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For vaccine - GLOBE NETWORK

How to determine the effectiveness

of Hib and pneumococcal conjugate

vaccines in developing countries?

Kim Mulholland

London School of Hygiene and Tropical

Medicine, and Menzies School of Health

Research, Darwin


We know that pneumococcal

conjugate vaccines are effective ‐

• From RCT’s

– Nth California (PCV‐7, Prevnar®, Wyeth)

– Gambia (PCV‐9, Wyeth)

– S Africa (PCV‐9, Wyeth)

• From post‐introduction surveillance

– USA (PCV‐7, Prevnar®, Wyeth)

– UK, Canada, Australia, etc (PCV‐7, Prevnar®,

Wyeth)


But difficult questions have arisen…

• Uncertain disease burden

– Few data on pneumococcal disease burden in Asia

– Philippines 11‐v PCV trial

• No impact on clinical pneumonia

• Serotype replacement

– Wherever PCV’s introduced, carriage and disease

due to non‐vaccine types (NVT) ↑


But difficult questions have arisen…

• Uncertain disease burden

– Few data on pneumococcal disease burden in Asia

– Philippines 11‐v PCV trial

• No impact on clinical pneumonia

• Serotype replacement

– Wherever PCV’s introduced, carriage and disease

due to non‐vaccine types (NVT) ↑


Bohol study of PCV‐11

• 12,194 infants randomized (individually) to

receive PCV‐11 (Sanofi Pasteur, never

licensed) or placebo at 6, 10 and 14 weeks

• Radiological pneumonia

– PCV‐11 – 93

– Placebo – 120

• Clinical pneumonia

– PCV‐11 – 934

– Placebo ‐ 930

Vaccine efficacy 23%, N/S

Vaccine efficacy 0

PIDJ 2009;28:456-62


Lombok study of Hib vaccine (PRP‐T)

• 55,073 infants randomized (by hamlet) to

receive PRP‐T+DTP or DTP at 6, 10 and 14

weeks

• Radiological pneumonia (rate/1000

chld.years)

– PRPT – 9.4

– Control– 8.9

• Clinical pneumonia

– PRP‐T – 380

– Control ‐ 395

Vaccine efficacy


But difficult questions have arisen…

• Uncertain disease burden

– Few data on pneumococcal disease burden in Asia

– Philippines 11‐v PCV trial

• No impact on clinical pneumonia

• Serotype replacement

– Wherever PCV’s introduced, carriage and disease

due to non‐vaccine types (NVT) ↑


Invasive pneumococcal disease in Alaskan

natives – under 2 years

450

400

350

300

250

200

150

all disease

vaccine type

non-vaccine type

100

50

0

1995-2000 2001-2003 2004-2006

JAMA 2007;297:1784‐92


So the key questions are…

• How to establish the effectiveness of Pnc

vaccines in settings where the contribution of

Pnc to pneumonia burden is in doubt?

• How to detect declining effectiveness that

may be due to serotype replacement?


How to establish the effectiveness of

Pnc vaccines in settings where the

impact is in doubt?

• Before and after?

• Case control study?

• RCT?


Before and after…

• Need consistent and complete case

ascertainment

• Outcomes:

– Invasive pneumococcal disease

– Pneumonia

– Mortality

• Problems

– Viral epidemics

– Changing referral patterns


Cumulative incidence per 1000 population per year, hospitalised

radiologically confirmed pneumonia, by study year and age group,

NT Indigenous children, April 1997 – March 2005

70

60

1-11mths

12-23mths

24-59mths

All children

50

Rate per 1000 population

40

30

20

10

0

Apr97 - Mar98 Apr98 - Mar99 Apr99 - Mar00 Apr00 - Mar01 Apr01 - Mar02 Apr02 - Mar03 Apr03 - Mar04 Apr04 - Mar05

Study year

Data courtesy of Dr Kerry‐Ann O’Grady, Menzies School of Health Research, Darwin


ARI surveillance system

Viet Nam

Target population:

Paediatric cases admitted with ARIs: fast and/or difficulty in breathing

Catchment area: 16 communes of Nha Trang city(total 27 communes)

Khanh Hoa District

Clinical‐epidemiological data:

Demographic, clinical and management data

Sample:

Nasopharyngeal swab for Nucleic acid extraction

Others:

Chest Xray and blood sample

CXR: standardized by MiASoft, Ltd. (Faringdon, UK) radiology training modules.


