1、Haemophilus influenzae type b Using vaccines to measure disease burden:A Tale of Two StudiesPresentation 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 causes disea
2、se in young children meningitis pneumonia epiglottitis septic arthritisHib 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,then meningitis m
3、eningitis 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 carriageGambia slides courtesy of Kim Mulholland,MD University of MelbourneStu
4、dy design individually randomized,double blind study major effort to detect Hib pneumonia randomization in 10 groups numbered 0 through 9:DTP+PRP-TDTP+placeboat 2,3 and 4 months of age5 numbers5 numbersFinal results,March 201942,848 infants enrolled PRP-T group 21,490 infants 1272 possible Hib disea
5、se 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 aspiratesDid the vaccine actually prevent pneumonia?PRP-T controls vaccine efficacy episodes prevented WHO pneumonia*526 570 8%44
6、radiological pneumonia 132 170 22%38 *cough+fast breathing or lower chest wall indrawingWhat 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 pneumon
7、ia due to Hib Very little“WHO pneumonia”which is not radiologically obvious is due to HibConclusions 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
8、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 AsiaAsiaMany Asian countries can afford Hib vaccineHib was known to be an important cause of bacterial meningitis in AsiaBut:Microb
9、iologically confirmed Hib incidence lower than elsewhere(one color vaccine Average age at enrollment(i.e.,first vaccine plus 2 week delay):13 weeksOutcomePrevented proportionControl group incidenceHib Vaccine group incidencePrevented Hib incidence (95%CI)-43(-185 to 98)52(-194 to 298)174(-153 to 500
10、)264(-101 to 629)1561(270 to 2,853)1+vaccine dosesRadiologically confirmed-4.90%893936Any infiltrate on chest radiology1.90%2,6772,625Hospitalized severe pneumonia3.80%4,5184,345Any severe pneumonia4.80%5,4605,196Clinical pneumonia4.00%39,51637,954All incidences are per 100,000 child-yearsPneumonia
11、OutcomesOutcomePrevented proportionControl group incidenceHib Vaccine group incidencePrevented Hib incidence (95%CI)-89(-248 to 71)-36(-322 to 249)-49(-416 to 318)6.9(-401 to 415)1,467(-60 to 2,994)3 vaccine dosesRadiologically confirmed-12.0%770859Any infiltrate on chest radiology-1.5%2,4682,504Hos
12、pitalized severe pneumonia-1.3%3,9063,955Any severe pneumonia0.15%4,7124,705Clinical pneumonia3.8%38,22636,759All incidences are per 100,000 child-yearsPneumonia OutcomesOutcomePrevented proportionControl group incidenceHib vaccine group incidencePrevented Hib incidence (95%CI)16(1.4 to 31)47(13 to
13、81)67(22 to 112)89(10 to 167)158(42 to 273)Meningitis admission or clinic evaluation for seizures22%701543Lumbar punctures26%346258Possible bacterial(incl.conf.Hib)50%13467Probable bacterial(incl.conf.Hib)55%86391+vaccine dosesMicrobiologically confirmed Hib86%192.6All incidences are per 100,000 chi
14、ld-yearsMeningitis OutcomesOutcomePrevented proportionControl group incidenceHib vaccine group incidencePrevented 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 dosesMicrobiologically confirmed Hib84%233.7Probable bacterial(incl.conf.Hib)57%7834
15、Possible bacterial(incl.conf.Hib)54%13764Lumbar punctures16%317265Meningitis admission or clinic evaluation for seizures20%656527All incidences are per 100,000 child-yearsMeningitis OutcomesRegionCountryRateNorth AmericaU.S.11-64South AmericaBrazil5-44EuropeIceland43Bulgaria6.1AfricaGambia57-60South
16、 Africa34Middle EastSaudi Arabia45Kuwait15AsiaChina8Hong Kong,Taiwan1Lombok(Based on under 2 rates,1+doses)63Published 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)Me
17、ningitis admission or seen at health center for seizures25.0%161121Clinical or verbal autopsy-defined pneumonia6.5%1,020954Clinical pneumonia-0.7%601606WHO-defined severe pneumonia-0.9%526531All deaths3.0%1,9361,877OutcomePrevented proportionControl group mortalityHib Vaccine group mortalityMortalit
18、y rates are per 100,000 child-yearsMortality after at least 1 dose30(-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 seizures46.0%16186Clinical or verbal autopsy-defined pneumonia3.3%583564Clin
19、ical pneumonia-4.2%341355WHO-defined severe pneumonia-1.6%305310All deaths2.6%1,1551,125OutcomePrevented proportionControl group mortalityHib Vaccine group mortalityMortality rates are per 100,000 child-yearsMortality after 3 dosesConclusions Hib vaccine not an effective intervention against ALRI(pn
20、eumonia)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 ResultsHib vaccine prevents about
21、 20%of radiological pneumonia in Gambian infantsVery little“WHO pneumonia”which is not radiologically obvious is due to HibProtection conferred after 3rd doseHib vaccine prevents little to no radiological pneumonia in Lombok infantsThe 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.GambiaLombok
