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Special issue: Molecular typing for public health purposes Perspectives O n-l i n e Gl O b a l /WHO-eu r O p e a n re G i O n a l Me a s l e s n u c l e O t i d e su r v e i l l a n c e S Gnaneshan (saravanamuttu.gnaneshan@hpa.org.uk) 1 , K E Brown 1 , J Green 1 , D W Brown 1 1. Centre for Infections, Health Protection Agency London, United Kingdom Measles virus causes an acute infection characterised by rash and fever. Measles infection is preventable by vaccination, but remains a significant cause of childhood mortality in the developing world with an estimated number of approximately 242,000 deaths by measles in 2006 [1]. The World Health Organization (WHO) is coordinating a global control programme for measles, and all WHO regions have identified targets for control or elimination of transmission of this disease. In the WHO European Region (WHO/Europe) the goal is to eliminate measles by 2010 [2]. Surveillance to document the elimination of transmission is in place, using case-based laboratory confirmation by detection of measles-specific IgM and by sequence characterisation of measles strains from outbreaks and chains of transmission. Measles virus is isolated and/or sequenced by the participating laboratories in the ‘Global Measles and Rubella Laboratory Network’ [3]. Following the success of HepSEQ [4], a public health database generated by the Centre for Infections of the United Kingdom Health Protection Agency, and a European Union-funded measles network called ‘Enhanced Laboratory Surveillance of Measles’ (ELSM) [5], we developed a web-based, quality-controlled database with epidemiological and nucleotide data for measles infection in the WHO/Europe region (MeaNS). The major objectives of the MeaNS initiative are to function as an epidemiological surveillance tool and to monitor progress of the measles control programme. Sequence data from the 450 nucleotide region encoding the C-terminal region of the measles virus nucleoprotein (N) and, optionally, the complete nucleotide sequence of the haemagglutinin (H) gene are deposited into MeaNS, together with epidemiological data. The data is quality checked and curated, first automatically by the database application and then manually by a curator. During the curation, specific identifiers called ‘WHO names’ [8] are created for each sample unless the names were provided by the depositors. In addition, the deposited sequences are assigned a genotype and a cluster identifying number by matching, respectively, against WHO reference sequences and the unique sequence clusters in the database. Dynamic reports and graphical charts can be created on any userselected fields in the MeaNS database (eg: genotype or sequence variation in a geographical location or time period). Relevant data can be exchanged between MeaNS and either GenBank or the WHO database on Surveillance of measles and rubella [6,7]. Bioinformatics tools in MeaNS allow one to find identical or similar sequences, assign a genotype, display phylogenetic trees, and to temporally and spatially track measles transmission chains. Regional laboratories from the European WHO Measles and Rubella Laboratory Network previewed the development of MeaNS, and the current release was well received. Further testing and development to enable uploading of sequence trace files and quality checking mechanisms are currently being undertaken, with an anticipated release for general use in mid-June 2008. The existing tools and the tools that are now being developed will be useful in the surveillance, sequence analysis, evolution, and genome annotation of measles. Currently, MeaNS is the only known publicly available global database on measles nucleotide sequences. After registering the purpose of their interest, researchers can access MeaNS at www. hpa-bioinformatics.org.uk/Measles/Public/Web_Front/main.php. References 1. Centers for Disease Control and Prevention. Progress in Global Measles Control and Mortality Reduction, 2000-2006. MMWR Morb Mortal Wkly Rep. 2007;56(47):1237-41. 2. World Health Organization Regional Office for Europe. Strategic plan for measles and congenital rubella infection in the European Region of WHO. Copenhagen; 2003. Accessed 23 April 2008. Available from: http://www.euro. who.int/document/e81567.pdf 3. Featherstone D, Brown D, Sanders R. Development of the Global Measles Laboratory Network. J Infect Dis. 2003;187(Suppl 1):S264-9. 4. Gnaneshan S, Ijaz S, Moran J, Ramsay M, Green J. HepSEQ: International Public Health Repository for Hepatitis B. Nucleic Acids Res. 2007;35(Database- Issue):D367-70. Accessed 23 April 2008. Available from: http://www. hepseqresearch.org 5. Enhanced Laboratory Surveillance of Measles [homepage on the Internet]. London: Health Protection Agency. Accessed 23 April 2008. Available from: http:// www.elsm.net/elsm/Enhanced_Laboratory_Surveillance_of_Measles.htm 6. World Health Organization Regional Office for Europe. Centralized information system for infectious diseases (CISID). Accessed 23 April 2008. Available from: http://data.euro.who.int/CISID/ 7. World Health Organization Regional Office for Europe. Surveillance of measles and rubella. Accessed 23 April 2008. Available from: http://data.euro.who.int/ DownloadArea/VPI/MEA/E200605_MeaslesPage.pdf 8. Expanded Programme on Immunization (EPI). Standardization of the nomenclature for describing the genetic characteristics of wild-type measles virus. Wkly Epidemiol Rec. 1998;73(35):265-9. This article was published on 8 May 2008. Citation style for this article: Gnaneshan S, Brown KE, Green J, Brown DW. On-line Global/WHO-European Regional Measles Nucleotide Surveillance. Euro Surveill. 2008;13(19):pii=18861. Available online: http://www.eurosurveillance.org/ViewArticle. aspx?ArticleId=18861 176 EUROSURVEILLANCE Vol. 13 · Issues 14–26 · Apr–Jun 2008 · www.eurosurveillance.org
