation of CD36 expression, 

PPARg activation and P. falciparum 

phagocytosis by different families 

of antimalarial drugs 

LSHTM investigators: Patrice Mimche, Livia Vivas 

External investigators/collaborators: Donatella 

Taramelli, Fausta Omodeo-Sale, Diego Monti 

(University of Milan, Italy) 

Funding body: AntiMal International PhD 

Programme 

Prof. Patrice Mimche working in the lab at LSHTM. 


The innate immune response represents 

the first line of defence against invading 

pathogens. Monocytes can bind and engulf 

P. falciparum parasitised erythrocytes (PE) 

in the absence of antibody, via CD36. CD36 

is a class B scavenger receptor under the 

transcriptional control of the Peroxisome 

Proliferator Activated Receptor-Retinoid 

X Receptor (PPARγ-RXR), a nuclear hormone involved in lipid transport 

and metabolism. PPAR-dependent CD36 expression can be up-regulated by 

PPAR-gamma agonists enhancing PE phagocytosis, inhibiting NFkB and the 

production of proinflamatory cytokines. The aim of this project is to investigate 

the potential modulatory effects of current and novel antimalarials on PPAR-γ 

activation, CD36 expression, release of pro-inflammatory cytokines by 

monocytes/macrophages and phagocytosis of PE. In addition, the structural 

and metabolic modifications of normal red blood cells induced by antimalarial 

drugs and their susceptibility to CD36-mediated phagocytosis will be studied. 

This work will be of particular interest in relation to innate immune responses 

that arise after malaria infection in non-immune and semi-immune individuals 

who are at the greatest risk of a malaria-adverse outcome. This “host targeted 

approach” represents a novel strategy to complement the direct anti-parasitic 

effect of anti-malarial drugs and, as such, could be a valuable tool in limiting 

the emergence of drug-resistant parasites and severe malaria infection. 

Further studies on the mode of action of the bis 4-aminoquinoline 

piperaquine (PQ) 

LSHTM investigators: David Warhurst, IS Adagu, PB Madrid, Quinton Fivelman 

External investigators/collaborators: J. C. Craig, R. K. Guy (Madrid PB: UCALSan 

Francisco) 

Funding body: UCAL San Francisco, HPA 

In areas of Plasmodium falciparum resistance to the 4-aminoquinoline 

chloroquine (CQ), PQ is proving valuable as a component of ACT. 

Results explain the effectiveness of PQ and previous findings that 

more hydrophobic 4-aminoquinolines (amodiaquine and metabolite


25 

desethylamodiaquine) are more active than CQ in resistance (CQ-R). CQ 

accumulates in acidic digestive vacuoles of the malaria parasite, preventing 

conversion of toxic haematin to B-haematin (haemozoin). In CQ-R, less 

CQ accumulates probably due to drug-efflux from the vacuole associated 

with changes in vacuolar membrane protein PfCRT. B-haematin inhibitory 

activity (BHIA) was assayed for several drugs, while antiparasitic potency 

was determined in CQ-S and CQ-R P. falciparum. From measured drug pKas 

and the pH-modulated distribution of base between water and lipid (logD), 

the vacuolar accumulation ratio (VAR) of charged drug from plasma water 

(pH7.4) into vacuolar water (pH4.8) and lipid accumulation ratio (LAR) were 

calculated using a new algorithm. All 4-aminoquinolines tested were active 

in BHIA. In CQ-S, PQ and CQ were equipotent. CQ with 2 basic centres 

(2 protons can be gained) has a VAR of 143482, while more hydrophobic 

PQ has 4 basic centres and achieves a similar VAR of 104378. Modifications 

of PQ with low VAR were 

impotent. Contrasting results 

were seen in CQ-R. PQ with 

LAR of 973492 (compared 

with 8.25 for CQ) showed 

similar potency in CQ-S and 

CQ-R. Importance of LAR 

for CQ-R potency probably 

reflects ability of the drug to 

block efflux by hydrophobic 

interaction with PfCRT but 

may also relate to B-haematin 

inhibition in vacuolar lipid. 

pH 7.3 CYTOPLASM 

[CQ2H+] 15.5nM 

pH 7.3 CYTOPLASM 

[CQ2H+] 15.5nM 

[CQ] 82.5nM pH 4.8 

[CQ2H+] 1.4mM 

[CQ] 82.5nM 

[CQ] 16.5nM pH 4.8 

[CQ2H+] 287.8µM 

VACUOLE [CQ] 82.5nM CYTOPLASM 

[CQ2H+] 15.5nM 

PfCRT 76K 

+ 

VACUOLE [CQ] 16.5nM CYTOPLASM 

[CQ2H+] 15.5nM 

[CQ] 16.5nM 

CQ2H+ 

DRUG 

Vacu 

ole 

pH 

VAR 

[vacuole] 

vs 

[plasma] 

LAR 

[lipid] 

vs 

[plasma] 

logD 

pH 4.8 

logD 

pH 7.4 

Resistance 

Index 

IC50 CQ-R 

/ IC50 CQ-S 

hydroxychloroquine 

4.8 

139,607 

4.46 

-4.50 

0.65 

79 

chloroquine 

4.8 

143,482 

8.25 

-4.24 

0.92 

14 

desethylamodiaquine 

4.8 

89,366 

40.8 

-3.34 

1.61 

5.4 

amodiaquine 

4.8 

47,410 

666 

-1.85 

2.82 

2.0 

piperaquine 

4.8 

104,378 

973,492 

0.97 

5.99 

2.5 

Table showing physicochemical parameters and Resistance index for five 

4-aminoquinoline drugs. 

Scheme for chloroquine (CQ) concentration in digestive vacuole of 

CQ-sensitive (CQ-S) P. falciparum parasite, and effect of replacement 

of positively-charged residue K-76 of PfCRT by uncharged T-76 in CQresistance 

(CQ-R). 

Top picture shows CQ-sensitive parasite at equilibrium with 10nM CQ in the 

plasma (pH 7.4). (Lipid membranes and intravacuolar lipid droplet are shown 

grey). CQ base enters the parasite cytoplasm from the RBC cytoplasm, enters 

the acidic vacuolar water, gains 2 protons and becomes concentrated 

there as CQ2H+, where it inhibits haematin dimerization to B-haematin. The 

CQ2H+ is unable to escape from the vacuole, being repelled by the positively 

charged K-76 of PfCRT. 

Lower picture shows snapshot of CQ-resistant parasite with the lowest projected 

reduction (1/5) in overall uptake of drug. After replacement of PfCRT 

K76 by neutral T76, hydrophilic CQ2H+ is shown leaking into the cytoplasm 

to be equilibrated through the RBC with the external medium. 

Piperaquine is much more hydrophobic than CQ, but can gain 4 protons in 

the vacuolar water, and so can accumulate as well as CQ in the digestive 

vacuole of CQ-S parasites. Because it is so very hydrophobic it binds to and 

blocks the hydrophobic T-76 of the CQ-R parasite’s PfCRT, and its accumulation 

in the vacuole and inhibition of haematin dimerization are relatively 

unaffected. 


26 Epidemiology 

The epidemiology of malaria is changing in many settings. With renewed interest in high-level control and in 

the potential for local elimination of malaria, it has become even more important to understand the disease 

burden, how it is changing, and to detect epidemics of malaria at the earliest possible stage. New epidemiological 

tools are being developed and tested by members of the Malaria Centre, who are involved in studies of the 

epidemiology of malaria in Africa, South Asia, Southeast Asia and the Middle East. The HPA Malaria Reference 

Laboratory responsible for UK surveillance of malaria is also sited within the Malaria Centre, and members of 

the Malaria Centre are investigating malaria in migrant groups in the UK. 

Blood Blood Blood Blood 

80 

70 

60 

% infected 

50 

40 

30 

20 

10 

0 

0 10 20 30 40 50 60 70 

Age (years) 


S. mansoni 

Hookworm 

P. falciparum 

Typical age profiles of prevalence of P. falciparum infection, hookworm 

and S. mansoni. 

Estimating the burden of malarial anaemia in children under-5 in 

sub-Saharan Africa 

LSHTM investigators: Ilona Carneiro, Arantxa Roca-Feltrer, Joanna Armstrong-Schellenberg 

Funding body: RBM, WHO 

Estimates of the malaria population attributable fraction (PAF) of anaemia 

in children aged 6-59 months in sub-Saharan Africa were developed. The 

comparability of haematocrit (Hct) and haemoglobin (Hb) as methods for 

measuring anaemia were assessed and the standard threefold conversion from 

Hct to Hb was shown to underestimate the prevalence of moderate and severe 

anaemia in malaria-endemic settings. 

Our analyses suggest that 50-70% of anaemia defined as Hb

SUMMARY 

Estimating the burden of malarial anaemia in children 

under-5 in sub-Saharan Africa 

Epidemiology of Plasmodium-Helminth co-infection in 

Africa: populations at risk, potential impact on anaemia, 

and prospects for combining control 

Intermittent Preventive Treatment for African Infants 

(IPTi): where and how should IPT be applied 

The causes of febrile illness in children admitted to a 

district hospital at high intensity of malaria transmission – 

preliminary data from an observational study 

The Cambodia Malaria Baseline Survey: mosquito net 

coverage in all malarious areas of Cambodia is surprisingly 

and uniformly high, but most nets are not treated 

Malaria chemo-prophylaxis policy research in Europe 

Extended haplotype analyses of haemoglobin C and 

haemoglobin S and the dynamics of the 

evolutionary response to malaria in Kasena 

Nankana District of Ghana 

Spatial epidemiology of Plasmodium 

vivax, Afghanistan 

New systems for predicting and detecting 

malaria epidemics in the East African Highlands (HIMAL) 

Malaria Transmission Consortium (MTC): highland 

malaria 

The effect of migration on malaria epidemiology in two 

highland sites, southwest Uganda 

Malaria in Swaziland: Assessment of malaria transmission 

trends over time and the prevalence of markers of 

antimalarial drug resistance 

The impact of access to healthcare, socioeconomic and 

Epidemiology 

27 

environmental factors on developing severe malaria in 

children in Yemen: a case-control study 

The socio-economic and environmental factors important 

for acquiring non-severe malaria in children in Yemen: a 

case-control study 

Determinants of falciparum malaria in people of Nigerian 

and Ghanaian descent living in London 

Imported malaria and high risk groups: an observational 

study of UK surveillance data 1987-2006 

related malarial disease burden. We suggest that both 

school-age children and pregnant women – groups which 

have the highest risk of anaemia – would benefit from an 

integrated approach to malaria and helminth control. 

Intermittent Preventive Treatment for African 

Infants (IPTi): where and how should IPTi be 

applied 

LSHTM investigators: Ilona Carneiro, Arantxa Roca-Feltrer, Joanna 

Armstrong-Schellenberg, David Schellenberg, Brian Greenwood 

External investigators/collaborators: Tom Smith, Amanda Ross, 

Marcel Tanner (STI) 

Funding body: Bill & Melinda Gates Foundation, DFID TARGETS 

Consortium 

IPTi involves the administration of treatment doses 

of antimalarial drugs to all infants alongside delivery 

of vaccines through the Expanded Programme on 

Immunisation (EPI). 

The work at LSHTM focuses on describing the agepattern 

of malaria morbidity and mortality in different 

epidemiological settings. Systematic literature reviews of 

malaria outcomes, entomological inoculation rate (EIR) 

and malaria prevalence were used to allocate research 

sites to a matrix. This consisted of three transmissionintensity 

settings (EIR: 100) and two 

seasonality types (Perennial, seasonal). Age-profiles of 

malaria prevalence, incidence of non-severe disease, 

hospital admissions for severe malaria and all-cause 

mortality were produced for each of the six matrix cells, 

illustrating the relative burden of malaria in infants for 

each setting. 

Colleagues at STI have developed models to replicate 

the results of published trials of IPTi and to predict the 

likely impact of introducing IPTi in different transmission 

settings. 

A web-based decision-support algorithm is under 

development to provide policy makers with estimates 

of the proportion of malaria disease and death occurring 

in infants in their epidemiological setting. This will be 

combined with the results of modelling at STI, and data on 

coverage of the EPI system, to estimate the effectiveness 

of implementing IPTi. 

Intestinal blood loss 

Chronic helminth 

(hookworm) 

ANAEMIA 

infection 

Chronic blood loss 

(schistsomiasis) 

IL-10 

• Inability to mount a rapid pro- 

T reg 

TFG-β 

• Suppression of IFN-g production 

inflammatory response 

• IgE-dependent activation of 

• Immune hyporesponsiveness 

IL-4 

CD23/NO pathway 

Th2 

IL-5 

IL-13 

IgE 

Initial plasmodium 

Chronic low level 

Advanced stage 

infection 

parasitaemia 

infection 

(acute malaria) 

(severe malaria) 

haemolysis 

dyserythropoiesis 

ANAEMIA 

ANAEMIA 

Plasmodium–helminth co-infection: hypothesized mechanisms through which helminths may 

alter the risk of malarial infection and disease and the mechanisms through which anemia 

arises. 

Chronic helminth infection induces a T-helper 2 (Th2) cytokine response, which may increase the risk 

of Plasmodium infection and allow development of chronic parasitaemia by inhibiting the production of 

pro-inflammatory cytokines important in controlling the first cycle of infection. 

However, helminth-associated induction of regulatory cytokines and high levels of IgE may in fact 

prevent severe pathology in the later stages of malaria infection with high levels of interleukin (IL)-10 

acting to down-modulate the effects of interferon gamma (IFN-g) and tumor necrosis factor alpha 

(TNF-a). Sequestration of infected red blood cells may by prevented IgE-dependent activation of the 

CD23/NO pathway. 

The coincidental distribution of 

Plasmodium falciparum and hookworm 

in sub-Saharan Africa. 

The map indicates areas where hookworm 

and malarial infection are both 

common (green), areas where malaria 

is common but hookworm is relatively 

rare or absent (light blue), areas where 

hookworm is common but malaria is 

relatively rare or absent (yellow), areas 

apparently free of hookworm and 

malaria (white), and areas where the 

estimated population density is below 

one person/km2 (grey). 



Other 

N=613 

(11 deaths, CFR 

1.8%) 

Frequency (N) and associated Case Fatality Rate (CFR) of children 

with combinations of: P. falciparum parasitaemia, bacteraemia or 

HIV infection in 2,356 children with acute febrile illness admitted to a 

district hospital in Tanzania. 

Malaria -ve 

21% 

3% 

7% 

2% 

Malaria +ve 

11% 

8% 

4% 

1% 

6% 

11% 

7% 

16% 

P. falciparum 

44% 


NTS 

Hib 

E coli 

Staph aureus 

Stp pneumo 

S typhi 

Other 

Blood culture isolates and associated case fatality by malaria blood 

slide result. 

Frequency of bacterial infections in case fatalities where children were also 

blood-slide negative (top) or positive (bottom) for malaria co-infection. 

Non-typhoidal salmonella (NTS) were relatively more frequent in children 

positive for P. falciparum, suggesting a real association between NTS and 

malaria. 

59% 

N=1424 

(41 deaths, 

CFR 2.9%) 

The causes of febrile illness in children admitted to a district 

hospital at high intensity of malaria transmission – preliminary 

data from an observational study 

LSHTM Investigators: Behzad Nadjm, Christopher Whitty, Hugh Reyburn 

External investigators/collaborators: Ben Amos, Rajabu Malahiyo (Teule Hospital, Tanzania) 

George Mtove, Christina Kiemi, Juma Kimera (NIMR, Tanzania) Kini Chonya (KCMC and 

Joint Malaria Programme) 

Funding body: EU, Sir Halley Stewart Trust & Pfi zer 

66 

(12, 18.2%) 

5 

(0) 

44 

(6, 13.6%) HIV 

N=43 

(1 death, CFR 

2.3%) 

Bacteraemia 

N=131 

(18 deaths, 

CFR 13.7%) 

16 

(5, 31.3%) 

To investigate the association between bacterial and 

HIV-related infections and severe malaria in an area 

of intense P. falciparum transmission, we studied all 

paediatric admissions aged between 2 months and 13 

years with a febrile illness over 1 year. All received 

a standardised clinical examination, blood culture, 

malaria slide and HIV test. 

Preliminary data on 2,356 children are presented 

here; 1,550 (66%) were slide-positive in whom there 

were 60 (3.9%) deaths and 806 were slide-negative 

with 35 (4.3%) deaths. Overall, 9% of blood cultures 

grew an invasive organism and 5.3% were positive 

for HIV antibody testing. 

Case fatality in children with P. falciparum alone was 

2.9% but rose to over 18% in children co-infected 

with invasive bacterial disease. Non-typhoidal salmonella (NTS) were the 

commonest invasive organisms and were relatively more frequent in children 

positive for P. falciparum, suggesting a real association between NTS and 

malaria that would justify routine use of appropriate antibiotics in children 

with severe malaria. 

Up to 30% of invasive bacterial infections were vaccine-preventable 

(Haemophilus influenza-type b and pneumococcal disease) and, partly as a 

result of these findings, the Ministry of Health in Tanzania intends to introduce 

Hib vaccine into routine schedules. Analysis of the full dataset is ongoing. 

The Cambodia Malaria Baseline Survey: mosquito net coverage 

in all malarious areas of Cambodia is surprisingly and uniformly 

high, but most nets are not treated 

LSHTM investigators: Jo Lines, Jane Bruce, and Jonathan Cox 

External investigators/collaborators: Sylvia Meek (Malaria Consortium), Duong Socheat 

(Cambodia National Malaria Control Programme (CNM)), Khol Vohith, Mao Bunsoth 

(National Institute of Public Health) 

Funding body: DFID TARGETS Consortium 

The Cambodia Baseline Malaria Survey was 

conducted in the malaria transmission season of 

2004, using a two-stage cluster sampling process. 

Villages were randomly selected by province from 

a national list of communities within forest or less 

than 2 km from forest. Data on net coverage were 

obtained for 3363 households, 15831 people and 6782 nets. 86% of people 

reported sleeping under a net (treated or untreated) the night before the 

survey: 23% reported sleeping under an insecticide-treated net (ITN). Overall 

coverage varied very little with distance from forest, but the proportion of 

nets that were treated was higher in villages within or close to the forest, 

presumably reflecting the policy of the national programme targeting ITN 

distribution to villages located inside or within 200m of the forest. 37% of

Epidemiology 

29 

nets came from Government/project sources and 57% from commercial 

sources, the latter being more common in villages more distant from the 

forest. There was surprisingly little variation in usage by age and sex, but 

some evidence that some pregnant women tended to use an untreated net rather 

than an ITN. There was also surprisingly little variation by socio-economic 

status: poorer families tended to have fewer nets in the household, but were 

equally likely to be sleeping under a net. The data were used to re-evaluate the 

relationship between usage and the person:net ratio within households. More 

than a quarter of all households in the survey have more than four people per 

net, and in these households only 61% of people reported sleeping under a 

net. By contrast, in households with 2.5 to 3 people per net, 94% of household 

members were sleeping under a net. There also needs to be enough nets in 

the house to allow one to be taken away on visits to the forest. Using this 

information, the Cambodia National Malaria Control Programme has adopted 

a combined strategy: free distribution of more LLINs and supplementary nettreatment 

programmes to treat the existing untreated nets. A follow-up survey 

was conducted in 2007 and the data are now being analysed. 

Malaria chemo-prophylaxis policy research in Europe 

LSHTM investigators: Ron Behrens 

External investigators/collaborators: Guido Calleri, Federico Gobbi (Amedeo di Savoia 

Hospital, Italy), Zeno Bisoffi (Centre for Tropical Diseases, Ospedale del Sacro Cuore, Italy), 

Anders Bjorkman (Karolinska Hospital, Sweden), Francesco Castelli (University of Brescia, 

Italy), Joaquim Gascon (International Health Centre, IDIBAPS, Spain), Martin P Grobusch 

(University of the Witwatersrand, South Africa) 

At a 0.95 male:female ratio, Cambodia has the most female-biased sex 

ratio in the region and more than 50% of the population is younger than 

25. UNICEF has also designated Cambodia the third most land-mined country 

in the world. 

Photo: http://www.travelinfocambodia.com/ 

In a European collaborative project, Ron Behrens, working with TropnetEurop 

partners from across Europe, has analysed imported malaria across Europe to 

assess regional risks of acquiring malaria and decide on appropriate prophylaxis 

policy. In a study of malaria imported into eight European countries from the 

Indian sub-continent, the proportion of cases ranged between 1.4%-4.6% of 

total imported cases into the contributing countries. Plasmodium falciparum 

cases made up 13% of all cases. Total reports between 1999-2004 fell from 

317 to 180. The malaria risk for UK residents visiting the region was > 1 case 

per 1,000 years exposed. 

Research into malaria acquired in Latin America and imported into the USA 

and nine European countries was also examined as a collaborative European 

project. Between 2000 and 2004, most countries reported declining malaria 

transmission. The major sources of travel-associated malaria were Honduras, 

French Guiana, Guatemala, Mexico and Ecuador. During 2004 there were 6.3 

million visits from the ten study countries and in 2005, 209 cases of malaria 

of which 22 (11%) were Plasmodium falciparum The rates in US and UK 

travellers to the whole region (excluding Mexico) reveal a similar incidence of 

0.3 and 0.8 per 10,000 visits, despite an increasing volume of travel over the 

study (237,526 UK and 4 .5 million US travellers in 2005). The risk of adverse 

events is high and the benefit of avoided benign vivax malaria is very low 

under current policy, which may be causing more harm than benefit. The data 

has been used in generating national guidelines in many of the collaborating 

countries. 

Map of TropNet Europ centres throughout Europe found on the 

frontpage of the website www.tropnet.net 

The Hospital for Tropical Diseases (HTD) is marked by the lower right circle 

on the British Isles. 



Extended haplotype analyses of haemoglobin C and haemoglobin 

S and the dynamics of the evolutionary response to malaria in 

Kasena Nankana District of Ghana 

LSHTM investigators: Anita Ghansah, Paul Milligan 

External collaborators: Dominic Kwiatkowski, Taane Clark, Kirk Rockett (Wellcome Trust 

Centre for Human Genetics, Oxford. Wellcome Trust Sanger Centre, Hinxton), Michael Wilson, 

Kwadwo Koram (Noguchi Memorial Institute for Medical Research, University of Ghana), Rex 

Oduro, Abraham Hudgson, Lucas Etego (Navrongo Health Research Centre, Navrongo-Ghana), 

William Rogers (Naval Medical Research Centre, Jakarta- Indonesia) 

Funding body: Government of Ghana, NIH, and the Wellcome Trust 

Rooftops in Ghana. 

http://www.bigfoto.com/ 

A 

% infected 

0 

0.1-0.9 

1.0-4.9 

>5 

N 

200 0 200 400 

B 

Probability 

0.005-0.19 

0.2-0.39 

0.4-0.49 

0.5-1.0 

N 

200 0 200 400 km 

Epidemiologic data obtained from a nationwide survey of 269 villages 

in Afghanistan conducted from August through September 2005. 

A) Prevalence of Plasmodium vivax in Afghanistan, according to a 2005 

survey (n = 269) and previous prevalence surveys conducted by HealthNet- 

TPO, 2000–2003 (n = 64). 

Lower right inset shows ecologic zones in Afghanistan according to 

differences in elevation, temperature, and land cover. White=high altitude 

rangeland; light blue=desert; dark blue/gray=grassland; black=irrigated/ 

marshland. 

B) Predicted probability of P. vivax transmission (prevalence >0%) in 

Afghanistan, according to logistic regression model. 


Haemoglobin S (HbS) and C (HbC) both protect against malaria. The HbS 

allele is widely distributed throughout sub-Saharan Africa, while the HbC 

allele is restricted, mainly to parts of West Africa. A population-based case 

control study is being used to estimate the association between HbC and 

severe malaria in Ghana. It is not clear how these two alleles have evolved 

in the central West African countries where they co-exist in high frequencies. 

Analysis of extended haplotypes in these populations can give insights into the 

evolution of these two HBB gene variants. The haplotype is the combination of 

alleles on the same chromosome: recent alleles tend to be associated with low 

haplotype diversity and hence the origin and age of a mutation can be inferred 

from haplotypic information. We analysed extended haplotype patterns in 

samples from the Kasena Nankana district of Ghana: these revealed extensive 

homogeneity for both HbS and HbC, which is suggestive of recent selection. 

We used the approximate likelihood coalescent-based software tool, ‘fullopt’, 

to estimate crossover rates and detect the presence of hotspots in the gene 

region using our data to determine whether selection has been strong enough 

to overcome the effect of a hot spot region where meiotic recombination may 

be likely to breakdown the haplotype structure and create more diversity. HbS 

maintained its haplotype structure within the β-globin hot spot and 74% of 

the HbC haplotypes also maintained their haplotype structure in the hot spot 

region, an indication of the strength of selection. 

Spatial Epidemiology of Plasmodium vivax, Afghanistan 

LSHTM Investigators: Simon Brooker, Toby Leslie, Kate Kolaczinaksi, Tim Freeman, Archie 

Clements, Jan Kolaczinski 

External Investigators/Collaborators: HealthNet-TPO, Ministry of Public Health, Afghanistan 

Funding body: European Commission Office of Humanitarian Aid (ECHO) 

Plasmodium vivax malaria is endemic to large areas of the sub-tropics. In most 

areas disease transmission is unstable and limited by climatic, environmental 

and human factors. In order to assist in targeting of interventions and 

improving malaria control efficiency, a nation-wide prevalence survey was 

conducted in 2005. Prevalence data from 269 randomly selected villages were 

collected by transect sampling in each village. These data, and data from an 

additional 64 villages from previous surveys in 2000-2003, included a total of 

40,350 participants. The location of each village was recorded using a global 

positioning system. Global satellite sensor-derived data was used to assess 

the effect of distance from rivers, normalised difference vegetation index and 

elevation on disease prevalence in each of four ecological zones. Logistic 

regression modelling was used to develop an environmental risk model 

for disease transmission. The final model was cross-validated using a jackknife 

procedure. Overall prevalence nationwide was 0.5%, but varied widely 

by geographical location, with Northern Afghanistan having the highest 

prevalence. No transmission occurred at >2000m elevation or >10km from 

rivers. This data was used to develop a spatial map delineating areas where

Epidemiology 

31 

transmission is most likely to occur and provides a useful tool for policy 

makers in targeting interventions. 

New Systems for Predicting and Detecting Malaria Epidemics in 

the East African Highlands (HIMAL) 

LSHTM investigators: Jonathan Cox, Tarekegn Abeku, Caroline Jones, James Beard, Mojca 

Kristan 

External investigators/collaborators: Simon Hay (University of Oxford); Willis Akhwale 

(Ministry of Health, Kenya); John Rwakimari (Ministry of Health, Uganda) 

Funding body: GMP, DFID TARGETS Consortium 

The need for robust systems for malaria epidemic early warning and detection 

has long been recognized by international and national health agencies, but 

development of such systems on the ground has been limited. The HIMAL 

collaboration began successfully developing and testing district-level epidemic 

monitoring systems in four districts in Kenya and Uganda in 2002 and in doing 

so has addressed a number of fundamental operational research questions 

relating to the design of appropriate surveillance systems, the management 

and analysis of data for successful outbreak detection, the economic costs of 

developing and maintaining such systems and the institutional factors that 

influence their sustainability. Although field-based research activities ceased 

in 2006, analysis of core datasets on clinical and parasitological case numbers, 

weekly vector densities and meteorological variables will continue into the 

first quarter of 2008. Plans exist in both Kenya and Uganda to scale up piloted 

HIMAL activities to cover other epidemic-prone districts. In Kenya, HIMAL 

sites will also support a number of new activities focusing on the monitoring 

and evaluation of malaria transmission in epidemic-prone settings (this work 

is planned under the Malaria Transmission Consortium). 

Automatic equipment powered by solar energy used for weather monitoring 

in four HIMAL districts of Kenya and Uganda. 

Malaria Transmission Consortium (MTC): highland malaria 

LSHTM investigators: Jonathan Cox, Chris Drakeley 

External investigators/collaborators: Willis Akhwale (Ministry of Health, Kenya); John 

Gimnig and Mary Hamel (CDC), Frank Collins (University of Notre Dame) 

Funding body: BMGF, DFID TARGETS Consortium 

The purpose of the MTC is to develop tools with which to establish an evidence 

base to help malaria control program managers monitor malaria transmission 

and implement and adjust malaria control interventions across a range of 

malaria transmission intensities. The MTC will work with malaria control 

programmes to (1) identify simple, standardized and inexpensive methods 

for measuring malaria transmission through entomological, parasitological 

and serological techniques and (2) in parallel, evaluate transmission-reducing 

malaria control techniques, both alone and in combinations across a range 

of malaria transmission environments. The MTC comprises a network of 

malaria research groups associated with active malaria control programmes 

in Indonesia, Kenya, Tanzania and Zambia. LSHTM staff members are taking 

a prominent role in the design of generic, consortium-wide activities and are 

also principally responsible for research activities in the MTC’s highland 

African site in Western Kenya. Funding for the MTC was approved in 2007; 

research protocols are currently being finalised and it is anticipated that field 

activities will begin in the second quarter of 2008. 

