Hib (Haemophilus influenzae type b) vaccine

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disease risks

post-acute and long-term sequelae

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vaccine safety and adverse events

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Invasive Haemophilus influenzae type b disease (meningitis, pneumonia, epiglottitis, bacteraemia) Haemophilus influenzae serotype b

Disease risks

Acute risks of the infection itself: complications, hospitalisation, ICU, death.

Outcome (O)	Population (P)	Estimate	Design (S)	Source
In-hospital death from Hib meningitis severity: death case definition: Laboratory-confirmed bacterial meningitis in African children aged 1 month to 15 years	1 month to 15 years vaccination status: not reported country: 21 African countries setting: LMIC, hospital period: studies to 2009 n: 6,029 children with confirmed meningitis (all pathogens) Infant <1y1-4y5-11y12-17y	25 median in-hospital CFR across studies (%) per Hib meningitis case admitted	systematic review	Ramakrishnan et al. 2009 BMC Med quote The highest in-hospital case fatality ratios observed were for pneumococcal meningitis (median = 35%) and Hib meningitis (median = 25%) compared to meningococcal meningitis (median = 4%). abstract, RESULTS Median across studies, so no confidence interval; in-hospital deaths only, and the same review found a further tenth of all-cause survivors died after discharge.
Death from Hib meningitis severity: death case definition: CSF-culture-confirmed Hib meningitis in children under 5, studies published 2010-2019	children <5 years vaccination status: mixed country: global (33 studies) period: 2010-2020 Infant <1y1-4y	11.21 (7.01–17.45) CFR (%) per Hib meningitis case	meta-analysis	Park et al. 2022 J Glob Health quote Pooled CFR in our meta-analysis was 11.21% (95% CI = 7.01-17.45). abstract, RESULTS Mixed vaccine-era studies; regional CFRs range widely (next two records).
Death from Hib meningitis severity: death case definition: CSF-culture-confirmed Hib meningitis in children under 5	children <5 years vaccination status: mixed country: WHO African Region setting: LMIC period: 2010-2020 Infant <1y1-4y	21.79 (13.65–32.92) CFR (%) per Hib meningitis case	meta-analysis	Park et al. 2022 J Glob Health quote However, considering regions with three or more data, African Region (AFR) had the highest CFR at 21.79% (95% CI = 13.65-32.92). abstract, RESULTS Subgroup restricted to regions with three or more data points.
Death from Hib meningitis severity: death case definition: CSF-culture-confirmed Hib meningitis in children under 5	children <5 years vaccination status: mixed country: WHO European Region setting: high-income period: 2010-2020 Infant <1y1-4y	4.13 (1.73–9.54) CFR (%) per Hib meningitis case	meta-analysis	Park et al. 2022 J Glob Health quote Eastern Mediterranean Region (EMR) had the highest CFR (26.92, 95% CI = 13.41-46.71) while EUR had the lowest (4.13, 95% CI = 1.73-9.54). abstract, RESULTS The same sentence reports the Eastern Mediterranean Region as highest at 26.92%, on fewer studies.
Hib meningitis incidence after vaccine introduction severity: meningitis case definition: CSF-culture-confirmed Hib meningitis in children under 5	children <5 years vaccination status: mixed country: global period: 2010-2020, post-vaccination study periods Infant <1y1-4y	0.67 (0.48–0.94) incidence per 100,000 child-years per 100,000 child-years under 5	meta-analysis	Park et al. 2022 J Glob Health quote Post-vaccination incidence (0.67 cases per 100 000-child-years, 95% CI = 0.48-0.94) was dramatically lower than Pre-vaccination incidence (4.84 cases per 100 000-child-years, 95% CI = 2.95-7.96). abstract, RESULTS Pooled across heterogeneous settings; the same sentence gives the pre-vaccination pooled incidence (next record).
Hib meningitis incidence before vaccine introduction severity: meningitis case definition: CSF-culture-confirmed Hib meningitis in children under 5	children <5 years vaccination status: unvaccinated country: global period: 2010-2020, pre-vaccination study periods Infant <1y1-4y	4.84 (2.95–7.96) incidence per 100,000 child-years per 100,000 child-years under 5	meta-analysis	Park et al. 2022 J Glob Health quote Post-vaccination incidence (0.67 cases per 100 000-child-years, 95% CI = 0.48-0.94) was dramatically lower than Pre-vaccination incidence (4.84 cases per 100 000-child-years, 95% CI = 2.95-7.96). abstract, RESULTS Much lower than the pre-vaccine Gambian and Burkina Faso rates earlier in this file; the review itself says extrapolating population at risk may have underestimated incidence.
Invasive Hib disease (cumulative risk before age 5) severity: any invasive disease case definition: Invasive Hib disease as described by CDC for the US prevaccine era	children younger than age 5 years vaccination status: unvaccinated country: United States period: prevaccine era (before 1988) Infant <1y1-4y	one in 200 cumulative risk of invasive Hib disease before age 5 (children per children) per child born, cumulative to age 5	expert body	cdc.gov quote Before the introduction of effective vaccines, H. influenzae type b (Hib) was the leading cause of bacterial meningitis and other invasive bacterial disease, primarily among children younger than age 5 years; approximately one in 200 children in this age group developed invasive Hib disease. Haemophilus influenzae type b (Hib), opening paragraph CDC Pink Book summary figure for the US before conjugate vaccines; no interval given.
Meningitis as the presenting form of invasive Hib disease severity: meningitis case definition: Clinical manifestation of invasive Hib disease, US prevaccine era	children (invasive Hib disease occurred primarily under age 5) vaccination status: unvaccinated country: United States period: prevaccine era Infant <1y1-4y	50 to 65 proportion of invasive Hib cases that were meningitis (%) per invasive Hib case	expert body	cdc.gov quote Meningitis, an infection of the membranes covering the brain and spinal cord, is the most common clinical manifestation of invasive Hib disease, accounting for 50% to 65% of cases in the prevaccine era. Clinical Features Range as stated by CDC; no interval.
Death from Hib meningitis severity: death case definition: Hib meningitis treated with appropriate antimicrobial therapy	children (invasive Hib disease occurred primarily under age 5) vaccination status: unvaccinated country: United States period: prevaccine era Infant <1y1-4y	3 to 6 CFR (%) per Hib meningitis case	expert body	cdc.gov quote The case fatality ratio is 3% to 6%, despite appropriate antimicrobial therapy. Clinical Features, meningitis paragraph High-income, treated setting. LMIC Hib meningitis case fatality in this file is several times higher (see the Burkina Faso, African systematic review and African Region meta-analysis records).
Invasive Hib disease incidence severity: any invasive disease case definition: Active surveillance estimates of invasive H. influenzae disease, US early 1980s	children younger than age 5 years vaccination status: unvaccinated country: United States period: early 1980s (prevaccine era) Infant <1y1-4y	40 to 50 incidence per 100,000 population (children under 5) per 100,000 population aged under 5 per year	surveillance	cdc.gov quote In the early 1980s, it was estimated that about 20,000 cases occurred annually in the United States, primarily among children younger than age 5 years (40 to 50 cases per 100,000 population). Secular Trends in the United States The same sentence gives the national estimate of about 20,000 cases per year, primarily in children under 5. Range, not a confidence interval.
Invasive Hib disease incidence severity: any invasive disease case definition: Invasive Hib disease in UK national surveillance	children aged <5 years vaccination status: unvaccinated country: United Kingdom period: prevaccine era (before 1992) Infant <1y1-4y	21 to 44 incidence per 100,000 (children under 5) per 100,000 children under 5 per year	surveillance	Ladhani 2012 Clin Ther quote RESULTS: The incidence of invasive Hib incidence in children aged <5 years fell from 21/100,000 to 44/100,000 in the prevaccine era to 0.63/100,000 in 1998, with an estimated vaccine failure rate of 2.2/100,000 vaccinees. abstract, RESULTS Review of UK surveillance; the range reflects different pre-vaccine studies. The same sentence gives the post-vaccine figure (next record).
Invasive Hib disease incidence after routine vaccination severity: any invasive disease case definition: Invasive Hib disease in UK national surveillance	children aged <5 years vaccination status: mixed country: United Kingdom period: 1998 (six years after vaccine introduction) Infant <1y1-4y	0.63 incidence per 100,000 (children under 5) per 100,000 children under 5 per year	surveillance	Ladhani 2012 Clin Ther quote RESULTS: The incidence of invasive Hib incidence in children aged <5 years fell from 21/100,000 to 44/100,000 in the prevaccine era to 0.63/100,000 in 1998, with an estimated vaccine failure rate of 2.2/100,000 vaccinees. abstract, RESULTS Incidence then rose again from the end of the decade to a peak before the booster campaign (see the UK resurgence efficacy records: screening-method VE, DTaP-Hib case-control and toddler case counts).
Invasive Hib disease in vaccinated children (vaccine failure) severity: any invasive disease case definition: True vaccine failure, invasive Hib disease after completed vaccination, UK surveillance	children aged <5 years vaccination status: vaccinated country: United Kingdom period: 1992-1998 Infant <1y1-4y	2.2 vaccine failure rate per 100,000 vaccinees per 100,000 vaccinated children	surveillance	Ladhani 2012 Clin Ther quote RESULTS: The incidence of invasive Hib incidence in children aged <5 years fell from 21/100,000 to 44/100,000 in the prevaccine era to 0.63/100,000 in 1998, with an estimated vaccine failure rate of 2.2/100,000 vaccinees. abstract, RESULTS A rate among the vaccinated, not a vaccine effectiveness estimate; compare with the unvaccinated-era incidence two records above.
Hib meningitis incidence severity: meningitis case definition: Hib meningitis cases in Western Australia 1984-1990	children under five years of age risk group: non-Aboriginal children vaccination status: unvaccinated country: Australia (Western Australia) period: 1984-1990 (prevaccine era) n: 257 cases Infant <1y1-4y	26.3 incidence per 100,000 (children under 5) per 100,000 children under 5 per year	surveillance	Bower et al. 1994 J Paediatr Child Health quote The incidence of Hib meningitis in children under five years of age was 26.3 per 100,000 for non-Aboriginal and 152.2 per 100,000 for Aboriginal children. abstract The same sentence gives the Aboriginal rate (next record); the two are reported together.
Hib meningitis incidence severity: meningitis case definition: Hib meningitis cases in Western Australia 1984-1990	children under five years of age risk group: Aboriginal children vaccination status: unvaccinated country: Australia (Western Australia) period: 1984-1990 (prevaccine era) Infant <1y1-4y	152.2 incidence per 100,000 (children under 5) per 100,000 children under 5 per year	surveillance	Bower et al. 1994 J Paediatr Child Health quote The incidence of Hib meningitis in children under five years of age was 26.3 per 100,000 for non-Aboriginal and 152.2 per 100,000 for Aboriginal children. abstract Roughly six-fold the non-Aboriginal rate in the same study (previous record); Indigenous and American Indian/Alaska Native children carry a much higher pre-vaccine risk.
Death from Hib meningitis severity: death case definition: Hib meningitis cases in Western Australia 1984-1990	children under five years of age risk group: non-Aboriginal children vaccination status: unvaccinated country: Australia (Western Australia) period: 1984-1990 (prevaccine era) Infant <1y1-4y	3.5 CFR (%) per Hib meningitis case	surveillance	Bower et al. 1994 J Paediatr Child Health quote The case fatality rate was 3.5% for non-Aboriginal children and 14.0% for Aboriginal children. abstract The same sentence gives 14.0% for Aboriginal children; filed here as the non-Aboriginal figure with the Aboriginal figure in the quote.
Invasive Hib disease incidence severity: any invasive disease case definition: Culture-confirmed invasive Hib disease, prospective surveillance before the Gambian vaccine trial	children aged <1 year (274) and <5 years (73) vaccination status: unvaccinated country: The Gambia (Western Region) setting: LMIC, hospital-based surveillance period: 3-year prevaccine surveillance before 1993 n: 182 children with invasive Hib disease Infant <1y1-4y	274 incidence per 100,000 per year per 100,000 children under 1 year per year	surveillance	Adegbola et al. 1996 Ann Trop Paediatr quote The estimated annual incidence rates for all invasive Hib diseases were 274 and 73 per 100,000 in children aged < 1 and < 5 years, respectively. abstract Value is the under-1 rate; the same sentence gives 73 per 100,000 for children under 5. Hospital-based ascertainment underestimates community incidence.
Hib meningitis incidence severity: meningitis case definition: Culture-confirmed Hib meningitis, prospective surveillance before the Gambian vaccine trial	children aged <1 year vaccination status: unvaccinated country: The Gambia (Western Region) setting: LMIC, hospital-based surveillance period: 3-year prevaccine surveillance before 1993 Infant <1y	222 incidence per 100,000 per year per 100,000 children under 1 year per year	surveillance	Adegbola et al. 1996 Ann Trop Paediatr quote For meningitis, the rate was 222 per 100,000 per year in children aged < 1 year. abstract Meningitis made up about three-quarters of the invasive cases found; median age seven months.
