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.,Hib - characteristics,Gram negative cocco-bacilli carried by 3% to 15% of young children in the world cau
2、ses disease in young children meningitis pneumonia epiglottitis septic arthritis,Hib disease,Industrialized countries 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, th
3、en 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 Unive
4、rsity of Melbourne,Study design,individually randomized, double blind study major effort to detect Hib pneumonia randomization in 10 groups numbered 0 through 9:,DTP + PRP-T,DTP + placebo,at 2, 3 and 4 months of age,5 numbers,5 numbers,Final results, March 1996 42,848 infants enrolled,PRP-T group 21
5、,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 w
6、all 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 o
7、bvious 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 arent Hib vaccines used everywhere?,Why are Hib vaccines not used all over the world?,cost varies, currently
8、 $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
9、 (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 proble
10、ms 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 ChinaConduct f
11、ield 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 vaccin
12、es. 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 onl
13、y 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 o
14、r 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 60 in children un
15、der 2 months Clinical pneumonia Severe pneumonia WHO defined ALRI (resp. rate 50 in under 1 yr, 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
16、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,All incidences are per 100,000 child-years,Pneumonia Outcomes,All incidences are per 100,000 child-years,Pneumonia Outcomes,All incidences are per 100,00
17、0 child-years,Meningitis Outcomes,All incidences are per 100,000 child-years,Meningitis Outcomes,Published rates of Hib meningitis (Children under 5 years per 100K person-years),Mortality rates are per 100,000 child-years,Mortality after at least 1 dose,Mortality rates are per 100,000 child-years,Mo
18、rtality after 3 doses,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 invasi
19、ve 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 radiolo
20、gical 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.,Gambia,Lombok,