Afghanistan, Panjshir. 

http://www.afghanistan.travelphotoguide.com 

A populated valley endemic for malaria in Eastern 

Afghanistan, taken from the grounds of Mehtarlam 

Hospital, Laghman Province. 



The effect of migration on malaria epidemiology in two highland 

sites, southwest Uganda 

LSHTM investigators: Caroline Lynch, Cally Roper, Jonathan Cox, Sarah Staedke, Patrick 

Corran 

External collaborators: Dr John Rwakimari (NMCP, Ministry of Health Uganda), Dr Tom 

Egwang (Biomed Labs, Uganda) 

Funding body: Central Research Fund (University of London), GMP, Wellcome Trust 

Blood spots being in taken Kabale district, Uganda, August 

2007. 

Taking GPS coordinates 

in Kabale district, 

Uganda, August 2007. 

Migration is thought to be a contributory factor to malaria epidemics and 

increases in malaria transmission in areas of unstable malaria transmission. 

Yet there are few studies which have examined the link between migration 

and malaria. This study examined the importance of migration on malaria 

incidence and prevalence in Ugandan highland sites of high and medium 

altitude, through case-control and community based cross-sectional studies. 

Results from case-control studies show a high rate of travel from highland 

districts with 26% of control individuals travelling outside their resident 

areas four weeks prior to presentation at health facilities. Travel from low 

transmission resident areas to areas of known malaria risk showed an odds 

ratio for parasitaemia in outpatients of 2.76 (p>0.001) in the high altitude 

site. 

Permanent, medium-term and circulatory migration were recorded and indexed 

during a cross-sectional survey in both sites from which associations between 

frequent migration and seropositivity for MSP1-19 malaria antibodies will 

be explored. Spatial analytical approaches will be used to test for spatial 

clustering of clinical and seropositive cases. 

This study was undertaken as part of the wider study on the emergence of 

highly resistant dhfr alleles in P. falciparum populations in Uganda with Dr 

Cally Roper. 

Malaria in Swaziland: Assessment 

of malaria transmission trends over 

time and the prevalence of markers of 

antimalarial drug resistance 

LSHTM Investigators: Sabelo Dlamini, Colin Sutherland 

Funding: Commonwealth Scholarships; WHO-TDR 

Sabelo Dlamini’s DrPH research project 

took him back to Swaziland in 2007 to try to capture a snapshot of malaria 

transmission there by sampling clinical cases across a series of health 

facilities. The number of cases presenting to clinics was very low in 2007 

and only a handful of isolates were obtained. These, and some stored samples 

going back to the late 90’s, are being evaluated for markers of drug resistance. 

This is of interest as government policy moves from the current practice of 

using chloroquine monotherapy for clinical malaria cases, to artemisinin 

combination therapy in the form of artemether-lumefantrine. 

We have also been evaluating historical data on rainfall patterns and recorded 

malaria cases over 3 decades. In Swaziland changes in the level of investment 

in malaria control programmes appear to be better predictors of malaria 

incidence than do fluctuations in rainfall patterns. 

The landlocked Kingdom of Swaziland consists mostly of high plateaus 

and mountains, surrounded on the north and south by South Africa, 

and on the east by Mozambique. 

With an area of just over 17,000 square kilometres, Swaziland is the smallest 

country in the southern hemisphere (comparable to the size of Wales in the 

United Kingdom). 


The impact of access to healthcare, socioeconomic and 

environmental factors on developing severe malaria in children in 

Yemen: a case-control study 

LSHTM investigators: Abdullah Al-Taiar, Shabbar Jaffar, Christopher Whitty 

External investigators/collaborators: Ali Assabri, Molham Al-Habori, Ahmed Azazy, Arwa Al- 

Gabri, Mohammed Al-Ganadi, Bothaina Attal

Epidemiology 

33 

Funding body: WHO-TDR 

Malaria is a major public heath problem in Yemen; identifying factors for 

progression from mild to severe malaria which can be modified or targeted is 

a priority. Few studies have investigated the impact of socio-economic and 

environmental factors for progressing from mild to severe 

malaria, and almost none outside Africa. To investigate the 

impact of socio-economic and environmental factors on 

developing severe malaria in comparison to mild malaria in 

Yemen, a case control-study was conducted comparing 343 

children aged 6 months-10 years diagnosed with WHOdefined 

severe malaria at the main children’s hospital in Taiz, 

with 445 children with mild malaria diagnosed in the health 

centres which serve the areas from which the cases came. 

In univariate analysis, age 2km was significantly 

associated with progression to severe disease in multivariate 

analysis. Environmental and vector control factors associated 

with protection from acquiring malaria at all (such as 

sleeping under bednets) were not associated with protection 

from moving from mild to severe disease. Innovative ways 

to improve access to antimalarial treatment for those living more then 2km 

away from health centres such as home management of malaria, especially 

for infants and young children, should be explored in malaria-endemic areas 

of Yemen. 

The socio-economic and environmental factors important for 

acquiring non-severe malaria in children in Yemen: a case-control 

study 

LSHTM investigators: Abdullah Al-Taiar, Christopher Whitty; Shabbar Jaffar 

External investigators/collaborators: Ali Assabri, Molham Al-Habori, Ahmed Azazy, Arwa 

Algabri; Mohammed Alganadi 


Little is known about the relative importance of environmental and socioeconomic 

factors for acquiring non-severe malaria in Yemen. A case-control 

study was conducted to determine the importance of various factors among 

children in Yemen. Cases of non-severe malaria were recruited from health 

centres and community controls from the neighbourhood of the cases. Data 

were collected by personal interview and direct inspection during home 

visits. 320 cases and 308 controls were recruited. In multivariate analysis, 

environmental factors (living near streams and freshwater marshes), earth roofs 

of houses and history of travel were all significantly and positively associated 

with the occurrence of malaria while regular spraying of insecticides at home 

was a protective factor. There was no association with socio-economic factors 

including crowding, education and occupation of the parents or ownership 

of house assets. An index created based on a number of indicators of wealth 

showed significant association with malaria in univariate analysis but was 

not significant in multivariate analysis. Control activities can be targeted on 

identifiable environmental factors such as stream and freshwater marshes 

although this needs further investigation. Extra protective measures may be 

needed by families of those who travel in Yemen. 

Taiz, Yemen. 

Yemen is a Middle Eastern country located on the Arabian Peninsula in 

Southwest Asia. With a population of more than 20 million people, Yemen is 

bordered by Saudi Arabia to the North, the Red Sea to the West, the Arabian 

Sea and Gulf of Aden to the South, and Oman to the east. Yemen’s territory 

includes over 200 islands, the largest of which is Socotra, about 415 kilometres 

(259 miles) to the south of Yemen, off the coast of Somalia. Yemen is the 

only republic on the Arabian Peninsula. 

The country can be divided geographically into four main regions: the coastal 

plains in the west, the western highlands, the eastern highlands, and the Rub 

al Khali in the east. 

The Tihamah (“hot lands”) form a very arid and flat coastal plain. Despite the 

aridity, the presence of many lagoons makes this region very marshy and a 

suitable breeding ground for malarial mosquitoes. 

Taiz is a city in the highlands, at the centre of a coffee-growing region, at an 

altitude of 1,400 m/4,593 ft. 

Muslim men praying at a mosque. 

Religion in Yemen consists primarily of two principal Islamic religious groups. 

55% of the population are Sunni and 42% are Shi’a. 



Determinants of falciparum malaria in people of Nigerian and 

Ghanaian descent living in London 

LSHTM investigators: Penny Neave, Peter Chiodini, David 

Bradley, Christopher Whitty 

Funding body: NHS 

Around half of falciparum malaria in the UK is in people from families of 

West African descent visiting friends and relatives in West Africa, especially 

Nigeria and Ghana. Rates of neural prophylaxis are low in this group. This 

study combined epidemiological and anthropological techniques to determine 

the causes of this very high rate in this group compared with other travellers. 

It includes case studies with members of these community groups living in 

London and healthcare providers, backed up by epidemiological data from 

the Malaria Reference Laboratory. The aim is to identify ways in which health 

messages and health behavior can be targeted in this group to reduce the risk 

of malaria. 

Reports 

1600 

1200 

800 

400 

P. falciparum 

P. vivax 

other species/ 

mixed 

0 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 

Reported Cases of malaria, 1987 to 2006. 

annual passenger numbers 

Linear (P. falciparum) R 2 -0.563 

Linear (P. vivax) R 2 -0.611 

Year 

4 

3 

2 

1 

0 

Imported malaria and high risk groups: an observational study of 

UK surveillance data 1987-2006 

LSHTM investigators: Adrian D Smith, David J Bradley, Valerie Smith, Marie Blaze, Ron 

Behrens, Peter Chiodini, Christopher Whitty 

Funding body: HPAUK 

This study examines temporal, geographic and socio-demographic trends 

in malaria imported to the UK, so as to identify high risk groups using the 

national Malaria Reference Laboratory surveillance data in the UK and data on 

destinations from the International Passenger Survey. A total of 39,300 cases of 

proven malaria in the UK between 1987-2006 were identified. Reported cases 

of imported malaria increased significantly over the 20 years of study, with an 

increasing proportion attributable to Plasmodium falciparum (P. falciparum/P. 

vivax reporting ratio: 1.3:1 in 1987-91 to 5.4:1 in 2002-06). 

There was a substantial decline in Plasmodium vivax over the 

same period. The prognosis of reported Plasmodium falciparum 

malaria did not improve over the period and mortality remained 

considerable (7.1 per 1000 reported cases). Travellers visiting 

friends and relatives, usually in a country from which members 

of their family migrated in Africa or Asia, accounted for 65% 

of all malaria reported, and malaria reports are geographically 

concentrated in areas where migrants from Africa and South 

Million trips to malarious 

countries (originating in 

the UK) 

Asia to the UK have settled. Individuals travelling for this 

purpose were at significantly higher risk of malaria than 

other travellers, and were less likely to report the use of any 

chemoprophylaxis (odds ratio of reported chemprophylaxis 

use 0.23, CI 0.21-0.25). Despite the availability of highly 

effective preventative measures, the preventable burden from 

falciparum malaria has steadily increased in the UK. Provision of targeted and 

appropriately delivered preventative messages and services for travellers from 

migrant families visiting friends and relatives should be a priority. 


Clinical Trials & Clinical Studies 

35 

Determining what interventions do and do not work in the 

field is essential if we are to have effective malaria control 

and treatment. In addition to Phase II and III trials of drugs 

and vaccines in children and pregnant women, members of 

the Malaria Centre have undertaken trials using new methodologies including studies of the effectiveness 

of intermittent preventive treatment (IPTc, IPTi, see box below), rapid diagnostic tests and health systems 

interventions in Africa and Asia. New drugs and diagnostics are of no use if they are not delivered to the 

right people, and the members of the Malaria Centre have a particular interest in developing and testing new 

methods of delivery. This is complemented by a wide range of observational clinical studies in severe and 

uncomplicated malaria to understand the disease better. 

SUMMARY 

The effectiveness, cost and cost effectiveness of IPTp or screening 

and treatment of malaria in pregnancy among women using long 

lasting insecticide treated bed nets: a randomised controlled trial 

IPTp: efficacy of sulphadoxine-pyrimethamine (SP) and amodiaquine 

(AQ) alone or in combination as IPTp in the Kassena-Nankana 

district of Ghana: a randomised controlled trial 

Drug options for IPTi in an area with high resistance to sulphadoxine/pyrimethamine 

(SP): an evaluation of short and long-acting 

antimalarial drugs 

Evaluation of IPTi and the effect of drug resistance on efficacy 

Assessment of the acceptability of IPTi in areas of high and low-tomoderate 

malaria transmission 

Cost effectiveness assessment of IPTi in areas of high and low to 

moderate malaria transmission 

In vivo efficacy study of sulphadoxine/pyrimethamine (SP) in symptomatic 

6-59 month old children and asymptomatic 2-10 month olds 

Seasonal IPTc for the prevention of anaemia and malaria in Ghanaian 

children: a randomised, placebo controlled trial 

A randomised trial to compare the safety, tolerability and efficacy 

of three potential drug combinations for IPTc in children aged 1 to 

5 years in an area of seasonal malaria transmission in Upper River 

Region, The Gambia 

Comparison of two strategies for the delivery of IPTc against 

malaria in an area of seasonal transmission 

Drug regimens for seasonal IPTc in Senegal 

IPTsc: Comparison of efficacy, safety and tolerability in Uganda 

IPTsc: malaria parasitaemia, anaemia & school performance 

The effectiveness, cost and cost effectiveness of IPT Combination 

therapy with sulphadoxine-pyrimethamine plus artesunate (SP+AS) 

for the treatment of vivax malaria in areas co-endemic for Plasmodium 

falciparum and P. vivax 

Sulphadoxine-pyrimethamine (SP), chlorproguanil-dapsone, or 

chloroquine (CQ) for the treatment of Plasmodium vivax malaria in 

Afghanistan and Pakistan: a randomised controlled trial 

A multi-arm placebo controlled randomised evaluation of an eight 

week primaquine regimen using single weekly doses for radical cure 

of vivax malaria in Pakistan 

Safety and tolerability of combination antimalarial therapies for 

uncomplicated falciparum malaria in Ugandan children 

Combination therapy for the treatment of uncomplicated falciparum 

malaria in a cohort of Ugandan children: a longitudinal randomised 

trial 

Evaluation of home-based management of fever in urban Ugandan 

children 

A trial of azithromycin+artesunate v artemether-lumefantrine (AL) 

among children in an area of high drug resistance in Tanzania 

An open label randomised comparison of injectable artesunate 

and quinine in children with severe falciparum malaria in Africa 

(AQUAMAT) 

A cluster randomised trial of 2 diagnostic tools to detect anaemia in 

rural dispensaries in Tanzania; the EARS study 

A randomised trial comparing artesunate+amodiaquine (AS+AQ), 

sulphadoxine-pyrimethamine+amodiaquine (SP+AQ), chlorproguanal-dapsone 

(CD) and SP-monotherapy for treatment of malaria in 

pregnancy in an area of high drug resistance, Tanzania 

A non-inferiority, open-labelled, randomised trial of the efficacy 

and safety of artesunate-amodiaquine (AS+AQ), artemetherlumefantrine 

(AL), and artesunate-lapdap (AS+CD) for treatment of 

uncomplicated P. falciparum malaria among children in Ghana 

Severe malaria in children in Yemen: two-site observational study 

A simple molecular diagnostic test for malaria using LAMP 

technology 

The effect of removing direct payment for healthcare on health 

service utilisation and health outcomes in Ghanaian children: a 

randomised controlled trial 

Intermittent Preventive Treatment (IPT) 

IPT is the administration of a treatment dose of an antimalarial drug at pre-specified times, regardless of the presence 

of infection or illness. IPT in pregnancy (IPTp) has been recommended by WHO for the last decade, but Malaria 

Centre scientists have been working on several new applications of IPT. For children less than one year of age, IPT in 

infants (IPTi) involves the administration of malaria drugs at the time of routine vaccination in perennial transmission 

settings. IPTi has been favourably reviewed by the Institute of Medicine and is now undergoing WHO review. IPT for 

children under five years of age (IPTc) is being evaluated in intensely seasonal transmission settings in West Africa. 

Finally, the potential of IPT in school-aged children (IPTsc) has been evaluated in terms of health and education. 

The first 12 projects in this section describe studies of IPTp, IPTi, IPTc and IPTsc. Details of further IPT studies can 

also be found in the sections for Epidemiology and Social & Economic Studies. 

The effectiveness, cost and cost effectiveness of IPTp or screening 

and treatment of malaria in pregnancy among women using long 

lasting insecticide treated bed nets: a randomised controlled trial 

LSHTM Investigators: Brian Greenwood, Daniel Chandramohan, Jane Bruce 

External investigators/collaborators: Harry Tagbor, Edmund Browne 


The primary objective is to demonstrate that the prevalence of severe anaemia 

(Hb < 8g/dl) at 34 to 36 weeks of gestation and low birth weight (BW < 2500g) 

is not greater in pregnant women sleeping under a long lasting insecticide 

treated net (LLIN) and receiving treatment for malaria parasitaemia identified 

using a rapid diagnostic test (RDT) than in women sleeping under LLIN and 

receiving intermittent treatment does of sulphadoxine-pyrimethamine (SP). 

The secondary objective is to show that prevalence of placenta parasitaemia 

and incidence of serious and non-serious adverse events in the LLIN plus 

RDT screening and treatment arm are not greater than in the LLIN plus IPTp 

arm. 

Project team screening eligible pregnant 

women at enrolment to the IPTp study in 

the Ejisu-Juaben and Effi duase districts 

Ghana. 


36 Clinical Trials & Clinical Studies 

In addition, the cost per cases of severe maternal anaemia averted by these two 

strategies is also assessed. 

Enrolment of pregnant women into the study is underway at five health 

facilities in Ejisu-Juaben and Effiduase districts in Ghana. A total of 1850 

pregnant women were enrolled into the study by end of February 2008. The 

required sample size is 3330 pregnant women. The schedule includes three 

passive follow-up visits at ANC after enrolment; follow-up at delivery and six 

weeks postpartum. By end of February 2008, 703 women have completed the 

third passive follow up visit at which the third trimester Hb was taken and 602 

had a birth outcome recorded. The enrolment is expected to be completed by 

end of December 2008 and follow-up by July 2009. 

Midwives assessing and recording basic 

indicators at antenatal clinic (ANC) in 

Ghana as part of an IPTp trial. 

Assessment of a pregnant woman at 

ANC by a midwife in Ghana. 

Pregnant couple making a living. 


IPTp: efficacy of sulphadoxine-pyrimethamine (SP) and 

amodiaquine (AQ) alone or in combination as IPTp in the 

Kassena-Nankana district of Ghana: a randomised controlled 

trial 

LSHTM investigators: Christine Clerk, Daniel Chandramohan, Brian Greenwood 

External investigators/collaborators: Abraham Hodgson 


In the context of increasing resistance to SP, we assessed the efficacy and 

safety of AQ and a combination of SP and AQ (SP+AQ) as alternatives for 

IPTp. 

The study was carried out in the Kassena-Nankana district of Ghana from June 

2004 to February 2007. Women with gestation between 18-32 weeks were 

randomised to receive 1-3 courses of IPTp with SP (n=1328), AQ (n=986) or 

SP+AQ (n=1328); enrolment into the AQ arm was discontinued by the Data 

& Safety Monitoring Board (DSMB). The prevalence of anaemia (Hb


37 

dapsone), is nearing its end. We hope to break the code in April 2008 and 

close the project in August 2008. This study has built capacity for doing Good 

Clinical Practice (GCP) quality studies in North – Eastern Tanzania and has 

prepared the Korogwe site for malaria vaccine trials. 

Evaluation of IPTi and the effect of drug resistance on efficacy 

LSHTM investigators: Roly Gosling, Azra Ghani, Rosalynn Ord, Daniel Chandramohan, 

Brian Greenwood, Cally Roper, David Schellenberg 

External investigators/collaborators: Imperial College, London; NIMR, KCMC, Tanzania; 

KEMRI, Kenya; CDC, USA; Manhiça Health Research Center, Mozambique; Fundació Clínic 

per a La Recerca Biomèdica , Spain; MRC, Gabon; Eberhard Karls University, Germany 

Funding body: BMGF 

The IPTi consortium drug resistance working group (DRWG) is evaluating 

the relationship between IPTi efficacy using sulphadoxine-pyrimethamine 

(SP) and both molecular and in vivo drug resistance to SP. So far the DRWG 

has co-ordinated in vivo efficacy studies in Kenya, Gabon and Tanzania, the 

results of which will soon be published. From this data and data collected 

at our collaborating sites (namely Kisumu in Kenya, Lambarene in Gabon, 

Mahnica in Mozambique and Mtwara/Lindi and Kilimanjaro in Tanzania), we 

are modelling both how resistance levels effect IPTi efficacy and how IPTi 

using SP effects resistance levels to SP in the community. As SP is no longer 

used for treatment in Africa, we are planning on mapping resistance genes to 

SP so as to help policy makers estimate likely resistance levels of malaria to 

SP. 

Assessment of the acceptability of IPTi in areas of high and lowto-moderate 

malaria transmission 

LSHTM investigators: Roly Gosling, Daniel Chandramohan, Robert Pool 

External investigators/collaborators: NIMR, KCMC, Tanzania; Fundació Clínic per a La 

Recerca Biomèdica , Spain 


IPTi is a promising strategy for reducing malaria in infants; it has been shown 

to reduce cases of malaria in children under the age of 1 year from between 

22 and 50%. The intervention is run through the existing national vaccination 

services so is thought to be a cost effective intervention and easy to implement. 

However, experience has shown that introducing new interventions to an 

unsensitised population can result in the intervention failing. 

A team of 6 social scientists is working to describe knowledge, perceptions, 

experiences and responses relating to IPTi and the Expanded Program of 

Immunisation (EPI), in order to identify and understand barriers to the uptake 

and adherence to IPTi. The study is based on established anthropological 

methods and is using a mix of structured and semi-structured interviews with 

individuals, key informants and focus groups. The study is taking place in the 

two Kilimanjaro IPTi study sites of Same and Korogwe Districts. 

(antibiotic) 

ACT 

AL 

AP 

AQ 

AS (ART) 

AS+CD 

CD 

CQ 

DHA 

DP 

MQ 

MQ-AS 

P 

PQ 

Q 

SP 


& their abbreviations 

azithromycin 

Artemisinin Combination Therapy 

artemether-lumefantrine (coartem) 

atovaquone / proguanil 

(4-aminoquinoline) amodiaquine 

artesunate 

Artesunate + chlorproguanil-dapsone 

(currently withdrawn from use) 

chlorproguanil-dapsone (lapdap) 

(4-aminoquinoline) chloroquine 

dihydroartemisinin 

dihydroartemisinin-piperaquine 

mefl oquine 

mefl oquine plus artesunate 

(bis 4-aminoquinoline) piperaquine 

primaquine 

quinine 

sulphadoxine-pyrimethamine 

KCMC study centre and laboratories 

in Moshi, Tanzania, overlooked by the 

snowy peaks of Kilimanjaro. 

Cost effectiveness assessment of IPTi in areas of high and low to 

moderate malaria transmission 

LSHTM investigators: Lesong Conteh, Roly Gosling, Daniel Chandramohan 

External investigators/collaborators: STI, Switzerland; Makarere University, Uganda; NIMR, 

KCMC, Tanzania; Fundació Clínic per a La Recerca Biomèdica , Barcelona, Spain 


This study aims to calculate health economic indices for IPTi. This is an 

international study including projects in Kenya, Mozambique, Gabon, 

Senegal, Ghana and Papua New Guinea. The intervention is run through the 

existing national vaccination services and thought to be cost effective. This 



proposal aims to define costs and give policy makers the information required 

to implement the strategy. The study is questionnaire-based and will take place 

in the two Kilimanjaro IPTi study sites of Same and Korogwe Districts. 

1.00 

no mutation at 581 

mutation at 581 

In vivo efficacy study of sulphadoxine/pyrimethamine (SP) in 

symptomatic 6-59 month old children and asymptomatic 2-10 

month olds 

LSHTM investigators: Roly Gosling, Cally Roper, Roslynn Ord, Brian Greenwood and Daniel 

Chandramohan 

External investigators/collaborators: Dr Samwel Gesase, Dr Jacklin Mosha, Dr Martha 

Lemnge, Professor Frank Mosha 


0.75 

0.50 

0.25 

0.00 

0 10 20 30 

follow-up days 

The cumulative proportion of children experiencing treatment failure 

to SP with parasites carrying the mutation in the dhps gene at position 

581 (A581G mutation) during enrolment. 

Kaplan Meier cumulative failure analysis, unadjusted effect dhps gene 

mutation at 581, p-value=0.0146. 

Korle Bu Hospital, Ghana. 


This study was designed to examine if in vivo efficacy of SP was better in 

asymptomatic infants (the target group for IPTi) as compared to symptomatic 

children. The study followed the standard WHO in vivo antimalarial 

efficacy format with 28 day follow up. The study was stopped early due to 

the unexpected high rate of failures in both groups. Out of an expected 292 

children, the study only recruited 112. Day 28 efficacy in the symptomatic was 

only 17.3% and was not statistically different from the asymptomatic study. 

Examination of the parasite genes associated with resistance to SP, namely 

dhps and dhfr, revealed a previously unreported combination of mutations: the 

“triple triple” (mutations at positions 51, 59 & 108 in dhfr and 437, 540 and 

581 in dhps). A survival analysis showed increased and earlier failure in those 

isolates with the 581 G mutation as shown in the figure left. 

Seasonal IPTc for the prevention of anaemia and malaria in 

Ghanaian children: a randomised, placebo controlled trial 

LSHTM Investigators: Daniel Chandramohan, Dongmei Liu, Brian Greenwood 

External investigators/collaborators: Margaret Kweku, Fred Binka, Mahmood Seidu 


The aim of the study was to investigate the effect of IPT with sulphadoxinepyrimethamine 

(SP) or artesunate plus amodiaquine (AS+AQ) on anaemia 

and malaria in children in an area of intense, prolonged, seasonal malaria 

transmission in Ghana. 

2551 children aged 3-59 months from 30 villages were enrolled and 

individually randomised to receive placebo or AS+AQ monthly or bimonthly, 

or SP bimonthly over a period of 6 months starting from June 2005. The 

primary outcome measures were episodes of anaemia (Hb


39 

A randomised trial to compare the safety, tolerability and efficacy 

of three potential drug combinations for IPT in children aged 1 

to 5 years in an area of seasonal malaria transmission in Upper 

River Region, The Gambia 

LSHTM investigator: Lesong Conteh, Paul Milligan, Brian Greenwood 

External investigators/collaborators: Kalifa Bojang, David Conway, Francis Akor, Momodou 

Jassey, Ousman Bittaye 

Funding Body: GMP, MRC 

IPT offers a potential way of preventing malaria infection without compromising 

the development of malaria immunity or encouraging drug resistance. The 

effect of IPT in infants and children and in the prevention of malaria has been 

evaluated in a number of trials. Results from these trials have shown that IPT 

provided significant protection against clinical malaria. It seems likely that a 

long-acting drug is needed for effective IPT and SP alone or in combination 

with other drugs has been used for IPT programmes. However, SP resistance 

is increasing in many parts of Africa. Thus it is important to investigate if 

other drug regimens might be equally effective in preventing malaria. During 

the 2007 malaria transmission season, 1009 children aged 1-5 years were 

individually randomised to receive amodiaquine plus SP, piperaquine plus SP 

or dihdroartemisinin plus piperaquine at monthly intervals on three occasions 

during the months of September, October, and November. To determine the 

prevalence of side effects following drug administration, participants in each 

treatment group were visited at home three and seven days after each round 

of drug administration and a side effects questionnaire completed. To help 

establish whether these adverse events are drug related, the same questionnaire 

was administered after each treatment round to 286 age-matched children who 

are not part of the trial. Morbidity was monitored throughout the rainy season 

and malaria smears were prepared and haemoglobin concentration measured 

whenever a study subject presented to one of the health centres in the study 

area with symptoms compatible with malaria. Analysis of the data is currently 

underway. 

Comparison of two strategies for the delivery of IPTc against 

malaria in an area of seasonal transmission 

LSHTM investigator: Paul Milligan, Lesong Conteh, Dongmei Liu, Brian Greenwood 

External investigators/collaborators: Kalifa Bojang, Francis Akor, Momodou Jassey, David 

Conway, Ousman Bittaye (MRC) 

Funding Bodies: GMP, MRC 

Antimalarial chemoprophylaxis can reduce morbidity and mortality from 

malaria in children. However, this approach to malaria control has never 

been widely implemented because of concerns over its possible effects on the 

development of resistance and natural immunity. IPT may be able to achieve 

some of the beneficial effects of chemoprophylaxis without its drawbacks. 

Recently, it was shown that IPT given to Senegalese children > 5 years of 

age on three occasions during the malaria transmission season reduced the 

incidence of clinical malaria by approximately 90%, but it is uncertain how 

such an intervention can be most effectively and sustainably delivered. 

Therefore, in August 2006, 26 Reproductive and Child Health (RCH) trekking 

clinics in Upper River Region, south of the River Gambia, each with an 

average catchment population of 400-500 children under 5 years of age, were 

randomly allocated to receive IPT from the RCH trekking team or from a 

village health worker (VHW). Treatment with a single dose of sulphadoxine/ 

pyrimethamine (SP) plus three doses of amodiaquine was given to all 

study subjects at monthly intervals on three occasions during the months of 

Photos from top to bottom: study 

nurses dispensing IPTc drugs (top 2 

photos), women queuing to receive 

IPTc drugs and the field site in The 

Gambia. 



of malaria 

taemia in December 

SP+3AQ 

% incidence of malaria or prevalence of 

parasitaemia 

% children with symptom on at least one occasion 


0.12 

0.1 

0.08 

0.06 

0.04 

0.02 

0 

0.35 

0.35 

0.3 

0.25 

0.2 

0.15 

0.1. 

0.5 

0.05 

0.0 

0 

cumulative incidence of malaria 

prevalence of parasitaemia in December 

SP+1AS SP+3AS 3AQ+3AS SP+3AQ 

Vomitting 

Headache 

Fever 

Any symptom 

SP+1A S SP+3A S 3AQ+3AS SP+3A Q 

SP+1AS SP+3AS 3AQ+3AS SP+3AQ 

Graphs showing the comparison between different drug regimens of 

IPTc on incidence of malaria and parasite carriage (top) and adverse 

events (bottom) in Senegal 


September, October and November. The treatment was safe and well tolerated. 