Hib meningitis incidence severity: meningitis case definition: Hib identified in CSF by PCR, culture or antigen detection in population-based meningitis surveillance	<1 year (97), <5 years (34), 5-14 years (2.1), 15+ years (0.55) vaccination status: unvaccinated country: Burkina Faso setting: LMIC, population-based surveillance in 3 districts period: 2002-2003 and 2004-2005 (prevaccine) n: 112 Hib meningitis cases Infant <1y1-4y5-11y12-17y18-49y	97 incidence per 100,000 per year per 100,000 children under 1 year per year	surveillance	Yaro et al. 2006 Pediatr Infect Dis J quote Persons <1, <5, 5-14 and 15+ years of age had annual Hib meningitis incidences of 97, 34, 2.1 and 0.55 per 100,000, respectively; overall case fatality proportion was 25%. abstract, RESULTS Value is the under-one rate; the quote carries the under-five, school-age and adult rates too. The same sentence reports the case fatality proportion (next record).
Death from Hib meningitis severity: death case definition: Hib meningitis in population-based surveillance, all ages	all ages (most cases under 5) vaccination status: unvaccinated country: Burkina Faso setting: LMIC, population-based surveillance period: 2002-2005 (prevaccine) n: 112 Hib meningitis cases All ages	25 CFR (%) per Hib meningitis case	surveillance	Yaro et al. 2006 Pediatr Infect Dis J quote Persons <1, <5, 5-14 and 15+ years of age had annual Hib meningitis incidences of 97, 34, 2.1 and 0.55 per 100,000, respectively; overall case fatality proportion was 25%. abstract, RESULTS Many patients were pretreated with antimalarials or received only one or two doses of oily chloramphenicol, so this reflects case management as well as the organism.
Invasive Hib disease incidence severity: any invasive disease case definition: Invasive H. influenzae serotype b disease, Active Bacterial Core surveillance, age- and race-standardised	all ages vaccination status: mixed country: United States (ABCs sites) period: 2009-2015 All ages	0.03 incidence per 100,000 population per 100,000 population per year	surveillance	Soeters et al. 2018 Clin Infect Dis quote Nontypeable H. influenzae had the highest incidence (1.22) and case fatality (16%), as compared with Hib (0.03; 4%) and non-b encapsulated serotypes (0.45; 11%). abstract, RESULTS All ages, so not directly comparable with the under-five prevaccine rate near the top of this file. The same sentence gives Hib case fatality (next record).
Death from invasive Hib disease severity: death case definition: Invasive H. influenzae serotype b disease, Active Bacterial Core surveillance	all ages vaccination status: mixed country: United States (ABCs sites) period: 2009-2015 All ages	4 CFR (%) per invasive Hib case	surveillance	Soeters et al. 2018 Clin Infect Dis quote Nontypeable H. influenzae had the highest incidence (1.22) and case fatality (16%), as compared with Hib (0.03; 4%) and non-b encapsulated serotypes (0.45; 11%). abstract, RESULTS Small numbers in the vaccine era; nontypeable H. influenzae had higher case fatality (16%) in the same analysis.
Invasive Hib disease cases in young children severity: any invasive disease case definition: Hib cases reported to Active Bacterial Core surveillance	children younger than age 5 years vaccination status: mixed country: United States (ABCs sites) period: 2009-2018 Infant <1y1-4y	36 count of cases over 10 years in ABCs sites cases in ABCs surveillance population, 10 years	surveillance	cdc.gov quote From 2009–2018, 36 Hib cases in patients younger than age 5 years were reported to ABCs. Secular Trends in the United States A count in surveillance sites, not national incidence. The chapter goes on to say a third of these were unvaccinated, a further third undervaccinated and about a fifth age-appropriately vaccinated.
Invasive Hib disease incidence severity: any invasive disease case definition: Hib infections in ABCs surveillance areas	all ages vaccination status: mixed country: United States (ABCs surveillance areas) period: 2018 All ages	0.02 incidence per 100,000 population per 100,000 population per year	surveillance	cdc.gov quote While the rate of invasive H. influenzae infections increased from 1.23 per 100,000 population in 1997 to 2.08 per 100,000 population in 2018 in the surveillance areas, the rate of Hib infections decreased from 0.1 per 100,000 population in 1997 to 0.02 per 100,000 population in 2018. Secular Trends in the United States All ages. Over the same period invasive non-b and nontypeable H. influenzae disease rose, which Hib vaccine does not cover.
Death within 30 days of invasive Hib disease severity: death case definition: Laboratory-confirmed invasive Hib disease, England and Wales	all ages vaccination status: mixed country: England and Wales period: 2012-2016 n: 67 Hib cases All ages	3.0 CFR (%) per laboratory-confirmed Hib case	surveillance	Collins et al. 2018 J Infect quote There were only two deaths within 30 days over the five-year period (case fatality rate, 3.0%). abstract, RESULTS Two deaths among the cases given in n; annual Hib incidence in the same period was below one per million population.
Death from invasive Hib disease severity: death case definition: Culture-confirmed Hib infection in 12 Canadian paediatric tertiary hospitals (IMPACT)	children (11 of 29 cases under 6 months) vaccination status: mixed country: Canada setting: hospital network period: 2001-2003 n: 29 cases Infant <1y1-4y5-11y	7 CFR (%) per hospitalised Hib case	surveillance	Scheifele et al. 2005 CMAJ quote Two deaths occurred (7% case-fatality ratio). abstract, RESULTS Two deaths among the cases given in n, so the percentage is unstable. Most cases were in children too young to have completed the primary series or unvaccinated by parental choice.
Epiglottitis incidence severity: hospitalisation case definition: Inpatient diagnosis of epiglottitis in a nationwide administrative database	children ≤5 years old vaccination status: unvaccinated country: Japan period: 2007-2008 (before Hib vaccine availability) n: 102 cases Infant <1y1-4y5-11y	3.2 incidence per 100,000 population per year per 100,000 children ≤5 per year	surveillance	Takeuchi et al. 2013 J Infect Chemother quote The annual incidence of epiglottitis in children ≤5 years old was estimated to be 3.2 per 100,000 population per year. abstract Administrative diagnosis, not culture-confirmed Hib; prevaccine Japan. Respiratory support in the same series is the next record.
Respiratory support for epiglottitis severity: respiratory support (including tracheotomy) case definition: Inpatient epiglottitis in children ≤5, nationwide database	children ≤5 years old vaccination status: unvaccinated country: Japan period: 2007-2008 (before Hib vaccine availability) n: 102 cases Infant <1y1-4y5-11y	30.4 proportion of cases requiring respiratory support (%) per epiglottitis admission	surveillance	Takeuchi et al. 2013 J Infect Chemother quote Among the 102 patients, 31 (30.4%) required respiratory support, including two cases with tracheotomy and one fatal case. abstract One fatal case and two tracheotomies in the same series.
Hib as the cause of acute epiglottitis severity: epiglottitis case definition: Correctly coded acute epiglottitis admissions in 11 Sydney hospitals	all ages (children predominated in the pre-vaccine era) vaccination status: unvaccinated country: Australia (New South Wales) period: July 1990-June 1992 (pre-vaccine era) n: 114 pre-vaccine era records All ages	62 proportion of epiglottitis cases with Hib bacteraemia (%) per epiglottitis case	surveillance	Wood et al. 2005 Intern Med J quote Hib bacteraemia was identified in 62% of cases in the pre-vaccine era compared to no cases in the vaccine era, despite equivalent blood cultures being taken between the two eras (84 vs 74%). abstract, RESULTS Blood culture rates were similar in the two eras (84 vs 74%), so the fall to zero Hib isolates in the vaccine era is not an artefact of testing; vaccine-era epiglottitis was mostly adult.
Invasive Hib disease incidence before vaccine introduction severity: any invasive disease case definition: Sterile-site culture of H. influenzae type b in children admitted to Kilifi County Hospital	children younger than 5 years vaccination status: unvaccinated country: Kenya (Kilifi) setting: LMIC, hospital with demographic surveillance denominator period: 2000-2001 (prevaccine) Infant <1y1-4y	62.6 (46.0–83.3) incidence per 100,000 children under 5 per year per 100,000 children under 5 per year	surveillance	Hammitt et al. 2016 Lancet Glob Health quote The incidence of invasive H influenzae type b disease in children younger than 5 years declined from 62·6 (95% CI 46·0-83·3) per 100,000 in 2000-01 to 4·5 (2·5-7·5) per 100,000 in 2004-14, giving a vaccine effectiveness of 93% (95% CI 87-96). abstract, FINDINGS The same sentence gives the routine-use era rate (next record) and the derived vaccine effectiveness (Kilifi efficacy record).
Invasive Hib disease incidence after vaccine introduction (3 doses, no booster) severity: any invasive disease case definition: Sterile-site culture of H. influenzae type b in children admitted to Kilifi County Hospital	children younger than 5 years vaccination status: mixed country: Kenya (Kilifi) setting: LMIC, hospital with demographic surveillance denominator period: 2004-2014 (routine-use era) Infant <1y1-4y	4.5 (2.5–7.5) incidence per 100,000 children under 5 per year per 100,000 children under 5 per year	surveillance	Hammitt et al. 2016 Lancet Glob Health quote The incidence of invasive H influenzae type b disease in children younger than 5 years declined from 62·6 (95% CI 46·0-83·3) per 100,000 in 2000-01 to 4·5 (2·5-7·5) per 100,000 in 2004-14, giving a vaccine effectiveness of 93% (95% CI 87-96). abstract, FINDINGS Only one case in a child under five in the final five years of observation.
Deaths from Hib disease (all syndromes) severity: death case definition: Modelled Hib pneumonia, meningitis and other serious disease deaths	children aged 1-59 months vaccination status: mixed country: global period: 2000 Infant <1y1-4y	371,000 (247,000–527,000) annual deaths (count, with uncertainty range) global deaths per year in children 1-59 months	modelling	Watt et al. 2009 Lancet quote We estimated that Hib caused 371,000 deaths (247,000-527,000) in children aged 1-59 months, of which 8100 (5600-10,000) were in HIV-positive and 363,000 (242,000-517,000) in HIV-negative children. abstract, FINDINGS Uncertainty range, not a confidence interval. Estimated for the year in the quote, before most LMIC vaccine introductions; the later global estimate is two records below.
Serious Hib illnesses (pneumonia, meningitis, other invasive) severity: serious illness case definition: Modelled serious Hib illness	children younger than 5 years vaccination status: mixed country: global period: 2000 Infant <1y1-4y	8.13 million (7.33 million–13.2 million) annual serious illnesses (count, with uncertainty range) global cases per year in children under 5	modelling	Watt et al. 2009 Lancet quote FINDINGS: We calculated that Hib caused about 8.13 million serious illnesses worldwide in 2000 (uncertainty range 7.33-13.2 million). abstract, FINDINGS Uncertainty range, not a confidence interval. Most of this is pneumonia inferred from vaccine-probe trials rather than culture-confirmed disease.
Deaths from Hib disease (all syndromes) severity: death case definition: Modelled Hib pneumonia, meningitis and other deaths in HIV-uninfected children	children aged 1-59 months immune status: HIV-uninfected vaccination status: mixed country: global period: 2015 Infant <1y1-4y	29 500 (18 400–40 700) annual deaths (count, with uncertainty range) global deaths per year in children 1-59 months	modelling	Wahl et al. 2018 Lancet Glob Health quote FINDINGS: We estimated that there were 294 000 pneumococcal deaths (uncertainty range [UR] 192 000-366 000) and 29 500 Hib deaths (18 400-40 700) in HIV-uninfected children aged 1-59 months in 2015. abstract, FINDINGS Uncertainty range, not a confidence interval. Compare with the much larger pre-introduction global estimate two records above; the same paper estimates the decline (next record).
Decline in Hib deaths after vaccine introduction severity: death case definition: Modelled Hib deaths in children 1-59 months	children aged 1-59 months vaccination status: mixed country: global period: 2000 to 2015 Infant <1y1-4y	90 (78–96) percentage decline in annual Hib deaths (%) relative to modelled 2000 deaths	modelling	Wahl et al. 2018 Lancet Glob Health quote We estimate that pneumococcal deaths declined by 51% (7-74) and Hib deaths by 90% (78-96) from 2000 to 2015. abstract, FINDINGS Ecological and modelled; attributes the decline to vaccine use but cannot separate it from improvements in child survival generally.
Severe Hib disease episodes severity: severe disease case definition: Modelled severe Hib pneumonia, meningitis and other syndromes	children aged 1-59 months vaccination status: mixed country: global period: 2015 Infant <1y1-4y	340 000 (196 000–669 000) annual severe episodes (count, with uncertainty range) global episodes per year in children under 5	modelling	Wahl et al. 2018 Lancet Glob Health quote We estimated 3·7 million episodes (UR 2·7 million-4·3 million) of severe pneumococcus and 340 000 episodes (196 000-669 000) of severe Hib globally in children in 2015. abstract, FINDINGS Uncertainty range, not a confidence interval.