Number of ARI/Pneumonia cases Nha Trang:

Jan 29th, 2007 to Jun 30th,2008: 1126 cases

Jan 2007 Jan 2008


Seasonal Prevalence of Major Pediatric Viral Respiratory Pathogens

60

Positive rate (%)

50

40

30

20

Rhino

RSV

Inf A

10

0

2007

Feb

2007

Mar

2007

April

2007

May

2007

June

2007

July

2007

Aug

2007

Sept

2007

Oct

2007

Nov

2007

Dec

2008

Jan

N=29 53 87 88 75 136 100 82 78 44 45 64 37 112

2008

Feb

2008

Mar

Slides courtesy of Dr Lay Myint, University of Nagasaki


Cumulative incidence per 1000 population per year, hospitalised

radiologically confirmed pneumonia, by study year and age group,

NT Indigenous children, April 1997 – March 2005

70

60

1-11mths

12-23mths

24-59mths

All children

50

Rate per 1000 population

40

30

20

10

0

Apr97 - Mar98 Apr98 - Mar99 Apr99 - Mar00 Apr00 - Mar01 Apr01 - Mar02 Apr02 - Mar03 Apr03 - Mar04 Apr04 - Mar05

Study year

Data courtesy of Dr Kerry‐Ann O’Grady, Menzies School of Health Research, Darwin


Before and after ‐ conclusions

• Under ideal conditions may be able to

produce plausible estimates of the impact of a

vaccine

For pneumonia and diarrhoea vaccines –

– Need to monitor all external factors, esp.

epidemics

– Very difficult to get convincing results unless the

effect is very big


Case control studies

• Provide estimate of VE, not vaccine impact

• Fundamental problem – vaccinated children have

different risk patterns to unvaccinated

– Especially for risk dependent conditions ‐ pneumonia

• Key questions:

– Are the cases being studied representative?

– Controls

• Community controls?

• Hospital controls?

• How many?

– How do we know the vaccination status of cases and

controls?


Community controls

• Usually match by neighbourhood or similar

– Hopefully risk of disease more or less similar,

apart from vaccination status

– Risk of overmatching (some villages all vaccinated)

• Main problem is access to care/careseeking

– Other community members may not use health

services in the same way

• Major practical on‐ground problems

– Persons inside do not open door

– No‐one home at houses with young children


Hospital controls

• Details of how selected usually not given

• Deal with the issue of access to care

• Chronic or recurrently hospitalized children?

• Malnutrition?

• Sometimes specify particular conditions:

– Pnc meningitis for Hib meningitis studies

– Gastroenteritis for pneumonia


Potential for bias

• Community controls

– Include non‐health care users

• Against vaccine

– Include “convenient” controls

For vaccine

• Hospital controls

– Include chronic, hospitalized patients

For vaccine

– Include malnourished children

• Against vaccine


Hib in Asia

• Perceptions among paediatricians:

– Hib meningitis not important in Asia

• Likely role of antibiotics in preventing meningitis

– Hib and Pnc may not contribute as much to

pneumonia as in Africa or the Pacific

• Becoming less important as vaccine price falls


Lau et al. Acta Paediatr 1995;84:173‐6

• 5 year study covering whole of Hong Kong

• service coverage and bacteriology good

• 57 cases detected:

– incidence of Hib meningitis 1.75/10 5 /year

– incidence of invasive Hib disease 2.67/10 5 /year

ie. lifetime risk 0.013%

(150 fold less than Africa)


Bacterial meningitis in Beijing Children’s Hospital, 1955-2000

DEATHS

60

50

40

30

20

10

0

NM outbreak

DEATHS

NM vaccination

ADMISSIONS

1955 1960 1965 1970 1975 1980 1985 1990 1995 2000

The past 35 years have seen a considerable decline in patient numbers and case

fatality (Previously unpublished data)

Data courtesy of Prof HK Yang

ADMISSIONS

2000

1800

1600

1400

1200

1000

800

600

400

200

0

year


An Effectiveness Trial of Hib Vaccine in

Bangladesh

• Objective:

– Determine proportion of pneumonia and meningitis in


Potential for bias

• Community controls

– Include non‐health care users

• Against vaccine

– Include “convenient” controls

For vaccine

• Hospital controls

– Include chronic, hospitalized patients

For vaccine

– Include malnourished children

• Against vaccine


How to establish the effectiveness of

Pnc vaccines in settings where the

impact is in doubt?