74 % and 47% of children in the VHW and RCH groups received all the three 

doses respectively. The incidence rate of malaria in children in the VHW arm 

was 2.4 per 1000 child months at risk while that for RCH arm was 3.6 per 

1000 child month at risk. Mean haemoglobin concentrations at the end of 

malaria 0.35 

transmission season were 10.6 g/dL and 10.3 g/dL in the VHW and 

Vomitting 

RCH groups respectively. 

0.3 

Headache 

Fever 

Drug regimens Any symptom 

for seasonal IPTc in Senegal 

0.25 

LSHTM investigators: Badara Cissé, Brian Greenwood, Rachel Hallett, Colin Sutherland, 

Geoffrey 0.2 Targett, Jo Lines, Paul Milligan 

External investigators/collaborators: Oumar Gaye, Sylvain Faye, Jean-Louis Ndiaye, Ernest 

Faye 0.15 (Universite Cheikh Anta Diop, Dakar); Cheikh Sokhna, El Hadj Ba, Kirsten Simondon, 

Jean-Francois Trape (IRD, Dakar); Oumar Faye, Yancouba Dial (Ministere de la Sante, 

0.1 

Senegal) 

Funding body: GMP, EDCTP 

0.05 

An important consideration for the implementation of seasonal IPT in children 

0 

is the possible SP+1A S impact SP+3A S on the 3AQ+3AS emergence SP+3Aand Q spread of drug resistant parasites; 

the choice of drug regimen is therefore critical. In a trial of four alternative 

regimens in Senegal, a combination of two non-artemisinin drugs with 

relatively long half-lives (sulphadoxine-pyrimethamine (SP) plus amodiaquine 

(AQ) over three days) was more effective in preventing malaria than three 

different artemisinin-containing combinations (SP with one or three doses of 

artesunate (AS), and AQ+AS over three days). Very few children developed 

parasitaemia, so the potential for drug resistance to spread was low. The short 

half-life of artemisinins makes them unsuitable for preventive treatment, 

a combination of two long-acting drugs for IPT may reduce the chance of 

resistance emerging. SP+AQ was associated with more frequent adverse events, 

especially vomiting. Piperaquine (PQ) is a 4-aminoquinoline antimalarial with 

a long half-life, making it a suitable choice for IPT. We compared SP plus AQ 

with two regimens, SP plus PQ, and PQ plus dihydroartemisinin. Preliminary 

results indicate that the PQ combinations were more acceptable and associated 

with fewer adverse events than SP+AQ. 

IPTsc: Comparison of efficacy, safety and tolerability in Uganda 

LSHTM investigators: Sarah Staedke, Sian Clarke, Simon Brooker, Daniel Chandramohan, 

Harparkash Kaur 

External investigators/collaborators: Ambrose Talisuna (Uganda Ministry of Health), Richard 

Ndyomugyenyi, Narcis Kabatereine (Uganda Vector Control Division), Benson Estambale 

(University of Nairobi) 



IPT in pregnancy (IPTp) is an important component of malaria control 

and may also benefit infants and children. We are currently conducting a 

randomised, blinded trial to compare the efficacy, safety and tolerability of 

sulphadoxine-pyrimethamine, amodiaquine + sulphadoxine-pyrimethamine, 

dihydroartemisinin-piperaquine and placebo among primary schoolchildren in 

Uganda, as a ‘pilot’ for future IPT research. Asymptomatic children aged 8 to 

12 years (girls) and 8 to 14 years (boys) were randomised to receive one of the 

study regimens and followed for 42 days. Repeat evaluations were performed 

on days 1, 2, 3, 7, 14, 28, and 42 (and any unscheduled day that a student is 

ill) and include assessment for the occurrence of adverse events. Treatment 

efficacy outcomes were assessed using revised WHO outcome classification 

criteria. To date, complete outcomes are available for 323 children, 43% of 

the target sample size. Almost half of the children (47%) were parasitaemic 

at baseline. Clinical treatment failure by day 42 occurred in only 21 children,


41 

while parasitological failure occurred in 164 (51%). At least one adverse event 

was reported in 67% of participants, but no serious adverse events occurred. 

The study is expected to complete in July 2008. 

IPTsc: malaria parasitaemia, anaemia & school performance 

LSHTM Investigators: Siân Clarke, Simon Brooker, Daniel Chandramohan, Dirk Mueller 

External Investigators/collaborators: Matthew Jukes (Harvard Graduate School for 

Education, Cambridge USA); Benson Estambale (University of Nairobi, Kenya); J Kiambo 

Njagi (National Malaria Control Programme, Ministry of Health, Kenya); Lincoln Khasakhala 

(African Mental Health Foundation, Nairobi, Kenya); Pascal Magnussen (DBL – Institute for 

Health Research and Development, Denmark) 


Malaria is a major cause of morbidity and mortality in early childhood, yet 

its consequences for health and education during the school-age years remain 

poorly understood. We examined the impact of IPT in reducing anaemia, 

improving classroom attention and educational achievement among semiimmune 

schoolchildren living in an area of high perennial transmission in 

western Kenya. A stratified, cluster-randomised, double-blind placebocontrolled 

trial of IPT was conducted in 30 primary schools, with schools 

allocated to receive either IPT; sulphadoxine-pyrimethamine given in 

combination with amodiaquine (SP/AQ) or dual placebo. Children, aged 

5-18 years, received three treatments per year, given at four month intervals 

(once each term). Prevalence of anaemia and other outcomes were evaluated 

through cross-sectional surveys 12-months post-intervention. Analysis was by 

intention-to-treat. 

IPTsc resulted in significant reductions in the prevalence of anaemia and 

asymptomatic Plasmodium falciparum parasitaemia. The risk of anaemia 

was halved among schoolchildren receiving IPT (n=2611) compared with 

controls (n=2305) [protective efficacy 48% (95% CI 8% to 71%); p=0.02]. 

Significant improvements were also seen in class-based tests of sustained 

attention, with a mean increase in test score of +6.05 (95% CI +2.83 to +9.27; 

p


Afghans waiting outside the basic 

health unit. 

significant proportion of vivax malaria being misdiagnosed and treated with 

the combination. SP was considered to have limited efficacy against vivax 

malaria in Asia and the efficacy of SP+AS against Plasmodium vivax had 

not been established in areas that are using SP+AS. A randomised, noninferiority 

trial comparing SP+AS with CQ monotherapy was undertaken on 

vivax patients in eastern Afghanistan. A total of 180 individuals completed 

the trial to day 42. Both regimens resulted in ≥96% treatment success at 28 d, 

but significantly more cases failed in the CQ arm (46%) than in the SP+AS 

arm (24%) by day 42. We later discovered that vivax is sensitive to SP in 

the region and suspect that with its longer half-life SP suppressed relapses 

for longer. In areas of Asia such as Pakistan and Afghanistan, where vivax 

infections might be misdiagnosed as falciparum infections and treated with 

SP+AS, patient management would be as good, or better, 

with the standard CQ treatment. 

Sulphadoxine-pyrimethamine (SP), 

chlorproguanil-dapsone, or chloroquine (CQ) 

for the treatment of Plasmodium vivax malaria 

in Afghanistan and Pakistan: a randomised 

controlled trial 

LSHTM Investigators: Toby Leslie, Christopher Whitty, Mark 

Rowland 

External Investigators/Collaborators: HealthNet-TPO, Peshawar, 

Pakistan 

Funding body: GSK Pharmaceuticals 

Laboratory workers in Afghanistan. 

Malaria microscopy at a field clinic in 

Afghanistan. 


In areas where Plasmodium falciparum and Plasmodium 

vivax coexist and treatments for the 2 species differ, 

misdiagnosis can lead to poor outcomes in either disease. 

A unified therapy effective against both species would 

reduce reliance on species-specific diagnosis, which 

in many areas is difficult to maintain. The antifolates are an important and 

affordable antimalarial class to which it is often assumed P. vivax malaria 

is intrinsically resistant. 767 patients with confirmed P. vivax malaria were 

enrolled and followed up for 28 days, between March 2004 and June 2006. 

By day 14, only 1 patient in the SP group had parasites. By day 28, failure 

rates were 1.3% in the CQ group, 1.7% in the SP group, and 9.9% in the 

chlorproguanil-dapsone group. Chlorproguanil-dapsone was less effective 

than SP (adjusted odds ratio [OR], 6.4; 95% confidence interval [CI], 2.4-17.0; 

P


43 

course of primaquine given for 8 weeks, once weekly provides adequate cure 

rates without associated adverse events. We conducted a randomised 3 arm 

placebo controlled trial of 14 day primaquine vs. 8 week once weekly single 

dose primaquine vs. 8 week placebo in 3 refugee villages in North-West 

Frontier Province, Pakistan. 200 patients were enrolled in the study. Both 

the 14 day and 8 week primaquine treatments were superior to placebo at 

preventing repeat episodes of malaria over the 11 month observation period 

(adjusted OR 14 day PQ: 0.02 (0.002-0.2); 8 week PQ: 0.07 (0.2-0.3)). 8 week 

primaquine and 14 day primaquine performed equally well (adjusted OR 3.3 

(0.4-30.5)). These results indicate that primaquine therapy could be more 

widely applied in areas where G6PD-deficiency is prevalent and testing for 

the condition not widely available. Further assessment is required to assess 

safety in G6PD deficient individuals and to ensure adherence to a long course, 

even after acute symptoms have passed. 

Safety and tolerability of combination antimalarial therapies for 

uncomplicated falciparum malaria in Ugandan children 

LSHTM investigators: Sarah Staedke 

External investigators/collaborators: Moses Kamya, Catherine Maiteki-Sebuguzi, Denise 

Njama-Meya, Bridget Nzarubara (Makerere University), Prasanna Jagannathan, Philip 

Rosenthal, Grant Dorsey, Tamara Clark (University of California, San Francisco), Vincent Yau 

(University of California, Berkeley) 

Funding body: US NIH, Division of Microbiology and Infectious Diseases 

The mainstreet in Kabale in Uganda. 

We compared the safety and tolerability of three combination antimalarial 

regimens in a longitudinal, single-blind, randomised clinical trial of Ugandan 

children. Upon diagnosis of the first episode of uncomplicated malaria, 

participants were randomised to receive amodiaquine + sulphadoxinepyrimethamine 

(AQ+SP), amodiaquine + artesunate (AQ+AS), or artemetherlumefantrine 

(AL), and received the same treatment for all subsequent 

episodes of uncomplicated malaria. At 14 days of follow-up, AQ+SP was 

associated with a higher risk of anorexia, weakness and subjective fever than 

AL and a higher risk of weakness, and subjective fever than AS+AQ. AL 

was associated with a higher risk of elevated temperature. Considering only 

children less than five years, those who received AQ+SP were at higher risk 

of developing anorexia and weakness than those treated with AL (anorexia: 

RR 3.82, 95% CI 1.59 – 9.17; weakness: RR 5.40, 95% CI 1.86 – 15.7), or 

AS+AQ (anorexia: RR 2.10, 95% CI 1.04 – 4.23; weakness: RR 2.26, 95% 

CI 1.01 – 5.05). Repeated episodes of neutropaenia associated with AS+AQ 

were detected in one participant. Our study confirms the safety and tolerability 

of AS+AQ and AL in Ugandan children, and suggests that AQ+SP is safe, but 

less well-tolerated, particularly in younger children. 

Combination therapy for the treatment of uncomplicated 

falciparum malaria in a cohort of Ugandan children: a 

longitudinal randomised trial 

LSHTM investigators: Sarah Staedke 

External investigators/collaborators: Moses Kamya, Denise Njama-Meya, Bridget Nzarubara, 

Catherine Maiteki-Sebuguzi (Makerere University), Philip Rosenthal, Grant Dorsey, Tamara 

Clark (University of California, San Francisco) 

Funding body: US NIH, Division of Microbiology and Infectious Diseases 

A longitudinal randomised clinical trial was conducted to compare the efficacy 

and safety of combination therapies for the treatment of uncomplicated malaria 

in Kampala, Uganda. We enrolled 601 healthy children aged 1-10 years 

randomly selected from a census population, and followed participants for 

Anopheles gambiae mosquito. 



HBMF team with Sarah Staedke 

(middle, Blonde). 

Treatment incidence density 

5 

4 

3 

2 

1 

0 

1.03 

2.53 

Clinic-based Standard care HBMF 

13-19 months. Upon diagnosis of the first episode of uncomplicated malaria, 

participants were randomised to receive amodiaquine + sulphadoxinepyrimethamine 

(AQ+SP), amodiaquine + artesunate (AQ+AS), or artemetherlumefantrine 

(AL), and received the same treatment for all subsequent 

episodes of uncomplicated malaria. Of enrolled children, 329 (55%) were 

diagnosed with at least one episode of uncomplicated malaria. The 28-day 

risks of treatment failure (unadjusted by genotyping) were 26%, 17%, and 

7% for AQ+SP, AQ+AS, and AL groups, respectively (p


45 

serious problem in much of Africa that there are no facilities to differentiate 

between the causes of significant febrile illness. Malaria and bacterial 

diseases, both of which can be fatal if untreated, and both of which are easily 

treated if caught early, are often mistaken for one another. It is therefore useful 

to consider antibiotic plus anti-malarial combinations for settings where 

diagnostic facilities are limited. Previous trials in Muheza, Tanzania have 

demonstrated that AL is the only currently available fixed-dose combination 

which is effective and affordable in this area. A trial is therefore being 

undertaken to compare AL (which is current first-line treatment in Tanzania) 

with azithromycin+artesunate in children with uncomplicated malaria. 

Azithromycin is an antibiotic with a wide spectrum of anti-bacterial activity 

but which also has significant anti-malarial properties. It has recently come 

off patent and it is expected that the price of this will drop. The trail should 

complete in early 2009. 

An open label randomised comparison of injectable artesunate 

and quinine in children with severe falciparum malaria in Africa 

(AQUAMAT) 

LSHTM investigators: Lorenz von Seidlein, Hugh Reyburn, Christopher Whitty, Brian 

Greenwood, Behzad Nadjm 

External investigators/collaborators: Nick White, Arjen Dondorp, Nick Day, Caterina Fanello, 

Ilse Hendricksen (Wellcome Trust Unit, Bangkok) 


Parenteral quinine is the most widely used treatment for severe malaria in 

Africa, but a recent large trial in Asia (SEAQUAMAT) showed that i.v. 

treatment with artesunate (ART) reduced mortality by 35% compared to quinine 

treatment. A meta-analysis of studies comparing artemether (a compound 

very similar to, but less well absorbed, than ART) with quinine indicated that 

results in Asian adults differed from those in African children, so the results 

of SEAQUAMAT may not be generalisable to Africa. The Wellcome Trust 

Unit Bangkok initiated a Wellcome Trust funded open-label randomised trial 

comparing parenteral ART and quinine in patients with severe malaria. The 

study will have power to detect a 25% reduction in overall mortality from 8% 

to 6%. The objective of this largest ever malaria mortality study (target 5300 

patients) is to determine whether ART is superior to quinine in the treatment 

of severe falciparum malaria in African children. The outcome of this study 

will determine the future treatment of severe malaria. As of March 2008 nine 

centres in 8 countries in sub-Saharan Africa (Mozambique, Tanzania, Kenya, 

Uganda, Rwanda, Nigeria, The Gambia, and Ghana) are collaborating on this 

trial. 2000 children have already been recruited. Recruitment is expected to 

continue through 2009. 

KCMC Laboratories, Moshi, Tanzania 

A child suffering from malaria recruited into the AQUATMAT trial. 

A cluster randomised trial of 2 diagnostic tools to detect anaemia 

in rural dispensaries in Tanzania; the EARS study 

LSHTM Investigators: Roly Gosling, David Schellenberg, Hugh Reyburn 

External investigators/collaborators: Godson Maro, Elias Ndhani, Steven Magesa (NIMR, 

Tanzania) 

Funding Body: EU 

We conducted a 1-year cluster-randomised trial of diagnostic tools for 

anaemia in 30 primary care dispensaries in a rural, malaria-endemic area of 

NE Tanzania; 10 were randomised to receive Hemocue meters and cuvettes, 

10 to receive the Copack colour scale and 10 to the control group that received 

basic IMCI training common to all arms. A rolling cross-sectional survey in 

the village near each dispensary provided a minimum estimate of anaemia 

Determining packed red blood cell volumes (Haematocrit) in the lab at 

Ifakara Health Research & Development Centre (IHRDC), Tanzania. 

Photo: Hugo Jaeggi. 



Biotech Laboratory, Tanzania 

prevalence in children attending study dispensaries. The primary outcome 

was the proportion of children attending each dispensary diagnosed with 

anaemia. 

In the first 3 months of the study 1,154 children were diagnosed with anaemia; 

almost half of these in the Hemocue arm and over a quarter in Copack arm were 

diagnosed as severe anaemia (Hb


A non-inferiority, open-labelled, randomised trial of the efficacy 

and safety of artesunate-amodiaquine (AS+AQ), artemetherlumefantrine 

(AL), and artesunate-lapdap (AS+CD) for 

treatment of uncomplicated P. falciparum malaria among children 

in Ghana 

LSHTM investigators: Seth Owusu-Agyei, Daniel Chandramohan, John Gyapong, Brian 

Greenwood 

External investigators/collaborators: Seth Owusu-Agyei, Kwaku-Poku Asante, Ruth Owusu, 

John Gyapong (KHRC) 


47 

AS+AQ and AL are now the most frequently recommended first line treatments 

for uncomplicated malaria in Africa. AS+CD is a potential alternative for 

treatment of uncomplicated malaria. A comparison of the efficacy and safety 

of these three drug combinations is necessary to make evidence based drug 

treatment policies. Methods: Children aged 6 months – 10 years were recruited 

between June 2005 and April 2006 from the Kintampo District Hospital. 534 

glucose-6-phosphate dehydrogenase (G6PD) normal children were randomised 

in blocks of 15 to the AS+AQ, AL or AS+CD groups. Administration of study 

drugs was supervised by project staff and the children were followed up at their 

homes on days 1,2,3,7,14 and 28 post-treatment. Parasitological and clinical 

failures and adverse events were compared between the study groups. Results: 

In a per-protocol analysis, the parasitological and clinical failure rate at day 

28 post treatment (PCF28) was lower in the AS+AQ group compared with the 

AL or AS+CD groups (corrected for re-infections: 6.6% vs 13.8% and 13.8% 

respectively, p=0.08; uncorrected: 14.6% vs 27.6% and 28.1% respectively, p= 

0.005). In the intention to treat analysis, the rate of early treatment failure was 

high with all three groups (AS+AQ 13.3%; AL 15.2%; AS+CD 9.3%, p=0.2) 

primarily due to vomiting. However, the PCF28 corrected for re-infection was 

lower, though not significantly, in the AS+AQ group compared to the AL or 

the AS+CD groups (AS+AQ 18.3%; AL 24.2%; AS+CD 20.8%, p=0.4) The 

incidence of adverse events was comparable between the groups. 

AS+AQ is an appropriate first-line treatment for uncomplicated malaria in 

Ghana and possibly in the neighbouring countries in West Africa. The efficacy 

and safety of AL and AS+CD need to be studied further in West Africa. KHRC 

has strengthened its capacity in conducting GCP compliant clinical trials. 

Severe malaria in children in Yemen: two-site observational study 

LSHTM investigators: Abdullah Al-Taiar, Shabbar Jaffar, Brian Greenwood, Christopher 

Whitty 

External investigators/collaborators: Ali Assabri, Molham Al-Habori, Ahmed Azazy 


This study set out to assess the burden of malaria on health services, describe 

the clinical presentation of severe malaria in children and identify factors 

associated with mortality by means of a prospective observational study. It 

took place in two public hospitals in Taiz (mountain hinterland) and Hodeidah 

(coastal plain), Yemen in children aged 6 months to 10 years. Of 12,301 

paediatric admissions, 2071 (17%) were for suspected severe malaria. The 

proportion of such admissions varied according to the season (from 1% to 

40%). Falciparum malaria was confirmed in 1332 children; 808 had severe 

disease as defined by the World Health Organization. Main presentations were 

respiratory distress (322/808, 40%), severe anaemia (291/800, 37%), and 

cerebral malaria (60/808, 8%). 22 of 26 children who died had a neurological 

presentation. No deaths occurred in children with severe anaemia but no other 

signs of severity. In multivariate analysis, a Blantyre coma score < or = 2, 

history of fits, female sex, and hyperlactataemia predicted mortality; severe 

anaemia, respiratory distress and hyperparasitaemia were not significant 

predictors of mortality. Severe malaria puts a high burden on health services 

in Yemen. Although presentation is similar to African series, some important 

differences exist. Case fatality is higher in girls. 

PCR analysis in KHRC lab. 

Yemeni House. 

Rare Dragon’s Blood (Dracaena cinnabari) 

trees, found only on the Yemeni 

island of Socotra, which can grow 

for 300 years. 



A simple molecular diagnostic test for malaria using LAMP 

technology 

LSHTM Investigators: Spencer Polley, Peter Chiodini, Colin Sutherland 

Funding body: FIND, Geneva 

Illustration of the amplification of 

parasite detection utilising LAMP 

technology 

Pre-amplification 

Post-amplification 

Based in the Department of Clinical Parasitology at the Hospital for Tropical 

Diseases, this project is aimed at developing new sensitive species-specific 

tests for malaria parasites utilising Loop-Activated Amplification (LAMP) 

technology, pioneered by the Eiken Chemical Co., Tokyo. Prototype assays 

tested against panels of known malaria DNA samples from 5 different 

Plasmodium species have been very promising, and we are hopeful of 

developing a low-tech 30-40 minute test that will detect a parasite density 

as low as 5 – 10 parasites per microlitre from a 50 microlitre sample with 

minimal sample preparation (e.g. 10 minutes boiling, 30 sec centrifugation). 

We are currently evaluating a variety of targets in all 5 species of human 

malaria parasites to enable rapid speciation and identification of mixed species 

infections without the need for skilled microscopists. 

The effect of removing direct payment for 

healthcare on health service utilisation and 

health outcomes in Ghanaian children: a 

randomised controlled trial 

LSHTM Investigators: Evelyn Ansah, Brian Greenwood, Anne 

Mills, Christopher Whitty 

External investigators/collaborators: Solomon Narh-Bana, Sabina 

Asiamah, Vivian Dzordzordzi, Kingsley Biantey, Kakra Dickson, 

John Owusu Gyapong, Kwadwo Ansah Koram 


Children in Ghana. 

http://www.bigfoto.com/ 

Delay in accessing care for malaria and other diseases 

can lead to disease progression and user fees are a 

known barrier to accessing healthcare. Governments are 

introducing free healthcare to improve health outcomes. 

This affects treatment seeking and it is assumed that this 

leads to improved health outcomes, but there is no direct 

trial evidence of the impact of removing out-of-pocket 

payments on health outcomes in developing countries. 

Methods: 2194 households containing 2592 Ghanaian 

children were randomised in a pre-payment scheme allowing free primary 

care including drugs, or in a control group whose families paid user fees for 

health care (normal practice); The primary outcome was moderate anaemia 

(Hb

Vector Control 

49 

Protecting people from mosquito vectors is the cornerstone 

of malaria control. Any attempt to have a significant impact 

on the burden of malaria in high-transmission countries has 

to start with vector control and personal protection. As with 

drugs, simply to stand still is insufficient - we have to innovate as the mosquitoes evolve resistance to 

insecticides and the greater the pressure on them the more likely this is to occur. Members of the Malaria 

Centre are involved in the development and testing of new insecticides and formulations, novel vector control 

measures and the impact of the new class of long-lasting insecticide-treated bednets. Vector control tools are 

not effective unless they are properly deployed or used and members are involved in evaluating different 

deployment strategies, including the private as well as the public sector. 

SUMMARY 

Investigating the role of community-based vector control 

A simple chemical test for the rapid detection of synthetic 

pyrethroids on bed nets and on sprayed walls 

Entomological effects of Long Lasting Insecticidal Nets 

in domestic use 

Reduced efficacy of insecticide-treated nets and indoor residual 

spraying in an area of pyrethroid resistance in Benin 

Application of long-lasting formulations of the synthetic 

repellent, DEET, on mosquito nets to protect against 

insecticide-resistant Anopheles gambiae and Culex quinquefasciatus 

mosquitoes 

Long-lasting insecticidal nets (LLINs) – collaboration 

with WHO Pesticide Evaluation Scheme on field evaluation 

in Africa 

Novel insecticides for malaria control 

Monitoring and evaluation of the Tanzania National 

Voucher Scheme for insecticide-treated nets 

LSHTM – helping to build the Innovative Vector Control 

Consortium 

Use of fungi for adult malaria mosquito control 

The costs and effects of a nationwide insecticide-treated 

net programme: the case of Malawi 

An economic analysis of the use of insecticide-treated 

hammocks in central Vietnam 

Screening homes to prevent malaria 

Scaling up ITN coverage in Tanzania: understanding the 

contribution and limitations of the private sector 

Anti-larval measures for malaria control in The Gambia 

Investigating the role of community-based vector control 

LSHTM investigators: Nigel Hill, Alexandra Hiscox, Mary Cameron, Ilona Carneiro 

External investigators/collaborators: Zhou Hong Ning (Yunnan Institute of Parasitic Diseases, 

P.R.China); Juliet Bryant, Rick Paul (Pasteur Institute, Laos & France); Abrahan Arnez 

(Ministry of Health, Bolivia) 

Funding body: GMP, SC Johnson, Institute Pasteur (Laos study only) 

Clinical studies – Results of a randomised placebo-controlled clinical 

evaluation of plant-based insect repellent in combination with ITN’s was 

recently published (BMJ 335, Nov 2007). Findings indicate that in areas such 

as South America where the local vector species feed in the early evening 

(20.00 – 22.00), the use of a skin-applied insect repellent at dusk can increase 

protection against malaria by around 80% compared with ITNs alone. In 

China, we have just completed the clinical phase of a trial with over 2,000 

households randomised to either commercial mosquito coils, LLIN, LLIN+ 

Coils or an untreated control. Whilst coils are very widely used worldwide and 

one of the largest household expenditures on “healthcare”, there is no robust 

evidence they can reduce malaria. Our study has collected P. falciparum & P. 

vivax from all members of our households each month by dipstick. 

Field evaluation – A variety of low cost, sustainable “appropriate-technology” 

methods of vector control which could be adopted at the household / village 

level have been evaluated in remote rural villages of malaria high-risk minority 

peoples living in the China / Laos / Myanmar border regions. The relatively 

common traditional practice of burning locally gathered plant material on 

indoor cooking fires in the evening has been studied. Results of controlled 

indoor CDC light trap collections suggest at least one local plant species can 

significantly reduce the numbers of vector mosquitoes entering houses and 

we are investigating this further. Surprisingly, the practice of housing buffalo 

under living areas of houses built on stilts was found to increase the number of 

anopheline vectors caught inside the house but the proportion of these feeding 

on humans was reduced. Further research is underway to elucidate this further 

to determine if zooprophylaxis may be possible against local vectors with low 

anthropophilic behaviour. In Laos, Alexandra Hiscox has just begun a 3 year 

study to observe how malaria, dengue & JE vector populations will change 

as a result of a huge dam and irrigation project in rural Laos. Alex will be 

Buffalo housed under houses in rural China increase the number of 

malaria vector mosquitoes entering but decrease the proportion which 

feed on humans - further work is needed to see if this common practice 

is a risk factor or may actually reduce malaria in those living above. 

Alex Hiscox, Research 

Degree student, DCVBU, 

hanging a CDC light trap to 

catch malaria vectors in a 

Lao House. 


50 Vector Control 

responsible for monitoring vector-borne disease risk as part of a team led by 

the Pasteur Institute to ensure the Nam Theun hydroelectric project will not 

negatively impact on the health of the displaced rural communities in the area 

when the main 450Km² reservoir is flooded later this year. 

A 

B 

Figures A and B; Colour intensity in the test reflects the decreasing 

deltamethrin concentration upon washing as shown by HPLC analyses 

of the same nets. 

Female Anopheles gambiae feeding. 

Only female mosquitoes bite, and all mosquitoes live on the sugar found in 

plant nectar, not on blood. Female mosquitoes, unlike males, have a proboscis. 

This is a long thin needle-like built-in syringe located at the mouth. They 

use this to impale their victims, in order to fill their abdomens with blood. 

Proteins in the blood are necessary to produce fertile eggs. Since males cannot 

produce eggs they have no need for blood. Females require a new blood 

‘meal’ for every nest they lay, and produce about 250 eggs per meal. 


A simple chemical test for the rapid detection of synthetic 

pyrethroids on bed nets and on sprayed walls 

LSHTM investigators: Harparkash Kaur 

External investigators/collaborators: Teunis A Eggelte (Academic Medical Centre, Division of 

Infectious Diseases, Amsterdam) 

Funding body: IVCC 

Insecticide treated nets (ITNs) and indoor residual spraying (IRS) are used 

as the major mode of intervention in the fight against malaria. Monitoring 

of bed net impregnation is generally restricted to reports from health staff 

and questioning the net users. Measuring the actual amount of deposits of 

insecticides on the bed nets and on the walls is essential for evaluation of 

quality control of the applied intervention as per instruction. 