Vaccine efficacy and effectiveness

Every estimate compiled, annotated by population (P), intervention (I), comparator (C), outcome (O) and study design (S).

Outcome (O)	Population (P)	Intervention / comparator	Estimate	Design (S)	Source
Invasive Hib disease severity: any invasive disease case definition: Invasive Hib disease as defined in 8 randomised trials	infants and young children country: multiple (including developing countries) Infant <1y1-4y	Hib conjugate vaccines (various) platform: polysaccharide-protein conjugate doses: as given in each trial vs placebo or no vaccine	84 (0.08–0.30 OR CI) VE (%) = 1 - OR	meta-analysis 8 randomised trials	Obonyo et al. 2006 Eur J Clin Microbiol Infect Dis quote From eight trials, the protective efficacy of the Hib conjugate vaccine was 84% (OR 0.16; 95%CI 0.08-0.30) against invasive Hib disease, 75% (OR 0.25; 95%CI 0.08-0.84) against meningitis, and 69% (OR 0.31; 95%CI 0.10-0.97) against pneumonia. abstract Confidence bounds are on the OR scale, as the review reports them. Random-effects pooling across products including the ineffective Alaska PRP-D trial.
Hib meningitis severity: meningitis case definition: Hib meningitis as defined in the included trials	infants and young children country: multiple Infant <1y1-4y	Hib conjugate vaccines (various) platform: polysaccharide-protein conjugate doses: as given in each trial vs placebo or no vaccine	75 (0.08–0.84 OR CI) VE (%) = 1 - OR	meta-analysis 8 randomised trials	Obonyo et al. 2006 Eur J Clin Microbiol Infect Dis quote From eight trials, the protective efficacy of the Hib conjugate vaccine was 84% (OR 0.16; 95%CI 0.08-0.30) against invasive Hib disease, 75% (OR 0.25; 95%CI 0.08-0.84) against meningitis, and 69% (OR 0.31; 95%CI 0.10-0.97) against pneumonia. abstract OR-scale interval. Lower point estimate than for all invasive disease because meningitis counts were small in most trials.
Hib pneumonia severity: pneumonia case definition: Hib pneumonia as defined in the included trials	infants and young children country: multiple Infant <1y1-4y	Hib conjugate vaccines (various) platform: polysaccharide-protein conjugate doses: as given in each trial vs placebo or no vaccine	69 (0.10–0.97 OR CI) VE (%) = 1 - OR	meta-analysis 8 randomised trials	Obonyo et al. 2006 Eur J Clin Microbiol Infect Dis quote From eight trials, the protective efficacy of the Hib conjugate vaccine was 84% (OR 0.16; 95%CI 0.08-0.30) against invasive Hib disease, 75% (OR 0.25; 95%CI 0.08-0.84) against meningitis, and 69% (OR 0.31; 95%CI 0.10-0.97) against pneumonia. abstract OR-scale interval; upper bound close to 1.
Invasive Hib disease severity: any invasive disease case definition: Invasive Hib disease in RCTs and quasi-RCTs with follow-up to at least 2 years	children under five years country: multiple (high- and low-income) Infant <1y1-4y	Hib conjugate vaccines (various) platform: polysaccharide-protein conjugate doses: as given in each trial vs placebo or no treatment	0.20 (0.07–0.54) RR	meta-analysis 4 trials (6 included)	Swingler et al. 2007 Cochrane Database Syst Rev quote The relative risk for invasive Hib disease was 0.20 (95% confidence interval (CI) 0.07 to 0.54; random-effects model), but there was statistically significant unexplained variation (heterogeneity) in the effects of the four trials in the meta-analysis (P = 0.002). abstract, MAIN RESULTS Random-effects model with statistically significant unexplained heterogeneity. This Cochrane review was later formally withdrawn; see the flag.
Hib-related death severity: death case definition: Hib-related mortality in the included trials	children under five years country: multiple Infant <1y1-4y	Hib conjugate vaccines (various) platform: polysaccharide-protein conjugate doses: as given in each trial vs placebo or no treatment	0.29 (0.07–1.20) RR	meta-analysis	Swingler et al. 2007 Cochrane Database Syst Rev quote Hib-related mortality data showed a non-significant trend towards benefit (relative risk was 0.29; 95% CI 0.07 to 1.20; random-effects model). abstract, MAIN RESULTS Interval crosses 1; few deaths in trials. Withdrawn review, see flag.
All-cause death severity: death case definition: All-cause mortality in two trials with data	children under five years country: multiple Infant <1y1-4y	Hib conjugate vaccines (various) platform: polysaccharide-protein conjugate doses: as given in each trial vs placebo or no treatment	1.01 (0.38–2.67) RR	meta-analysis 2 trials	Swingler et al. 2007 Cochrane Database Syst Rev quote The relative risk for all cause mortality in the two trials from which data were available were 1.01 (95% CI 0.38 to 2.67, random-effects model) and 0.97. abstract, MAIN RESULTS No detectable effect on all-cause mortality in trial populations; a null result filed as such. Withdrawn review, see flag.
Confirmed invasive Hib disease severity: any invasive disease case definition: Confirmed invasive Hib disease in 9 randomised studies	infants country: multiple Infant <1y1-4y	Hib conjugate vaccines (various) platform: polysaccharide-protein conjugate doses: 3 primary doses vs placebo or no vaccine	82 (73–87) VE (%)	meta-analysis 9 randomised studies	Thumburu et al. 2015 Ther Adv Vaccines quote Pooled vaccine efficacy using a fixed effects model against confirmed invasive Hib disease following the 3, 2 and 1 primary dose schedule were 82% [95% confidence interval (CI) 73-87], 79% (95% CI 54-90) and 65% (95% CI 23-84), respectively, and the overall efficacy was 80% (95% CI 72-85). abstract Fixed-effects pooling. The same sentence gives two-dose, one-dose and overall estimates (next three records).
Confirmed invasive Hib disease severity: any invasive disease case definition: Confirmed invasive Hib disease in 9 randomised studies	infants country: multiple Infant <1y1-4y	Hib conjugate vaccines (various) platform: polysaccharide-protein conjugate doses: 2 primary doses vs placebo or no vaccine	79 (54–90) VE (%)	meta-analysis 9 randomised studies	Thumburu et al. 2015 Ther Adv Vaccines quote Pooled vaccine efficacy using a fixed effects model against confirmed invasive Hib disease following the 3, 2 and 1 primary dose schedule were 82% [95% confidence interval (CI) 73-87], 79% (95% CI 54-90) and 65% (95% CI 23-84), respectively, and the overall efficacy was 80% (95% CI 72-85). abstract Two-dose estimate; the authors conclude two doses are as good as three, but the interval is wide.
Confirmed invasive Hib disease severity: any invasive disease case definition: Confirmed invasive Hib disease in 9 randomised studies	infants country: multiple Infant <1y1-4y	Hib conjugate vaccines (various) platform: polysaccharide-protein conjugate doses: 1 primary dose vs placebo or no vaccine	65 (23–84) VE (%)	meta-analysis 9 randomised studies	Thumburu et al. 2015 Ther Adv Vaccines quote Pooled vaccine efficacy using a fixed effects model against confirmed invasive Hib disease following the 3, 2 and 1 primary dose schedule were 82% [95% confidence interval (CI) 73-87], 79% (95% CI 54-90) and 65% (95% CI 23-84), respectively, and the overall efficacy was 80% (95% CI 72-85). abstract Single-dose protection is clearly lower than two or three doses in RCT data, consistent with the observational meta-analysis records that follow.
Confirmed invasive Hib disease severity: any invasive disease case definition: Confirmed invasive Hib disease in 9 randomised studies	infants country: multiple Infant <1y1-4y	Hib conjugate vaccines (various) platform: polysaccharide-protein conjugate doses: any (pooled across schedules) vs placebo or no vaccine	80 (72–85) VE (%)	meta-analysis 9 randomised studies	Thumburu et al. 2015 Ther Adv Vaccines quote Pooled vaccine efficacy using a fixed effects model against confirmed invasive Hib disease following the 3, 2 and 1 primary dose schedule were 82% [95% confidence interval (CI) 73-87], 79% (95% CI 54-90) and 65% (95% CI 23-84), respectively, and the overall efficacy was 80% (95% CI 72-85). abstract Overall fixed-effects estimate across dose schedules.
Hib meningitis severity: meningitis case definition: Hib meningitis in case-control studies with community controls	children (as in included studies) country: 17 countries (30 studies overall) Infant <1y1-4y	Hib conjugate vaccines other than PRP-OMP platform: polysaccharide-protein conjugate doses: 1 vs unvaccinated community controls	55 (2–80) VE (%)	meta-analysis 3 case-control studies	Jackson et al. 2013 Pediatr Infect Dis J quote Meta-analysis of case-control studies using community controls produced VE estimates against Hib meningitis of 55% (95% confidence interval: 2-80%, based on 3 studies), 96% (86-99%, 3 studies) and 96% (86-99%, 4 studies) after 1, 2 and 3 doses of vaccines other than the polyribosyl ribitol phosphate outer membrane protein vaccine. abstract, RESULTS Observational; one dose of a non-PRP-OMP vaccine gives partial protection only. The same sentence gives the two- and three-dose estimates (next two records).
Hib meningitis severity: meningitis case definition: Hib meningitis in case-control studies with community controls	children (as in included studies) country: 17 countries (30 studies overall) Infant <1y1-4y	Hib conjugate vaccines other than PRP-OMP platform: polysaccharide-protein conjugate doses: 2 vs unvaccinated community controls	96 (86–99) VE (%)	meta-analysis 3 case-control studies	Jackson et al. 2013 Pediatr Infect Dis J quote Meta-analysis of case-control studies using community controls produced VE estimates against Hib meningitis of 55% (95% confidence interval: 2-80%, based on 3 studies), 96% (86-99%, 3 studies) and 96% (86-99%, 4 studies) after 1, 2 and 3 doses of vaccines other than the polyribosyl ribitol phosphate outer membrane protein vaccine. abstract, RESULTS Two-dose estimate; identical point estimate and interval to three doses in this meta-analysis.
Hib meningitis severity: meningitis case definition: Hib meningitis in case-control studies with community controls	children (as in included studies) country: 17 countries (30 studies overall) Infant <1y1-4y	Hib conjugate vaccines other than PRP-OMP platform: polysaccharide-protein conjugate doses: 3 vs unvaccinated community controls	96 (86–99) VE (%)	meta-analysis 4 case-control studies	Jackson et al. 2013 Pediatr Infect Dis J quote Meta-analysis of case-control studies using community controls produced VE estimates against Hib meningitis of 55% (95% confidence interval: 2-80%, based on 3 studies), 96% (86-99%, 3 studies) and 96% (86-99%, 4 studies) after 1, 2 and 3 doses of vaccines other than the polyribosyl ribitol phosphate outer membrane protein vaccine. abstract, RESULTS Three-dose estimate. Estimates were similar with hospital controls.
Invasive Hib disease severity: any invasive disease case definition: Invasive Hib disease in case-control studies	children (as in included studies) country: 17 countries (30 studies overall) Infant <1y1-4y	Hib conjugate vaccines platform: polysaccharide-protein conjugate doses: 1 vs unvaccinated controls	59 (30–76) VE (%)	meta-analysis 3 case-control studies	Jackson et al. 2013 Pediatr Infect Dis J quote VE against invasive Hib disease in case-control studies was estimated as 59% (30-76%, 3 studies) and 97% (87-99%, 3 studies) for 1 and 3 doses (insufficient data were identified to estimate 2-dose VE). abstract, RESULTS Insufficient data for a two-dose estimate against all invasive disease; the three-dose estimate is the next record.
Invasive Hib disease severity: any invasive disease case definition: Invasive Hib disease in case-control studies	children (as in included studies) country: 17 countries (30 studies overall) Infant <1y1-4y	Hib conjugate vaccines platform: polysaccharide-protein conjugate doses: 3 vs unvaccinated controls	97 (87–99) VE (%)	meta-analysis 3 case-control studies	Jackson et al. 2013 Pediatr Infect Dis J quote VE against invasive Hib disease in case-control studies was estimated as 59% (30-76%, 3 studies) and 97% (87-99%, 3 studies) for 1 and 3 doses (insufficient data were identified to estimate 2-dose VE). abstract, RESULTS Three-dose estimate against all invasive Hib disease.
Invasive Hib disease severity: any invasive disease case definition: Invasive Hib disease in cohort studies	children (as in included studies) country: 17 countries (30 studies overall) Infant <1y1-4y	Hib conjugate vaccines platform: polysaccharide-protein conjugate doses: 3 vs unvaccinated children in the same cohorts	94 (88–97) VE (%)	meta-analysis 4 cohort studies	Jackson et al. 2013 Pediatr Infect Dis J quote Using data from 4 cohort studies, 3-dose VE was estimated as 94% (88-97%). abstract, RESULTS Cohort rather than case-control design; the review also found some evidence of lower effectiveness when Hib was given with acellular rather than whole-cell pertussis vaccine, and weak evidence that a booster adds protection.
Hib meningitis / invasive Hib disease severity: any invasive disease case definition: As defined in the two PRP-OMP studies	infants country: as in the two studies Infant <1y	PRP-OMP (Hib polysaccharide conjugated to meningococcal outer membrane protein) platform: polysaccharide-protein conjugate doses: 1 vs unvaccinated	>90 VE (%), point estimates only	systematic review 2 studies (not meta-analysed)	Jackson et al. 2013 Pediatr Infect Dis J quote Point estimates from 2 studies suggested VE>90% after 1 dose of the polyribosyl ribitol phosphate outer membrane protein vaccine, but meta-analysis was not possible. abstract, RESULTS No pooled estimate or interval; the direction (high protection after one PRP-OMP dose, unlike other products) matches the Navajo RCT single-dose record.