• Before and after?

• Case control study?

• RCT?


An RCT of a vaccine of proven efficacy

to determine the vaccine‐preventable

burden of disease? (“vaccine probe”)

• Ethical issues

• Financial issues

• Study quality


Lancet 2005;365:43‐52


Pneumonia results

Numbers of events in children less than 2 years

Outcome

Control

group

Hib vaccine

group

Clinical pneumonia 6179 6273

Any severe

932 975

pneumonia

Pneumonia

1651 1657

hospital admission

X-ray confirmed 330 361


Pneumonia results

Incidences per 100,000 child-years in children less than 2 years

Outcome

Control

group

Hib vaccine

group

Preventable

disease incidence

Clinical pneumonia 39,516 37,954 1,561 (270 – 2,853)

Any severe

5,460 5,196 264 (-101 - 629)

pneumonia

Pneumonia

4,518 4,345 -174 (-153 - 500)

hospital admission

X-ray confirmed 893 936 -43 (-185 - 98)

Fatal pneumonia 1020 954 66 (-126-259)


Meningitis results

Incidences per 100,000 child-years in children less than 2 years

Outcome

Control

group

Hib vaccine

group

Preventable

disease

incidence

Laboratory

19 2.6 16 (1.4 – 31)

confirmed Hib

Purulent bacterial 86 39 47 (13 – 81)

meningitis

All meningitis or 701 543 158 (42 – 273)

acute seizures*

Meningitis deaths 161 121 40 (-17 – 97)

* Many of these children were not admitted


Consider country X

• East Asia

• Moderate mortality, pneumonia a big problem

• Under pressure to introduce pneumococcal

vaccine

• Wary about

– IPD burden

– Burden of pneumonia due to Pnc

– Serotype issues

– Future cost of the vaccine

• Country needs better evidence


Phased introduction

• In part or all of the country

• Stage 1

– At least 30 administrative units randomized to receive

or not receive vaccine

– Annual analysis of pneumonia (and possibly mortality)

rates

• Compare rates of disease in vaccinated and unvaccinated

sectors

• Support with case control study

• Stage 2

– Introduce vaccine into other areas

– Consider introduction of second vaccine and continue

analysis


Phased introduction

• Risks

– May delay vaccine introduction

– Interim analyses may produce misleading results

– Measured effectiveness may decline later due to

serotype replacement

– Groups may be unbalanced with respect to:

• Risk of disease

• Access to health care


Phased introduction

• Advantages

– Real data for country and region

– Accurate cost‐effectiveness analysis

– What alternatives are there?

• Blind introduction?


What of serotype replacement?

• Options

– Ignore and hope for the best

– Monitor carriage patterns

– Monitor IPD in sentinel sites

– Monitor IPD in high risk groups

– Try to monitor impact on pneumonia rates


Monitoring IPD

• May indicate when replacement has

neutralized effectiveness (eg. Alaska)

• May miss this altogether

– Pnc serotypes vary with respect to:

• Disease patterns

• Probability of disease given carriage

• Probability of bacteraemia given disease

– In US replacement was identified because 19A

was dominant replacing serotype and quite likely

to cause bacteraemia


IPD in high risk groups

• Immunocompromised are more susceptible to

disease due to replacement serotypes

• Monitoring IPD in HIV+ may be a useful way of

monitoring replacement in settings with many

HIV+ cases (eg. S Africa)


• Hib

Conclusions

– Burden issues in Asia less important as vaccine is

becoming inexpensive

• Pneumococcal

– Burden issues important due to vaccine cost and

extra injection

– Monitoring effectiveness essential

• Case control studies and sentinel monitoring

of IPD alone is inadequate

• Monitoring for impact of replacement must

involve monitoring pneumonia rates

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