Current tools used to gain this information include the costly and 

sophisticated techniques of gas chromatography (GC) or high performance 

liquid chromatography (HPLC) that cannot be used in the field. Bioassays in 

which mosquitoes are exposed to the impregnated netting material are labour 

-intensive. We have developed a simple chemical test that is cost effective and 

suitable for field conditions with the added advantage that it can be carried out 

by non specialist persons. 

The test comprises adding a reagent to dissolve the insecticide followed by 

the second reagent which produces the colour to indicate the presence of the 

insecticide (see Figure B). This simple test can be formatted to give qualitative/ 

(semi) quantitative results on the nets (see results of HPLC Figure A). 

Entomological effects of Long Lasting Insecticidal Nets in 

domestic use 

LSHTM investigators: Caroline Maxwell, Ian Weerakone, Chris Curtis 

External investigators/collaborators: Stephen Magesa (NIMR, Tanzania) 

Funding body: WHO 

Data is so far available for the first 30-36 months of a multi-village trial near 

Muheza comparing the entomological effects of nets conventionally treated 

with alphacypermethrin, Olyset nets and Permanet 2 nets. Monitoring has 

been by bioassay with 3 minutes exposure of lab reared An. gambiae plus 24 

hrs holding, and by trapping with CDC light traps set beside occupied bednets 

with ELISA testing for P. falciparum CSP. 

In the bioassays (data corrected for any control mortality), the Olyset nets 

demonstrated a mean mortality of 61% (range 18-92%). The mean increased 

to 72% (range 22-96%) after heating these nets in black plastic bags in the 

sun (believed to enhance diffusion of insecticide to the fibre surface). ITNs 

from a village where annual re-treatment with alphacypermethrin was not 

done owing to an administrative error, showed the surprisingly high mortality 

of 49% (range 2-95%) after 3 years use of the nets. This confirms that it is 

misleading to believe that if re-treatment is not done at least annually, nets lose 

all insecticidal power. The wide ranges between individual nets are presumed 

to be due to different intensities of washing of nets in different households. 

It is concluded that from the bioassay data so far, there is nothing to choose 

between the different types of nets. Entomological trapping data showed 

significant reduction in villages with each type of net, compared with the 

villages with no donated nets, on the numbers of Anopheles and Culex and the


51 

CSP rates, with no significant difference between the different types of nets. 

New brands of LLIN have recently been added to the trial. 

A re-check of pyrethroid resistance in bedbugs associated with long term use 

in villages of treated nets showed that in 2007 the situation was no better and 

no worse that it was in 2003. 

Reduced efficacy of insecticide-treated nets and indoor residual 

spraying in an area of pyrethroid resistance in Benin 

LSHTM Investigators: Raphael N’Guessan, Mark Rowland 

External Investigators/Collaborators: Vincent Corbel (IRD, France); Martin Akogbéto (Centre 

de Recherche Entomologique, Benin) 


Pyrethroid resistance due to kdr site insensitivity is common in An. gambiae 

in West Africa. ITN control trials in Ivory Coast show that nets continue to 

protect despite resistance. However, in Benin, where An. gambiae of the M 

molecular biotype predominates, kdr appears to be protective. To assess the 

continuing effectiveness of IRS and ITN in West Africa, we compared the 

impact of the two approaches under controlled conditions in experimental 

huts in insecticide resistant and susceptible regions of the country. In the 

susceptible north, 96% of An. gambiae were inhibited from blood-feeding 

through the deliberately holed ITNs, whereas in the resistant south the 

mosquitoes freely penetrated the holed ITNs and fed without inhibition. The 

mortality rate of susceptible An. gambiae was 98% but was only 30% among 

the resistant population. The efficacy of IRS was equally compromised - only 

29% of resistant mosquitoes were killed by the IRS treatments inside the huts. 

Resistant mosquitoes showed higher oxidase and esterase activity than in a 

laboratory-susceptible strain, but it is not clear whether this contributed to the 

resistance. A key difference is that An. gambiae from southern Benin is the M 

molecular biotype, whereas that from Ivory Coast is the S form. The resistant 

M form is spreading fast – it has reached high frequency in parts of Burkina 

Faso within a year, and on the island of Bioko IRS campaigns failed to control 

populations of kdr resistant M form. This resistance problem is serious for the 

future of pyrethroids and insecticide treated nets. 

Application of long-lasting formulations of the synthetic repellent, 

DEET, on mosquito nets to protect against insecticide-resistant 

Anopheles gambiae and Culex quinquefasciatus mosquitoes 

LSHTM Investigators: Raphael N’Guessan, Mark Rowland 

External Investigators/Collaborators: Pierre Carnevale, Traore-Lamizana Moumouni (Centre 

Pierre Richet, Côte d’Ivoire), Bart G.J. Knols, (Wageningen University, The Netherlands) 


Because resistance to pyrethroid insecticides in Anopheles gambiae is 

spreading, there is an urgent need to develop alternative compounds. 

Impregnation of nets with DEET repellent is promising. Surprisingly, when 

applied to netting, DEET acts not just as a conventional repellent but also 

as a toxicant, killing the majority of mosquitoes that come into contact 

with it. Any formulation that requires frequent replenishment is unlikely 

to find favour even where pyrethroids are no longer effective. Advances in 

microencapsulation formulation technology, in which the active ingredient 

is enclosed within a polymer capsule and gradually leaches to the outside, 

have greatly extended the residual activity of insecticides being used as longlasting 

indoor residual spray treatments. SDS Biotech K.K., with Sumitomo 

Corporation, has developed a microencapsulated formulation of DEET in 

which the active ingredient diffuses slowly through a polymer membrane over 

Setting a light trap, run from a rechargable battery, beside a bednet. 

Catches are proportional to human landing catches but the traps are preferable 

as a monitoring method. 

Nets in villages (no. 

villages) 

Mean trap of 

Anopheles per 

night 

% circumsporozoite 

+ve (no. tested) 

Mean trap 

catch of Culex 

per night 

None donated (7) 236 4.0% (1083) 2,53 

Treated with Alphacypemethrin 

(13) 

1.10 0 (439) 1.44 

Olyset (4) 0.93 0 (305) 1.62 

Permanet (4) 0.92 0.69% (291) 1.12 

Results of over 30 months of light trapping (with testing the Anopheles 

caught for P. falciparum cicumsporozoite protein) in villages near Muheza, 

Tanzania, where different types of insecticidal nets had been distributed for 

all sleeping places. 

SUSCEPTIBLE AREA 

RESISTANT AREA 

% mortality 

% blood-fed 

% mortality 

% blood-fed 

0 20 40 60 80 100 

Reduced efficacy of ITN against Anopheles gambiae in pyrethroid resistant 

area of Benin. 



Blood-feeding inhibition (%) 

Passage inhibition (%) 

Mortality (%) 

A 

100 

80 

60 

40 

20 

0 

0 1 3 6 

Month after impregnation 

B 

100 

80 

60 

40 

20 

0 

0 1 3 6 


C 

100 

80 

60 

40 

20 

0 

0 1 3 6 


Deet MC 

Formulated Deet 

Deet MC 


Deet MC 


Comparison of microencapsulated DEET MC versus conventional Formulated 

DEET on netting against An. gambiae. 

The A-Z factory in Arusha, Tanzania, making Olyset bednets. 


a period of months. Its potential as a fabric or net treatment was tested against 

An. gambiae. It repelled, inhibited blood-feeding and killed mosquitoes for 

a period of at least 6 months. Such formulations may have potential for use 

on nets against pyrethroid-resistant mosquitoes or on clothing or bedding 

materials distributed in disasters, emergencies or refugee camp situations. 

Long-lasting insecticidal nets (LLINs) – collaboration with WHO 

Pesticide Evaluation Scheme on field evaluation in Africa 

LSHTM Investigators: Mark Rowland, Caroline Maxwell 

External Investigators/Collaborators: Morteza Zaim (WHO), Stephen Magesa, Robert 

Malima, Patrick Tunga (NIMR, Tanzania), Frank Mosha (KCMC, Tanzania) 

Funding body: WHO 

Development of new types of LLIN is a very active area of research and 

development in chemical and textile industry. LLIN are designed to withstand 

the effects of washing and to remain insecticidal throughout their normal 

lifespan. Specific LLIN products need to obtain approval from the WHO 

Pesticide Evaluation Scheme (WHOPES) before many governments or 

funding agencies’ countries are willing to buy them. WHOPES commissioned 

LSHTM and the field sites in Tanzania to evaluate the candidate LLIN 

submitted by manufacturers. To gain interim approval, the LLIN need to show 

insecticidal activity in experimental hut trials after 20 standardized washes. 

In 2006-2007, LSHTM with its Tanzanian collaborators evaluated five LLINs 

and 2 long-lasting net treatment kits submitted to WHO from BASF, Syngenta, 

Bayer, Clarke and other companies. Several products achieved the required 

standard and obtained interim WHO approval. As a result, the market for 

LLIN has diversified and expanded, and the LLIN shortages that have beset 

control agencies are being overcome. Interim approval is time-limited and to 

gain full WHO approval the companies need to demonstrate that their LLIN 

remain effective after 3 years of household use. LSHTM is now working 

with WHOPES to initiate 3 year trials of specific LLIN products in endemic 

African villages. 

Novel insecticides for malaria control 

LSHTM Investigators: Mark Rowland, Raphael N’Guessan 

External Investigators/Collaborators: Morteza Zaim (WHO Pesticide Evaluation Scheme); 

Martin Akogbeto (Centre de Recherche de Entomologique, Benin); Stephen Magesa, Robert 

Malima, Patrick Tunga (NIMR, Tanzania); Frank Mosha (KCMC, Tanzania); Robert Farlow 

(BASF, USA) 


Resistance to pyrethroids has become widespread in Anopheles gambiae in 

Western Africa. The resistance occurring in the M form of An. gambiae in 

Benin, Burkina Faso and Bioko is protective against pyrethroids. There is an 

urgent need to develop alternative insecticides to replace or supplement the 

pyrethroids. The primary characteristics required are contact activity, long 

residual activity and low mammalian toxicity. These criteria are less essential 

in agro-insecticides where most industrial R&D is focused. Two exceptions 

that may meet the vector control criteria are chlorfenapyr, a member of the 

pyrrole class, and indoxacarb, an oxadiazine, both used in crop protection. 

Chlorfenapyr is a mitochondrial electron transport inhibitor whose mode of 

action is to disrupt the conversion of ADP to ATP in mitochondria of cells. 

Because chlorfenapyr’s mode of action is novel, it is unlikely to show crossresistance 

to standard neurotoxic insecticides. Oxadiazine is active against the 

insect’s nervous system but at a different site to pyrethroids. In laboratory tests 

neither insecticide showed cross resistance to pyrethroid (kdr) or OP (Ace-1)


53 

resistance mechanisms. When applied to netting, both insecticides controlled 

the pyrethroid resistant An. gambiae and Culex that occur in Benin. Trials of 

chlorfenapyr in experimental huts showed that it has potential as a residual 

spray treatment in houses. New formulations will be required to improve their 

residual activity. 

Monitoring and evaluation of the Tanzania National Voucher 

Scheme for insecticide-treated nets 

LSHTM investigators: Kara Hanson, Tanya Marchant, Jo Mulligan, Caroline Jones, Jane 

Bruce, Joanna Armstrong Schellenberg 

External investigators/collaborators: Rose Nathan, Hadji Mponda, Godlove Stephen, Yovitha 

Sedekia (IHRDC, Tanzania) 

Funding body: Ministry of Health, Tanzania; GMP; DfiD TARGETS Consortium; US 

President’s Malaria Initiative 

The Tanzania National Voucher Scheme (TNVS) is a Reproductive and Child 

Health (RCH) clinic-based delivery system distributing discount vouchers 

to pregnant women and infants. The vouchers are used as part-payment for 

insecticide-treated bednets purchased at a shop. The scheme was originally 

funded by the Global Fund to fight AIDS, TB and Malaria and since 2007 is 

also substantially supported by the US President’s Malaria Initiative. IHRDC 

and LSHTM were contracted to undertake the Monitoring and Evaluation 

(M+E) of the TNVS activities from baseline 2005-2007 and again for the 

period 2008-2012. The M+E plan is multifaceted and includes repeat national 

household and facility surveys, qualitative investigations, retail audits and 

voucher tracking. Figures 1 and 2 show key bednet indicators for the period 

2005-2007. Further details are available in Marchant et al. (2008), Hanson et 

al. and Mulligan et al. (in press). 

The next phase of TNVS activities will include national mass bednet 

retreatment with longer-lasting insecticide and the mass free distribution of 

bednets to children under five, along with ongoing voucher programmes. The 

M+E plan during the next phase of activity will be adapted to include impact, 

coverage and relevant process indicators for the different delivery strategies 

over time. 

% 60 

50 

40 

30 

20 

under 1 

under 5 

currently preg 

total pop 

% 40 

30 

20 

10 

0 

under 1 

under 5 

currently preg 

total pop 

Summary coverage estimates for all population 

groups: Use of any net on night before survey 

(TNVS Household Survey 2005-07) 

2005 

32.9 

27.5 

25.2 

23.4 

2005 

15.9 

12.2 

10.7 

9.8 

2006 

47.8 

40.9 

33.9 

31.8 

2006 

27.7 

21.1 

17.6 

15.4 

Summary results from three surveys carried out. 

Key bednet indicators from the baseline in 2005 are shown above. 

2007 

55.5 

47 

38.9 

38.4 

Summary coverage estimates for all population 

groups: Use of a recently treated net on night before 

survey (TNVS Household Survey 2005-07) 

2007 

34.3 

26.2 

23.2 

20.5 

LSHTM – helping to build the Innovative Vector Control 

Consortium 

LSHTM Investigators: Mark Rowland, Raphael N’Guessan, Richard Oxborough, Seth Irish, 

Harparkash Kaur 

External Investigators/Collaborators: Janet Hemingway (LSTM); Martin Akogbeto (Centre de 

Recherche de Entomologique, Benin); Stephen Magesa, Robert Malima, Patrick Tunga (NIMR, 

Tanzania); Frank Mosha (KCMC, Moshi, Tanzania) 

Funding body: Bill and Melinda Gates Foundation 

The Innovative Vector Control Consortium (IVCC) is a five-year programme, 

funded by the Gates Foundation, designed through public–private partnership 

with industry to improve the tools and technologies available for malaria and 

dengue vector control. Led by the Liverpool School of Tropical Medicine, five 

partner institutions in Africa, Europe and the USA, including LSHTM, were 

instrumental in establishing the IVCC. It has two distinct objectives: (i) to 

produce improved insecticides and formulations, and (ii) to provide improved 

tools for a decision support system to reduce disease transmission. 

Some specific aims of the IVCC are to develop: 

- alternatives to existing pyrethroids for ITNs and IRS treatments 

- longer lasting insecticide formulations for such materials and sprays 

- insecticide combinations, such as bi-treated ITNs, which are useful in areas 

Nigel Hill, allowing mosquitos to bite 

in the ‘arm test’. 



Proportion surviving (± s.e.) 

1 

0.8 

0.6 

0.4 

0.2 

0 

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 

Days 

Control 

Low dose B. Bassiana 

High dose B. bassiana 

where insecticide resistance might otherwise be a problem 

- a field kit for quantifying the amount of pyrethroid insecticide on ITNs 

- to develop field tools for monitoring characteristics of local vector populations 

(e.g. insecticide resistance) 

LSHTM is helping to evaluate new insecticides and formulations 

developed by industrial partners. The field sites in Tanzania and Benin 

built up by LSHTM have a key role in testing the new control products. 

LSHTM is also involved in developing the field kit for quantifying 

pyrethroids on ITNs. 

Use of fungi for adult malaria mosquito control 

LSHTM investigators: J.C. Stevenson, S. Blanford, C.F. Curtis 


Cumulative proportion (±s.e.) of female An.stephensi surviving after a 6 

hour exposure to B.bassiana-treated surfaces at low and high dose. 

Mosquito cadavers sporulating with B.bassiana. 

Mycelia of B.bassiana growing internally from mosquito cuticle. 


Laboratory studies demonstrated the effectiveness of treating surfaces that 

adult mosquitoes may rest on with oil suspensions of hyphomycete spores 

to reduce mosquito survival. Comparisons of two entomopathogenic fungi, 

Metarhizium anisopliae var. anisopliae ICIPE30 and Beauveria bassiana 

IMI391510 isolates, against female Anopheles stephensi, demonstrated 

higher mortalities with B. bassiana at a range of doses. By optimising the 

concentration of spores applied, the extent of the area treated and the materials 

used for impregnation, 100% mortality of An. stephensi was achieved 10 days 

after exposure. Blood-fed mosquitoes were equally susceptible to B. bassiana 

as non-blood-feds indicating the suitability of targeting mosquitoes after blood 

feeding. 

Older mosquitoes were found to be more susceptible to lower doses of B. 

bassiana and to normally avirulent fungal isolates than younger insects. This 

indicates that entomopathogenic fungi could cause greatest reductions in 

survival of the epidemiologically most dangerous, older mosquitoes. Several 

strains of An. gambiae s.s. were shown to be as susceptible to B. bassiana as 

An. stephensi, with less than 3% surviving 14 days after exposure. Pyrethroidresistant 

An. gambiae were at least as susceptible to fungi as pyrethroidsusceptible 

mosquitoes, and there was an indication of negative crossresistance 

of mosquitoes carrying both kdr and metabolic pyrethroid resistant 

mechanisms to B. bassiana. These results give support to the suitability of 

fungal malaria control in Africa, particularly in areas where pyrethroid resistant 

mosquitoes occur. It is expected that the selective pressure on mosquitoes to 

develop resistance to fungi would be low due to the delayed kill and complex 

pathogenesis of fungi. Thus fungal control may offer a more sustainable 

method for control of malaria mosquitoes than chemical insecticides. 

The costs and effects of a nationwide insecticide-treated net 

programme: the case of Malawi 

LSHTM investigators: Virginia Wiseman, Warren Stevens 

External investigators/collaborators: D.Chavasse 

Funding body: PSI 

Insecticide-treated nets (ITNs) are a proven intervention to reduce the burden 

of malaria, yet there remains a debate as to the best method of ensuring 

they are universally utilized. This study was a cost-effectiveness analysis of 

an intervention in Malawi that started in 1998, in Blantyre district, before 

expanding nationwide. Over the 5-year period, 1.5 million ITNs were sold. 

The costs were calculated retrospectively through analysis of expenditure 

data. Costs and effects were measured as cost per treated-net year (cost/TNY) 

and cost per net distributed. The mean cost/TNY was calculated at $4.41, and 

the mean cost/ITN distributed at $2.63. The study also shows evidence of 

economies of scale, with the cost/TNY falling from $7.69 in year one (72,196 

ITN) to $3.44 in year five (720,577 ITN). Cost/ITN distributed dropped from

$5.04 to $1.92. Combining targeting and social marketing has the potential of 

being both cost-effective and capable of achieving high levels of coverage and 

it is possible that increasing returns to scale can be achieved. 


55 

An economic analysis of the use of insecticide-treated hammocks 

in central Vietnam 

LSHTM investigators: Chantal Morel, Anne Mills 

External investigators/collaborators: Prince Leopold Institute of Tropical Medicine 

Funding body: Prince Leopold Institute of Tropical Medicine 

A study is being carried out into the effectiveness of insecticide-treated 

hammocks in the forests of central Vietnam. Alongside this, the economic 

implications of insecticide-treated hammocks are being examined. A study 

of the economic impact of malaria on households has been completed. It 

estimated that each episode of malaria costs the patient’s household an average 

of 11.79USD (2005 prices), direct costs for travel and treatment representing 

6% of the total, while the rest was loss in annual income. Whilst government 

provision of malaria treatment keeps the direct costs relatively low, the overall 

loss in income due to illness can still be significant given the poverty amongst 

this population. 

The cost of the intervention has also been studied, and will be matched with 

effectiveness evidence in order to calculate the cost-effectiveness of insecticidetreated 

hammocks. These results will be very important for assessing the true 

usefulness of insecticide-treated hammocks in future and will provide much 

needed information to advise policy makers in Vietnam and elsewhere on the 

merits of this intervention. 

Screening homes to prevent malaria 

LSHTM investigator: Paul Milligan 

External Collaborators: Steve Lindsay, Matt Kirby 

(University of Durham); David Conway (MRC The Gambia) 


a 

b 

Mosquito-proofing of houses was one of the 

principal methods of environmental management 

for vector control in the early part of the 20th 

Century. This approach could be expected to be effective against malaria in 

Africa since the majority of people receive infective bites indoors at night. We 

did a pilot study in The Gambia using experimental huts which demonstrated 

that netting ceilings reduced exposure to malaria vectors by 80%, but further 

studies were needed to estimate the impact of this intervention when used in 

real houses and to assess the acceptability of house-screening to householders. 

A randomised, controlled trial design was used. Houses in villages near 

Farafenni in The Gambia were randomised to receive full screening (200 

houses), or screened ceilings (200 houses), or no screening (100 houses). 

Then through one transmission season, exposure to mosquitoes was measured 

in each house using a light trap fitted near a participant sleeping under an 

untreated bednet. Householders were interviewed to determine what housing 

and personal factors may influence mosquito house entry. Haemoglobin 

concentration at the end of the transmission season was measured using a 

haemocue machine in all children under 10 years of age. To determine the 

acceptability of the interventions, follow-up focus group discussions were held 

with householders, and objective measurements of the internal environment 

were made by monitoring with a maximum and minimum thermometer and 

an evaporimeter every two weeks. A survey of screen damage to record the 

number, position and size of holes after 6 months will determine the durability 

of the interventions. House screening has the potential benefit of protecting 

everyone in the room, avoiding issues of inequity within the household, and 

could be a useful component of an integrated malaria control strategy. 

Fishermen on the water, Vietnam. 

c 

d 

Installing a screened ceiling: 

a) Assessing rose height, 

b) installing ceiling and rose, 

c) installing battens, 

d) plastering up to batten. 

Eaves 

Window 

Door 

Mosquito entry routes 

A screened door. 

In fully screened houses all doors and windows are 

screened and the eaves are closed with mortar. 



Scaling up ITN coverage in Tanzania: understanding the 

contribution and limitations of the private sector 

LSHTM investigators: Virginia Wiseman, Kara Hanson, Eve Worrall, Jo Mulligan, Anne Mills, 

Tanya Marchant 

External investigators/collaborators: Salim Abdulla, Godlove Stephen (IHRDC, Tanzania) 


This study addresses two questions that are currently of critical importance to 

Roll Back Malaria (RBM): [a] how can private sector markets in ITN goods 

(nets and insecticide) best be exploited to increase ITN coverage, and [b] how 

can subsidised access to ITN goods be targeted to those most in need, and can 

this be done without adverse effects on private markets The Tanzania ITN 

Implementation Plan is built on partnership with an exceptionally vigorous 

private sector, but also recognises the need for targeted subsidies. We are: 

1. Tracking the continuing development of the commercial market, in four 

selected areas using retail audit and detailed household surveys, and at National 

level using suppliers’ and distributors’ sales data and basic household surveys. 

2. Monitoring one or more systems of targeting subsidies (e.g. vouchers) 

in terms of effectiveness in reaching the target group, sustainability and 

equity, and impact on the commercial market. Data collection and analysis 

is being carried out in partnership with the national ITN Steering Committee, 

and conclusions will be drawn for both national and international policies. 

The study is being co-ordinated with other planned ITN market-monitoring 

studies in Kenya and in the Netmark project (e.g. Nigeria, Zambia, Senegal). 

The Tanzanian government has been successful in obtaining funds from the 

GFATM for a large scale voucher programme. Our project is providing vital 

monitoring and evaluation throughout the implementation of this voucher 

scheme. 

Anti-larval measures for malaria control in The Gambia 

LSHTM investigator: Paul Milligan 

External investigators/collaborators: S. Majambere, M. Pinder, D. Ameh, R. Hutchinson, U. 

Fillinger, S.W. Lindsay, University of Durham; D Conway (MRC The Gambia) 

Funding body: NIH 

Anti-larval measures for malaria control in The Gambia. 

We have investigated the impact of larviciding with microbial larvicide 

Bacillus thuringiensis var. israelensis (Bti) on mosquito populations and 

malaria incidence and prevalence in The Gambia, West Africa. Four study 

zones each approximately 100 km2 were selected east of Farafenni town, two 

on each bank of the River Gambia. After one year of baseline entomological 

surveys, two zones were sprayed with Bti while the other zones served as 

controls. In each zone, 40 sites were surveyed daily by dipping for presence 

or absence of mosquito larvae and larval density was measured by dipping 

weekly, and indoor collections of adult mosquitoes were performed using CDC 

light traps in sentinel houses. In each zone, malaria incidence was recorded by 

passive detection in a cohort of children aged 6 months to 10 years, and the 

incidence of malaria infection was measured in a cohort of adults. In the third 

year of the study, intervention and control zones were swapped and monitoring 

continued through the malaria transmission season. From preliminary results, 

it is clear that larviciding in The Gambia can reduce significantly the density 

of immature mosquitoes in the field. However, its impact on adult mosquitoes 

and consequently on malaria transmission is not clearly illustrated. Among 

other factors hampering the success of larval control in these settings could 

be the vastness of breeding sites and the impact of tides, the flight range of 

mosquitoes and their fast development rate. The effect of larval control on 

malaria incidence, if any, may depend on factors such as use of insecticide 

treated bednets and distance from major breeding sites. 


Social & Economic Studies 

57 

Malaria is a disease of communities that are living in 

poverty with very stretched and under-resourced 

healthcare systems. Cost-effective and acceptable interventions 

and delivery approaches are therefore even 

more important than in other healthcare settings. It has been repeatedly shown that human behavior, on both 

demand and supply sides, is the key to making potentially effective interventions work (or fail completely) 

in practice. Members of the Malaria Centre undertake a wide range of economic and social studies to examine 

these issues, ranging from cost-effectiveness studies through to health systems and policy analyses, 

so as to determine the best way to deploy the tools we have to fight malaria. This includes examination of 

drugs, diagnostics, vector control measures, home-based care and IPT, delivered through both the private 

and public sectors. 

Pharmacovigilance of antimalarial treatment in Uganda: 

Community perceptions and suggestions for reporting adverse 

events 

LSHTM investigators: Sarah Staedke and Clare Chandler 

External investigators/collaborators: Hasifa Bukirwa, Susan Nayiga (Uganda Malaria 

Surveillance Project), Rosalind Lubanga, Norah Mwebaza (Makerere University), Heidi 

Hopkins (University of California, San Francisco), Ambrose Talisuna (Uganda Ministry of 

Health) 

Funding body: CDC, USA 

To inform strategies for reporting adverse events in Uganda, we investigated 

local perceptions and experiences of antimalarial treatment and evaluated 

existing and potential systems for pharmacovigilance. Between April and 

July 2006, focus group discussions (FGDs) were conducted with community 

members and health workers from selected urban and rural areas of Uganda. 

We explored knowledge of fever/malaria, perceptions and expectations of 

treatment, understanding of adverse effects and experiences with adverse 

events. We conducted 25 FGDs; 16 with community members and 9 with 

health workers. Community members commonly recognised adverse effects 

of antimalarial therapy but certain events were often interpreted as signs of 

successful treatment and events were uncommonly reported. Community 

members often felt that the costs of reporting or seeking additional care 

outweighed the potential benefits. Health workers were unfamiliar with 

formal pathways for reporting and were deterred by the additional work of 

reporting and fear of incrimination. Respondents provided suggestions for 

incentives and methods of reporting, emphasizing that pharmacovigilance 

should ideally encompass the public and private sector and the community. To 

be successful, pharmacovigilance relying on voluntary reporting will require 

active participation of patients and health workers. Addressing the costs and 

benefits of reporting, and providing sensitisation, training and feedback will 

be important. 

Abbreviations used in this section 

AER .......................adverse effects reporting 

ANC .......................antenatal clinic 

ARI .........................acute respiratory infection 

AL ..........................artemether-lumefantrine (coartem) 

AS ..........................artesunate 

AQ..........................(4-aminoquinoline) amodiaquine 

CEA .......................cost effectiveness analysis 

CHW ......................community health worker 

CT ..........................Combination Therapy 

ACT........................Artemisinin-based CT 

DALY ......................Disability-Adjusted Life Years 

DeMTAP.................The Demand for Malaria Treatment and 

Prevention study 

DOMC ....................Division of Malaria Control 

EPI .........................Expanded Programme on Immunisation 

FGD .......................focus group discussions 

FHI .........................Family Health International 

GSMF ....................Ghana Social Marketing Foundation 

IPTc, p, i .................Intermittent Preventative Treatment of 

malaria in children, pregnancy, infants 

IRS .........................indoor residual spraying 

LLITNs ...................long-lasting insecticide-treated nets 

LBW .......................low birth weight 

LCS ........................licensed chemical sellers 

MAM ......................Mobilise Against Malaria 

PSI .........................Population Studies International 

RBM .......................Roll Back Malaria 

RCT .......................randomised controlled trial 

RDT .......................Rapid Diagnostic Test 

SEG .......................socio-economic groups 

SP ..........................sulphadoxine-pyrimethamine 

SRP .......................suggested retail price 

WTP .......................willingness to pay 

Artemisinin based combination therapy for the treatment of 

malaria: an economic and policy analysis 

LSHTM investigators: Anne Mills, Shunmay Yeung 

External investigators/collaborators: Nick White (Wellcome-Oxford-Mahidol Research 

Programme) 

Funding body: The Wellcome Trust 

This work created a comprehensive, dynamic, bio-economic model of malaria 

transmission and the spread of drug resistance, which incorporates vector 

factors, human immunity, human behaviour, drug characteristics and costs. 

