2 Doses Versus 0 Doses.
VE against Hib meningitis after 2 doses ranged from 87% (95% CI: 14–100%)27 to 99% (95% CI: 90–100%)24 (Fig. 2). The corresponding range for invasive Hib disease was 89% (95% CI: 60–97%)31 to 100% (95% CI: 68–100%).31
The pooled estimates of 2-dose VE against Hib meningitis were 96% (95% CI: 86–99%) based on community controls and 92% (95% CI: 75–97%) based on hospital controls (Fig. 2). For invasive Hib disease, only 2 studies that used vaccines other than PRP-OMP were identified and so meta-analysis was not performed. The 2 estimates of 2-dose VE for PRP-OMP were 99% (95% CI: 69–100%) and 100% (95% CI: 68–100%) (Fig. 3).
3 Doses Versus 0 Doses.
Estimates of 3-dose VE ranged from 65% (95% CI: −190 to −100%)23 to 98% (95% CI: 89–100%)24 against Hib meningitis and from 94% (in 2 studies, 95% CI: 68–99% or 62–99%)30,31 to 100% (95% CI: 64–100%) against invasive Hib disease.17 The estimate of 65% was an outlier and was based on comparing cases to community controls (the VE against Hib meningitis using hospital controls in this study was 86% [95% CI: −8 to 100%]).23
Meta-analysis produced 3-dose VE estimates of 96% (95% CI: 86–99%) and 94% (95% CI: 80–98%) against Hib meningitis, based on studies using community and hospital controls, respectively, with little evidence of statistical heterogeneity (Fig. 2). The corresponding estimate for invasive Hib disease was 97% (95% CI: 87–99%), but with moderate heterogeneity (I2 = 46.7%, Fig. 3). One additional study estimated VE of 3 doses of PRP-OMP as 99% (95% CI: −57 to 100%, Fig. 3).
Other Numbers of Doses Versus 0 Doses
Estimates of VE following different numbers of doses are summarized in Appendix Table 3, Supplemental Digital Content 1, http://links.lww.com/INF/B654.
Age at Initiation of Hib Vaccination
Where reported for the case-control studies, the intended age at initiation of Hib vaccination was either 6 weeks or 2 months (2 months in all studies of invasive Hib disease). For Hib meningitis, dose-specific VE did not appear to vary with age at initiation (Fig. 2).
In a study from Uganda, the median age at receipt of the third dose was greater for vaccinated cases than for controls (32 weeks for cases, 20 weeks for neighborhood controls, 17 weeks for hospital controls), but the difference was not assessed formally, only 3 cases had received 3 doses, and potential confounders were not considered.24
Interval Between Doses
In most reported schedules, the intended dosing interval was 1 or 2 months. This interval did not clearly influence VE (Figs. 2 and 3). In a case-control study of radiologically confirmed pneumonia from Colombia, the median delay between doses was slightly greater for cases (70 days between doses 1 and 2; 72 days between doses 2 and 3) than for controls (66 and 66.5 days), but the study did not find evidence against these being chance findings.29
Coadministration of Hib With Other Vaccines
Two studies investigated the receipt of Hib with diphtheria, tetanus and acellular pertussis (DTaP-Hib) vaccine as a risk factor for vaccine failure in UK children who had received 3 doses of Hib-containing vaccine18,19 (the studies appear to share some cases, but not controls). In 1 study, the ORs for invasive Hib disease comparing children who had received 1, 2 or 3 doses of DTaP-Hib (out of a total of 3 Hib-containing vaccines received) to children who had received 3 doses of DTwP-Hib were 1.13 (95% CI: 0.54–2.39), 2.70 (1.24–5.88) and 8.40 (3.77–18.68), respectively.19
In the second study of DTaP-Hib,18 point estimates from matched analysis suggested an increasing relative risk of invasive Hib disease with an increasing number of DTaP-Hib doses among children receiving 3 doses of any Hib-containing vaccine, although the CIs were wide and included 1 (eg, the OR comparing children who had received 3 doses of DTaP-Hib to those receiving 3 doses of other Hib vaccines was 7.29 [95% CI: 0.4–128]).