Hib meningitis severity: meningitis case definition: Hib meningitis morbidity in case-control studies from low- and middle-income countries	children less than five years old country: low- and middle-income countries setting: LMIC Infant <1y1-4y	Hib conjugate vaccines platform: polysaccharide-protein conjugate doses: 1 vs unvaccinated controls	0.64 (0.38–1.06) RR	meta-analysis 4 case-control studies	Davis et al. 2013 BMC Public Health quote A meta-analysis of four case-control studies examined the dose-specific effect of Hib conjugate vaccines on Hib meningitis morbidity (1 dose: RR=0.64, 95% CI 0.38-1.06; 2 doses: RR=0.09, 95% CI 0.03-0.27; 3 doses: RR=0.06, 95% CI 0.02-0.22), consistent with results from single RCTs. abstract, RESULTS One-dose interval crosses one in LMIC case-control data. Dose-response continues in the next two records.
Hib meningitis severity: meningitis case definition: Hib meningitis morbidity in case-control studies from low- and middle-income countries	children less than five years old country: low- and middle-income countries setting: LMIC Infant <1y1-4y	Hib conjugate vaccines platform: polysaccharide-protein conjugate doses: 2 vs unvaccinated controls	0.09 (0.03–0.27) RR	meta-analysis 4 case-control studies	Davis et al. 2013 BMC Public Health quote A meta-analysis of four case-control studies examined the dose-specific effect of Hib conjugate vaccines on Hib meningitis morbidity (1 dose: RR=0.64, 95% CI 0.38-1.06; 2 doses: RR=0.09, 95% CI 0.03-0.27; 3 doses: RR=0.06, 95% CI 0.02-0.22), consistent with results from single RCTs. abstract, RESULTS Two doses already give most of the protection seen with three.
Hib meningitis severity: meningitis case definition: Hib meningitis morbidity in case-control studies from low- and middle-income countries	children less than five years old country: low- and middle-income countries setting: LMIC Infant <1y1-4y	Hib conjugate vaccines platform: polysaccharide-protein conjugate doses: 3 vs unvaccinated controls	0.06 (0.02–0.22) RR	meta-analysis 4 case-control studies	Davis et al. 2013 BMC Public Health quote A meta-analysis of four case-control studies examined the dose-specific effect of Hib conjugate vaccines on Hib meningitis morbidity (1 dose: RR=0.64, 95% CI 0.38-1.06; 2 doses: RR=0.09, 95% CI 0.03-0.27; 3 doses: RR=0.06, 95% CI 0.02-0.22), consistent with results from single RCTs. abstract, RESULTS Used by the authors as a proxy for meningitis mortality in LiST; it is a morbidity estimate.
Seropositivity (anti-PRP ≥1.0 μg/mL) 6 months after the last primary dose - immunological surrogate, not disease severity: surrogate (antibody) case definition: Anti-PRP antibody threshold in randomised schedule-comparison trials	infants country: 15 countries (20 trials) Infant <1y	PRP-T (Hib polysaccharide conjugated to tetanus toxoid) platform: polysaccharide-protein conjugate doses: 3 primary doses vs 2 primary doses, no booster schedule: 3p+0 vs 2p+0 time since vaccination: 6 months after last primary dose vs 2p+0 schedule of the same vaccine	-0.02 (-0.10–0.06) risk difference in seropositivity, 3p+0 minus 2p+0	meta-analysis 20 trials (immunological outcomes)	Low et al. 2013 Pediatr Infect Dis J quote Comparing polyribosylribitol phosphate conjugated to tetanus toxoid 3p+0 with 2p+0, there was no difference in seropositivity at the 1.0 μg/mL threshold by 6 months after the last primary dose (combined risk difference -0.02; 95% confidence interval: -0.10, 0.06). abstract, RESULTS Surrogate endpoint only: no trial in this review assessed clinical disease or carriage. The review found no clear evidence that any 2p+1, 3p+0 or 3p+1 schedule protects better than another.
Invasive Hib disease severity: any invasive disease case definition: CDC summary of clinical efficacy of Hib conjugate vaccines	infants and children country: United States Infant <1y1-4y	Hib conjugate vaccines (PRP-T, PRP-OMP, and combinations) platform: polysaccharide-protein conjugate doses: primary series vs unvaccinated	95 to 100 VE (%)	expert body	cdc.gov quote Clinical efficacy has been estimated at 95% to 100%. Immunogenicity and Vaccine Efficacy Summary range without interval or citation. The same paragraph says efficacy studies have not been performed in populations at increased risk (asplenia, HIV); immunogenicity only.
All invasive Hib disease (culture-positive) severity: any invasive disease case definition: Culture-positive invasive Hib disease among children investigated for signs of invasive disease	infants vaccinated at 2, 3 and 4 months (median 11, 18 and 24 weeks), followed 5-36 months country: The Gambia setting: LMIC period: 1993-1995 n: 42,848 infants Infant <1y1-4y	PRP-T mixed with DTP platform: polysaccharide-protein conjugate doses: 3 schedule: 2, 3, 4 months (3p+0) vs DTP alone	95 (67–100) VE (%)	RCT	Mulholland et al. 1997 Lancet quote The efficacy of the vaccine for the prevention of all invasive disease after three doses was 95% (PRP-T vaccinees 1, controls 19 [95% CI 67-100]), for the prevention of Hib pneumonia after two or three doses, 100% (vaccinees 0, controls 10 [55-100]), and for the prevention of radiologically defined pneumonia at any time after enrollment, 21.1% (PRP-T vaccinees 198, controls 251 [4.6-34.9]). abstract, FINDINGS One case in vaccinees versus nineteen in controls. Double-blind. Most children received all three doses.
Culture-positive Hib pneumonia severity: pneumonia case definition: Hib pneumonia confirmed by blood culture or lung aspirate	infants vaccinated at 2, 3 and 4 months, followed 5-36 months country: The Gambia setting: LMIC period: 1993-1995 n: 42,848 infants Infant <1y1-4y	PRP-T mixed with DTP platform: polysaccharide-protein conjugate doses: 2 or 3 schedule: 2, 3, 4 months vs DTP alone	100 (55–100) VE (%)	RCT	Mulholland et al. 1997 Lancet quote The efficacy of the vaccine for the prevention of all invasive disease after three doses was 95% (PRP-T vaccinees 1, controls 19 [95% CI 67-100]), for the prevention of Hib pneumonia after two or three doses, 100% (vaccinees 0, controls 10 [55-100]), and for the prevention of radiologically defined pneumonia at any time after enrollment, 21.1% (PRP-T vaccinees 198, controls 251 [4.6-34.9]). abstract, FINDINGS No cases in vaccinees versus ten in controls; culture-confirmed Hib pneumonia is a small fraction of all pneumonia (next record).
Radiologically defined pneumonia (any cause) severity: pneumonia case definition: Pneumonia with chest radiograph changes, any aetiology, any time after enrolment	infants vaccinated at 2, 3 and 4 months, followed 5-36 months country: The Gambia setting: LMIC period: 1993-1995 n: 42,848 infants Infant <1y1-4y	PRP-T mixed with DTP platform: polysaccharide-protein conjugate doses: 1 or more (any time after enrolment) schedule: 2, 3, 4 months vs DTP alone	21.1 (4.6–34.9) VE (%)	RCT	Mulholland et al. 1997 Lancet quote The efficacy of the vaccine for the prevention of all invasive disease after three doses was 95% (PRP-T vaccinees 1, controls 19 [95% CI 67-100]), for the prevention of Hib pneumonia after two or three doses, 100% (vaccinees 0, controls 10 [55-100]), and for the prevention of radiologically defined pneumonia at any time after enrollment, 21.1% (PRP-T vaccinees 198, controls 251 [4.6-34.9]). abstract, FINDINGS The vaccine-probe estimate: 198 vs 251 episodes. Implies about a fifth of radiological pneumonia in young Gambian children was due to Hib, far more than culture detects. Not transferable to high-income settings.
Verified bacteraemic Hib disease severity: any invasive disease case definition: Culture-verified bacteraemic H. influenzae type b disease between about 7 and 24 months of age	vaccinated at 3, 4, 6 and 14-18 months; outcomes at approximately 7 to 24 months country: Finland period: from 1986 n: 114,000 infants Infant <1y1-4y	PRP-D (Hib polysaccharide conjugated to diphtheria toxoid) platform: polysaccharide-protein conjugate doses: 3 (after the primary series) schedule: 3, 4, 6 months with a booster at 14-18 months vs same vaccine given at 24 months (unvaccinated during follow-up)	94 (83–98) VE (%)	RCT	Eskola et al. 1990 N Engl J Med quote The protective efficacy of the vaccine was thus 94 percent (95 percent confidence interval, 83 to 98). abstract, RESULTS Open trial randomised by odd/even birth date; four cases versus sixty-four. The same PRP-D product failed in Alaska Native infants (see that RCT record), showing product-population interaction.
Systemic Hib infection before 18 months severity: any invasive disease case definition: Systemic H. influenzae type b infection (13 of 22 placebo-group cases were meningitis)	first dose at 42-90 days, second at 70-146 days; outcomes before 18 months risk group: Navajo infants (high-risk population) country: United States (Navajo Nation) n: 2588 vaccine, 2602 placebo Infant <1y1-4y	PRP-OMP (Hib polysaccharide conjugated to N. meningitidis outer-membrane protein complex) platform: polysaccharide-protein conjugate doses: 1 or 2 (intention-to-treat) schedule: 2 and 4 months vs placebo	95 (72–99) VE (%)	RCT	Santosham et al. 1991 N Engl J Med quote Before the age of 18 months, there was 1 systemic H. influenzae type b infection in the vaccine group, as compared with 22 in the placebo group (P less than 0.001; point estimate of efficacy, 95 percent; 95 percent confidence interval, 72 to 99 percent). abstract, RESULTS Double-blind, placebo-controlled; one versus twenty-two infections. Mean follow-up under a year.
Systemic Hib infection between first and second dose severity: any invasive disease case definition: Systemic H. influenzae type b infection	between about 2 and 4 months of age risk group: Navajo infants (high-risk population) country: United States (Navajo Nation) Infant <1y	PRP-OMP platform: polysaccharide-protein conjugate doses: 1 schedule: 2 and 4 months vs placebo	100 (41–100) VE (%)	RCT	Santosham et al. 1991 N Engl J Med quote Between the first and second doses there were no H. influenzae type b infections in the vaccine group and eight in the placebo group (P less than 0.005; point estimate of efficacy, 100 percent; 95 percent confidence interval, 41 to 100 percent). abstract, RESULTS Protection after a single dose of PRP-OMP, 0 vs 8 cases, is why ACIP prefers PRP-OMP for American Indian and Alaska Native infants, in whom disease peaks early.
Systemic Hib infection before 18 months among recipients of both doses severity: any invasive disease case definition: Systemic H. influenzae type b infection	outcomes before 18 months risk group: Navajo infants (high-risk population) country: United States (Navajo Nation) n: 2056 vaccine, 2105 placebo (both doses) Infant <1y1-4y	PRP-OMP platform: polysaccharide-protein conjugate doses: 2 schedule: 2 and 4 months vs placebo	93 (53–98) VE (%)	RCT	Santosham et al. 1991 N Engl J Med quote Among the children who received both doses, there was 1 H. influenzae type b infection in the vaccine group (n = 2056) and 14 in the placebo group (n = 2105) (P less than 0.001; point estimate of efficacy, 93 percent; 95 percent confidence interval, 53 to 98 percent). abstract, RESULTS One versus fourteen infections among two-dose recipients; the single vaccine-group case was osteomyelitis in the second year of life.
Invasive Hib disease severity: any invasive disease case definition: Invasive H. influenzae type b disease in a placebo-controlled trial	vaccinated at approximately 2, 4 and 6 months risk group: Alaska Native infants (very high-risk population) country: United States (Alaska) n: 2102 infants Infant <1y1-4y	PRP-D (Hib polysaccharide conjugated to diphtheria toxoid) platform: polysaccharide-protein conjugate doses: 3 schedule: 2, 4, 6 months vs saline placebo	35 (-57–73) VE (%)	RCT	Ward et al. 1990 N Engl J Med quote After one, two, or three doses there was no significant protective efficacy with the vaccine; after three doses the efficacy was only 35 percent (95 percent confidence interval, -57 to 73). abstract, RESULTS A null result: no significant protection after one, two or three doses, paralleling poor immunogenicity (fewer than half reached the lower antibody threshold after dose three). The same product was highly efficacious in Finland (see that RCT record) with a later start. PRP-D is no longer used for infants.
Anti-PRP ≥0.15 microg/ml after primary series - immunological surrogate, not disease severity: surrogate (antibody) case definition: Anti-PRP antibody post third dose in a randomised comparison	infants vaccinated at 2, 3 and 4 months country: United Kingdom n: 241 infants Infant <1y	DTaP-IPV-Hib (Pediacel), given with meningococcal C conjugate platform: PRP-T in acellular pertussis combination doses: 3 schedule: 2, 3, 4 months vs DTwP-Hib (100%, 95% CI 96.4 to 100, in the same sentence)	93.2 (86.6–96.7) proportion seroprotected at the short-term threshold (%)	RCT	Kitchin et al. 2007 Arch Dis Child quote RESULTS: Post vaccination, the proportion of infants with anti-polyribosylribitol phosphate (PRP) levels > or =0.15 microg/ml was 93.2% (95% confidence interval (CI) 86.6 to 96.7) in the Pediacel group compared with 100% (95% CI 96.4 to 100) in the diphtheria-tetanus-whole-cell pertussis-Haemophilus influenzae type b (DTwP-Hib) group. abstract, RESULTS Surrogate endpoint. The acellular-pertussis combination gave a lower anti-PRP response than the whole-cell combination, and co-administered MCC-CRM lowered it further. Antibody thresholds are not disease outcomes.