Central is a biological model which outputs the proportion of drug resistant 

infections and the incidence of new and recrudescent infections. Parasite 

biomass is also tracked in order that human “infectiousness” be measured 

and fed-back into the model. Sub-models are used to calculate severe malaria, 

Bunyonyi lake in Uganda. 


58 Social & Economic Studies 

SUMMARY 

Pharmacovigilance of antimalarial treatment in Uganda: 

Community perceptions and suggestions for reporting 

adverse events 

Artemisinin based combination therapy for the treatment 

of malaria: an economic and policy analysis 

Cost-effectiveness of combination therapy in Tanzania 

Cost effectiveness of the intermittent preventive treatment 

of children (IPTc) in Basse, The Gambia, and how 

different delivery strategies may lead to different equity 

conclusions 

Cost effectiveness of ITPc with amodiaquine plus artesunate 

(AQ+AS) versus sulphadoxine-pyrimethamine (SP) 

in the Hohoe district of Ghana 

Delivery of intermittent preventive treatment of malaria to 

Ghanaian children: a cost effectiveness study 

Cost-effectiveness analysis of insecticide-treated net 

distribution as part of the Togo Integrated Child Health 

Campaign 

Economic modelling of the use of RDTs and ACT for 

diagnosis and treatment of malaria 

The cost-effectiveness of malaria diagnostic methods in 

Sub-Saharan Africa in an era of combination therapy 

The cost-effectiveness of combination therapy for the 

outpatient treatment of malaria in Tanzania children 

Differences in willingness to pay for 

amodiaquine+artesunate (AQ+AS), 

amodiaquine+sulphadoxine-pyrimathamine (AQ+SP), 

artemether-lumefantrine (AL) or monotherapy (AQ): 

experiences from Tanzania 

Investigation of the determinants of the demand for 

malaria treatment and prevention in Tanzania and The 

Gambia 

The cost-effectiveness of Intermittent Preventive Treatment 

for malaria in Gambian multigravidae, including 

examination of indirect costs 

Technical support to Clinton Foundation’s pilot ACT 

subsidy in Tanzania 

ACTwatch 

Economic analysis of the market for antimalarials in rural 

Tanzania 

The cost-effectiveness of improving malaria home management: 

shopkeeper training in rural Kenya 

Malaria knowledge and practices in Yemen: the importance 

of gender in planning health education 

Equity in malaria treatment and prevention: An analysis of 

the socio-economic dimension in Tanga District, Tanzania 

Context of clinical decision-making for malaria diagnoses 

Private and public providers of malaria services in Anambra 

State, Nigeria 

Evaluation of local mechanisms for staff motivation to 

improve treatment and reduce mortality due to malaria at 

the paediatric ward 

Evaluating the community effectiveness of IPTi in southern 

Tanzania 

Delivery of ACTs in Ghana, Kenya and Senegal 

Perceptions of a malaria vaccine trial in The Gambia 

Community response to intermittent preventive treatment 

delivered to infants (IPTi) through the EPI system in 

Manhiça, Mozambique 

Understanding the implementation and reception of indoor 

residual spraying (IRS) in Manhiça, Mozambique 

Evaluation of the public health impact and cost effectiveness 

of seasonal intermittent preventive treatment for 

children in Senegal 

Delivery of seasonal IPT in Senegal 

The Impact of Retail Sector Delivery of Artemether- 

Lumefantrine on Effective Malaria Treatment of Children 

under five in Kenya 

Cambodia country name in Khmer script. 

A hamlet in Handeni district, Tanga region, Tanzania. 

Malaria attacks are common amongst children in this area. 


deaths, costs and cost-effectiveness. Data were obtained to develop and 

populate the model, including a community drug usage survey in Cambodia 

undertaken to document the adherence and coverage rates to ACT following 

the implementation of locally blister-packaged ACT. Application of the 

model in a low transmission setting suggested that with a 10-year time-frame, 

switching from monotherapy to an ACT is very cost-effective and results 

in overall cost savings in a range of scenarios. High coverage rates with an 

ACT are required to delay the spread of drug resistance if resistance has 

already arisen to one of the partner drugs. Running the model with data from 

Cambodia suggested that even in settings with low coverage, the change will 

be cost-effective and significant benefits are gained from increasing coverage 

through specific delivery interventions. 

Cost-effectiveness of combination therapy 

in Tanzania 

LSHTM investigators: Catherine Goodman, Anne Mills 

External investigators/collaborators: Salim Abdulla, Joseph 

Njau (IHRDC, Tanzania); Patrick Kachur (CDC) 

Funding body: USAID 

Combination therapy (CT) comes at a far higher 

cost than using either chloroquine or SP alone. 

However, it also offers benefits in terms of 

reduction in the development of drug resistance, 

malaria transmission and more effective treatment 

of uncomplicated malaria, reducing the number of 

severe cases. The cost effectiveness of adopting CT 

as a first line treatment for malaria is a complex 

question. Objectives of the costing component 

of the study were to calculate the recurrent and 

development costs to providers and households of 

introducing CT, to calculate savings or additional 

costs generated with using CT, to determine the 

costs of scaling up CT from district to national level 

and assess financial sustainability and to use cost 

effectiveness analysis to assess the allocative efficiency of allocating resources 

to CT. Within the timeframe of the evaluation, a significant impact may be 

found only on intermediate outcomes, such as the prevalence of mutations


59 

encoding for resistance to SP which will require extrapolation to final health 

outcomes in order to calculate cost-effectiveness. 

Cost effectiveness of the intermittent preventive treatment of 

children (IPTc) in Basse, The Gambia, and how different delivery 

strategies may lead to different equity conclusions 

LSHTM investigators: Lesong Conteh, Virginia Wiseman, Paul Milligan, Brian Greenwood 

External investigators/collaborators: Kalifa Bojang (MRC; The Gambia) 


This work was part of a cluster- randomised trial funded by GMP, comparing 

two strategies for the delivery of IPTc in rural communities: one using village 

health workers, the other qualified nurses in monthly trekking clinics of the 

expanded programme for immunization. Economists working on the study 

have concentrated on assessing the cost effectiveness and health inequalities 

associated with the two different delivery methods. 

Cost effectiveness of Intermittent Preventive Treatment in 

Children (ITPc) with amodiaquine plus artesunate (AQ+AS) 

versus sulphadoxine-pyrimethamine (SP) in the Hohoe district of 

Ghana 

LSHTM investigators: Lesong Conteh, Edith Patouillard, Jayne Webster, Brian Greenwood, 

Daniel Chandramohan 

External investigators/collaborators: Margaret Kweku, Ghana Health Services; Fred Binka, 

Samuel Abudey, INDEPTH Network 


Intermittent preventive treatment for malaria in children (IPTc) is a promising 

new approach to malaria control. Preliminary studies of IPTc in Senegal and 

Mali have indicated that this approach can be very effective. As yet, no cost 

effectiveness analysis has been undertaken alongside clinical trials. This 

study is the first to evaluate the effectiveness of IPTc in reducing anaemia and 

malaria in an area with up to 6 months of transmission. 2240 children aged 

3-59 months have been randomly allocated to four groups (560 per arm) to 

receive AQ+AS, given at two different intervals (monthly or bimonthly), SP 

or placebo. Costs are being collected from both the provider and household 

perspective. Cost effectiveness outcomes include the net costs/savings of the 

different drug regimens during the intervention period as well as the costs/ 

savings associated with a full one year follow up. The costs of scaling up the 

intervention using the different drug regimens to the district level are being 

modelled. 

Old, canceled stamp from Ghana 

depicting Fire Crowned Bishop Bird. 

Delivery of intermittent preventive treatment of malaria to 

Ghanaian children: a cost effectiveness study 

LSHTM investigators: Edith Patouillard, Lesong Conteh, Jayne Webster, Brian Greenwood, 

Daniel Chandramohan 

External investigators/collaborators: Margaret Kweku, Ghana Health Services; Fred Binka, 

Samuel Abudey, INDEPTH Network 

Funding body: GMP, DFID TARGETS consortium 

Intermittent Preventive Treatment of children (IPTc) is a relatively new and 

efficacious strategy for malaria control. It involves the administration of 

a full course of anti-malarial treatment drugs at specified time intervals to 

asymptomatic children under five years of age. Finding a way to efficiently 

achieve high and sustainable coverage among this most vulnerable population 

group is, however, challenging given that children are unlikely regularly 

to visit routine health facilities after immunisation is complete. Delivery 

strategies are therefore likely to include channels outside the routine health 

Fishing harbor - Ghana. 



Togoan Children diligently helping their mother do the laundry in the 

river that forms the border between Ghana and Togo. 

Photo taken by Andy of HoboTraveler.com 

system. The objective of this study was to assess the cost-effectiveness of 

IPTc delivered through (1) the routine health system, including static and 

outreach clinics offering EPI/growth monitoring services and (2) communitybased 

volunteers. Effectiveness data was obtained from an open label trial 

implemented in 12 villages of a district of Ghana. Villages were randomised to 

receive IPTc through the routine health system or community-based volunteers 

(mother co-ordinators). Children in both arms received four courses of antimalarial 

treatment (a three-day regimen of amodiaquine and sulphadoxinepyrimethamine) 

during the first and last two months of the high intensity 

transmission period. The effectiveness of IPTc through each delivery channel 

was expressed in terms of (i) the level of coverage achieved defined as the 

proportion of children who received the full four IPTc courses (ii) the level of 

adherence defined as the proportion of children who completed the three doses 

in each of the four courses and (iii) the incidence of clinical malaria. Costs 

were estimated from the perspective of the health provider. They included the 

cost per child reached and the cost per child who adhered to the IPT regimen 

in each delivery system as well as the cost per clinical malaria case treated 

through the ongoing standard case management strategy (no IPTc). Sensitivity 

analysis was undertaken on the most uncertain parameters. Results present the 

incremental cost-effectiveness ratios of IPTc delivered within the community 

compared with IPTc delivered through static and/or outreach routine health 

services. 

Cost-effectiveness analysis of insecticide-treated net distribution 

as part of the Togo Integrated Child Health Campaign 

LSHTM investigators: Dirk Mueller, Virginia Wiseman 

External investigators/collaborators: Dankom Bakusa, Kodjo Morgah, Aboudou Daré, 

Potougnima Tchamdja 

Funding body: International Federation of Red Cross and Red Crescent Societies, Canadian 

International Development Agency, CDC, GMP 

An insecticide-treated bed net protecting 

a family. 

http://www.malariafreefuture.org 

The aim of this study was to evaluate the cost-effectiveness of the first 

nationwide delivery of long-lasting insecticide-treated nets (LLITNs) as part 

of the 2004 measles vaccination campaign in Togo to all children between 

nine months and five years. An incremental approach was used to calculate 

the economic costs and effects from a provider perspective. Effectiveness was 

estimated in terms of malaria cases averted, deaths averted and Disability- 

Adjusted Life Years (DALYs) averted. Malaria cases were modelled using 

regional estimates. Programme and treatment costs were derived through 

reviews of financial records and interviews with key stakeholders. Uncertain 

variables were subjected to a univariate sensitivity analysis. Assuming equal 

attribution of shared costs between the LLITN distribution and the measles 

vaccination, the net costs per LLITN distributed were $4.41 USD when saved 

treatment costs were taken into account. Assuming a constant utilization 

of LLITNs by the target group over three years, 1.2 million cases could be 

prevented at a net cost per case averted of $3.26 USD. The net costs were 

$635 USD per death averted and $16.39 USD per DALY averted, respectively. 

The costs per case, death and DALY averted are well within commonly agreed 

benchmarks set by other malaria prevention studies. Varying transmission 

levels are shown to have a significant impact on cost-effectiveness ratios. 

Results also suggest that substantial efficiency gains may be provided from 

the joint delivery of vaccination campaigns and malaria interventions. 



61 

Economic modelling of the use of RDTs and ACT for diagnosis 

and treatment of malaria 

LSHTM investigators: Anne Mills, Yoel Lubell, Christopher Whitty, Hugh Reyburn, Sarah 

Staedke 

External investigators/collaborators: Heidi Hopkins (UCSF) 


This work is developing economic models that advise policy makers on 

the efficiency of diagnostics and treatments for malaria. The work aims 

to increase the comprehensiveness of the models, accounting for factors 

beyond immediate costs and intermediate outcomes, and to modify the 

models for use as decision support tools for different settings, providing upto-date 

and locally relevant results. Broadening the comprehensiveness of 

the models requires that, for instance, when evaluating the cost-effectiveness 

of RDTs, evaluations also include the degree to which clinicians act in 

consistency with test results. Analysis of this factor demonstrated that, in 

some settings, rollout of RDTs would be an inefficient intervention if current 

levels of prescription of antimalarials to patients with negative test results 

continues. In addition, a decision support tool has been developed to assist 

policy makers in choice of RDT. This interactive model is based on a decisiontree 

structure and cost-benefit framework. Variables included can be modified 

by users, including RDT and treatment costs, test accuracies (sensitivity and 

specificity), probabilities for developing severe illness, case-fatality rates and 

clinician response to negative test results. The output panels indicate which of 

the RDTs or presumptive treatment is the preferred option in different 

settings. 

Screenshot of the decision support tool for diagnostics and malaria 

treatment choice. 

RDT and drug costs, and test accuracies, can be accessed and changed 

using the assigned button on the left hand panel, as can the probabilities 

of developing severe illness and case fatality rates. Other parameters can 

be adjusted or excluded using scroll bars on the left panel. The updated 

results appear on the right hand side. The bars in the top right panel show 

the total cost for each RDT by varying levels of prevalence, and the trendline 

depicts the costs for presumptive treatment (PT). The bottom graph displays 

the relative cost savings for each of the RDTs using PT as a baseline, again 

by prevalence level. 

The cost-effectiveness of malaria diagnostic methods in Sub- 

Saharan Africa in an era of combination therapy 

LSHTM investigators: Catherine Goodman, Anne Mills, Samuel Shillcutt, Chantal 

Morel, Paul Coleman, Christopher Whitty 

External investigators/collaborators: David Bell (WHO - Regional Office for the 

Western Pacific) 

Funding body: UNICEF, UNDP, World Bank, WHO-TDR 

The objective was to evaluate the relative cost-effectiveness in different 

Sub-Saharan African settings of presumptive treatment, field-standard 

microscopy and rapid diagnostic tests (RDTs) to diagnose malaria. 

We used a decision-tree model and probabilistic sensitivity analysis 

applied to malaria-suspected outpatients presenting at rural health 

facilities. Costs and effects encompassed those for both RDT-positive 

patients (assuming artemisinin-based combination therapy (ACT) 

treatment) and RDT-negative febrile patients (assuming antibiotic 

treatment). Interventions were defined as cost-effective if they were 

dominant (less costly and more effective) or had an incremental cost per 

Disability-Adjusted Life Year averted of 50% likely to be cost-saving below 

58% prevalence. Relative to microscopy, RDTs were more than 85% likely 

to be cost-effective across all prevalence levels, reflecting their expected 

better accuracy under operational conditions. Results were robust to extensive 

sensitivity analysis. The cost-effectiveness of RDTs mainly reflected improved 

This baby was suffering from convulsions and prostration. 

The band around his wrist confers protection to infants according to local 

traditions. 



treatment and health outcomes for non-malarial febrile illness, plus savings 

in antimalarial drug costs. Results were dependent on the assumption that 

prescribers used test results to guide treatment decisions. (See Lubell et al 

2008 for an analysis which relaxes this assumption). 

In conclusion, RDTs have the potential to be cost-effective in most parts of 

Sub-Saharan Africa. Appropriate management of malaria and non-malarial 

febrile illnesses is required to reap their full benefits. 

Masai warriors, Tanzania. 

The cost-effectiveness of combination therapy for the outpatient 

treatment of malaria in Tanzania children 

LSHTM investigators: Virginia Wiseman, Christopher Whitty 

External investigators/collaborators: TK Mutabingwa (NIMR, Tanzania); Michelle Kim 


An economic evaluation of drug combinations was designed around a 

randomised effectiveness trial of combinations recommended by the WHO, 

used to treat Tanzanian children with non-severe slide-proven malaria. Drug 

combinations were: amodiaquine (AQ), AQ+ sulphadoxine-pyrimethamine 

(AQ+SP), AQ+artesunate (AQ+AS) and artemether-lumefantrine (AL, six 

dose regimen). Effectiveness was measured in terms of resource savings 

and cases of malaria averted (based on parasitological failure rates at days 

14 and 28). All costs to providers and to patients and their families were 

estimated and uncertain variables were subjected to univariate sensitivity 

analysis. Incremental analysis comparing each combination revealed that 

from a societal perspective AL was most-cost-effective at day 14. At day 28 

there was negligible difference between AL and AQ+AS; both resulting in a 

gross saving of approximately $1.70 USD or a net saving of $22.40 USD per 

case averted. In an area of high drug resistance, there is evidence that AL and 

AQ+AS are the most cost-effective drugs despite being the most expensive 

because they are significantly more effective than other options and therefore 

reduce the need for further treatment. This will not necessarily be the case in 

parts of Africa where recrudescence following SP and AQ 

treatment (and their combination) is lower, so the relative 

advantage of ACTs is smaller, or where diagnostic services 

are not accurate, so much of the drug goes to those who do 

not have malaria. 

Differences in willingness to pay for 

amodiaquine+artesunate (AQ+AS), 

amodiaquine+sulphadoxine-pyrimathamine 

(AQ+SP), artemether-lumefantrine (AL) or 

monotherapy (AQ): experiences from Tanzania 

LSHTM investigators: Virginia Wiseman, Christopher Whitty 

External investigators/collaborators: TK Mutabingwa (NIMR, 

Tanzania); Obinna Onwujekwe (Health Policy Research Group, 

University of Nigeria) 


On the paediatric ward at Handeni hospital, Tanzania. 

Mothers and babies are frequently three to a bed during the rainy season. 

Mothers conduct laundry and cooking chores themselves in and around the 

ward. Post-admission infections acquired during hospital stays are common. 


The cost of combination treatment is thought to be one of 

the greatest barriers to their deployment, but this has not 

been tested directly. Estimates of willingness to pay (WTP) 

were compared across four drug combinations used to treat Tanzanian children 

with uncomplicated malaria. The reasons behind respondents’ valuations and 

the effect of socio-economic status on WTP were explored. 180 mothers 

whose children had been recruited into a recently completed randomised 

effectiveness trial of AQ+AS, AQ+SP, AL (co-artemether) or monotherapy


63 

(AQ) were interviewed about their WTP for these medicines two 

weeks after treatment. WTP estimates were elicited using the 

bidding game technique. A significant difference was detected 

in the mean amounts respondents were willing to pay with those 

receiving AQ+AS paying the most, followed by co-artemether, 

AQ+SP and finally, AQ. The amounts they were willing to pay 

for the artemisin-based combinations fell well short of the market 

costs, however. Socio-economic status was not found to have 

a statistically significant effect on mean WTP scores for any 

treatment group. This study demonstrates that families living in an 

area where drug resistance to monotherapy is very high are willing 

to pay more for more effective artemisin based combination 

therapies (ACTs). However these amounts are nowhere near the 

real costs of delivering the new medicines. Only with subsidy will 

ACTs realistically make any impact. 

Investigation of the determinants of the demand for 

malaria treatment and prevention in Tanzania and The 

Gambia 

LSHTM investigators: Virginia Wiseman, Lesong Conteh, Robert Pool 

External investigators/collaborators: Warren Stevens, William Mwengee, Fred Matovu 


The Demand for Malaria Treatment and Prevention (DeMTAP) study 

assessed the importance of factors influencing demand for bed net ownership 

and malaria treatment seeking behaviour in The Gambia and Tanzania using 

household surveys and logit regression models. Households were interviewed 

about their consumption and expenditure on malaria prevention and treatment 

over the previous 2 weeks, with interviews staggered over 12 months to capture 

the effect of seasonality. Community spokespersons were also surveyed about 

the extent to which community level factors such as the quality of roads and 

access to market centres influence demand. Pictorial health expenditure diaries 

were maintained for 12 months by a sub-set of 300 households in both sites. 

The cost-effectiveness of Intermittent Preventive Treatment for 

malaria in Gambian multigravidae, including examination of 

indirect costs 

LSHTM investigators: Virginia Wiseman, Anne Mills, Pa Lemin Beyai 

Funding body: GMP, Commonwealth Scholarship Commission 

The aim of this study was to estimate the cost-effectiveness of intermittent 

preventive treatment of pregnant women (IPTp) with sulphadoxinepyrimethamine 

(SP) to prevent Low Birth Weight (LBW) and anaemia due 

to malaria in pregnancy in Gambian multigravidae, including an examination 

of indirect costs. The study was piggy-backed on a Randomised Controlled 

Trial (RCT) of the effectiveness of IPTp conducted in the rural area of the 

country from July 2002 to February 2004. The cost data was combined 

with the effectiveness data from the trial to estimate incremental costs and 

consequences for Base case I (trial sample) and Base case II (non-users of 

bednets in trial sample).The study results showed that the net costs of IPTp 

with SP for multigravidae with and without indirect costs were Gambian 

Dalasi (D) 1,221,771 and D1,887,607 respectively for Base case I. The 

corresponding figures for Base case II were D315,933 and D453,620. In terms 

of effectiveness, the DALYs averted in Base cases I and II were -125.8 and 

-0.13, respectively so the intervention was more costly and less effective than 

Sign in The Gambia promoting bednet use. 

Photo: Galen R Frysinger www.galenfrysinger.com 

The Gambian flag. 

Photo: Galen R Frysinger www.galenfrysinger.com 

Banjul to Basse Ferry, The Gambia. 



Senegal wattled plover. 

routine practice. Except for the use of the opportunity cost method of valuing 

indirect costs in Base case I that led to a 12% decrease in net costs, the use 

of all other human capital wage rates led to a less than 10% change in net 

costs for both base cases. Sensitivity analysis of giving IPTp to all pregnant 

women found that IPTp dominated routine practice for the two base cases. The 

domination remained regardless of whether indirect costs were included. The 

general conclusion is that giving IPTp with SP to multigravidae alone is not 

cost-effective. If IPTp were to be given to all pregnant women without regard 

to gravidae, IPTp was dominant with and without indirect costs. However, 

there may be a policy dilemma associated with giving IPTp to all women 

knowing that the trial showed it conferred no benefits, and even might carry 

some risks, for multigravidae. 

Technical support to Clinton Foundation’s pilot ACT subsidy in 

Tanzania 

LSHTM investigators: Catherine Goodman 

External investigators/collaborators: Bruce Mackay, David Bishop (HLSP), Lorrayne Ward, 

Oliver Sabot (Clinton Foundation) 

Funding body: Clinton Foundation 

A ward in Handeni hospital, Tanzania. 


The principal objectives of this project are to 1) substantially increase 

access to affordable, effective, high-quality malaria treatment in the targeted 

intervention areas of Maswa and Kongwa, and (2) assess the impact of a 

subsidy introduced at the top of the private sector supply-chain on a) the 

final price paid by patients for ACTs, and b) the purchase and use of ACTs 

compared with other anti-malarials (i.e. to what extent have subsidized 

ACTs displaced currently available anti-malarials in the private sector). An 

additional objective is to assess the impact of the inclusion of a manufacturer 

suggested retail price (SRP) on the above outcomes. These data are intended 

to inform policymaking at both the national and global levels, particularly 

related to the introduction of a global ACT subsidy. 

The initial findings of this project are cause for cautious optimism. In total, 

30% of the over 400 customers who were interviewed after purchasing an 

anti-malarial product from a drug store in November bought a subsidized 

ACT. Uptake was greater among customers seeking treatment for children 

under the age of five years, with 40% buying a subsidized ACT. No customer 

paid more than $1 USD for a subsidized ACT and the median price paid by 

consumers for a subsidised adult dose in Maswa ($0.42 USD) was equal to 

that paid for common alternatives such as sulphadoxine-pyramethamine (SP) 

and amodiaquine (AQ). Prices paid for adult doses of subsidized ACTs in 

Kongwa were substantially higher (median $1.00 USD) in line with the SRP, 

indicating that, thus far, the SRP seems to have artificially inflated prices. 

Two findings may be cause for concern and warrant further exploration. Only 

26% of subsidised ACT purchases were for children under five. The data 

also indicate that poorer individuals in the project districts were much less 

likely to seek malaria treatment at drug stores, with only 10% of individuals 

interviewed categorised in the two poorest socioeconomic quintiles. It will be 

important continually to monitor these trends as the project progresses. 

ACTwatch 

LSHTM investigators: Catherine Goodman, Kara Hanson, Edith Patouillard 

External investigators/collaborators: Kate O’Connell, Stephen Chapman (PSI) 

Funding body: Bill & Melinda Gates Foundation 

ACTwatch aims to provide and promote evidence and recommendations for 

policy makers on methods to increase availability and decrease the consumer


65 

price of quality assured artemisinin-based combination therapies through the 

private sector. The study is taking place in 8 countries in Africa and South East 

Asia, and encompasses assessment of: 

1. The availability, price and quality of antimalarial drugs at retail outlets 

2. The distribution chain for antimalarials 

3. Consumer treatment-seeking behaviour 

LSHTM is leading the second component on the distribution chain. We will 

(1) develop a map of the supply chain for antimalarial retailers in each country, 

including types, numbers and characteristics of suppliers, antimalarial sales 

volumes flowing through the chain by antimalarial type and markups at 

each stage of the chain; (2) investigate factors affecting drug selection, sales 

volumes and prices; (3) compare supply chains within and between countries; 

(4) monitor and explain changes in supply chain over time; and (5) develop 

and communicate policy recommendations. The analytical framework for the 

research will draw on insights from economic theories of competition and 

industrial organization. 

Tanzania Flag 

Economic analysis of the market for antimalarials in rural 

Tanzania 

LSHTM investigators: Catherine Goodman, Anne Mills 

External investigators/collaborators: Salim Abdulla (IHRDC, Tanzania), Patrick Kachur 

(CDC, USA) 

Funding body: Wellcome Trust, USAID 

In low-income countries the majority of health care is sought in the private 

sector, often through drug retailers, but little information is available on retail 

competition and regulation. This work addressed this gap, in the context of the 

market for fever and malaria treatment in rural Tanzania. Data were collected 

in three districts where the main treatment providers were public and private 

health facilities, drug stores and general shops. Retailers were an important 

source of fever/malaria treatment, with the majority of retail antimalarial sales 

occurring through drug stores. Retail providers increased the accessibility, 

range and reliability of drug stocks, but several market failures were evident. 

Market concentration was high, price competition was weak, information on 

treatment quality was poor and negative externalities arose from inappropriate 

drug use. These failures contributed to low antimalarial coverage, use of 

ineffective antimalarials, under-dosing, and inequitable access to quality care. 

Government failures were also evident, in the form of poor quality public 

sector treatment and inadequately implemented regulation. To optimise the 

planned introduction of antimalarial combination therapy, public facility care 

must be improved. However, facility-only provision will not improve treatment 

for the majority of fever/malaria visits, which are likely to remain to shops. 

Implications for widening combination therapy provision to the retail sector 

are outlined, including the selection of appropriate retailers, maintenance of 

affordable prices, effective communication with consumers and providers and 

a constructive role for regulation. 

The cost-effectiveness of improving malaria home management: 

shopkeeper training in rural Kenya 

LSHTM investigators: Catherine Goodman 

External investigators/collaborators: Vicki Marsh, Wilfred Mutemi, Karisa Baya, Annie Willets 

(KEMRI-Wellcome Trust Collaborative Research Programme) 

Funding body: DFID; KEMRI; Wellcome Trust, UNDP, World Bank, WHO-TDR 

An educational programme for general shopkeepers and communities in Kilifi 

District, rural Kenya, was associated with major improvements in the use of 

Duka La Dawa (Pharmacy) in Dar es Salaam, Tanzania. 

Photo: Namit Arora, www.shunya.net 

Mosquitos. 



anti-malarial drugs for childhood fevers. The two main components were 

workshop training for drug retailers and community information activities. This 

study calculated the cost and cost-effectiveness of the programme, evaluating 

both its measured cost-effectiveness in the first area of implementation (early 

implementation phase) and the estimated cost-effectiveness of the programme 

recommended for district-level implementation (recommended district 

programme). The proportion of shop-treated childhood fevers receiving an 

adequate amount of a recommended antimalarial rose from 2% to 15% in 

the early implementation phase, at an economic cost of $4.00 per additional 

appropriately treated case ($2000 USD). If the same impact were achieved 

through the recommended district programme, the economic cost per additional 

appropriately treated case would be $0.84, varying between $0.37 and $1.36 

in the sensitivity analysis. Extrapolation of the results to estimate the cost per 

DALY averted indicates that the intervention is likely to be considered highly 

cost-effective in comparison with standard benchmarks. 