Six eligible cohort studies were identified (reported in 7 papers; Appendix Tables 4 and 5, Supplemental Digital Content 1, http://links.lww.com/INF/B654). Four estimated VE against invasive Hib disease,36–40 1 estimated VE against Hib meningitis41 and 1 estimated rate ratios for bacteraemia/septicaemia, meningitis, viral pneumonia and bacterial pneumonia associated with Hib vaccination.42 Three of these studies38,40,41 were included in the previous review.4 Two studies used a “case-cohort” design whereby VE was estimated using data on all cases of invasive Hib disease nationally and vaccination coverage in a sample of the general population.36,37
The intended Hib vaccination schedules were 6, 10, 14 weeks in South Africa39,39; 2, 4, 6 months in Chile38; and 2, 3, 4 months, with a booster at ≥11 months, in Germany.36,37 In Denmark, the schedule was initially 5, 6 months with a booster at 15–16 months, changing later to 3, 5, 12 months.41,42
There was a high prevalence of HIV infection among children participating in the South African study, and results were stratified by HIV infection status.38,39 We present only the VE estimates for HIV-negative children.
Potential Biases in Included Cohort Studies
Four of the 6 cohort studies adjusted for confounding by age but not socioeconomic status36,37,41,42 and 2 conducted sensitivity analyses around potential biases.36,37 The remaining 2 studies did not control for confounding38–40 (Appendix Table 5, Supplemental Digital Content 1, http://links.lww.com/INF/B654).
In the earlier of the 2 German case-cohort studies, it was unclear how the vaccination status of cases was ascertained.37 Presumably an issue in both German studies, in 1 paper the authors state that vaccine coverage among noncases might have been overestimated, as the survey population over-represented wealthier families.36 The authors conducted a sensitivity analysis assuming twice as many noncases were unvaccinated as in the main analysis; this brought down the VE estimates slightly (eg, 86% for 3 doses compared with 90% in the main analysis).
Number of Doses
1 Dose Versus 0 Doses.
Only 1 study, from Denmark, reported a 1-dose VE. This was estimated as 98% (95% CI: 91–99%) against Hib meningitis following 1 dose of PRP-T.41
2 Doses Versus 0 Doses.
The same Danish study41 was the only one to provide an estimate of VE following 2 doses, reported as 99% (95% CI: 96–100%) against Hib meningitis.
3 Doses Versus 0 Doses.
Sufficient data for meta-analysis were identified for 3-dose VE only against invasive Hib disease (Fig. 4). For the South African study, only the estimate for HIV-uninfected children is included in the meta-analysis. The pooled VE estimate was 94% (95% CI: 88–97%), with little heterogeneity. The Chilean and German studies suggest that 3 doses provide higher protection than 1–2 doses against invasive Hib disease (3-dose VE was 90–97%; VE for 1–2 doses was 68–90%).36–38
Other Numbers of Doses Versus 0 Doses.
Appendix Table 6, Supplemental Digital Content 1, http://links.lww.com/INF/B654, summarizes estimates of VE following unspecified numbers of doses.
Implications of a Booster Dose
In the German study of quadrivalent or pentavalent vaccines, VE against invasive Hib disease for 3 doses plus a booster at ≥11 months (or any dose in the second year of life regardless of the number of primary doses received) was 99% (95–100%), compared with a 3-dose VE of 97% (88–99%).37 In the German study of hexavalent vaccine, VE against invasive Hib disease was 90% (71–97%) for 3 doses and 100% (53–100%) for 3 doses plus booster.36 The point estimates from this study are also consistent with a booster compensating for an incomplete primary series: VE was 100% (CI reported as 0–100%) and 68% (19–88%) for incomplete primary series with and without booster, respectively.36
Age at Initiation of Hib Vaccination
In Denmark, the intended age at first vaccination was 2, 3 or 5 months of age, and 3-dose VE against Hib meningitis was 99% (95–100%).41 In the South African study, initiation was intended at 6 weeks; 3-dose VE against invasive Hib was 97% (74–100%) among children who were not HIV infected.40 Three-dose VEs against invasive Hib from the Chilean and German studies (intended age at initiation 2 months) ranged from 90% to 97%.36–38
Interval Between Doses
The German and South African schedules have 1-month intervals and report 3-dose VE of 90–97%.36,37,39 The Chilean schedule has 2-month intervals; the 3-dose VE was 92% (65–100%),38 within the range of estimates for a 1-month interval.