Anti-PRP geometric mean concentration one month after dose 3 - immunological surrogate, not disease severity: surrogate (antibody) case definition: Anti-PRP GMC in a randomised open-label non-inferiority trial	infants vaccinated at 2, 4, 6 months country: South Korea n: 418 infants (206 separate, 208 combined) Infant <1y	DTaP-IPV//Hib pentavalent combination (Pentaxim) platform: PRP-T in acellular pertussis combination doses: 3 schedule: 2, 4, 6 months vs separate DTaP-IPV and Hib (PRP~T) vaccines (GMC 23.9 μg/mL)	11.0 anti-PRP GMC (μg/mL), combined vaccine	RCT	Kang et al. 2016 J Korean Med Sci quote In separate and combined groups geometric mean concentrations of anti-PRP~T antibodies were 23.9 and 11.0 μg/mL, respectively, but 98.3% and 97.4% had titers ≥ 1 μg/mL, indicative of long-term protection. abstract Surrogate endpoint. The combined vaccine roughly halved the anti-PRP GMC relative to separate injection, yet nearly all infants in both groups still reached the long-term threshold (next record). Non-inferiority was declared on the threshold, not the GMC.
Anti-PRP ≥1 μg/mL one month after dose 3 - immunological surrogate, not disease severity: surrogate (antibody) case definition: Anti-PRP threshold in a randomised open-label non-inferiority trial	infants vaccinated at 2, 4, 6 months country: South Korea Infant <1y	DTaP-IPV//Hib pentavalent combination (Pentaxim) platform: PRP-T in acellular pertussis combination doses: 3 schedule: 2, 4, 6 months vs separate DTaP-IPV and Hib (PRP~T) vaccines (98.3%)	97.4 proportion reaching the long-term protective threshold (%), combined vaccine	RCT	Kang et al. 2016 J Korean Med Sci quote In separate and combined groups geometric mean concentrations of anti-PRP~T antibodies were 23.9 and 11.0 μg/mL, respectively, but 98.3% and 97.4% had titers ≥ 1 μg/mL, indicative of long-term protection. abstract Surrogate endpoint; no interval reported in the abstract.
Invasive Hib disease severity: any invasive disease case definition: Haemophilus influenzae type b disease in a health maintenance organisation population	vaccinated at 2, 4 and 6 months; outcomes 7 to 18 months country: United States (Northern California Kaiser Permanente) period: 1988-1990 n: 61,080 children (20,800 vaccinated) Infant <1y1-4y	HbOC (Hib oligosaccharide conjugated to CRM197) platform: oligosaccharide-protein conjugate doses: 3 schedule: 2, 4, 6 months vs unvaccinated children in the same population	100 (68–100) VE (%)	cohort	Black et al. 1991 Pediatr Infect Dis J quote The efficacy of three doses of vaccine was 100% with the lower bound of the 95% confidence interval for the three analyses at 68, 71, and 64%, respectively. abstract Non-randomised prelicensure cohort; 0 cases after three doses. The three analyses gave lower bounds of 68, 71 and 64%; the primary analysis bound is recorded. Upper bound taken as the point estimate of 100%.
Invasive Hib disease severity: any invasive disease case definition: Haemophilus influenzae type b disease in a health maintenance organisation population	infants after two doses (2 and 4 months) country: United States (Northern California Kaiser Permanente) period: 1988-1990 Infant <1y1-4y	HbOC platform: oligosaccharide-protein conjugate doses: 2 schedule: 2, 4 months vs unvaccinated children in the same population	100 (47–100) VE (%)	cohort	Black et al. 1991 Pediatr Infect Dis J quote There were no cases of disease resulting from two doses of HbOC vaccine yielding an estimate of 100% efficacy (95% confidence interval, 47 to 100) for two doses of HbOC vaccine. abstract No cases after two doses.
Invasive Hib disease severity: any invasive disease case definition: Haemophilus influenzae type b disease in a health maintenance organisation population	infants after one dose country: United States (Northern California Kaiser Permanente) period: 1988-1990 Infant <1y	HbOC platform: oligosaccharide-protein conjugate doses: 1 schedule: first dose at 2 months vs unvaccinated children in the same population	26 VE (%)	cohort	Black et al. 1991 Pediatr Infect Dis J quote However, for children who had received only one dose of HbOC vaccine, vaccine efficacy was estimated to be 26% and the possibility that one dose of HbOC vaccine had no efficacy could not be excluded.(ABSTRACT TRUNCATED AT 250 WORDS) abstract Three of the cases were in one-dose recipients; no interval given and zero efficacy not excluded. Contrast with one dose of PRP-OMP (Navajo single-dose record).
Vaccine failure (confirmed Hib infection despite full immunisation) severity: any invasive disease case definition: Confirmed Hib infection in fully immunised children born after 1 January 1993	children born after 1993 presenting 1998-2002 country: England period: 1998-2002 Infant <1y1-4y5-11y	DTaP-Hib combination vaccine (acellular pertussis) for all three primary doses platform: polysaccharide-protein conjugate in combination doses: 3 schedule: 2, 3, 4 months vs fully immunised children who received other (whole-cell pertussis-containing) Hib vaccines	2.88 (0.99–8.37) OR of vaccine failure, DTaP-Hib for all three doses vs other primary-course vaccines	case-control	McVernon et al. 2008 Arch Dis Child quote In fully immunised children, receipt of all three doses of the primary course as an acellular pertussis-containing combination vaccine (DTaP-Hib) increased the risk of vaccine failure (OR 2.88 (95% CI 0.99 to 8.37), p = 0.01). abstract, RESULTS Interval touches 1 (p = 0.01 reported). Matched case-control on postal questionnaire; also found higher risk with frequent antibiotic use and sole-parent households, and lower risk with day-care attendance.
Radiologically confirmed pneumonia (substantial alveolar consolidation), any cause severity: pneumonia case definition: Chest radiograph read independently by a radiologist and a paediatrician	children age <2 years country: Bangladesh (Dhaka) setting: LMIC, urban n: 475 pneumonia cases Infant <1y1-4y	Hib-DPT combination vaccine platform: polysaccharide-protein conjugate doses: at least 2 vs matched community controls	17 (-10–38) VE (%) (preventable fraction)	case-control	Baqui et al. 2007 Pediatr Infect Dis J quote Following at least 2 doses of Hib vaccine, the preventable fractions [95% confidence intervals (CI)] using community and hospital controls were 17% (-10% to 38%) and 35% (13% to 52%) respectively. abstract, RESULTS Vaccine-probe estimate for all-cause radiological pneumonia; the interval includes zero with community controls, the hospital-control estimate is the next record. Uptake of each dose was low.
Radiologically confirmed pneumonia (substantial alveolar consolidation), any cause severity: pneumonia case definition: Chest radiograph read independently by a radiologist and a paediatrician	children age <2 years country: Bangladesh (Dhaka) setting: LMIC, urban n: 475 pneumonia cases Infant <1y1-4y	Hib-DPT combination vaccine platform: polysaccharide-protein conjugate doses: at least 2 vs matched hospital controls	35 (13–52) VE (%) (preventable fraction)	case-control	Baqui et al. 2007 Pediatr Infect Dis J quote Following at least 2 doses of Hib vaccine, the preventable fractions [95% confidence intervals (CI)] using community and hospital controls were 17% (-10% to 38%) and 35% (13% to 52%) respectively. abstract, RESULTS Hospital controls gave a higher estimate than community controls (previous record); choice of control group matters here.
Confirmed Hib meningitis severity: meningitis case definition: Laboratory-confirmed Hib meningitis	children age <2 years country: Bangladesh (Dhaka) setting: LMIC, urban n: 15 Hib meningitis cases Infant <1y1-4y	Hib-DPT combination vaccine platform: polysaccharide-protein conjugate doses: at least 2 vs matched community controls	89 (28–100) VE (%) (preventable fraction)	case-control	Baqui et al. 2007 Pediatr Infect Dis J quote Fifteen confirmed Hib meningitis cases were identified; the preventable fractions (95% CI) using community and hospital controls, respectively, were 89% (28% to 100%) and 93% (53% to 100%). abstract, RESULTS Fifteen cases only, hence the wide interval. The hospital-control estimate was 93% (53% to 100%) in the same sentence.
Invasive Hib infection severity: any invasive disease case definition: Confirmed Hib infection in children eligible for vaccination, England and Wales	children eligible for infant vaccination or the under-4 catch-up country: England and Wales period: October 1993-December 2001 n: 443 cases (363 fully vaccinated) Infant <1y1-4y5-11y	Hib conjugate vaccine (UK programme, PRP-T predominantly; DTaP-Hib combination for those born 2000-2002) platform: polysaccharide-protein conjugate doses: full primary course (3 doses, no booster) schedule: 2, 3, 4 months with no booster vs unvaccinated (screening method, by coverage)	56.7 (42.5–67.4) VE (%)	screening method	Ramsay et al. 2003 J Infect Dis quote Vaccine effectiveness was estimated to be 56.7% (95% confidence interval, 42.5-67.4). abstract Much lower than trial efficacy: effectiveness fell with time since vaccination, was lower for infant than catch-up vaccinees, and lower for the birth cohorts that received the acellular-pertussis combination. This is the UK resurgence that led to the booster campaign and the routine second-year booster.
Invasive Hib cases in toddlers after the 2003 booster campaign severity: any invasive disease case definition: Confirmed Hib disease reported to the Health Protection Agency, England and Wales	1-3-year-old children country: England and Wales period: 2004-2006 1-4y	Hib conjugate primary course without a routine booster (children born after the 2003 campaign) platform: polysaccharide-protein conjugate doses: 3 primary, no booster vs cohorts that received the 2003 booster campaign dose	32 annual case count in 1-3-year-olds	surveillance	Ladhani et al. 2008 Arch Dis Child quote Since the campaign, however, there has been an increase in the number of cases reported among 1-3-year-old children (13 cases in 2004, 26 cases in 2005 and 32 cases in 2006), primarily in children who were too young to be vaccinated in the booster campaign. abstract, RESULTS Value is the final-year count; the rise across the three years in the quote occurred mainly in children too young for the booster campaign and supported the routine second-year booster introduced afterwards. A count, not a rate.
Long-term protective anti-Hib antibody concentration - immunological surrogate, not disease severity: surrogate (antibody) case definition: Serum Hib antibody above the long-term protective threshold in a cross-sectional serosurvey	4-35 months country: Kenya (Kilifi) setting: LMIC period: 2009 serosurvey n: 117 children Infant <1y1-4y	Hib conjugate vaccine (in pentavalent DTwP-HepB-Hib) platform: polysaccharide-protein conjugate doses: 3 primary, no booster schedule: 3p+0 vs none (cross-sectional proportion)	79 (70–86) proportion with long-term protective antibody (%)	surveillance	Hammitt et al. 2016 Lancet Glob Health quote In the 2009 serosurvey, 92 (79%; 95% CI 70-86) of 117 children aged 4-35 months had long-term protective antibody concentrations. abstract, FINDINGS Surrogate marker. The authors read the antibody profile as waning only after the age of greatest risk.
Anti-PRP IgG ≥0.15 µg/mL (putative short-term protection threshold) - immunological surrogate, not disease severity: surrogate (antibody) case definition: Residual serum samples from children up to 8 years, national serosurvey	children up to 8 years, cohort eligible for the 12-month booster country: England and Wales period: 2013-2014 n: 817 children with results (1000 samples) Infant <1y1-4y5-11y	Hib conjugate vaccine (UK programme: 3 primary doses in DTaP-IPV-Hib plus 12-month Hib/MenC booster) platform: polysaccharide-protein conjugate doses: 3 primary + 12-month booster schedule: 2, 3, 4 months + 12 months vs none (cross-sectional proportion)	89 proportion above short-term protective threshold (%)	surveillance	Collins et al. 2018 J Infect quote Overall, 89% of children (719/817) had anti-PRP concentrations ≥0.15 µg/mL, the putative threshold for short-term protection against invasive Hib disease. abstract, RESULTS Surrogate. Median titres were highest at age one and fell rapidly after the booster, which the authors note may leave toddlers able to carry Hib even while protected from disease.
Invasive Hib disease (sterile-site culture) severity: any invasive disease case definition: Invasive H. influenzae type b disease in children under 5 admitted to Kilifi County Hospital	children younger than 5 years country: Kenya (Kilifi) setting: LMIC period: prevaccine 2000-01 vs routine-use 2004-14 Infant <1y1-4y	Hib conjugate vaccine (in pentavalent DTwP-HepB-Hib) platform: polysaccharide-protein conjugate doses: 3 primary, no booster schedule: 3p+0 (6, 10, 14 weeks) vs prevaccine-era incidence in the same population	93 (87–96) VE (%) = 1 - incidence rate ratio	ecological	Hammitt et al. 2016 Lancet Glob Health quote The incidence of invasive H influenzae type b disease in children younger than 5 years declined from 62·6 (95% CI 46·0-83·3) per 100,000 in 2000-01 to 4·5 (2·5-7·5) per 100,000 in 2004-14, giving a vaccine effectiveness of 93% (95% CI 87-96). abstract, FINDINGS Before-after comparison, so secular trends and herd effects are included in the estimate; it is population impact rather than individual effectiveness. Fifteen-year follow-up with no booster and no resurgence.

