1. Haemophilus influenzae type b Using vaccines to measure disease burden: A Tale of Two Studies
Presentation to PABIO 550
Diseases of Public Health Importance and Their Control
David Mercer, Ph.D.

2. Hib - characteristics Gram negative cocco-bacilli
carried by 3% to 15% of young children in the world
causes disease in young children
meningitis
pneumonia
epiglottitis
septic arthritis

3. Hib disease Industrialized countries Developing countries (Africa)
median age 1-2 years
most meningitis then epiglottitis?
meningitis mortality under 5%
affects 1-2/1000 children
Developing countries (Africa)
median age 6-9 months
most pneumonia, then meningitis
meningitis mortality 20-50%
affects 10/1000 children?

5. Gambian PRP-T trial
42,000 infants randomized to receive PRP-T or placebo at 2, 3 and 4 months of age
population studied for:
Hib meningitis
Hib pneumonia
all pneumonia
Hib carriage
Gambia slides courtesy of Kim Mulholland, MD
University of Melbourne

6. Study design individually randomized, double blind study
major effort to detect Hib pneumonia
randomization in 10 groups numbered 0 through 9:
5 numbers
5 numbers
DTP + PRP-T
DTP + placebo
at 2, 3 and 4 months of age

7. Final results, March 1996 42,848 infants enrolled
PRP-T group
21,490 infants
1272 possible Hib disease
616 chest radiographs
173 lumbar punctures
71 lung aspirates
Control group
21,358 infants
1342 possible Hib disease
653 chest radiographs
192 lumbar punctures
75 lung aspirates

8. Did the vaccine actually prevent pneumonia?
*cough + fast breathing or lower chest wall indrawing

9. What did the Gambia trial tell us about the epidemiology of Hib pneumonia in West Africa?
Hib is responsible for about 20% of radiological pneumonia in Gambian infants
Previous studies had suggested 5-10% of pneumonia due to Hib
Very little “WHO pneumonia” which is not radiologically obvious is due to Hib

10. Conclusions
PRP-T effectively prevented meningitis and pneumonia due to Hib in The Gambia
Hib vaccines have been proven in Finland, USA, UK, Chile and other countries…
Why aren’t Hib vaccines used everywhere?

12. Why are Hib vaccines not used all over the world?
cost
varies, currently $2 per dose
affordable for most Asian countries
understanding of burden of disease is the major problem in Asia

13. Asia Many Asian countries can afford Hib vaccine
Hib was known to be an important cause of bacterial meningitis in Asia
But:
Microbiologically confirmed Hib incidence lower than elsewhere (<10/100,000/yr under 5)
Asian physicians believe that Hib disease and bacterial meningitis are not numerically important in Asia
Few pneumonia data from Asia

14. What is going on in Asia? Really similar to elsewhere but:
effect of antibiotics (making cultures negative)
problems with bacteriology
problems with epidemiology
Substantially lower than elsewhere because:
effect of antibiotics (chemical vaccination)
ethnic advantage
sociological factors

15. First Asian Hib Meeting – Bali 1996
Improve and intensify population-based microbiologic Hib surveillance in several sites
Thailand
Vietnam
China
Conduct field studies to examine the impact of vaccination on morbidity – indirectly measuring the amount of disease attributable to Hib
Lombok Vaccine ‘Probe’ Study

16. Lombok Vaccine Probe Study Design
Double blind, prospective, randomized, controlled ‘field trial’
818 hamlets randomized to receive one of two vaccines.
55,073 enrolled infants
Half received DTP and half received DTP-Hib during during routine Indonesian DTP immunization sessions.
Vaccine vials coded with one of four different colors.

17. Vaccine-preventable Hib disease incidence
Definition: (Incidencecontrols – IncidenceHib vaccine group)
Measures only incidence rate actually preventable by vaccine.
Does not require microbiological identification
Randomization controls for:
Cold chain
Vaccine coverage
Age at vaccination
Vaccine efficacy

18. Primary outcome of study
Radiologically confirmed pneumonia
Defined by WHO Trialists Group:
Obvious alveolar or lobar infiltrate or pleural effusion
Agreed upon by pediatrician and radiologist
With disagreement, WHO panel made final decision
Readings independent without reference to clinical findings

19. Secondary outcomes of study
Any infiltrate pneumonia
Severe pneumonia
Indrawing
Resp. rate ³ 60 in children under 2 months
Clinical pneumonia
WHO defined ALRI (resp. rate ³ 50 in under 1 yr, ³ 40 in 1-2yr
Meningitis
Confirmed Hib
Probable and possible bacterial (by CSF findings)
Hospital or clinic visit for seizures consistent with meningitis

20. Vaccination of children
Vaccination phase: December 1998 to September 2002
55,073 vaccinated
20 received > one color vaccine
Average age at enrollment (i.e., first vaccine plus 2 week delay): 13 weeks

21. Pneumonia Outcomes
All incidences are per 100,000 child-years

22. Pneumonia Outcomes
All incidences are per 100,000 child-years

23. Meningitis Outcomes
All incidences are per 100,000 child-years

24. Meningitis Outcomes
All incidences are per 100,000 child-years

25. Published rates of Hib meningitis
(Children under 5 years – per 100K person-years)

27. Mortality after at least 1 dose
Mortality rates are per 100,000 child-years

28. Mortality after 3 doses
Mortality rates are per 100,000 child-years

29. Conclusions
Hib vaccine not an effective intervention against ALRI (pneumonia) in Lombok
Hib meningitis burden underestimated by microbiology – true burden 10X greater
Hib vaccine may significantly reduce meningitis mortality
1 in 33 unvaccinated children on Lombok develop invasive Hib disease before age 2.

30. Comparison of Gambia and Lombok Results
Hib vaccine prevents about 20% of radiological pneumonia in Gambian infants
Very little “WHO pneumonia” which is not radiologically obvious is due to Hib
Protection conferred after 3rd dose
Hib vaccine prevents little to no radiological pneumonia in Lombok infants
The predominant pneumonia prevented by Hib vaccine is non-severe WHO pneumonia.
Protection conferred after first dose.
For every case of laboratory-diagnosed Hib disease on Lombok, there were 10 cases of Hib meningitis, and 100 cases of Hib pneumonia.