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.

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

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?

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

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

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

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

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

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?

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

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

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.

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.