Vaccine safety and adverse events

Harms measured after vaccination against an unvaccinated or baseline comparator. Kept separate from post-acute sequelae, which follow the disease, not the vaccine.

Outcome (O)	Population (P)	Intervention / comparator	Estimate	Design (S)	Source
Fever after vaccination severity: fever case definition: Fever as reported in randomised and open-label trials of combination vaccines	children in infant combination-vaccine trials country: multiple Infant <1y1-4y	DTaP-HBV-IPV-Hib hexavalent combination platform: PRP conjugate in hexavalent combination doses: as given in each trial vs DTaP-HBV-IPV combined plus separate Hib vaccination	1.13 (1.02–1.26) RR	meta-analysis 25 articles overall	Liu et al. 2022 Vaccines (Basel) quote However, the group that received the DTaP−HBV−IPV−Hib vaccine had a higher risk of fever than the group that received DTaP−HBV−IPV and separate Hib vaccinations (RR = 1.13; 95% CI: 1.02, 1.26; p = 0.021). abstract, Results Both arms received Hib; this compares formulations, not Hib vaccine against no vaccine. The same review found lower pain and swelling with the hexavalent product (next record).
Injection-site pain after vaccination severity: injection-site reaction case definition: Pain as reported in randomised and open-label trials of combination vaccines	children in infant combination-vaccine trials country: multiple Infant <1y1-4y	DTaP-HBV-IPV-Hib hexavalent combination platform: PRP conjugate in hexavalent combination doses: as given in each trial vs DTaP-HBV-IPV combined plus separate Hib vaccination	0.79 (0.69–0.91) RR	meta-analysis 25 articles overall	Liu et al. 2022 Vaccines (Basel) quote The individuals injected with the DTaP−HBV−IPV−Hib vaccine had a lower risk of pain and swelling than those injected with the combined DTaP−HBV−IPV and separate Hib vaccines (pain: RR = 0.79; 95% CI: 0.69, 0.91; p = 0.001; swelling: RR = 0.87; 95% CI: 0.78, 0.98; p = 0.020). abstract, Results Fewer injections, fewer local reactions. Swelling RR 0.87 (0.78-0.98) is in the same sentence.