Yemeni couple at their wedding. 

http://jewishnation.blogspot.com/ 

The Masai Steppe in Tanga region, Tanzania. 

Malaria is common in this area where co-morbidity with anaemia is also a 

serious problem. Access to health care is poor, especially amongst pastoralist 

communities who find payment difficult as well as language and cultural 

barriers with health workers. 


Malaria knowledge and practices in Yemen: the importance of 

gender in planning health education 

LSHTM investigators: Abdullah al-Taiar, Clare Chandler, Christopher Whitty 

External investigators/collaborators: Ali Assabri, Samira Al Eryani, Arwa Algabri 


We explored malaria-related treatment seeking, and also prevention practices 

and knowledge of transmission amongst parents in order to inform health 

education strategies. Yemen is culturally very distinct from most malariaendemic 

countries. We hypothesised that household gender relationships might 

impact on practice. We conducted focus group discussions amongst women and 

men in urban, semi-urban and rural areas of Taiz province and followed this 

with researcher-administered structured questionnaires to parents or guardians 

of children with severe malaria admitted to the main referral hospital; mild 

malaria who attended public health centres; and healthy children from the 

community. Whilst malaria was viewed as severe and recognition of malarial 

symptoms was good (all focus groups recognised fever as a key symptom of 

malaria), we found that delays to medical treatment after symptom onset were 

common. 78% parents reported having delayed before attending any health 

facility or healer. Delays usually related to financial constraints but also to 

difficulties with treatment-seeking when fathers or male family members were 

not available. When contact with a health worker occurred prior to admission 

to the hospital, the treatment was potentially inappropriate in 29% and 

ineffective in 57%. There were distinct differences between men 

and women in their perspective on malaria. This has implications 

both for treatment-seeking and prevention strategies. Knowledge 

of malaria transmission was vague, particularly amongst mothers, 

and bednets were reported to be used rarely and without insecticide 

treatment, and some beliefs were potential barriers to malaria 

prevention strategies. 

Equity in malaria treatment and prevention: An 

analysis of the socio-economic dimension in Tanga 

District, Tanzania 

LSHTM investigators: Virginia Wiseman, Catherine Goodman 

External investigators/collaborators: Fred Matovu 


This study examined the extent of inequalities in the expenditure and utilisation 

of bed nets (both treated and all nets combined) across socioeconomic groups


67 

living in the Tanga District of north-eastern Tanzania. The reasons for 

inequalities were also investigated. An interviewer-administered questionnaire 

was administered to heads of 1603 households drawn from rural and urban 

areas. Households were categorised into socioeconomic groups (SEGs) 

using both an asset-based wealth index and education level of 

the household head. Concentration indices and regressionbased 

measures of inequality were then computed to analyse 

inequalities in utilisation of bednets across SEGs both in rural 

and urban areas. FGDs were also used to explore community 

perspectives on the causes of inequalities. Use of ITNs and 

any net remain appallingly low compared with the RBM target 

of 80% coverage. Inequalities in utilisation and expenditure 

on ITNs and all nets combined were significantly pro-rich 

and were much more pronounced in rural areas. In addition, 

FGDs revealed that lack of money was the key factor for 

not using ITNs. The other reason was negative perceptions 

about the effect of insecticides on the health of net users. 

Multivariate analysis revealed that household SES, living 

within the urban areas and being under 5 years of age were 

positively associated with bednet utilisation, and family size 

had a negative association with using any type of net. The 

results highlight the need for a community-wide programme 

to treat all nets which are not currently treated, and the concurrent promotion 

of use of LLINs or longer-lasting net treatment. The rural and under-five 

populations, for which utilisations rates remain disturbingly low, should 

be targeted through highly subsidised 

schemes and mass distribution of free 

nets. Public campaigns are also needed to 

encourage people to use treated nets and 

mitigate the negative perceptions about 

insecticides used in net treatment. 

Beautiful Flamboyant tree, Tanzania. 

Context of clinical decisionmaking 

for malaria diagnoses 

LSHTM investigators: Clare Chandler, 

Christopher Whitty, Hugh Reyburn, Caroline Jones 

Funding body: ESRC/MRC, Sir Halley Stewart 

Trust 

This project aims to understand the 

context of decisions made during 

clinician-patient consultations resulting 

in malaria tests, malaria diagnoses 

or antimalarial treatment in district 

hospitals in northeast Tanzania. The 

overdiagnosis of malaria is now widely 

reported but reasons for this are as yet 

unclear. The corresponding misdiagnosis 

of alternative causes of febrile illness, 

together with the need for malaria 

control programs to target new and more 

expensive antimalarials at true malaria cases, means 

reducing this overdiagnosis is a public health priority. 

An understanding of contextual factors and their 

Mawenzi peak on Mount Kilimanjaro. 

This high altitude area on the boarder of Tanzania and Kenya has little malaria epidemiologically, but malaria is still perceived 

as the greatest cause of both morbidity and mortality in the area. It is likely conditions presenting with fever in this 

context are not malaria. 



This baby was suffering from Stevens Johnson Syndrome (skin reaction) 

as a result of the prescription of SP (Sulphadoxine Pyrimethamine). 

In this case the child actually had a negative microscopy test result for 

malaria. 

influence on decisions related to malaria diagnoses 

may help the design of interventions to improve 

prescribing behaviour. We used quantitative and 

qualitative methods to explore this topic. Quantitative 

methods involved observing over 2000 consultations 

with a check-sheet to record clinical and non-clinical 

factors during each consultation and clinic session, 

analysed in conjunction with clinician and hospitalspecific 

data. We found decisions to be affected by 

clinician factors, such as number of training sessions 

attended and sex of clinician; clinic session factors, 

such as patient-load and number of other clinicians 

working during that clinic; patient factors such as age 

as well as clinical presentation. Qualitative methods 

involved 6 months of non-participant observation 

and interviews with clinical and administrative staff 

at two district hospitals as well as interviews with 10 

tutors and students at a clinical officer training college 

and a questionnaire for 177 clinicians at 13 hospitals. 

We found that the decision to diagnose malaria and prescribe antimalarials 

even when tests showed no parasitaemia was embedded in medical culture. 

Initial training emphasised the importance of malaria; clinicians were found 

then to conform to perceived expectations from colleagues and from patients; 

and diagnostic support, including resource management, motivation and 

supervision, were targeted more towards malaria than other causes of febrile 

illness. These influences led clinicians to be more inclined to diagnose malaria 

and prescribe antimalarials because this was easier than diagnosing alternative 

diseases; it was more acceptable than alternative diagnoses and missing 

malaria was seen as indefensible in this setting where malaria is so heavily 

emphasised. 

Private and public providers of malaria services in Anambra 

State, Nigeria 

LSHTM investigators: Kara Hanson, Anne Mills, Obinna Onwujekwe 

External investigators/collaborators: Health Policy Research Unit, College of Medicine, 

University of Nigeria 


Nigeria National Mosque 

A truly outstanding example of Nigerian architecture. This is one of the most 

famous new buildings in the new Nigerian capital of Abuja. It sits on a hilltop 

and dominates the nearby countryside. The sky tone is real - the Harmattan 

winds carry dust from the Sahara and leave the skies over Nigeria gray for 

months at a time. 

Photo: Scott Bidstrup, http://www.bidstrup.com/wallpaper.htm 


Levels and determinants of the costs, equity and overall contributions of 

private and public health care providers to appropriate, effective and equitable 

treatment of malaria are not well known in Nigeria and other sub-Saharan 

African countries, but are needed for the improvement of malaria treatment 

services. This research aimed to generate new knowledge about the provision 

and utilisation of malaria treatment in Nigeria in order to inform policy makers 

on areas for intervention with high potential impact to improve utilisation of 

adequate quality malaria treatment services. This was achieved by: a) assessing 

the factors influencing the supply of malaria treatment; b) assessing the factors 

influencing the demand for malaria treatment; c) examining the degree of socioeconomic 

and spatial segmentation of the market for malaria treatment; and 

d) providing guidance to policy makers and other stakeholders about potential 

areas for intervention. The study lasted for 3 years and was conducted in three 

urban and three rural towns from the three senatorial zones of Anambra State 

in Southeast Nigeria. Participatory methods were used to catalyse the research 

findings into practice. The study contributes to strengthening the evidence base


69 

for policy and programmes relating to malaria treatment as well as enhancing 

research capacity in social and economic aspects of malaria in Anambra state 

and Nigeria in general. 

Evaluation of local mechanisms for staff motivation to improve 

treatment and reduce mortality due to malaria at the 

paediatric ward 

LSHTM investigators: Amabelia Rodrigues; Joanna Schellenberg; Brian 

Greenwood 

External investigators/collaborators: Sidu Biai, Poul Erik Kofoed, Sodemann 

Morten, Peter Aaby 

Funding body: GMP, Bandim Health Project 

Previous observation in Guinea-Bissau has shown high mortality at 

the paediatric ward. We demonstrated in a randomised intervention 

trial that mortality due to malaria could be reduced by almost half 

(Risk ratio: 0.48; 95%CI: 0.29-0.79) by adding a small monetary 

incentive to the staff and strict follow-up of a standard protocol to available 

drugs. However, financial incentive to staff is difficult to implement in a 

sustainable manner. Thus, we decided to evaluate whether better control of 

the generated funds through the existing cost recovery system, and its use 

for incentives to staff based on performance indicators (mortality, parent’s 

perception of quality), would improve the quality of care and reduce hospital 

and post-discharge mortality. This is a challenging study and is on-going, but 

preliminary results based on 576 hospitalised children are promising: in the 

first month of the study, no difference in mortality was seen comparing January 

2008 with January 2006 (RR:1.04; 95% CI: 0.67-1.55), however in the second 

month a decline started to be observed (RR: 0.68; 95%CI: 0.43-1.08). We do 

not compare to 2007 because in the first months of the year mortality had 

been particularly high. If the results of this study are positive, it could be 

recommended and implemented in our settings without major external funds, 

but would improve the quality of care and reduce child mortality. 

Evaluating the community effectiveness of IPTi in southern 

Tanzania 

LSHTM investigators: David Schellenberg, Cally Roper, Robert Pool, Joanna Armstrong 

Schellenberg 

External investigators/collaborators: Clara Menendez, Pedro Alonso (Hospital Clinic, 

Barcelona, Spain), Guy Hutton, Marcel Tanner (STI, Switzerland), Salim Abdulla, Hassan 

Mshinda, Fatuma Manzi, Mwifadhi Mrisho, Adiel Mushi, Yuna Hamisi, Werner Maokola, 

Mwjuma Chemba, Kizito Shirima (IHRDC, Tanzania) 


The purpose of this project is to generate the key information required to enable 

prompt programme-based application of a strategy to deliver Intermittent 

Preventive Treatment to Infants (IPTi), following a policy recommendation. 

This is being achieved through three sets of activities: 

(i) Development of the IPTi strategy, led by the project team 

(ii) Implementation of the strategy, led by the routine health service 

teams 

(iii) Evaluation of the effects, costs and acceptability of the IPTi 

strategy. 

In 2004, baseline household, health facility and rapid ethnographic surveys 

were done. These enabled detailed planning of the IPTi strategy in conjunction 

with health actors at national, regional, district and facility levels. A system 

of safety monitoring was established before implementation began in half of 

the 24 divisions (sub-districts) the Project works in. A network of village- 

Results of the previous intervention trial in 

Guinea Bissau (Biai et. al, 2007). 

Pictures showing the on-going registration system of all consulting 

children and controls at the paediatric ward in Guinea-Bissau. 



based informants has provided information on the acceptability of IPTi at 

community level and a system of sentinel health facilities is evaluating the 

effects of IPTi on illness episodes presenting to the health system. Health 

facility and household surveys in 2006 demonstrated the feasibility of largescale 

implementation and revealed opportunities to enhance performance. In 

2007, we surveyed over 240,000 households in order to assess the effects 

of IPTi on health and survival at the community level. The project is also 

evaluating the effect of IPTi on the development of drug resistance and the 

financial and economic costs of IPTi. Information from this project has been 

channeled into a specially-convened WHO IPTi technical review committee 

to help inform policy-related discussions. 

Delivery of ACTs in Ghana, Kenya and Senegal 

LSHTM investigators: Jayne Webster, Caroline Jones, Jane Bruce, Lucy Smith, Suzanne Welsh 

External investigators/collaborators: Sylvia Meek 

Funding body: Pfizer International, DFID TARGETS Consortium 

Interventions to enhance prompt and effective treatment for malaria in children 

under five years of age are being developed through the Pfizer International 

Mobilise Against Malaria (MAM) project. These interventions are targeted 

at three different delivery systems in the three focus countries. In Ghana, the 

focus is delivery of ACTs by Licensed Chemical Sellers (LCS), in Kenya, 

malaria messaging by antenatal clinic (ANC) staff and public sector treatment 

providers, and in Senegal, treatment by Community Health Workers (CHW). 

We have developed a global evaluation framework to enable assessment of 

the impact of the interventions on knowledge and practices of both providers 

and beneficiaries. Novel adaptations of simple monitoring techniques to 

improve the performance of delivery systems have been developed and will be 

implemented in this project. The project includes implementation partners in 

each country: Family Health International (FHI) and Ghana Social Marketing 

Foundation (GSMF) in Ghana, Population Services International (PSI) and 

the Great Lakes University in Kenya, and Intrahealth in Senegal. Evaluation 

partners in the three countries are Health Partners Ghana, KEMRI-Wellcome 

Trust in Kenya and Intrahealth in Senegal. A systematic literature review of 

the evidence for the impact of interventions to improve prompt and effective 

treatment of children under five years with malaria is nearing completion. 

Perceptions of a malaria vaccine trial in The Gambia 

LSHTM investigators: Robert Pool, Tunde Imoukhuede, Wenzel Geissler, Vasee Moorthy, Baba 

Balajo, Sisawo Konteh, Paul Milligan, Brian Greenwood, Ann Kelly 

External investigators/collaborators: Babatunde Imoukhuede (European Malaria Vaccine 

Initiative, Formerly Medical Research Council Laboratories, Fajara, The Gambia), Barcelona 

School of Hygiene, Spain 


Field workers doing their weekly active case detection visits as part 

of the vaccine trial, including finger pricks when a child is found to 

have fever. 


The objectives of this project were to study local understandings of malaria 

vaccines, immunisation and medical research and, in particular, malaria 

vaccine trials. The study focused on perceptions of a recently completed trial 

of the RTS,S vaccine. 

Local response to the vaccine trial was generally positive and people were 

enthusiastic about anything seen to contribute to curing disease or promoting 

health. Both participants in the trial and community members had a limited 

understanding of medical research, immunisation and malaria vaccines, and 

no clear distinction was made between research and health care. People also 

had a limited understanding and suspicion of the role and motives of medical 

researchers, and a deep underlying ambivalence about medical research.


71 

Researchers and study participants had very different perspectives. Senior 

researchers saw the vaccine trial as disinterested, short-term scientific research 

to test a product. They assumed that well-informed and consenting villagers 

participated in the research to help medical science. The local villagers, 

on the other hand, saw the project more in terms of a long-term indirect 

exchange relationship with improved general health care and other benefits 

for the village as the main goal. They were unclear about what the benefits 

were for the researchers, and as a result, rumours of the researchers enriching 

themselves by selling participants blood were common. Locally recruited and 

more junior members of the research team saw the trial as part of a short-term 

scientific endeavour, but they also developed reciprocal longer-term kinshiplike 

relations with villagers that implied the provision of services such as 

health care and transport. 

Community response to intermittent preventive treatment 

delivered to infants (IPTi) through the EPI system in Manhiça, 

Mozambique 

LSHTM investigators: Robert Pool, Clara Menéndez Santos 

External investigators/collaborators: Susanna Hausmann-Muela, Eusebio Macete, Xavier 

Gomez-Olive, Pedro Alonso, Ricardo Thomson, Martinho Dgedge, Joao Schwalbach, Francisco 

dos Santos & Dr Arnaldo Timane, Marcel Tanner, Khatia Munguambe 

Funding body: GMP, Banco de Bilbao, Vizcaya, Argentaria Foundation, the Bill and Melinda 

Gates Foundation 

This anthropological study explored attitudes to EPI and IPTi and perceptions 

of the relationship between them. In particular it focused on whether the 

introduction of IPTi would negatively affect community attitudes to, or 

utilisation of, EPI (for example, whether perceived negative effects of IPTi 

would lead to a reduction in utilisation of EPI); or, conversely, whether the 

concurrent delivery of IPTi and immunisation would influence perceptions 

of IPTi (for example, whether IPTi would be misinterpreted as immunisation 

against malaria, leading to a reduction of other preventive measures or delay 

in treatment seeking). 

The results showed that, in this particular setting, IPTi was generally 

acceptable. Perceived negative aspects of IPTi did not affect perceptions of 

EPI, and IPTi was not misinterpreted as immunisation against malaria. Initial 

resistance was related more to the trial and trial procedures than to IPTi per se, 

but both rejection and acceptance were embedded in a complex constellation 

of local and wider contextual factors. 

IPTi delivered together with EPI may be easily accepted and routinised by 

local populations. Although the factors that led to suspicion or rejection in this 

study were largely local and trial related (e.g. ideas about blood stealing), they 

did resonate with much wider cultural themes that span many countries across 

sub-Saharan Africa (e.g. rumours about research and health interventions, 

and more general ethical concerns about global inequality and the unequal 

distribution of resources on which these rumours are based). The prior 

acceptance and routinisation of EPI played a key role in the acceptance of 

IPTi in this community. 

Mozambique flag. 

Mozambican woman in traditional dresses. 

Understanding the implementation and reception of indoor 

residual spraying (IRS) in Manhiça, Mozambique 

LSHTM investigators: Robert Pool, Catherine Montgomery, Khatia Munguambe 


This anthropological study is examining the social, cultural and historical 



Emperor Scorpions (Pandinus imperator) found in Senegal. 

Community health volunteers issue malaria cards and deliver preventive 

treatment in Tivaouane district, Senegal. 

Household enumeration in Bambey district, Senegal. 


factors that play a role in the reintroduction and reception of indoor residual 

spraying (IRS) for malaria prevention in Mozambique. This study goes beyond 

“acceptability” issues, and aims to understand the more informal processes 

and practices through which health interventions such as IRS are implemented 

and received. This understanding is essential to the long-term success of any 

new health intervention. Beyond this immediate context, the acceptance (or 

rejection) of interventions such as IRS cannot be adequately understood in 

isolation from the implementation process, and this in turn cannot be understood 

independently of the wider context of policy debates, media coverage, local 

and regional politics and historical processes. Understanding current IRS 

policy and implementation in Mozambique and the southern African region 

more generally, therefore requires historical analysis of the political, social 

and cultural factors involved in the previous attempt (and failure) to control 

malaria through spraying with DDT, and of the discourse through which 

current IRS programmes are presented and the rhetorical strategies that are 

used to justify them. 

Evaluation of the public health impact and cost effectiveness of 

seasonal intermittent preventive treatment for children in Senegal 

LSHTM investigators: Badara Cisse, Lesong Conteh, Colin Sutherland, Brian Greenwood, 

Paul Milligan 

External collaborators: Oumar Gaye, Jean-Louis Ndiaye, Babacar Faye, Ernest Faye 

(University Cheikh Anta Diop, Dakar), Cheikh Sokhna, El Hadj Bâ, Jean Francois Trape, 

Cecile Cames, Kirsten Simondon (IRD, Dakar), Oumar Faye, Yancouba Dial (Ministere de la 

Sante, Senegal) 


In the Sahel, morbidity and mortality from malaria is greatest among children 

1-5 years old and occurs in a short transmission season; in randomised trials 

chemoprevention by administration of a therapeutic dose of antimalarial 

drugs once a month has proven highly effective in protecting children from 

clinical malaria. The aim of this project is to evaluate the feasibility and 

cost effectiveness of delivering this intervention on a large scale to rural 

communities and its public health impact. The project is a collaboration 

between LSHTM and the University Cheikh Anta Diop, Dakar and the Institut 

pour le Recherche et la Development, Dakar, funded by a grant from the Bill 

and Melinda Gates Foundation to the University of Dakar. The intervention 

will be delivered to children under 5 yrs in 3 districts in Senegal over a period 

of 3 years. Delivery of the intervention will be coordinated by district health 

staff and delivered by the community health volunteers attached to each health 

post. The impact on all causes of mortality and on malaria morbidity will 

be estimated by comparing areas receiving the intervention with the areas 

where the intervention has not yet been introduced, through a demographic 

surveillance system. The study will seek to assess how introducing this new 

intervention affects other functions of the health system; we will also determine 

to what extent the method of delivery can ensure that different sections of the 

community have equitable access to malaria prevention and can contribute 

to reducing health inequalities. Long term follow-up will be maintained to 

monitor drug resistance and to record the net benefit taking into account any 

effects on naturally acquired immunity to malaria in older children. 

Delivery of seasonal IPT in Senegal 

LSHTM investigators: Badara Cissé, Brian Greenwood, Paul Milligan 

External collaborators: Sylvain Faye, Oumar Gaye, Jean-Louis Ndiaye, Ernest Faye 

(Universite Cheikh Anta Diop, Dakar) Oumar Faye, Yancouba Dial (Ministere de la Sante, 

Senegal) 

Funding body: GMP


73 

In trials of seasonal IPT intervention, drugs have been administered by 

research teams. In this project we investigated the feasibility of delivering 

the intervention to children in rural areas through the routine health service 

in Senegal, and the acceptability of the intervention to communities. A series 

of consultations were held with national and district level public health staff, 

health centre nurses and community health workers, to identify the preferred 

method of delivery in rural communities. Implementation of monthly 

administration of sulphadoxine-pyrimethamine and amodiaquine (SP+AQ) 

to children was then piloted in the population served by three health posts, 

organised by the district health services with drugs delivered door to door 

by community health volunteers (relais communitaires) paid a daily rate. 

Acceptability by the community was investigated using direct observation, indepth 

interviews and focus group discussions. Carers were visited after each 

treatment round to ask about adverse events and compliance. For comparison, 

carers of children living in nearby villages outside the study area, who did 

not receive IPT, were asked the same questions about adverse events. IPT 

coverage was measured by a cluster sample survey. High coverage of IPTc 

with SP+AQ was achieved when delivered by community health volunteers in 

Senegal, good adherence was achieved despite complaints about the bitterness 

of AQ, as parents recognised of the risks of malaria in children under 5 yrs 

and the importance of malaria prevention; a message reinforced during home 

visits by health workers. The most common reason for not receiving IPT doses 

was being away from the village at the time of the treatment round. Incidence 

of solicited adverse events recorded on day 4 after the IPT treatment was 

similar among children who received IPT and children who did not receive 

IPT treatments. 

Fruit vendor in Kenya market holding an enormous breadfruit. 

The Impact of Retail Sector Delivery of Artemether- 

Lumefantrine on Effective Malaria Treatment of Children under 

five in Kenya 

LSHTM investigators: Catherine Goodman, Simon Brooker, Greg Fegan 

External investigators/collaborators: Beth Kangwana, Abdisalan Noor, Bob Snow (KEMRI- 

Wellcome Trust Research Programme); Willis Akhwale, (Division of Malaria Control, Kenya) 

Funding body: DFID, Wellcome Trust 

In 2006, Kenya introduced artemisinin-based combination therapy (ACT) 

through the public sector free of charge, but access remains low. The aim of 

this study is to evaluate to what extent the provision of pre-packed, subsidised 

ACT, delivered through private sector retailers, will increase the proportion of 

children under five, with fever, receiving appropriate anti-malarial treatment. 

The intervention will be implemented by the Division of Malaria Control 

(DOMC) in collaboration with Population Services International (PSI). 

KEMRI/ Wellcome Trust Research Program will be responsible for the 

evaluation of the intervention. The effectiveness of this intervention will be 

evaluated through a pre-post cluster randomised controlled trial. Baseline data 

will be collected before the intervention and follow up data 9 months after the 

start of the intervention from both households and retail outlets. The data will 

be collected using six data collection activities: 1) Retail census 2) Household 

survey 3) Provider survey 4) Mystery shopper 5) Focus group discussions 

and 6) Documentation of context. The results from this study will support 

the DOMC in national strategic planning for improving access to effective 

malaria treatment. 


74 

Facilities 

The Malaria Repository 

Aims of the Repository 

The Malaria Centre has as one of its objectives the 

setting up of a Malaria Repository to enable previously 

collected samples to be organised and integrated to facilitate 

their use in future research. There have been many studies 

conducted under the auspices of The School: cross-sectional, 

longitudinal as well as intervention studies, which provide 

a valuable resource for future research both with respect 

to samples and data. The types of samples available differ 

between studies, but include serum samples, DNA, placental 

samples and blood spots. 

In order to make the Repository a valuable resource for 

future malaria research, it would be beneficial if anyone 

storing samples that are not presently being utilised, were to 

offer these samples for incorporation into the collection. This 

will ensure that valuable samples are not wasted, will enable 

them to be properly stored and means they will be available 

for future research. 

The samples themselves are aliquoted (if possible), entered 

into a master database and stored in -80ºC freezers, in a 

secure long-term storage facility in the basement of Keppel 

Street, using a racking system which provides easy access 

to the samples. Archive and aliquot samples are stored 

separately in case of any unforeseen problem with the storage 

arrangements. 

Since these samples are unique and finite, it is important to 

ensure that these specimens are only utilised for research of 

the highest quality. To this end, guidelines have been drawn 

up for those interested in using Repository samples in their 

research, and all requests for access to materials maintained 

in the specimen repositories will require a formal application 

which will be assessed by the Repository Advisory 

Committee. 

The Currently, a number of sample sets from West Africa, dating 

from the 1960’s to the 1990’s have been incorporated into the 

repository, resulting in a longitudinal set of samples spanning 

over thirty years. At present, the repository contains over 

3000 samples with thousands more in the process of being 

aliquoted. 

Each sample is featured in a database that the original PI has 


Repository so far 

Code of conduct 

• It is hoped that the Repository will encourage the 

establishment of specific collaborations with the 

investigator(s) who collected the data or the specimens. 

• The evaluation of every request entails consideration of 

its scientific merit in the context of other investigations 

and the limited availability of specimens. This evaluation 

will be undertaken by the Repository Advisory 

Committee. 

• Due to the finite nature of the resources available in the 

repository, collaborating investigators should request 

the smallest volume needed to undertake their research. 

• The specimens available have been collected for 

investigational research purposes only. Specimens and/ 

or products resulting from this research must not be sold 

or used for commercial purposes, nor can specimens 

be further distributed to third parties, without prior 

written approval from the PI and the respective Ethics 

Committees. 

• Specimens provided to the collaborating investigator 

can only be used for the proposed research - permission 

to use samples in other studies should be obtained by 

submission of an addendum request prior to the use of 

the sample in the additional study. 

• It is important to ensure that the approval of the ethical 

committees and the informed consent of the participants 

are appropriate for the proposed work. If further ethical 

approval is required, it is up to the investigator to 

approach the relevant institutions. 

• Patient identifiers will not be made available to ensure 

complete confidentiality for the research subjects. 

Specimens are stored in the repository with unique 

identifiers. 

• In general, specimens collected by contractors are the 

property of LSHTM; specimens collected by grantees 

(including co-operative agreements) are the property of 

the awarding body. 

made available for the Repository. For each sample an ID 

number, date of collection, age, sex and, where applicable, 

ethnicity of the individual are present in the master database 

and the majority also have information on parasite count, 

packed cell volume and any treatment that has been 

undertaken. This set-up facilitates the ability to search for 

appropriate samples that can then be made available for 

novel research. 

Contact for Repository matters is Jackie Cook (Jackie.Cook@ 

lshtm.ac.uk).

Facilities 

75 

The Malaria Reference Laboratory 

Hospital for Tropical Diseases 

The UK Health Protection Agency 

Malaria Reference Laboratory (MRL), 

directed by Professor Peter Chiodini, is 

the national reference centre for malaria 

diagnosis in the UK. It provides specialist 

diagnostics and speciation on malaria for 

NHS laboratories throughout the country, is the national centre for 

epidemiological monitoring of malaria and is an advisory service 

for complex questions on malaria prophylaxis for doctors and 

nurses in the UK. 

In addition to this work, the MRL is developing new molecular 

assays for malaria diagnosis and for identifying molecular 

markers of drug resistant P. falciparum parasites. For further 

details on the work of the MRL, please visit the website: 

http://www.malaria-reference.co.uk 

Terms of Reference 

• to provide a reference diagnostic service for malaria 

parasitology, checking the diagnosis and species diagnosis 

on all suspected malaria blood films submitted to it following 

primary diagnosis. 

• to provide a primary diagnostic service for malaria 

parasitology for the NHS on request. 

• to collect and analyse all records of imported malaria into 

the UK, by whatever route they may arrive, to seek to make 

reporting as complete as possible, to provide data to all 

levels of health authorities and trusts and work with them on 

prevention, as resources permit, and to liaise with the Centre 

for Infection (CfI) of the HPA. 

• to provide the evidence which can be utilized by the Advisory 

Committee for Malaria Prevention (ACMP) to develop 

national policy on prevention of imported malaria. 