Special issue: Molecular typing for public health purposes Perspectives H e pSeQ – a n In t e g r at e d He pat I t I S B ep I d e m I o l o g y a n d S e Q u e n c e an a ly S I S pl a t f o r m R Myers (richard.meyers@hpa.org.uk) 1 , S Gnaneshan 1 , S Ijaz 2 , R Tedder 2 , M Ramsay 3 , J Green 1 , HepSEQ Steering Committee 1. Bioinformatics Unit, Centre for Infections, Health Protection Agency, London, United Kingdom 2. Virus Reference Department, Centre for Infections, Health Protection Agency, London, United Kingdom 3. Immunisation Department, Centre for Infections, Health Protection Agency, London, United Kingdom Hepatitis B virus (HBV) is a major human pathogen. The outcome of acute hepatitis B is variable but usually followed by a complete recovery. A small proportion of infections in adults and a higher proportion of infections in early childhood continue in a chronically infected state in which the virus persists in the liver. Patients with chronic hepatitis B usually have no initial symptoms of infection, but over time the major disease sequelae, cirrhosis and hepatocellular carcinoma, can develop. It is estimated that some 350 million people worldwide are currently chronically infected with HBV, but many more will have been infected and recovered. HBV exists in its human host as eight clusters of viruses (genotypes A to H [1]), each cluster displaying a similarity of sequences and variable antigenicity (serotypes) [2]. Traditionally, HBV genotypes have a distinct geographical distribution, with genotypes A and D predominant in Europe, the Middle East and India, and genotypes B and C in Asia and the Far East. Genotype E is mainly found in West Africa, and genotypes F and H are associated with Central and South America. There is some evidence that different genotypes may be associated with alternative disease profiles and differing responses to antiviral therapy [3-5]. The influx of non-European HBV genotypes represents increasing population movement or migration and may have a significant effect on management of the disease within Europe. The mixing of genotypes within a European population may also promote increased genetic diversity within HBV (due to recombination), the epidemiological effects of which are impossible to predict. Therefore, surveillance of HBV genotypes is important within a national and a European context. HepSEQ (http://www.hepseqresearch.org) [6] is a freely accessible web resource for the public health aspects of HBV management, with specific focus on epidemiological, virological, clinical, nucleotide sequence and mutational aspects of HBV infection. HepSEQ is comprised of a relational database with a web-enabled interface, which allows inserting and retrieving epidemiological and sequenced-based information. The database currently contains 1,769 patient records from acute and chronic hepatitis B cases in the United Kingdom (UK) and 2,182 sequences, of which 1,679 cover the surface/polymerase region and 497 cover the X/pre-core/core region. The HepSEQ website also provides access to tools that predict the genotype and characterise the genetic polymorphisms of sequences entered by the user. The HBV genotyper tool assigns a genotype to an HBV sequence provided by the user. Sequence alignment and statistical modelling are used to ensure that predictions of the genotype are accurate. HepSEQ allows rapid and dynamic generation of genotypic data within the database and contains 43.6% A, 5.6% B, 12.4% C, 28.4% D and 9.3% E genotypes. The presence of approximately 20% non-A or non-D genotypes highlights the changing dynamic of HBV sequences within the UK and raises questions about the origins and transmission of these infections. The majority of countries in Europe have a low prevalence of chronic hepatitis B infection, and the acquisition of hepatitis B is often associated with medical interventions or with specific adult risk behaviour such as sex between men, injecting drug use. As HepSEQ contains information on viruses associated with acute hepatitis B infections, it has the potential to further highlight patterns of disease transmission. The database is currently being enriched by attempting to link in exposure categories so that viruses associated with different routes of transmission in the UK can be identified. This will help to identify the emergence of new variants in specific sub-populations and to evaluate the impact of control measures to reduce the incidence, and therefore the prevalence of specific variants, in these populations. Antiviral therapy targeting the reverse transcription function of polymerase is increasingly used in clinical practice to suppress viral replication. Six polymerase inhibitors have either been licensed or are in development for treatment of chronic hepatitis B: lamivudine, adefovir dipivoxil, entecavir, tenofovir, telbivudine and clevudine. Not surprisingly, long term use of mono or dual therapy in the face of continued replication is associated with viral mutational escape from the drug and this can be monitored by direct sequencing of the polymerase gene [7,8]. Additional variability in the genome has been shown to arise as a result of the natural emergence of strains which may have a selective advantage during the course of chronic HBV infection in a patient. These include pre-core mutants, deletions in the core gene, and mutations in the preS1 and pre S2 regions [9]. It is speculated that these variants are driven by the immune system but it currently remains unknown which, if any, are clinically significant. The necessity to recognise and interpret HBV anti-viral resistance mutations has driven the development of a mutation annotation tool within HepSEQ. This publicly available tool takes a polymerase nucleotide sequence as input, performs a genotype assignment and compares both the nucleotide and translated amino acid sequence EUROSURVEILLANCE Vol. 13 · Issues 14–26 · Apr–Jun 2008 · www.eurosurveillance.org 177