Sequelae of Hib meningitis (hearing loss, neurodisability) Haemophilus influenzae serotype b

Post-acute and long-term sequelae

What can follow the acute illness: chronic disease, disability, cancers, congenital syndromes, post-infectious conditions.

Outcome (O)	Population (P)	Comparator	Estimate	Design (S)	Source
At least one major sequela after Hib meningitis (cognitive deficit, bilateral hearing loss, motor deficit, seizures, visual impairment, hydrocephalus) severity: major disabling sequela case definition: Major sequelae assessed after hospital discharge in published studies 1980-2008	all ages in included studies (predominantly children) vaccination status: not reported country: global (132 papers) period: 1980-2008 All ages	vs survivors of Hib meningitis with no sequela (risk, not a ratio)	9.5 median risk of at least one major sequela across studies (%) per Hib meningitis survivor discharged from hospital follow-up: after hospital discharge, as reported by each study	systematic review	Edmond et al. 2010 Lancet Infect Dis quote The median (IQR) risk of at least one major sequela was 24.7% (16.2-35.3%) in pneumococcal meningitis; 9.5% (7.1-15.3%) in Haemophilus influenzae type b (Hib), and 7.2% (4.3-11.2%) in meningococcal meningitis. abstract The bracketed range in the quote is an interquartile range across studies, not a confidence interval, so no ci_low or ci_high is recorded. Pneumococcal meningitis in the same review carried a much higher risk; Hib sat between pneumococcal and meningococcal.
Hearing loss as the most common major sequela of bacterial meningitis severity: hearing loss case definition: Distribution of major sequelae types among survivors with major sequelae, all pathogens	all ages in included studies (predominantly children) vaccination status: not reported country: global (132 papers) period: 1980-2008 All ages	vs other types of major sequela (distribution, not a risk ratio)	33.9 proportion of major sequelae that were hearing loss (%) per survivor with a major sequela, all bacterial meningitis	systematic review	Edmond et al. 2010 Lancet Infect Dis quote The most common major sequela was hearing loss (33.9%), and 19.7% had multiple impairments. abstract All-cause bacterial meningitis, not Hib-specific; a share of sequelae, not a risk per case. The same sentence reports that 19.7% had multiple impairments.
At least one major sequela after bacterial meningitis (all pathogens) severity: major disabling sequela case definition: Major sequelae after hospital discharge, random-effects pooled by WHO region	all ages in included studies (predominantly children) vaccination status: not reported country: WHO African Region setting: LMIC period: 1980-2008 All ages	vs European Region survivors (9.4% in the same sentence)	25.1 (18.9–32.0) pooled risk of at least one major sequela (%) per bacterial meningitis survivor	meta-analysis	Edmond et al. 2010 Lancet Infect Dis quote In the random-effects meta-analysis, all-cause risk of a major sequela was twice as high in the African (pooled risk estimate 25.1% [95% CI 18.9-32.0%]) and southeast Asian regions (21.6% [95% CI 13.1-31.5%]) as in the European region (9.4% [95% CI 7.0-12.3%]; overall I(2)=89.5%, p<0.0001). abstract All-cause bacterial meningitis, included to show the LMIC-high-income gradient; roughly twice the European Region pooled risk (next record). Heterogeneity was very high.
At least one major sequela after bacterial meningitis (all pathogens) severity: major disabling sequela case definition: Major sequelae after hospital discharge, random-effects pooled by WHO region	all ages in included studies (predominantly children) vaccination status: not reported country: WHO European Region setting: high-income period: 1980-2008 All ages	vs African and South-East Asian Region survivors in the same sentence	9.4 (7.0–12.3) pooled risk of at least one major sequela (%) per bacterial meningitis survivor	meta-analysis	Edmond et al. 2010 Lancet Infect Dis quote In the random-effects meta-analysis, all-cause risk of a major sequela was twice as high in the African (pooled risk estimate 25.1% [95% CI 18.9-32.0%]) and southeast Asian regions (21.6% [95% CI 13.1-31.5%]) as in the European region (9.4% [95% CI 7.0-12.3%]; overall I(2)=89.5%, p<0.0001). abstract All-cause bacterial meningitis, not Hib-specific.
Hearing impairment or other neurologic sequelae after Hib meningitis severity: hearing impairment or neurologic sequelae case definition: Survivors of Hib meningitis, CDC summary	children (Hib meningitis occurred primarily under age 5) vaccination status: unvaccinated country: United States period: prevaccine era Infant <1y1-4y	vs survivors without sequelae (risk, not a ratio)	15 to 30 proportion of survivors with sequelae (%) per Hib meningitis survivor	expert body	cdc.gov quote Hearing impairment or other neurologic sequelae occur in 15% to 30% of survivors. Clinical Features, meningitis paragraph CDC range without an interval or source list; sits above the Edmond review median for major sequelae (first post-acute record) because it includes milder impairments.
Any sequela after Hib meningitis severity: any sequela (mild to severe) case definition: Sequelae identified by medical record review and parental interview, Western Australia 1984-1990	children under five years of age risk group: non-Aboriginal children vaccination status: unvaccinated country: Australia (Western Australia) period: 1984-1990 Infant <1y1-4y	vs Aboriginal survivors (22.4% in the same sentence)	17.1 proportion of survivors with recorded sequelae (%) per Hib meningitis survivor follow-up: to 1990 (up to 6 years)	cohort	Bower et al. 1994 J Paediatr Child Health quote Sequelae were recorded for 17.1% of non-Aboriginal and 22.4% of Aboriginal children who survived Hib meningitis. abstract Chart review plus parental interview; the authors say mild and moderate disabilities are subject to recall and ascertainment bias. Severe sequelae are in the next record.
Severe sequelae after Hib meningitis (cerebral palsy, profound intellectual and physical disability) severity: severe sequelae case definition: Sequelae identified by medical record review, Western Australia 1984-1990	children under five years of age risk group: Aboriginal children vaccination status: unvaccinated country: Australia (Western Australia) period: 1984-1990 Infant <1y1-4y	vs non-Aboriginal survivors (3.6% in the same sentence)	10.5 proportion of survivors with severe sequelae (%) per Hib meningitis survivor follow-up: to 1990 (up to 6 years)	cohort	Bower et al. 1994 J Paediatr Child Health quote Surviving Aboriginal children experienced severe sequelae following Hib meningitis almost three times more frequently than surviving non-Aboriginal children (10.5% vs 3.6%), although mild and moderate sequelae were not more common in Aboriginal children. abstract Value is the Aboriginal figure; the non-Aboriginal figure is 3.6% in the same quote. Severe outcomes are less subject to the ascertainment bias the authors note for milder sequelae.
Severe hearing loss after Hib meningitis severity: severe hearing loss case definition: Population-based cohort of Navajo children with Haemophilus meningitis before age 5, assessed 3.6-15 years later	meningitis at less than 5 years of age; assessed at school age risk group: Navajo children (high-incidence population) vaccination status: unvaccinated country: United States (Navajo reservation) period: meningitis 1975-1986, follow-up 1990 n: 41 of 76 eligible survivors assessed Infant <1y1-4y5-11y12-17y	vs nearest-age siblings and unrelated age-matched controls (no sibling or control had any severe sequela other than intellectual disability)	5 proportion of survivors with severe hearing loss (%) per Hib meningitis survivor assessed follow-up: 3.6 to 15.0 years	cohort	D'Angio et al. 1995 Arch Pediatr Adolesc Med quote Twenty-nine percent of cases had severe neurologic sequelae, including mental retardation (24%), severe hearing loss (5%), cerebral palsy (7%), and seizure disorder (12%). abstract, RESULTS Only about half of eligible survivors consented, so selection bias is possible in either direction; the sibling comparison controls for family and socioeconomic environment, the age-matched comparison does not. Severe hearing loss is one component of the severe sequelae the quote lists.
Intellectual disability (mental retardation) after Hib meningitis severity: intellectual disability case definition: Standard intelligence testing of Navajo survivors versus siblings	meningitis at less than 5 years of age; assessed at school age risk group: Navajo children vaccination status: unvaccinated country: United States (Navajo reservation) period: meningitis 1975-1986, follow-up 1990 5-11y12-17y	vs nearest-age siblings (8% had intellectual disability)	8.0 relative risk vs nearest-age siblings per survivor follow-up: 3.6 to 15.0 years	cohort	D'Angio et al. 1995 Arch Pediatr Adolesc Med quote Eight percent of siblings (relative risk for cases vs siblings, 8.0; P = .05) and 2% of age-matched controls (relative risk vs cases, 10.0; P = .01) had mental retardation. abstract, RESULTS Sibling comparator reduces confounding by household and socioeconomic factors; the relative risk against unrelated age-matched controls was higher still in the same abstract. Small numbers.
Mean IQ after Hib meningitis severity: cognitive deficit case definition: Standard intelligence test scores	meningitis at less than 5 years of age; assessed at school age risk group: Navajo children vaccination status: unvaccinated country: United States (Navajo reservation) period: meningitis 1975-1986, follow-up 1990 5-11y12-17y	vs nearest-age siblings (mean IQ 87) and age-matched controls (mean IQ 95)	79 mean IQ score (cases vs siblings) per survivor assessed follow-up: 3.6 to 15.0 years	cohort	D'Angio et al. 1995 Arch Pediatr Adolesc Med quote RESULTS: The mean IQ for cases was lower than that for siblings (79 vs 87, P = .006) or age-matched controls (79 vs 95, P < .001). abstract, RESULTS Sibling scores were themselves below those of unrelated controls, pointing to shared environmental disadvantage; the case-sibling gap is the less confounded contrast.
Intellectual disability (mental retardation) after Hib meningitis severity: intellectual disability case definition: Population-based cohort of Navajo children with Haemophilus meningitis before age 5, assessed 3.6-15 years later	meningitis at less than 5 years of age; assessed at school age risk group: Navajo children (high-incidence population) vaccination status: unvaccinated country: United States (Navajo reservation) period: meningitis 1975-1986, follow-up 1990 n: 41 of 76 eligible survivors assessed Infant <1y1-4y5-11y12-17y	vs nearest-age siblings and unrelated age-matched controls (no sibling or control had any severe sequela other than intellectual disability)	24 proportion of survivors with intellectual disability (%) per Hib meningitis survivor assessed follow-up: 3.6 to 15.0 years	cohort	D'Angio et al. 1995 Arch Pediatr Adolesc Med quote Twenty-nine percent of cases had severe neurologic sequelae, including mental retardation (24%), severe hearing loss (5%), cerebral palsy (7%), and seizure disorder (12%). abstract, RESULTS Same cohort and caveats as the severe hearing loss record; the sibling and control comparison for this outcome is the relative-risk record that follows the hearing loss record. The quote also gives cerebral palsy and seizure disorder proportions.