• to assist the National Travel Health Network and Centre 

(NaTHNaC) to incorporate malaria into their advisory 

activities and in collaboration with NaTHNaC to respond 

to telephone queries from doctors, practice nurses and the 

public within the constraints of available resources. 

• to carry out applied research on diagnostic and other related 

methodology, on drug resistance, and on any other relevant 

aspects of the diagnosis, prevention and control of imported 

malaria. 

• to assist Health Trusts and other public health bodies in 

developing measures for prevention and control of imported 

malaria. 

• to integrate the preceding activities in order to optimise the 

reference, epidemiological and advisory work of the MRL 

and the HPA. 

The Hospital for Tropical Diseases is one of the leading 

clinical tropical centres in the world. It provides 

treatment for people with tropical diseases such as malaria, 

advice for other centres in the UK and elsewhere in the world 

on the treatment of severe malaria, and travel advice for 

those traveling to malaria-endemic areas. Several members 

of the Malaria Centre hold honorary or substantive positions 

as doctors at the Hospital for Tropical Diseases and help to 

ensure that, in addition to the work of the Malaria Centre in 

battling malaria in endemic countries, it also provides advice 

for the prevention and treatment of malaria for travellers 

from the UK to malaria endemic countries. 

The Hospital for Tropical Diseases is an NHS hospital 

and can provide a walk-in service for the diagnosis of 

malaria in those recently returned from the tropics. Diagnosis 

and treatment of malaria is free for all, wherever they come 

from, since malaria in the UK is a notifiable disease. In 

addition to malaria, the Hospital 

for Tropical Diseases has expertise 

across the range of infectious 

tropical diseases and has the 

UK’s only clinical parasitologist, 

clinical nephrologist, tropical 

ophthalmologist and specialists in 

a range of tropical diseases, many 

of which interact with malaria. As 

well as out-patient and travel-health sections, there is an inpatient 

ward at University College Hospital’s NHS Trust for 

the treatment of severe malaria and other tropical diseases. 


76 

Executive Summaries 

Research Capacity, Development and Training 

In addition to undertaking research and policy work, the 

Malaria Centre staff support an extensive programme of 

training and capacity development of scientists in endemic 

countries, particularly in Africa where the greatest burden 

of deaths from malaria are found. The LSHTM has an extensive 

programme of residential Masters programmes and 

short courses in which malaria features prominently, aimed 

at basic scientists, clinicians, epidemiologists and public health professionals. There is a cross-disciplinary 

malaria unit, and additionally there is a malaria study unit by distance-based learning; offered as standalone 

short courses (which will be available soon on a CD) or as an optional advanced module in the PG 

Diploma and MSc in Infectious Diseases. A grant from the CDC has allowed scientists with a track record 

of interest in malaria from East Africa to undertake distanced-based masters courses. 

We have been fortunate that the Gates Malaria Partnership 

was given funds by the Bill & Melinda Gates 

Foundation (BMGF) for a substantial PhD programme for 

endemic-country scientists which continued during the period 

covered by this report. Many of the 33 PhD students 

recruited by GMP have successfully defended their theses 

– in April 2008 the number was 26, with 7 expected to finish 

before the end of 2008. 23 of the first 24 students to 

graduate are back in Africa working on a malaria research or related projects. A personal development 

programme (PDP) was established to help GMP students through the final phase of their PhD programme 

and to provide them with guidance on their training needs following their return home. 

The PhD programme could not receive further support 

from the BMGF because of changes in the strategic directives 

of the Foundation. Thus, LSHTM has been fortunate 

in obtaining a generous grant from the Wellcome Trust to 

allow its post-graduate malaria capacity development programme 

to continue. Other endemic-country scientists from 

Africa and Asia have also completed their PhDs on malaria 

in the period of this report, and most are working in their own 

or other endemic-country settings. The Malaria Centre has several senior endemic-country scientists working 

in leadership roles in their own institutions among its members. 

Four training centres funded by GMP in The Gambia, Ghana, Malawi and Tanzania outlined in the last 

Report have become autonomous and two GMP-funded scientific laboratories in Tanzania are now 

fully operational. An additional laboratory planned in collaboration with other members of the Joint Malaria 

Programme in Korogwe, Tanzania, is nearing completion with funds from MVI. 


Translational Research 

To combat malaria and improve human health, scientific 

discoveries must be translated into products. Such discoveries 

often begin with basic research – typically in a laboratory 

– and then, through several iterative phases of optimisation 

and safety testing, progress to the clinical level. Basic 

scientific research provides new knowledge, techniques and 

tools. Translational research is needed to turn this innovative 

research towards product development and thence to the 

clinic. The interaction with the clinic and the field is essential 

from the beginning of translational research to define the 

product specifications (also known as target product profile). 

As there remains an urgent need to develop and deliver new 

products (drugs, vaccines, and diagnostics) for the prevention 

and treatment of malaria, staff at the School contribute 

worldwide to investing in high quality, innovative research 

in malaria which will translate into new tools for diagnosis, 

management and control of malaria. 

The creation of several public-private partnerships (PPP) 

such as the Medicines for Malaria Venture (MMV); 

Foundation for Innovative New Diagnostics (FIND); and 

the Drugs for Neglected Diseases Initiative (DNDi), Malaria 

Vaccine Initiative (MVI) and Program for Appropriate Technology 

in Health (PATH), has galvanised the development of 

new anti-malarial therapies, vaccines and diagnostics. These 

not-for-profit organisations facilitate and manage interactions 

between academia, the pharmaceutical / biotech sector 

and clinical trial centres to ensure development of safe, effective 

products suitable for use in endemic countries. Our 

active engagement with these partnerships allows for crossfertilisation 

of ideas, skills, knowledge, models and compounds, 

resulting in more focused research and valuable new 

tools with a clear ‘lab to market’ route in mind. 

Executive Summaries 

77 

One example of current translational research at LSHTM 

is provided by studies in the HPA Malaria Reference 

Laboratory (MRL) and the Department of Clinical Parasitology, 

Hospital for Tropical Diseases (HTD) to develop new 

molecular diagnostics for malaria infections. Quantitative 

(real-time) PCR methods for the detection of five Plasmodium 

species infecting humans have been developed in-house, 

and are being validated against the bank of isolates in the 

MRL. Two of these assays, for P. falciparum and P. vivax, are 

well advanced and their performance for routine diagnosis 

will be compared with established conventional PCR methods 

in the HTD. Our work has also attracted funding from 

FIND, in partnership with the EIKEN Chemical Co., Tokyo, 

to develop Loop-activated amplification assays (LAMP) for 

malaria that could be developed into commercial kits. This 

work is well advanced, and Dr Yasuyoshi Mori from EIKEN 

will be joining our team for 6 months in 2008 to participate 

as we advance this work further. 

Other examples of translational research on drug development 

include the MMV-supported projects for lead 

optimisation of dihydrofolate reductase (DHFR) inhibitors 

and PK PD studies on the pyronaridine-artesunate (Pyromax) 

combination. In the field, artemisinin based drugs are 

increasingly being faked as both demand and cost increase. 

Reports from SE Asia indicate that around 50% of the drug 

artesunate sold is faked with tablets containing little or no 

active ingredient. In an example of translational research, we 

have developed two simple, easy to use, robust, inexpensive 

and rapid colour assays that can be used in the field to check 

drug quality. These assays are highly specific as they only 

detect and measure the artemisinin derivative component in 

the formulation., We have also developed another simple and 

semi-quantitative colour test to detect the amount of insecticide 

on bed nets. This approach will also indicate compliance 

of internal residual spraying of walls with insecticide to 

help evaluate the quality control of the interventions in the 

fight against malaria. 

Molecular Diagnosis of P. ovale by real-time qPCR 

Novel quantitative method for detecting P. ovale in human blood samples developed 

by Spencer Polley and Colin Sutherland at HTD. This method is entering a validation 

phase with Martina Burke and Debbie Nolder in the HPA Malaria Reference Laboratory 

at LSHTM. If successfully validated, the assay will be introduced for routine diagnostic 

work in the Department of Clinical Parasitology, HTD and in the MRL 

Eight isolates of Plasmodium ovale of diverse origin 

P. vivax, P. falciparum 

and negative control 

containing water only 

Rapid colour assays that can be used in the field to check 

drug quality 

Photo shows the analyses of Cotexcin® samples collected from Nigeria with the detection 

of a fake Cotexcin® (left hand side, note the lack of colour on TLC when compared 

with other samples and DHA reference drug on the far right hand side). 


78 

Malaria Centre Publications 

Aarnoudse A, van Schaik R H N, Dieleman J, 

Molokhia M, van Riemsdijk M M, Ligthelm R J, 

Overbosch D, van der Heiden I P and Stricker 

B H C. 2006. MDR1 gene polymorphisms are 

associated with neuropsychiatric adverse effects of 

mefloquine. Clinical Pharmacology & Therapeutics, 

80:367-374. 

Abeku T A. 2007. Response to malaria epidemics in 

Africa. Emerging Infectious Diseases, 13:681-686. 

Abuya T O, Mutemi W, Karisa B, Ochola S A, 

Fegan G and Marsh V. 2007. Use of over-thecounter 

malaria medicines in children and adults 

in three districts in Kenya: implications for private 

medicine retailer interventions. Malaria Journal, 6. 

Adams D P. 2007. ‘Malaria discipline’ and 

neurcipsychiatric cases among us troops in SE Asia: 

1960-1975. American Journal of Tropical Medicine 

and Hygiene, 77:143-143. 

Adjuik M, Smith T, Clark S, Todd J, Garrib A, 

Kinfu Y, Kahn K, Mola M, Ashraf A, Masanja 

H, Adazu U, Sacarlal J, Alam N, Marra A, 

Gbangou A, Mwageni E and Binka F. 2006. 

Cause-specific mortality rates in sub-Saharan 

Africa and Bangladesh. Bulletin of the World Health 

Organization, 84:181-188. 

Agak G W, Bejon P, Fegan G, Gicheru N, Villard 

V, Kajava A V, Marsh K and Corradin G. 

2008. Longitudinal analyses of immune responses 

to Plasmodium falciparum derived peptides 

corresponding to novel blood stage antigens in 

coastal Kenya. Vaccine, 26:1963-1971. 

Ajayi I O, Browne E N, Garshong B, Bateganya F, 

Yusuf B, Agyei-Baffour P, Doamekpor L, Balyeku 

A, Munguti K, Cousens S and Pagnoni F. 2008. 

Feasibility and acceptability of artemisinin-based 

combination therapy for the home management of 

malaria in four African sites. Malaria Journal, 7. 

Akech S, Gwer S, Richard I, Fegan G, Eziefula 

A C, Newton C, Levin M and Maitland K. 2006. 

Volume expansion with albumin compared to 

gelofusine in children with severe malaria: Results 

of a controlled trial. Plos Clinical Trials, 1. 

Akpogheneta O J, Duah N O, Tetteh K K A, 

Dunyo S, Lanar D E, Pinder M and Conway D 

J. 2008. Duration of naturally acquired antibody 

responses to blood-stage Plasmodium falciparum 

is age dependent and antigen specific. Infection and 

Immunity, 76:1748-1755. 

Al-Taiar A, Jaffar S, Assabri A, Al-Habori M, 

Azazy A, A-Mahdi N, Ameen K, Greenwood B 

M and Whitty C J M. 2006. Severe malaria in 

children in Yemen: two site observational study. 

British Medical Journal, 333:827-830A. 

Al-Taiar A, Jaffar S, Assabri A, Al-Habori M, 

Azazy A, Al-Gabri A, Al-Ganadi M, Attal B and 

Whitty C J M. 2008. Who develops severe malaria 

Impact of access to healthcare, socio-economic and 

environmental factors on children in Yemen: a casecontrol 

study. Tropical Medicine & International 

Health, 13:762-770. 

Alexander N, Sutherland C, Roper C, Cisse B 

and Schellenberg D. 2007. Modelling the impact 

of intermittent preventive treatment for malaria 

on selection pressure for drug resistance. Malaria 

Journal, 6. 

Alifrangis M, Dalgaard M B, Lusingu J P, 

Vestergaard L S, Staalsoe T, Jensen A T R, Enevold 

A, Ronn A M, Khalil I F, Warhurst D C, Lemnge 

M M, Theander T G and Bygbjerg I C. 2006. 

Occurrence of the southeast Asian/south American 

SVMNT haplotype of the chloroquine-resistance 

transporter gene in Plasmodium falciparum in 

Tanzania. Journal of Infectious Diseases, 193:1738- 

1741. 

Amewu R, Stachulski A V, Ward S A, Berry N G, 

Bray P G, Davies J, Labat G, Vivas L and O’Neill 

P M. 2006. Design and synthesis of orally active 

dispiro 1,2,4,5-tetraoxanes; synthetic antimalarials 

with superior activity to artemisinin. Organic & 

Biomolecular Chemistry, 4:4431-4436. 

Anders K, Marchant T, Chambo P, Mapunda 

P and Reyburn H. 2008. Timing of intermittent 

preventive treatment for malaria during pregnancy 

and the implications of current policy on early 

uptake in north-east Tanzania. Malaria Journal, 7. 

Anthony T G, Polley S D, Vogler A P and Conway 

D J. 2007. Evidence of non-neutral polymorphism 

in Plasmodium falciparum gamete surface 

protein genes Pfs47 and Pfs48/45. Molecular and 

Biochemical Parasitology, 156:117-123. 

Anyona S B, Hunja C W, Kifude C M, Polhemus 

M E, Heppner D G, Leach A, Lievens M, Ballou 

R, Cohen J, Sutherland C and Waitumbi J N. 

2007. Impact of RTS,S/AS02A and RTS,S/AS01B 

on multiplicity of infections and CSP t-cell epitopes 

of Plasmodium falciparum in adults participating in 

a malaria vaccine clinical trial. American Journal of 

Tropical Medicine and Hygiene, 77:166-166. 

Atkinson S H, Mwangi T W, Uyoga S M, Ogada 

E, Macharia A W, Marsh K, Prentice A M 

and Williams T N. 2007. The haptoglobin 2-2 

genotype is associated with a reduced incidence 

of Plasmodium falciparum malaria in children on 

the coast of Kenya. Clinical Infectious Diseases, 

44:802-809. 

Atkinson S H, Rockett K, Sirugo G, Bejon P A, 

Fulford A, O’Connell M A, Bailey R, Kwiatkowski 

D P and Prentice A M. 2006. Seasonal childhood 

anaemia in West Africa is associated with the 

haptoglobin 2-2 genotype. Plos Medicine, 3:652- 

658. 

Attaran A, Barnes K I, Bate R, Binka F, 

d’Alessandro U, Fanello C I, Garrett L, 

Mutabingwa T K, Roberts D, Sibley C H, 

Talisuna A, Van Geertruyden J P and Watkins 

W M. 2006. The World Bank: false financial and 

statistical accounts and medical malpractice in 

malaria treatment. Lancet, 368:247-252. 

Barnes K I, Little F, Mabuza A, Mngomezulu 

N, Govere J, Durrheim D, Roper C, Watkins B 

and White N J. 2008. Increased gametocytemia 

after treatment: An early parasitological indicator of 

emerging sulfadoxine-pyrimethamine resistance in 

falciparum malaria. Journal of Infectious Diseases, 

197:1605-1613. 

Bauer H, Fritz-Wolf K, Winzer A, Kuhner S, 

Little S, Yardley V, Vezin H, Palfey B, Schirmer 

R H and Davioud-Charvet E. 2006. A fluoro 

analogue of the menadione derivative 6-[2 ‘-(3 

‘-methyl)-1 ‘,4 ‘-naphthoquinolyl]hexanoic acid is 

a suicide substrate of glutathione reductase. Crystal 

structure of the alkylated human enzyme. Journal of 

the American Chemical Society, 128:10784-10794. 

Behrens R H, Bisoffi Z, Bjorkman A, Gascon J, 

Hatz C, Jelinek T, Legros F, Muhlberger N and 

Voltersvik P. 2006. Malaria prophylaxis policy for 

travellers from Europe to the Indian Sub Continent. 

Malaria Journal, 5. 

Behrens R H, Carroll B, Beran J, Bouchaud 

O, Hellgren U, Hatz C, Jelinek T, Legros F, 

Muhlberger N, Myrvang B, Siikamaki H and 

Visser L. 2007. The low and declining risk of 

malaria in travellers to Latin America: is there 

still an indication for chemoprophylaxis Malaria 

Journal, 6. 

Bejon P, Mwacharo J, Kai O, Mwangi T, Milligan 

P, Todryk S, Keating S, Lang T, Lowe B, Gikonyo 

C, Molyneux C, Fegan G, Gilbert S C, Peshu 

N, Marsh K and Hill A V S. 2006. A phase 2b 

randomised trial of the candidate malaria vaccines 

FP9 ME-TRAP and MVA ME-TRAP among 

children in Kenya. Plos Clinical Trials, 1. 

Bejon P, Ogada E, Mwangi T, Milligan P, Lang 

T, Fegan G, Gilbert S C, Peshu N, Marsh K and 

Hill A V S. 2007. Extended follow-up following a 

phase 2b randomized trial of the candidate malaria 

vaccines FP9 ME-TRAP and MVA ME-TRAP 

among children in Kenya. Plos Clinical Trials, 2. 

Bhutta Z A, Ahmed T, Black R E, Cousens S, 

Dewey K, Giugliani E, Haider B A, Kirkwood B, 

Morris S S, Sachdev H P S and Shekar M. 2008. 

Maternal and Child Undernutrition 3 - What works 

Interventions for maternal and child undernutrition 

and survival. Lancet, 371:417-440. 

Billingsley P F, Baird J, Mitchell J A and Drakeley 

C. 2006. Immune interactions between mosquitoes 

and their hosts. Parasite Immunology, 28:143-153. 

Biran A, Smith L, Lines J, Ensink J and Cameron 

M. 2007. Smoke and malaria: are interventions to 

reduce exposure to indoor air pollution likely to 

increase exposure to mosquitoes Transactions of 

the Royal Society of Tropical Medicine and Hygiene, 

101:1065-1071. 

Blackie M A L, Beagley P, Croft S L, Kendrick H, 

Moss J R and Chibale K. 2007. Metallocene-based 

antimalarials: An exploration into the influence of 

the ferrocenyl moiety on in vitro antimalarial activity 

in chloroquine-sensitive and chloroquine-resistant 

strains of Plasmodium falciparum. Bioorganic & 

Medicinal Chemistry, 15:6510-6516. 

Bogh C, Lindsay S W, Clarke S E, Dean A, Jawara 

M, Pinder M and Thomas C J. 2007. High spatial 

resolution mapping of malaria transmission risk in 

The Gambia, West Africa, using landsat TM satellite 

imagery. American Journal of Tropical Medicine 


Bonnet M, Roper C, Felix M, Coulibaly L, 

Kankolongo G M and Guthmann J P. 2007. 

Efficacy of antimalarial treatment in Guinea: in 

vivo study of two artemisinin combination therapies 

in Dabola and molecular markers of resistance 

to sulphadoxine-pyrimethamine in N’Zerekore. 


Boulanger D, Dieng Y, Cisse B, Remoue F, 

Capuano F, Dieme J L, Ndiaye T, Sokhna C, 

Trape J F, Greenwood B and Simondon F. 2007. 

Antischistosomal efficacy of artesunate combination 

therapies administered as curative treatments for 

malaria attacks. Transactions of the Royal Society of 


Bousema J T, Drakeley C J, Kihonda J, Hendriks 

J C M, Akim N I J, Roeffen W and Sauerwein R 

W. 2007. A longitudinal study of immune responses 

to Plasmodium falciparum sexual stage antigens in 

Tanzanian adults. Parasite Immunology, 29:309- 



79 

317. 

Bousema J T, Drakeley C J, Mens P F, Arens T, 

Houben R, Omar S A, Gouagna L C, Schallig H 

and Sauerwein R W. 2008. Increased Plasmodium 

falciparum gametocyte production in mixed 

infections with P. malariae. American Journal of 


Bousema J T, Schneider P, Gouagna L C, Drakeley 

C J, Tostmann A, Houben R, Githure J I, Ord 

R, Sutherland C J, Omar S A and Sauerwein 

R W. 2006. Moderate effect of artemisinin-based 

combination therapy on transmission of Plasmodium 

falciparum. Journal of Infectious Diseases, 

193:1151-1159. 

Bousema J T, Schneider P, Gouagna L C, Drakeley 

C J, Tostmann A, Houben R, Sutherland C J, 

Omar S A and Sauerwein R W. 2006. Moderate 

effect of artemisinin-based combination therapy on 

transmission of Plasmodium falciparum. European 

Journal of Epidemiology, 21:32-32. 

Bousema T, Shekalaghe S, Drakeley C 

and Sauerwein R. 2007. Primaquine clears 

submicroscopic Plasmodium falciparum gametocytes 

that persist after treatment with sulphadoxinepyrimethamine 

and artesunate. Tropical Medicine & 

International Health, 12:101-101. 

Bray P G, Mungthin M, Hastings I M, Biagini 

G A, Saidu D K, Lakshmanan V, Johnson D J, 

Hughes R H, Stocks P A, O’Neill P M, Fidock D 

A, Warhurst D C and Ward S A. 2006. PfCRT 

and the trans-vacuolar proton electrochemical 

gradient: regulating the access of chloroquine to 

ferriprotoporphyrin IX. Molecular Microbiology, 

62:238-251. 

Brooker S, Akhwale W, Pullan R, Estambale 

B, Clarke S E, Snow R W and Hotez P J. 2007. 

Epidemiology of plasmodium-helminth co-infection 

in Africa: Populations at risk, potential impact 

on anemia, and prospects for combining control. 

American Journal of Tropical Medicine and 

Hygiene, 77:88-98. 

Brooker S, Clarke S, Snow R W and Bundy D A 

P. 2008. Malaria in African schoolchildren: options 

for control. Transactions of the Royal Society of 


Brooker S, Clements A C A, Hotez P J, Hay S I, 

Tatem A J, Bundy D A P and Snow R W. 2006. 

The co-distribution of Plasmodium falciparum and 

hookworm among African schoolchildren. Malaria 

Journal, 5. 

Brooker S, Leslie T, Kolaczinski K, Mohsen 

E, Mehboob N, Saleheen S, Khudonazarov 

J, Freeman T, Clements A, Rowland M and 

Kolaczinski J. 2006. Spatial epidemiology 

of Plasmodium vivax, Afghanistan. Emerging 

Infectious Diseases, 12:1600-1602. 

Bukirwa H, Yeka A, Kamya M R, Talisuna A, 

Banek K, Bakyaita N, Rwakimari J B, Rosenthal 

P J, Wabwire-Mangen F, Dorsey G and Staedke 

S G. 2006. Artemisinin combination therapies for 

treatment of uncomplicated malaria in Uganda. 

PLoS Clin Trials, 1:e7. 

Cairns M, Carneiro I, Milligan P, Owusu- 

Agyei S, Awine T, Gosling R, Greenwood B and 

Chandramohan D. 2008. Duration of protection 

against malaria and anaemia provided by intermittent 

preventive treatment in infants in Navrongo, Ghana. 

PLoS ONE, 3:e2227. 

Calleri G, Gobbi F, Behrens R H, Bisoffi Z, 

Bjorkman A, Castelli F, Gascon J, Grobusch M P, 

Jelinek T, Schmid M L, Niero M and Caramello 

P. 2007. Malaria chemoprophylaxis in VFRs: a 

study with the Delphi method. Tropical Medicine & 


Campbell-Lendrum D and Woodruff R. 2006. 

Comparative risk assessment of the burden of 

disease from climate change. Environmental Health 

Perspectives, 114:1935-1941. 

Carneiro I A, Drakeley C J, Owusu-Agyei S, 

Mmbando B and Chandramohan D. 2007. 

Haemoglobin and haematocrit: is the threefold 

conversion valid for assessing anaemia in malariaendemic 

settings Malaria Journal, 6. 

Carneiro I A, Smith T, Lusingu J P A, Malima 

R, Utzinger J and Drakeley C J. 2006. Modeling 

the relationship between the population prevalence 

of Plasmodium falciparum malaria and anemia. 



Carter V, Shimizu S, Arai M and Dessens J T. 

2008. PbSR is synthesized in macrogametocytes and 

involved in formation of the malaria crystalloids. 

Molecular Microbiology, 68:1560-1569. 

Casimiro E, Calheiros J, Santos F D and Kovats 

S. 2006. National assessment of human health 

effects of climate change in Portugal: Approach and 

key findings. Environmental Health Perspectives, 

114:1950-1956. 

Chandler C I, Chonya S, Boniface G, Juma K, 

Reyburn H and Whitty C J. 2008. The importance 

of context in malaria diagnosis and treatment 

decisions - a quantitative analysis of observed clinical 

encounters in Tanzania. Trop Med Int Health. 

Chandler C I R, Drakeley C J, Reyburn H and 

Carneiro I. 2006. The effect of altitude on parasite 

density case definitions for malaria in northeastern 

Tanzania. Tropical Medicine & International Health, 

11:1178-1184. 

Chandler C I R, Jones C, Boniface G, Juma K, 

Reyburn H and Whitty C J M. 2008. Guidelines 

and mindlines: Why do clinical staff over-diagnose 

malaria in Tanzania A qualitative study. Malaria 

Journal, 7. 

Chandler C I R, Mwangi R, Mbakilwa H, Olomi 

R, Whitty C J M and Reyburn H. 2008. Malaria 

overdiagnosis: is patient pressure the problem. 

Health Policy and Planning, 23:170-178. 

Chandramohan D, Webster J, Smith L, Awine 

T, Owusu-Agyei S and Carneiro I. 2007. Is 

the Expanded Programme on Immunisation the 

most appropriate delivery system for intermittent 

preventive treatment of malaria in West Africa 

Tropical Medicine & International Health, 12:743- 

750. 

Checchi F, Cox J, Balkan S, Tamrat A, Priotto 

G, Alberti K P, Zurovac D and Guthmann J P. 

2006. Malaria epidemics and interventions, Kenya, 

Burundi, Southern Sudan, and Ethiopia, 1999-2004. 

Emerging Infectious Diseases, 12:1477-1485. 

Checchi F, Piola P, Fogg C, Bajunirwe F, Biraro S, 

Grandesso F, Ruzagira E, Babigumira J, Kigozi 

I, Kiguli J, Kyomuhendo J, Ferradini L, Taylor 

W R J and Guthmann J P. 2006. Supervised 

versus unsupervised antimalarial treatment with 

six-dose artemether-lumefantrine: pharmacokinetic 

and dosage-related findings from a clinical trial in 

Uganda. Malaria Journal, 5. 

Checkley A M and Hill D R. 2007. Prevention 

of malaria in long-term travelers. Trends in 

Parasitology, 23:462-465. 

Checkly A M and Whitty C J. 2007. Artesunate, 

artemether or quinine in severe Plasmodium 

falciparum malaria Expert Review of Anti-Infective 

Therapy, 5:199-204. 

Cheeseman I, Gomez-Escobar N, Carret C, Ivens 

A, Tetteh K, Stewart L and Conway D. 2008. 

A genome-wide survey of gene amplifications 

and deletions in laboratory and field isolates of 

Plasmodium falciparam. International Journal for 

Parasitology, 38:S69-S70. 

Cheung Y B, Jeffries D, Thomson A and Milligan 

P. 2008. A simple approach to test for interaction 

between intervention and an individual-level 

variable in community randomized trials. Tropical 

Medicine & International Health, 13:247-255. 

Chuma J, Gilson L and Molyneux C. 2007. 

Treatment-seeking behaviour, cost burdens and 

coping strategies among rural and urban households 

in Coastal Kenya: an equity analysis. Tropical 


Cisse B, Sokhna C, Boulanger D, Milet J, Ba 

E H, Richardson K, Hallett R, Sutherland C, 

Simondon K, Simondon F, Alexander N, Gaye 

O, Targett G, Lines J, Greenwood B and Trape J 

F. 2006. Seasonal intermittent preventive treatment 

with artesunate and sulfadoxine-pyrimethamine 

for prevention of malaria in Senegalese children: a 

randomised, placebo-controlled, double-blind trial. 

Lancet, 367:659-667. 

Cisse B, Sokhna C, Boulanger D, Milet J, Ba 

el H, Richardson K, Hallett R, Sutherland C, 

Simondon K, Simondon F, Alexander N, Gaye 

O, Targett G, Lines J, Greenwood B and Trape J 

F. 2006. Seasonal intermittent preventive treatment 

with artesunate and sulfadoxine-pyrimethamine 

for prevention of malaria in Senegalese children: a 

randomised, placebo-controlled, double-blind trial. 

Lancet, 367:659-667. 

Clark T D, Greenhouse B, Njama-Meya D, 

Nzarubara B, Maiteki-Sebuguzi C, Staedke S G, 

Seto E, Kamya M R, Rosenthal P J and Dorsey 

G. 2008. Factors Determining the Heterogeneity of 

Malaria Incidence in Children in Kampala, Uganda. 

J Infect Dis, 198:393-400. 

Clarke S E, Brooker S, Jukes M C, Njagi K, 

Khasakhala L, Otido J, Crudder C, McGlone B, 

Magnussen P and Estambale B. 2006. Randomised 

controlled trial of intermittent preventive treatment 

in schoolchildren: Impact on malaria, anaemia and 

school performance. American Journal of Tropical 

Medicine and Hygiene, 75:123-123. 