Page 1 and 2: EUROPEAN CENTRE FOR DISEASE PREVENT
Page 3 and 4: Special issue: World Hepatitis Day
Page 5 and 6: oth measles and mumps in certain ag
Page 7 and 8: to be done. Twenty-nine of the 53 c
Page 9 and 10: Editorial W o r l d He pat i t i s
Page 11 and 12: Editorials M o l e c u l a r t y p
Page 13 and 14: 5. Fooks A. Rabies remains a ‘neg
Page 15 and 16: Statistical analysis The antibody p
Page 17 and 18: mumps that we noticed between males
Page 19 and 20: Among the cases, 3,683 (61.8%) were
Page 21 and 22: [5] Given the periodicity of outbre
Page 23 and 24: sequences (GenBank NIH, Bethesda) p
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Page 31 and 32: No. of reported rubella cases Speci
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Page 35 and 36: From these discussions, and by test
Page 37 and 38: 15. Hæggman S, Rhod Larsen A, Vain
Page 39 and 40: Table 1 SeqNet.org participating me
Page 41 and 42: first line typing method, besides o
Page 45 and 46: criteria are combined, (iii) the or
Page 47: Retrospective surveillance data fro
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Page 55 and 56: Table Number of notifications of he
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Page 67 and 68: Table 1 Summary of hepatitis B surv
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Page 79 and 80: Table 1 Definitions of HCV infectio
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analysable fragment of 457 bp, and
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the application of HNIG to close co
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HCV co-infection was defined as pos
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[18] had been observed in HIV-HBV c
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Microbiological investigation All h
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References 1. American Public Healt
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Telephone calls are handled by a tw
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At that time, the daily monitoring
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Research articles S u r v e i l l a
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It has been suggested that longer d
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Virological data collection Stool s
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Discussion Our combined epidemiolog
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Acknowledgements We are grateful to
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The total study sample consisted of
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Table Multivariate model of associa
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Euroroundups S u r v e y o f eu r o
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event. The survey included question
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Laboratories report anonymised case
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8. European Union. Commission decis
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two females aged six years and 56 y
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Table 2 Salmonella infections with
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17. The Community Summary Report on
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the number of registered cases in E
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protected vaccinees annually) [6].
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Romania Risk of tick-borne encephal
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34. Pavlidou V, Geroy S, Diza E, An
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European Commission and the EU Memb
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10. Strauss R, Muchl R, Kunze M, Hr
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Existing monitoring efforts in Euro
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with existing efforts in influenza
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Obtaining a true picture of the bur
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of being too clean, concerns about
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single case of the disease while in
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Rapid communications E m E rg E n c
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Development and Food. More specific
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Rapid communications I n c r e a s
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immunity was high enough to prevent
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Control measures Information about
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• The importance of ensuring that
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Letters A u t h o r s r e p ly : pr
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UNITED KINGDOM England and Wales He
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