Gaps

The WHO Hib position paper (July 2013, WER 88:413-426) could not be snapshotted: the IRIS PDF endpoints returned an empty DSpace placeholder and the who.int item page returned 404 or an unrelated page. Only the Vaccine journal summary (PMID 24156921), which carries no numbers, is cached. WHO's own burden and schedule statements are therefore absent.
No record for Hib disease in HIV-infected children or other immunocompromised groups: the Cochrane review of Hib vaccine in sickle cell disease (PMID 30125338) found no RCTs, and the Pink Book states efficacy studies have not been performed in populations at increased risk. Searches for Hib VE in HIV/sickle cell returned nothing usable.
No record for Hib vaccination in pregnancy or infants of vaccinated mothers: the only Cochrane review on the topic (PMID 26059051) was not fetched because the question is outside routine infant Hib programmes; not compiled.
No explicit booster-dose vaccine effectiveness estimate with a confidence interval was found: the Jackson 2013 meta-analysis describes only weak evidence from 2 studies that a booster adds protection, and the UK booster effect is captured as surveillance counts (hib-eff-035) and the 2012 review narrative, not as a VE.
No time-since-vaccination VE stratification with numbers: Ramsay 2003 (hib-eff-033) reports that effectiveness declined with time since vaccination (P=.0008) but the abstract gives no per-interval estimates; the full text was not cached.
No hearing-loss-specific risk per Hib meningitis case with a confidence interval from a Hib-only cohort: Edmond 2010 gives hearing loss as a share of all-pathogen major sequelae; D'Angio gives severe hearing loss in a small Navajo cohort without an interval (hib-pa-009).
Ramakrishnan 2009 (PMID 19751516) reports that about a quarter of African children surviving Hib meningitis had neuropsychological sequelae at discharge, but the abstract gives the Hib figure only in words; the schema requires a digit in value, so the record was dropped. The exact median is in the full text, which was not cached.
No record of Hib vaccine effectiveness in Latin America (Chile, Uruguay, Colombia, Brazil case-control studies): the search returned nothing, although such studies exist in the Jackson 2013 pool.
No Lombok (Indonesia) vaccine-probe trial record: the search returned no PubMed hit under the terms used.
No pre-vaccine epiglottitis incidence for the US or UK; the epiglottitis records are Japan (2007-2008) and Sydney (1990-1992).
Mulholland 1998 (PMID 9781744) is cached but not used: its '5 to 10 of episodes of severe pneumonia' sentence has a missing % sign in the PubMed abstract, so no number could be safely recorded.
Safety records are limited to combination-vaccine formulation comparisons; no Hib-versus-placebo adverse event rate with an interval was found in the cached abstracts (the trials and reviews report only that serious adverse events were rare or absent).

Flags for review

The 2007 Cochrane review of Hib conjugate vaccines (PMID 17443509, records hib-eff-004 to hib-eff-006) was formally WITHDRAWN in 2009 (PMID 19821280). The pooled RRs are kept because they are from RCTs and the withdrawal notice gives no reason in the search listing; a reviewer should decide whether withdrawn Cochrane estimates may be displayed, and if so they must be labelled as withdrawn.
The WHO Hib position paper could not be reached (see #GAP). If the IRIS PDF becomes reachable, the file needs WHO's own burden and schedule statements, which currently come from CDC and journal sources only.
hib-eff-001 to hib-eff-003 (Obonyo 2006) report VE as a percentage with the interval on the OR scale, so they carry ciscale=OR; a reader will misread '84 (0.08-0.30)' as a percentage interval unless the scale is printed. Same issue as the MMR Cochrane records.
Pre-vaccine incidence denominators differ: hib-bur-002 (US) and hib-bur-005 (UK) are per 100,000 children under 5; hib-bur-011 and hib-bur-013 give under-1 rates; hib-bur-026 and hib-bur-029 are all-ages rates. Do not line these up as a before/after without matching the age denominator.
Global death and case counts (hib-bur-021 to hib-bur-025) are modelled from vaccine-probe attributable fractions applied to all-cause pneumonia and meningitis deaths; their ranges are uncertainty ranges, not confidence intervals, and the 2000 and 2015 figures use different methods and should not be subtracted.
The Pink Book sentence 'Among children younger than age 5 years in 2018, the rate of invasive H. influenzae disease was 0.08 per 100,000 population and 38 cases of invasive disease due to Hib were reported' is internally ambiguous (0.08 looks like a Hib rate, not an all-serotype rate) and was not compiled. A reviewer may want to check it against the ABCs report.
The UK effectiveness of 56.7% (hib-eff-033) is a screening-method estimate from the 1999-2002 resurgence period with a 3p+0 schedule and partly acellular-pertussis combination product. It is a real finding about that programme, not a general statement about Hib vaccines, and should sit next to the trial estimates with that context.
Five records are immunological surrogates (hib-eff-021, hib-eff-037, hib-eff-042 to hib-eff-045): antibody thresholds and GMCs, not disease. They are filed as efficacy because the schema has no other kind, but the outcome field says 'immunological surrogate, not disease' on each and they must not be rendered as vaccine effectiveness.
hib-pa-002 to hib-pa-004 (Edmond 2010 hearing-loss share and regional pooled risks) are for ALL bacterial meningitis, not Hib alone; the Hib-specific figure from that review is hib-pa-001 only. hib-pa-009 and hib-pa-012 come from a single sentence of a small Navajo cohort (D'Angio 1995) and are component proportions of the same survivors; do not add them.
Three stray web snapshots were created while trying to reach the WHO position paper (iris-who-int-95a581152e, iris-who-int-3ca49e2e7b, who-int-3f29406b29); they are unused, contain no Hib content, and can be deleted by whoever maintains sources/web.
The Pink Book snapshot (cdc-gov-ab2e5483ef) only succeeded with PYTHONUTF8=1: tools/websource.py writes with the platform default encoding on Windows and fails on U+202F in the CDC page. Other agents hitting 'charmap' errors need the same workaround, or the tool needs an explicit encoding.
The brief named the disease ids hib_disease and hib_sequelae; schema/ rejects underscores in disease ids (pattern ^[a-z0-9-]+$), so this file uses hib-disease and hib-sequelae. Other agents following the same brief will hit the same schema error.

Search log (36 searches)

Haemophilus influenzae type b conjugate vaccine efficacy randomized trial · PubMed → Found the Obonyo 2006 meta-analysis (16491301), Thumburu 2015 (25984342), Low 2013 (24145955), Gambia PRP-T trial (9130939), Finnish PRP-D trial (2233904), Navajo PRP-OMP (1903846), Alaska PRP-D (2233906), Davis 2013 (24564188).
Haemophilus influenzae type b vaccine Gambia pneumonia trial · PubMed → Found 9130939 (Mulholland 1997 RCT), 9781744 (burden commentary), 8790673 (Adegbola prevaccine surveillance).
Haemophilus influenzae type b meningitis sequelae hearing loss systematic review · PubMed → Found Edmond 2010 (20417414) and Ramakrishnan 2009 (19751516); the rest were corticosteroid Cochrane reviews.
Hib vaccine schedule systematic review effectiveness doses booster · PubMed → Found Low 2013 trials review (24145955) and Jackson 2013 observational review (23811746).
Haemophilus influenzae type b global burden estimates children under 5 · PubMed → Found GBD and vaccine-impact modelling papers; Watt 2009 and Wahl 2018 found via the targeted searches below.
Hib vaccine failure United Kingdom resurgence booster waning · PubMed → Found Ladhani 2012 review (22244051).
Watt Haemophilus influenzae type b burden of disease in children younger than 5 years global estimates · PubMed → Found 19748399 (Watt 2009).
Wahl burden of Streptococcus pneumoniae and Haemophilus influenzae type b disease in children 2000-15 · PubMed → Found 29903376 (Wahl 2018).
Haemophilus influenzae type b booster dose United Kingdom campaign effectiveness Ramsay · PubMed → No hit; Ramsay 2003 found with a later search.
Haemophilus influenzae type b invasive disease epidemiology United States prevaccine era incidence · PubMed → Found 9746431 (California MMWR); prevaccine US figures taken from the Pink Book instead.
CDC Pink Book Chapter 8 Haemophilus influenzae · websource → Snapshotted as cdc-gov-ab2e5483ef (needed PYTHONUTF8=1 because the page contains narrow no-break spaces).
Hib conjugate vaccine booster campaign England effectiveness 2003 · PubMed → Found Ramsay 2003 screening-method VE (12898433).
Haemophilus influenzae type b vaccine effectiveness case-control England toddlers · PubMed → No hit.
Haemophilus influenzae type b meningitis case fatality children · PubMed → Found Park 2022 meta-analysis (35265327), van Ettekoven 2024 (39093565), Bower 1994 (7833072), Yaro 2006 (16645505), Scheifele 2005 (15632405), Collins 2018 (29289561), Wilfert 1990 (2179852).
epiglottitis Haemophilus influenzae type b incidence children vaccine era · PubMed → Found Takeuchi 2013 Japan (23512615) and Wood 2005 Sydney (16105154).
DTaP-IPV-Hib combination vaccine immunogenicity anti-PRP randomized · PubMed → Found Kang 2016 (27510380) and Kitchin 2007 (16670121).
HbOC Haemophilus influenzae type b oligosaccharide conjugate vaccine efficacy Northern California · PubMed → Found Black 1991 (2062621) and Black 1992 (1523069).
Haemophilus influenzae type b invasive disease incidence United States surveillance 2009-2015 Active Bacterial Core · PubMed → Found Soeters 2018 (29509834).
Hib vaccine effectiveness low-income countries case-control meningitis Africa Asia · PubMed → No hit under these terms.
Haemophilus influenzae type b vaccine effectiveness Kenya Uganda Bangladesh case-control · PubMed → No hit; Kilifi and Dhaka found with later searches.
Hib vaccine effectiveness acellular pertussis combination England case-control McVernon · PubMed → Found McVernon 2008 (17804596).
Haemophilus influenzae type b vaccine long-term effectiveness duration protection booster · PubMed → Found Hammitt 2016 Kilifi (26853149) and a booster model (28903749, not used).
Hib vaccine effectiveness immunocompromised sickle cell HIV · PubMed → No hit.
McVernon Haemophilus influenzae type b vaccine effectiveness acellular pertussis combination · PubMed → Found 17804596 only.
Hib vaccine probe study Bangladesh Lombok Indonesia effectiveness meningitis pneumonia · PubMed → No hit.
Haemophilus influenzae type b vaccine effectiveness Chile Uruguay Colombia Brazil case-control · PubMed → No hit.
WHO Hib position paper July 2013 WER8839 · websource → who.int item page 404; IRIS PDF returned an empty DSpace placeholder (two URL variants); the WHO publications search landed on an unrelated dracunculiasis page. Vaccine journal summary 24156921 fetched instead (no numbers).
Haemophilus influenzae type b vaccine Cochrane review · PubMed → Found Swingler 2007 (17443509, withdrawn 2009 as 19821280), the sickle-cell review (30125338, no trials) and Liu 2022 combination-vaccine meta-analysis (35335107).
Hib vaccine effectiveness Europe post-licensure vaccine failure incidence Netherlands Germany · PubMed → No hit.
Hib vaccine effectiveness Lombok Indonesia meningitis pneumonia trial · PubMed → No hit.
Hib conjugate vaccine effectiveness Bangladesh case-control meningitis pneumonia · PubMed → Found Baqui 2007 (17596795) and Chen 2014 herd protection (24397901, not used).
Haemophilus influenzae type b vaccine effectiveness Latin America case-control · PubMed → No hit.
Hib meningitis hearing loss survivors cohort outcome children · PubMed → Found D'Angio 1995 Navajo (7655584) and Taylor 2000 (11055253, no usable numbers in abstract).
Haemophilus influenzae type b vaccine Alaska Native Navajo effectiveness PRP-OMP post-licensure · PubMed → No hit.
Ladhani Haemophilus influenzae type b booster campaign impact England Wales 2003 · PubMed → Found Ladhani 2008 (17942585).
Hib vaccine failure England Wales children booster era epidemiology 2000-2012 · PubMed → No hit.