Clarke S E, Jukes M, Estambale B, Njagi K, 

Khasakhala L, Crudder C, Otido J, McGlone 

B, Magnussen P, Greenwood B and Brooker S. 

2007. Randomised controlled trial of intermittent 

preventive treatment in schoolchildren: impact on 

malaria, anaemia and school performance. Tropical 


Collinson A C, Ngom P T, Moore S E, Morgan 

G and Prentice A M. 2008. Birth season and 

environmental influences on blood leucocyte and 

lymphocyte subpopulations in rural Gambian 

infants. Bmc Immunology, 9. 

Conteh L, Stevens W and Wiseman V. 2007. The 


80 


role of communication between clients and health 

care providers: implications for adherence to malaria 

treatment in rural Gambia. Tropical Medicine & 


Conway D J. 2007. Molecular epidemiology of 

malaria. Clinical Microbiology Reviews, 20:188-+. 

Corbel V, N’Guessan R, Brengues C, Chandre F, 

Djogbenou L, Martin T, Akogbeto A, Hougard 

J M and Rowland M. 2007. Multiple insecticide 

resistance mechanisms in Anopheles gambiae and 

Culex quinquefasciatus from Benin, West Africa. 

Acta Tropica, 101:207-216. 

Corbel V, N’Guessan R, Brengues C, Chandre F, 

Djogbenou L, Martin T, Akogbeto M, Hougard 

J M and Rowland M. 2007. Multiple insecticide 

resistance mechanisms in Anopheles gambiae and 

Culex quinquefasciatus from Benin (West Africa) 

and operational challenge for malaria vector 

control. American Journal of Tropical Medicine and 


Coro J, Atherton R, Little S, Wharton H, Yardley 

V, Alvarez A, Suarez M, Perez R and Rodriguez 

H. 2006. Alkyl-linked bis-THTT derivatives as 

potent in vitro trypanocidal agents. Bioorganic & 

Medicinal Chemistry Letters, 16:1312-1315. 

Corran P, Coleman P, Riley E and Drakeley 

C. 2007. Serology: a robust indicator of malaria 

transmission intensity Trends in Parasitology, 

23:575-582. 

Couper K N, Blount D G, de Souza J B, Suffia 

I, Belkaid Y and Riley E M. 2007. Incomplete 

depletion and rapid regeneration of Foxp3(+) 

regulatory T cells following anti-CD25 treatment 

in malaria-infected mice. Journal of Immunology, 

178:4136-4146. 

Couper K N, Blount D G, Hafalla J C R, van 

Rooijen N, de Souza J B and Riley E M. 2007. 

Macrophnge-mediated but gamma interferonindependent 

innate immune responses control the 

primary wave of Plasmodium yoelii parasitemia. 

Infection and Immunity, 75:5806-5818. 

Couper K N, Blount D G and Riley E M. 2008. 

IL-10: the master regulator of immunity to infection. 

J Immunol, 180:5771-5777. 

Couper K N, Blount D G, Wilson M S, Hafalla 

J C, Belkaid Y, Kamanaka M, Flavell R A, De 

Souza J B and Riley E M. 2008. IL-10 from CD4(+) 

CD25(-)Foxp3(-)CD127(-) adaptive regulatory T 

cells modulates parasite clearance and pathology 

during malaria infection. Plos Pathogens, 4. 

Cox-Singh J, Davis T M E, Lee K S, Shamsul 

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Tetteh K K A and Polley S D. 2007. Progress and 

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Todd J and Corran P. 2008. Statistical 

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Vivas L, Rattray L, Stewart L, Bongard E, 

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Vivas L, Rattray L, Stewart L B, Robinson B L, 

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Vyas S, Hanson K and Lines J. 2007. Investigating 

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Waka M, Hopkins R J, Glinwood R and Curtis 

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Walther M, Gomez-Escobar N, Deininger S, 

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Walther M, Woodruff J, Edele F, Jeffries D, 

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Warhurst D C. 2007. Understanding resistance to 

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R K, Madrid P B and Fivelman Q L. 2007. 

Activity of piperaquine and other 4-aminoquinoline 

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Wassmer S C, de Souza J B, Frere G, Candal F J, 

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Brabin B J. 2006. The impact of endemic and 

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90 

Malaria Centre Staff & Students 2006 - 07 

Department of Infectious and Tropical Diseases (ITD) 

Clinical Research Unit (CRU) 

Professor of International Health: 

Christopher Whitty Clin Epidemiology, HTD Consultant, Dir., Malaria Centre 

Professor of Tropical Medicine: 

Robin Bailey Clinical Epidemiology, HTD consultant 

Senior Lecturers: 

Ron Behrens Tropical and Travel Medicine, HTD Consultant 

Tom Doherty Tropical Medicine, HTD Consultant 

Sarah Staedke Clinical Epidemiologist 

Theonest Mutabingwa Clinical Trials- 

Lecturers: 

Harparkash Kaur Pharmacology 

Sara Atkinson Course Director: PGDip/MSc Infectious Diseases DBL 

Research Fellows: 

Dirk H. Mueller Health Economics & Health Systems 

Honorary Professor: 

Peter Chiodini HTD Consultant, Parasitologist 

Honorary Senior Lecturer: 

Paul Newton Tropical Medicine 

Honorary Lecturers: 

Evelyn Ansah 

Behzad Nadjm 

Administrative: 

Becky Wright Manager Malaria Centre 

Alexandra Miller Programme Manager, TARGETS Consortium 

Susan Sheedy Unit Administrator 

Research Degree Students: 

Clare Chandler The context of clinical decision making in hospitals in 

Northeast Tanzania 

Aldiouma Guindo G6PD Deficiency and its differential protection against 

malaria 

Penny Neave The determinants of malaria in the Nigerian and Ghanaian 

populations in London 

Sarah Staedke Evaluation of home-based management of fever in urban 

Ugandan children 

Harriet Mpairwe Does elimination or prevention of helminth infection lead 

to an association between socio-economic development and 

increased incidence of allergic conditions in young children 

Research Degree Theses submitted 2006-07: 

Evelyn Ansah The effect of reducing the direct cost of health care on health 

care utilization and health outcomes in Ghana: a randomised 

controlled trial 

Kalifa Bojang Chemoprophylaxis with sulfadoxinepyrimethamine to 

prevent morbidity in Gambian children treated for severe 

anaemia 

Pathogen Molecular Biology Unit (PMBU) 

Professor of Molecular Biology: 

John Kelly 

Readers: 

David Conway Molecular Biology 

David Baker 

Parasite Molecular Biology, Deputy Director Malaria Centre 


Cally Roper 

Molecular Population Genetics 

Johannes Dessens Molecular Genetics 

Lecturers: 

Kevin Tetteh Molecular Biology/Immunology 

Ipemida Adagu Molecular biology, Pharmacology 

Research Fellows & Research Assistants: 

Thomas Anthony Molecular Biology 

Quinton Fivelman Molecular Biology and Parasitology 

Louisa McRobert Parasitology 

Susana Nery 

Molecular Biology 

Debbie Nolder Molecular Biology 

Richard Pearce Molecular Biology 

Spencer Polley Molecular Biology 

Federica Verra Molecular Biology 

Jenny Spence Cell & Molecular biology 

Rosalynn Ord Molecular Biology 

Annie Tremp 

Victoria Carter 

Nikki DArcy Molecular Biology 

Hirva Pota 

Molecular Biology 

Lindsay Stewart Immunology 

Rebecca Plowden 

Christine Hopp Molecular Biology 

Honorary: 

David Warhurst Emeritus Professor of Protozoan Chemotherapy 


Ross Cummings Phosphodiesterases and their role in Plasmodium falciparum 

sexual differentiation and development 

Nancy Duah 

Factors controlling differences in human antibody isotype 

profiles to Plasmodium falciparum blood stage antigens and 

their effect in malaria infection 

Werner Leber Investigation of P. falciparum enzyme activating protein 

Inbarani Naidoo Temporal and spatial analysis of anti-malarial drug resistance 

in Africa 

Ian Cheeseman An analysis of gene deletion and copy number polymorphisms 

in clinical and in vitro cultured isolates of Plasmodium 

falciparum 

Claire Reynolds (Nee Swales) Sexual commitment and development of Plasmodium 

falciparum gametocytes in vitro 

Sadia Saeed 

Malarial studies 

Marta Staff 

The role of topoisomerase II in Plasmodium falciparum 

centromeres function 

Annie Tremp Functional characterization of a family of putative membrane 

skeleton proteins in Plasmodium 


Onome Akpogheneta Determinants of the longevity of antibody responses to 

Plasmodium falciparum antigens 

Watcharee Chokejindachai Rational approaches to identify parasite genetic 

determinants of severe malaria 

Cathy Taylor The role of two cyclic nucleotide phosphodiesterases in the 

sexual development of Plasmodium falciparum and Plasmodium 

berghei 

Gareth Weedall Applications of molecular evolutionary analyses of Plasmodium 

genomes to detect genes under natural selection 

Immunology Unit (IMM) 

Professor of Infectious Disease Immunology: 

Eleanor Riley Head of Immunology 

Professor of Parasitology: 

Simon Croft 


Chris Drakeley Epidemiology, Parasitology 

Colin Sutherland Genetics, Epidemiology 

Lecturers: 

Livia Vivas 

Parasitology 

Helena Helmby Immunology 

Research Fellows: 

Kevin Couper Immunology 

Julius Hafalla Immunology 

Rachel Hallett Molecular Epidemiology 

Georgina Humphreys Molecular Epidemiology 

Kirsty Newman Immunology 

Daniel Blount Immunology 

Reem Al-Torki Immunology 

Research Assistants/Technical staff: 

Emily Bongard Parasitology 

Elizabeth King Immunology 

Susan Little 

Immunology 

Anna Randall Immunology 

Tahmina Syeda Immunology 

Eloise Thompson Molecular Biology 

Rosalynn Ord Molecular Biology 

Carolyn Stanley Laboratory Manager 

Jackie Cook 

Immunology 

Denise Dekker Epidemiology 


Siobhan Renihan Unit Administrator 

Honorary: 

Geoffrey Targett Emeritus Prof. of Immunology of Parasitic Diseases, Prof. of 

Immunology and Protozoal Diseases, Deputy Director, GMP 

J. Brian de Souza Senior Lecturer in Immunology at UCL 

Patrick Corran Lecturer (secondment from NIBSC), Immunology, vaccines 

Siske Struik 

Research Fellow in Immunology 


Jackie Cook 

Serological indicators of malaria transmission 

Sabelo Dlamini In vitro analysis of Artemether-lumefantrine [AL] combination 

treatment on the survival and transmission of Plasmodium 

falciparum: the role of pfcrt and pfmdr1 mutations and 

their prevalence in malaria endemic regions of Swaziland 

Patrice Mimche Modulation of CD36 expression, PPARg activation and P. 

falciparum phagocytosis by different families of antimalarial 

drugs 

Olivia Finney Natural regulatory T cells in individuals exposed to P. falciparum 

in The Gambia 



91 

Department of Infectious and Tropical Diseases (ITD) 

Nahla Gadalla Gene expression studies of the drug-resistance-associated 

loci pfcrt and pfmdr1 in P. falciparum parasites from Sudanese 

patients treated for malaria 

Rachel Greig Role of immune regulation in susceptibility to murine 

celebral malaria 

Amir Horowitz Characterization of the human NK cell response to Plasmodium 

falciparum 

Jin Phang (Jimmy) Loh Malaria diagnostics development and assessment or transmission 

risk in Singapore 

Alphaxard Manjurano Musalika Identification of genes that regulate the immune 

response to malaria 

Lucy Okell 

Modelling the potential impact of artemisinin combination 

therapies on malarial transmission intensity 

Maha Saeed 

Antigens on the surface of erythrocytes infected with Plasmodium 

falciaprum are targets of natural immune responses 

to malaria 

Samana Schwank Studies on the sex ratio of gametocytes in P. falciparum 

malaria 


Daniel Korbel Human natural killer cell response to Plasmodium falciparum 

malaria 

Brenda Okech The fine specificities of IgG responses to Plasmodium falciparum 

MSP119, a Malaria Vaccine Candidate 

Rosalynn Ord Genetic diversity of Merozoite surface antigens of Plasmodium 

vivax and Plasmodium falciparum co-circulating 

among the same hosts in the Venezuelan Amazon 

Sarah Sharp 

Expression of the var and stevor Multigene Families in 

Plasmodium falciparum Gametocytes 

Disease Control and Vector Biology Unit (DCVBU) 

Nigel Hill 

Entomology, Head of DCVBU 

Manson Professor of Clinical Tropical Medicine: 

Brian Greenwood 

Ross Professor of Tropical Hygiene (Emeritus): 

David Bradley 

Emeritus Professor of Medical Entomology: 

Chris Curtis 

Professor of Malaria and International Health: 

David Schellenberg 

Readers: 

Clive Davies Vector Control and Epidemiology 

Mark Rowland Medical Entomology and Epidemiology 

Jo Lines 

Malaria Control & Vector Biology 

Simon Brooker Epidemiology 

Daniel Chandramohan Epidemiology, Head of DCVBU 2006-7 


Hugh Reyburn Clinical Epidemiology 

Lorenz von Seidlein Clinical Epidemiology 

Lecturers: 

Tarekegn Abeku Epidemiology 

Ilona Carneiro Infectious Disease Epidemiology 

Sian Clarke 

Malaria Research and Control 

Jonathan Cox Epidemiology 

Caroline Jones Anthropology 

Francesco Checchi Epidemiology 

Badara Cisse Epidemiology 

Roly Gosling Clinical Epidemiology 

Jayne Webster Public Health in Developing Countries 

Research Fellows and Research Assistants: 

Stephanie Dellicour Epidemiology 

Caroline Maxwell Medical Entomology 

Wilfred Mbacham Molecular Biology 

Hadji Mponda Health Promotion 

Raphael NGuessan Entomology 

Seth Owusu-Agyei Epidemiology 

Arantxa Roca-Feltrer Epidemiology 

Amabelia Rodrigues Epidemiology 

Lucy Smith 

Epidemiology 

Francis Cox 

Patricia Aiyenuro Senior Insectary manager/ medical entomologist 

Technical Staff: 

Mojca Kristan Medical Entomology 

Alison Yates 

Entomology 

Patricia Aiyenuro Entomology 

Lucy Smith 

Epidemiology 


Suzanne Welsh 

Mary Marimootoo 

Administrator, TARGETS Consortium 

Unit administrator 

James Beard 

Computing/data manager 

Amit Bhasin 

GMP Manager 

Kate Jackson IVCC Administrator 

Jo Moore 

IVCC Manager 

Karen Slater 

PA to Brian Greenwood 

Honorary Professor: 

Frank Cox 

Parasitology 

Honorary Lecturer: 

Caterina Fanello Epidemiology 

Honorary: 

Paul Coleman Epidemiology/Modelling 

Jan Kolaczinski Entomology 

Sylvia Meek 

Malaria Control Specialist, Director, Malaria Consortium 


Adama Demba Management of childhood illnesses: the role of traditional 

healers in promoting family and community practices 

Ana Franco 

Effects of livestock ownership and insecticide treatment on 

the risk of human malaria: A case-control study in Ethiopia 

Natasha Howard Malaria epidemiology and cost-effectiveness issues in 

refugee camps in Pakistan and villages in Afghanistan 

(1995-2005) 

Toby Leslie 

New treatments for vivax malaria and anthroponotic cutaneous 

leishmaniasis in Pakistan and Kabul, Afghanistan 

Caroline Lynch How important is imported malaria in highland areas 

Robert Malima Insecticide resistance in mosquitoes in Northern Tanzania 

and studies on the effectiveness of insecticide treated nets 

and materials 

Jenny Stevenson Use of fungi against adult malaria mosquitoes [MRC CRF] 

Kwaku Poko Asante Malaria in pregnancy and infants 

Raymund (Matthew) Chico Randomised clinical trial to establish the safety, 

efficacy and tolerability of alternative antimalarial drugs to 

replace sulphadoxine-pyrimethamine for use in preventative 

treatment of malaria in pregnancy in Rwanda 

Roly Gosling Community interventions to reduce anaemia in children in a 

malaria endemic area of East Africa 

Alexandra Hiscox Moniotring effects of Nam Theun 2 hydroelectric project 

on local mosquito vector populations with an aim to reduce 

potential public health impact 

Devanand (Patrick) Moonasar Evaluating the performance and usage of ICT 

P.f. Malaria Rapid Diagnostic Test, in the Limpopo South 

Afirca 

Abraham Oduro Evaluating different indices for monitoring temporal and 

spatial changes in malaria transmission and disease in The 

Gambia 

Richard Oxborough Evaluation of novel insecticides for public health. 

Rachel Pullan Micro-epidemiology of multiple species infection: exploring 

patterns, determinants and health impacts of polyparasitism 

in rural communities 

Arantxa Roca Feltrer Estimating the burden of malaria-related morbidity in under 

fives in sub-Saharan Africa 

Wolf-Peter Schmidt Sampling Strategies for Measuring the Longitudinal Prevalence 

of Recurrent Infections 

Hugh Sturrock Epidemiology and control of neglected tropical diseases 

Patrick Tungu Evaluation of new insecticide and long lasting treatment 

for nets, residual sprays and other materials used in vector 

control and personal protection 

Beatrice Wasunna Evaluating a programme aimed at changing fever treatment 

seeking behaviours in Bondo district, Kenya 

Alison Yates 

Investigation of insecticide bioassy testing technique for 

mosquito control compounds on nets and other surfaces 


Christine Clerk Efficacy of Sulphadoxine-pyrimethamine and Amoiaquine 

alone or in combination as Intermittent Preventative Treatments 

in pregnancy in the Kassena-Nankana district of 

Ghana: a randomised controlled trial 

Kate Graham Malaria Control in Complex Emergencies: Appropriate Tools 

for the Acute and Post-Emergency Phases 

Margaret Kweku Impact of intermittant preventative treament in children 

(IPTc) with amodiaquine (AQ) plus artesunat (AS) versus 

sulphadoxine-pyrimethamine (SP) alone on haemoglobin 

levels and malaria morbidity in the Hohoe district of Ghana 

Annemarie ter Veen The determinants of Malaria transmission in the United 

States between 1900 and 1946 


92 


Department of Epidemiology & Population 

Health (EPH) 

Medical Statistics Unit (MSU) 

Hilary Watt 

Nutrition and Public Health Interventions Research 

Unit (NPHIRU) 

Lecturers: 

Sharon Cox 

Nutrition 

Andrew Prentice 

Infectious Disease Epidemiology Unit (IDEU) 

Professor of Tropical Epidemiology: 

Peter Smith 

Professor of Epidemiology & Medical Statistics: 

Simon Cousens 

Reader in Infectious Disease Modelling: 

Azra Ghani 

Readers: 

Paul Milligan Epidemiology & Medical Statistics 

Neal Alexander Medical Statistics and Epidemiology 

Joanna Schellenberg Epidemiology & International Health 


Immo Kleinschmidt Medical Statistics and Epidemiology 

Lecturers: 

Greg Fegan 

Babis Sismanidis 

Research Fellows & Research Assistants: 

Joao Filipe 

Infectious Disease Modelling 

Dongmei Liu Medical Statistics 

Bonnie McGlone Medical Statistics 

Honorary: 

Fred Binka 

Professor 


Anita Ghansah Haemoglobin C as a model for haplotype based analysis 

of studies of disease association and recent positive 

selection in Ghana 

Lucy Okell 

Mathematical models of interventions to reduce malaria 

transmission 

Matthew Cairns Impact of Intermittent Preventive Treatment 

Health Protection Agency/ 

Malaria Reference Laboratory 

Peter Chiodini 

Colin Sutherland 

Christopher Whitty 

Debbie Nolder 

Marie Blaze 

Val Smith 

Director 

Senior Lecturer/Hon Clinical Scientist: 

Consultant Epidemiologist 

Biomedical Scientist 

Advisory 

Advisory 

Department of Public Health & Policy (PHP) 

Anne Mills 

Health Policy Unit (PHU) 

Head of PHP and Professor of Health Economics and 

Policy 


Wenzel Geissler Anthropology 

Robert Pool 

Anthropology 

Kara Hanson Health Economics 

Virginia Wiseman Health Economics 

Lecturers: 

Catherine Goodman Health Economics 

Natasha Palmer Health Economics 

Lesong Conteh Health Economics 

Tanya Marchant Epidemiology 

Jo Mulligan 

Health Economics 

Research Fellows and Research Assistants: 

Catherine Montgomery Anthropology 

Lindsay Mangham Health Economics 

Dirk H. Mueller Health Economics & Health Systems 


Nicola Lord 

Coordinator - HEFP 

Honorary Research Fellow: 

Obinna Onwujekwe Health Economics 

Honorary Lecturer: 

Shunmay Yeung 


Ann Kelly 

Anthropological study of anti-malarial mosquito control 

in The Gambia and Tanzania 

Maurice Kongongo Studying illnesses in the context of local cultures: An 

ethnographic study of severe infant malaria and other 

illnesses in Tanga District, Tanzania 

Yoel Lubell 

An economic evaluation of case management strategies 

for malaria suspected patients in the age of ACT 

Hadji Mponda Mechanisms for targeted delivery of ITNs in Tanzania 

and their effectiveness in reaching the poor 

Adiel Mushi 

Assessment of factors influencing acceptability of IPT 

in southern Tanzania 

Edith Patouillar An economic analysis of the retail supply chain for 

malaria treatment 


Pa Lamin Beyai Moving towards more relevant measurement of indirect 

costs in economic evaluation: evaluation of Sulphadoxine- 

Pyrimethamine (SP) as Intermittent Preventive 

Treatment (IPT) for multigravidae in rural Gambia 

Lesong Conteh Investigating the Role and Measurement of Perceived 

Quality in the Demand for Malaria Treatment 

Fred Matovu Equity in Malaria treatment and Prevention: An Analysis 

of the Socioeconomic Dimension in Tanga District, 

Tanzania 

Shunmay Yeung Antimalarial drug resistance and artemisinin based 

combination therapy: A bio-economic model for elucidating 

policy choices 

Contact information 

Email addresses for LSHTM staff and students is in the format: 

firstname.lastname@lshtm.ac.uk 


Dr Becky Wright 

Tel. +44 (0)20 7927 2295 

Fax. +44 (0)20 7637 4314 

E-mail: malaria@lshtm.ac.uk 

Website: www.lshtm.ac.uk/malaria 

HPA Malaria Reference Laboratory 

London School of Hygiene and Tropical Medicine 

Keppel Street 

LondonWC1E 7HT 

Website: www.malaria-reference.co.uk/ 

Autumn view of LSHTM building from GowerStreet 

Hospital for Tropical Diseases 

Mortimer Market, 

Capper Street, 

London WC1E 6AU 

Telephone: 0845 155 5000 or 020 7387 4411 

Travel Clinic appointments: 0207 388 9600 

Website: www.thehtd.org 


Abbreviations 

93 

AMANET......... The African Malaria Network Trust 

ANC ................ Antenatal Clinic 

APPMG ............ All Party Parliamentary Malaria Group 

ARI .................. Acute Respiratory Infection 

BHIA .............. B-haematin inhibitory activity 

CDC ................. Centres for Disease Control, USA 

CM ................... Cerebral Malaria 

CNRFP ............. Centre National de Recehrche et Formation sur le 

Paludisme 

CNRS .............. Centre National de la Recherche Scientifique 

CNV ................ Copy Number Variation 

DeMTAP .......... The Demand for Malaria Treatment and Prevention 

DIFD ............... Department for International Development 

DRWG ............. Drug Resistance Working Group 

ECHO .............. European Commission Office of Humanitarian Aid 

EDCTP ............. European and Developing Countries Clinical Trials 

Partnership 

EIR ................... Entomological Inoculation Rate 

EPI ................... Expanded Programme on Immunisation 

ESRC................ The Economic and Social Research Council 

EU .................... European Union 

FGD ................. Focus Group Discussion 

FIND ................ Foundation for Innovative New Diagnostics 

G6PD................ glucose-5-phosphate dehydrogenase 

GCP ................. Good Clinical Practice 

GFATM ............ Global Fund to Fight AIDS, Tuberculosis and Malaria 

GMP ................. Gates Malaria Programme 

GSK ................. GlaxoSmithKlein 

Hb .................... Haemoglobin 

HBMF .............. Home-Based Management of Fever 

Hct ................... Haematocrit 

HTD ................. Hospital for Tropical Diseases 

IFAT ................ Immuno-Fluorescent Antibody Test 

IHRDC ............. Ifakara Health Research & Development Centre, 

Tanzania 

IMCI ................. The Integrated Management of Childhood Illness 

IMPACT-Tz ...... Interdisciplinary Monitoring Project for Antimalarial 

Combination Therapy in Tanzania 

IPTp,i,c,sc ........ Intermittent Preventive Treatment in pregnancy, infants, 

children, school children 

ITN .................. Insecticide-Treated Nets 

IVCC ................ The Innovative Vector Control Consortium 

KEMRI ............ Kenya Medical Research Institute 

KHRC .............. Kintampo Health Research Centre 

LAR ................. Lipid Accumulation Ratio 

LLINs ............... Long-Lasting Insecticidal Nets 

LLITN .............. Long-Lasting Insecticide-Treated Nets 

LSTM ............... Liverpool School of Tropical Medicine 

MAM ............... Mobilise Against Malaria 

MBL ................ Molecular Biology Laboratories 

MCTA............... Malaria Clinical Trial Alliance 

MIM ................ The Multilateral Initiative on Malaria 

MMV ................ Medicines for Malaria Venture 

MRC ................ Medical Research Council (UK unless stated) 

MVI ................. Malaria Vaccine Initiative 

NFkB ................ nuclear factor-kappa B 

NHS ................. National Health Service (UK) 

NIH .................. National Institute of Health, USA 

NIMR .............. National Institute for Medical Research (UK unless 

stated) 

NTS ................. Non-Typhoidal Salmonella 

OR ................... Odds Ratio 

PAF ................... Population Attributable Fraction 

PATH ................ Program for Appropriate Technology in Health 

PE ..................... Parasitised Erythrocytes 

PPAR-g ............. Peroxisome Proliferator Activated Receptor 

PSI ................... Population Services International 

RBM ................ Roll Back Malaria 

RCT .................. Randomised Controlled Trial 

RDT .................. Rapid Diagnostic Test 

RR .................... Relative Risk 

SME ................ Small-Medium Enterprises 

TNVS .............. Tanzanian National Voucher Scheme 

UCSF ............... University of California, San Francisco 

HPAUK ............ Health Protection Agency UK 

UNDP ............... United Nations Development Programme 

UNICEF ........... The United Nations Children’s Fund 

USAID ............. United States Agency for International Development 

VAR ................. Vacuolar Accumulation Ratio 

WEHI .............. The Walter and Eliza Hall Institute of Medical Research 

WHO ................ World Health Organisation 

WHOPES ......... WHO Pesticide Evaluation Scheme 

WHO-TDR ....... WHO Special Programme for Research and Training in 

Tropical Diseases 

WIMM ............. Weatherall Institute of Molecular Medicine 


(antibiotic) ........ azithromycin 

ACT .................. Artemisinin Combination Therapy 

AL .................... artemether-lumefantrine (coartem) 

AP ..................... atovaquone / proguanil 

AQ .................... (4-aminoquinoline) amodiaquine 

AS (ART) ......... artesunate 

AS+CD ............. Artesunate + chlorproguanil-dapsone (currently 

withdrawn from use) 

CD .................... chlorproguanil-dapsone (lapdap) 

CQ .................... (4-aminoquinoline) chloroquine 

DHA ................. dihydroartemisinin 

DP ..................... dihydroartemisinin-piperaquine 

MQ .................. mefloquine 

MQ-AS ............. mefloquine plus artesunate 

P ....................... (bis 4-aminoquinoline) piperaquine 

PQ .................... primaquine 

Q ....................... quinine 

SP ..................... sulphadoxine-pyrimethamine 


Malaria Centre Retreat 2008, Clare College, Cambridge

Photograph of Mosquito Day at the Ross Institute, 20th August 1931. A tea party was held to celebrate the 34th 

anniversary of the day on which Sir Ronald Ross discovered the mosquito transmission of malaria. 

Image courtesy of the Ross Institute Collection, Library & Archive Service.

In memory of Prof. Chris Curtis, one of the leading entomologists 

of malaria, a great teacher and advocate for the 

disadvantaged in society. 

This shows Chris in typical pose, demonstrating mosquito 

feeding in Parliament.

Notes 

Edited by Becky Wright, Christopher Whitty, David Baker and Rebecca Tremain 

Designed by Becky Wright 

Printed by Greenford Printing Company Limited. 

Except where otherwise acknowledged, photographs taken by staff and students of LSHTM with 

subject’s consent.



Keppel Street 

London 

WC1E 7HT 

www.lshtm.ac.uk/malaria 

Tel: +44 (0) 20 7 636 2295 

Director: Prof. Christopher Whitty 

Deputy Director: Dr David Baker 

Manager: Dr Becky Wright 

Copies of this report may be obtained from the above website or address

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