Coadministration of Hib With Other Vaccines
In the Chilean, German and South African cohort studies, VE against invasive Hib for 3 doses of quadrivalent or pentavalent vaccine was 92–97%.37,38,40 The 3-dose VE against invasive Hib afforded by hexavalent vaccine in Germany was similar (90%).36 Comparing the point estimates from the 2 German studies, 1–2 doses of quadrivalent/pentavalent vaccine (DTaP-Hib with or without inactivated polio vaccine) appeared to be more effective (VE 90%, 95% CI: 67–97%)37 than 1–2 doses of hexavalent vaccine (DTaP-Hib with inactivated polio vaccine and hepatitis B vaccine, VE 68%, 95% CI: 19–88%),36 although the CIs overlap.
The Chilean and South African studies presented 3-dose VE against invasive Hib for DTwP-Hib of 90–92%.38,40 In the German studies, vaccines were coadministered with DTaP and 3-dose VEs against invasive Hib disease were 90% (95% CI: 71–97%) for hexavalent vaccine and 97% (95% CI: 88–99%) for quadrivalent/pentavalent vaccines. As these study circumstances may not be comparable, and the VE estimates overlap, there is no strong evidence from cohort studies for a difference in VE according to whether Hib is coadminstered with DTaP or DTwP vaccine.
Screening Method Studies
Three studies43–45 included in the previous review,4 and 1 additional study46 estimated VE against invasive Hib disease using the screening method (in screening method studies, vaccine effectiveness is calculated as 1−[PCV(1−PPV)]/[(1−PCV)PPV], where PCV is the proportion of the cases who are vaccinated and PPV is the proportion of the population vaccinated [ie, vaccine coverage]) (Appendix Table 7, Supplemental Digital Content 1, http://links.lww.com/INF/B654). In England and Wales during 1993 to 2003 (intended schedule 2, 3, 4 months), VE for full primary vaccination or a single catch-up dose at ≥13 months was estimated as 57% (95% CI: 43–67%), or 72% in a sensitivity analysis which assumed that vaccination coverage in the population was 2% higher than reported.45 The authors suggested that their relatively low VE estimate might partly reflect the use of the DTaP-Hib vaccine used at that time in the United Kingdom. Again considering either full primary vaccination or 1 catch-up dose, VE was higher within 2 years of scheduled vaccination (66%, 95% CI: 51–76%) than after 2 years (37%, 95% CI: −3 to −62%). This is consistent with waning immunity, although the CIs overlap.45
A German screening method study reported VE against invasive Hib disease as 68% (95% CI: 33–84%), 95% (93–97%) and 99% (98–99%) for 1, 2 and 3 doses, respectively; the intended schedule was DTaP-Hib or DTaP-IPV-Hib at 2, 3, 4 months, with a booster at 11–15 months.44 Another screening method study reported on invasive Hib disease in Valencia, Spain (December 1995 to November 1996)46: VE for ≥1 dose was 91% (95% CI: 28–99%). A screening method study from Australia in the period 1993 to 1996 presents an overall VE of 89% (no CI is given) for full vaccination (defined differently depending on the child’s age and the type of vaccine given).43 These latter 2 studies did not include information on coadministered vaccines.
This review confirms previous results3,4,6–8 that 2 or 3 doses of Hib vaccine are highly effective against Hib disease. Estimates of VE for 1, 2 and 3 doses from meta-analysis of case-control studies using community controls were 55%, 96% and 96%, respectively, against Hib meningitis (estimates were similar for studies using hospital controls). For invasive Hib disease, the VE estimates for 1 and 3 doses were 59% and 97%. Cohort studies also showed high 3-dose VE of 94%. Comparison between studies was restricted by the heterogeneity of vaccines used and limited variation in schedules, but did not favor any particular schedule. Immunogenicity data from trials are also inconclusive regarding the most effective schedule.9
There was moderate heterogeneity in the 3 estimates of 3-dose VE against invasive Hib disease from case-control studies (I2 = 46.7%). The practical implications of this statistical heterogeneity are unclear, as all of the 3-dose estimates that contributed to this pooled estimate were high (≥90%). Most of the estimates of dose-specific VE were based on only 3, and all on ≤4, studies, which limits the certainty with which conclusions can be drawn. The screening method allows only limited adjustment for confounding, so estimates from studies using this method must also be treated cautiously.
