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1、Haemophilus influenzae type b Using vaccines to measure disease burden: A Tale of Two Studies Presentation to PABIO 550Diseases 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 caus

2、es 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, the

3、n 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 Univer

4、sity 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 + placeboat 2, 3 and 4 months of age5 numbers 5 numbers Final results, March 199642,848 infants enrolled PRP-T group 21,490

5、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? PRP-T controls vaccine efficacy episodes prev

6、ented WHO pneumonia* 526 570 8% 44 radiological pneumonia 132 170 22% 38 *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 Previ

7、ous 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

8、 Why arent 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 im

9、portant cause of bacterial meningitis in Asia But: Microbiologically confirmed Hib incidence lower than elsewhere ( one color vaccine Average age at enrollment (i.e., first vaccine plus 2 week delay): 13 weeks Outcome Prevented proportion Control group incidence Hib Vaccine group incidence Prevented

10、 Hib incidence (95% CI) -43 (-185 to 98) 52 (-194 to 298) 174 (-153 to 500) 264 (-101 to 629) 1561 (270 to 2,853) 1+ vaccine doses Radiologically confirmed -4.90% 893 936 Any infiltrate on chest radiology 1.90% 2,677 2,625 Hospitalized severe pneumonia 3.80% 4,518 4,345 Any severe pneumonia 4.80% 5,

11、460 5,196 Clinical pneumonia 4.00% 39,516 37,954All incidences are per 100,000 child-years Pneumonia Outcomes Outcome Prevented proportion Control group incidence Hib Vaccine group incidence Prevented Hib incidence (95% CI) -89 (-248 to 71) -36 (-322 to 249) -49 (-416 to 318) 6.9 (-401 to 415) 1,467

12、 (-60 to 2,994) 3 vaccine doses Radiologically confirmed -12.0% 770 859 Any infiltrate on chest radiology -1.5% 2,468 2,504 Hospitalized severe pneumonia -1.3% 3,906 3,955 Any severe pneumonia 0.15% 4,712 4,705 Clinical pneumonia 3.8% 38,226 36,759All incidences are per 100,000 child-years Pneumonia

13、 Outcomes Outcome Prevented proportion Control group incidence Hib vaccine group incidence Prevented Hib incidence (95% CI) 16 (1.4 to 31) 47 (13 to 81) 67 (22 to 112) 89 (10 to 167) 158 (42 to 273)Meningitis admission or clinic evaluation for seizures 22% 701 543 Lumbar punctures 26% 346 258 Possib

14、le bacterial (incl. conf. Hib) 50% 134 67 Probable bacterial (incl. conf. Hib) 55% 86 39 1+ vaccine doses Microbiologically confirmed Hib 86% 19 2.6 All incidences are per 100,000 child-years Meningitis Outcomes Outcome Prevented proportion Control group incidence Hib vaccine group incidence Prevent

15、ed Hib incidence (95% CI) 20 (-0.42 to 40) 45 (3.9 to 86) 74 (19 to 128) 52 (-41 to 144) 129 (-6.7 to 265) 3 vaccine doses Microbiologically confirmed Hib 84% 23 3.7 Probable bacterial (incl. conf. Hib) 57% 78 34 Possible bacterial (incl. conf. Hib) 54% 137 64 Lumbar punctures 16% 317 265 Meningitis

16、 admission or clinic evaluation for seizures 20% 656 527All incidences are per 100,000 child-years Meningitis Outcomes Region Country Rate North America U.S. 11 - 64 South America Brazil 5 - 44 Europe Iceland 43 Bulgaria 6.1 Africa Gambia 57 - 60 South Africa 34 Middle East Saudi Arabia 45 Kuwait 15

17、 Asia China 8 Hong Kong, Taiwan 1 Lombok (Based on under 2 rates, 1+ doses) 63 Published rates of Hib meningitis(Children under 5 years per 100K person-years) 59 (-249 to 367) -4.9 (-136 to 126) -4.5 (-147 to 138) 66 (-126 to 259) 40 (-17 to 97) Preventable Hib mortality (95% CI) Meningitis admissio

18、n or seen at health center for seizures 25.0% 161 121 Clinical or verbal autopsy-defined pneumonia 6.5% 1,020 954 Clinical pneumonia -0.7% 601 606 WHO-defined severe pneumonia -0.9% 526 531 All deaths 3.0% 1,936 1,877 Outcome Prevented proportion Control group mortality Hib Vaccine group mortality M

19、ortality rates are per 100,000 child-years Mortality after at least 1 dose 30 (-201 to 261) -4.8 (-109 to 99) -14 (-124 to 96) 19 (-126 to 164) 75 (8.1 to 141) Preventable Hib mortality (95% CI) Meningitis admission or seen at health center for seizures 46.0% 161 86 Clinical or verbal autopsy-define

20、d pneumonia 3.3% 583 564 Clinical pneumonia -4.2% 341 355 WHO-defined severe pneumonia -1.6% 305 310 All deaths 2.6% 1,155 1,125 Outcome Prevented proportion Control group mortality Hib Vaccine group mortality Mortality rates are per 100,000 child-years Mortality after 3 doses Conclusions Hib vaccin

21、e 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 G

22、ambia 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 3 rd 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.Gambia Lombok