We included only studies that used concurrent comparison groups, as these studies measure only the direct effect of vaccination, whereas studies using historical comparison groups estimate the combined direct and indirect effects. Estimates from the 2 designs are therefore not comparable.45 Two additional cohort studies that used historical comparison groups reported VE as 98% following 3 doses in the United Kingdom47 and 98% following “adequate immunisation” (“2 weeks after receiving a second dose of Hib vaccine before the age of 12 months or 2 weeks after receiving one dose of vaccine after the age of 12 months”) with PRP-OMP in Australia.48
Two cohort studies suggest that a booster dose after the full primary series may enhance VE against invasive Hib. One of these studies also suggests that a booster can compensate for an incomplete primary course. This is consistent with immunogenicity data from trials showing increases in antibody titers following a booster dose of Hib vaccine.49,50 Studies of the impact of Hib vaccine in the United Kingdom also suggest that a booster is beneficial.51 Hib vaccination was introduced in a 2-, 3-, 4-month schedule in the United Kingdom, together with a catch-up campaign, and substantially reduced disease incidence. Nine years later, incidence began to rise, leading to a booster campaign targeting children aged 6 months to 4 years. A routine booster dose at age 12 months was subsequently introduced and the incidence of Hib disease in the United Kingdom has remained low.51 However, other factors besides the absence of a booster dose (including the temporary effects of the catch-up campaign and a change from DTwP-Hib to DTaP-Hib) may have contributed to the observed increase in incidence.51
We assessed Hib VE in general populations and did not consider special groups. One important such group is children who are HIV positive, in whom VE appears lower compared with children who are HIV negative. For example, in the South African study, VE estimates were stratified by HIV status, and VE of 1 or more vaccine doses was 55% (95% CI: −5 to 80%) and 91% (95% CI: 79–96%) among children with and without HIV infection, respectively.39,40 As noted in a separate systematic review of Hib disease and vaccination in HIV-positive children, a booster dose may be particularly important for children who are HIV positive.52 Thus vaccine scheduling decisions may need to consider the epidemiology of HIV in the target population, as well as that of Hib disease.
Two case-control studies from England and Wales, which appear to share some cases, concluded that vaccination with DTaP-Hib is less effective against invasive Hib disease than vaccination with DTwP-Hib18,19 (children in these studies were born between October 1999 and June 200119 or after July 199318). As noted above, the history of Hib vaccination in England and Wales is complicated,51 and it is difficult to separate the effects of several factors on vaccine effectiveness and impact. Serological data from the United States as well as the United Kingdom have reported lower immunogenicity of DTaP-Hib compared with Hib vaccine given with DTwP or separately from (but simultaneously with) DTaP.53–55 The generalizability of these results to currently used acellular pertussis combination vaccines, and the extent to which any effect may differ between vaccine formulations (depending, eg, on the number of pertussis or other antigens included), is unclear.
Possible differences in study design and conduct, in adherence to intended vaccination schedules, and in Hib epidemiology between settings mean that comparisons between studies should be interpreted cautiously. Although any additional benefit of 3 doses compared with 2 may be small, other authors have summarized arguments against recommending a 2-dose schedule3: 2-dose effectiveness may vary with vaccine type, and dose-specific effectiveness against carriage is unclear. Also, 2-dose VE as measured in the studies may partly reflect the short-term effect of vaccination (ie, for the relatively short period between the second and third doses), whereas 3-dose VE may be measured over a longer time period over which protection may wane. Thus, it is possible that the apparently high VE for 2 doses may not be maintained in the long term. Finally, a 3-dose schedule is practical if Hib vaccine is administered with the diphtheria, tetanus and pertussis vaccine (under current recommendations for 3 primary doses of the diphtheria, tetanus and pertussis vaccine).3
At least 2 doses of Hib vaccine are required to achieve high effectiveness (eg, >85%), particularly for vaccines other than PRP-OMP. A booster dose may be beneficial, but further data on the level and duration of immunity following primary vaccination, and on the effect of boosters at different times, would be helpful to optimize the timing of a booster.
We thank Ana Maria Henao Restrepo and Ximena Laurie for support in conducting this review. We are also grateful to Pippa Scott, Shelagh Redmond and Nahara Martinez for carrying out and sharing the results of the literature search and initial screening. We thank Kenda Cunningham, Rein Houben and John Bradley for assistance with translations.
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Haemophilus influenzae type b; conjugate vaccines; vaccine schedules; systematic reviews; meta-analysis
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