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Pediatric Infectious Disease Journal:
doi: 10.1097/INF.0b013e3182a14e57
Vaccine Reports

Effectiveness of Haemophilus influenzae Type b Vaccines Administered According to Various Schedules: Systematic Review and Meta-analysis of Observational Data

Jackson, Charlotte BA, MSc, PhD*†; Mann, Andrea BSc, MSc, PhD; Mangtani, Punam BSc, MBBS, MRCP, MSc, MD; Fine, Paul AB, VMD, MSc, PhD

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Author Information

From the *Research Department of Infection and Population Health, University College London; Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London, United Kingdom.

Accepted for publication June 18, 2013.

This work was funded by the World Health Organization. The authors have no other funding or conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Address for correspondence: Charlotte Jackson, University College London, Mortimer Market Centre (4th Floor), Off Capper Street, London, WC1E 6JB. E-mail:

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Background: Conjugate vaccines against Haemophilus influenzae type b (Hib) are widely used. The full implications of Hib vaccination schedule for vaccine effectiveness (VE) are unclear.

Methods: We searched the literature for observational studies reporting the effectiveness of conjugate Hib vaccines administered according to different schedules. We summarized dose-specific VE estimates, where appropriate, using random effects meta-analysis.

Results: Thirty-one eligible articles (reporting 30 studies conducted in 17 countries) were identified. 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. Estimates were similar using hospital controls. 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). 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. Using data from 4 cohort studies, 3-dose VE was estimated as 94% (88–97%). There was some evidence that Hib vaccine was less effective when administered with acellular (rather than whole cell) pertussis vaccine. Weak evidence from 2 studies suggested that a booster confers some additional protection following full primary vaccination and may compensate for an incomplete primary series.

Conclusions: Observational data suggest that ≥2 doses of Hib vaccine are required for high effectiveness, but do not strongly favor any particular schedule.

Haemophilus influenzae type b (Hib) causes an estimated 371,000 deaths and >8 million cases of severe disease annually.1 Currently used conjugate Hib vaccines are immunogenic2 and clinically effective.3,4 The Expanded Programme on Immunization recommends 3 primary doses of Hib conjugate vaccine administered with the diphtheria, tetanus and pertussis vaccine, starting at 6 weeks of age, with 4–8 weeks between doses.

In 2010, the World Health Organization launched the Optimizing Immunization Schedules project to evaluate whether, and how, the effectiveness of vaccines including Hib is related to the vaccination schedule.5 This review forms part of that evaluation. Together with similar reviews of other vaccines, it aims to inform decisions regarding the scheduling of childhood vaccinations.

Previous reviews have summarized estimates of overall and dose-specific effectiveness of Hib vaccination from observational studies4,6 and randomized controlled trials.3,6–8 In this review of observational studies, we consider in more detail the implications of schedule relevant factors: the number of doses of Hib-containing vaccine, age at initiation of vaccination, dosing interval and the implications of a booster dose or coadministration with other vaccines. Data from trials are summarized in a separate review.9

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Search Strategies

The following databases were searched in May 2010 and again in June 2012, without date or language restrictions: Medline, the Cochrane Library, African Index Medicus, Indian Medlars Centre, Latin American and Caribbean Health Sciences Literature (see Appendix, Supplemental Digital Content 1,, for the Medline search strategy). Clinical trial registries and regulatory authority dossiers were also searched in May 2010. Reference lists of 2 reviews4,10 were hand-searched. Further details of the literature search are provided in the appendix of the accompanying review of trial data.9

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Eligibility Criteria

We included observational studies conducted in general populations, which allowed assessment of vaccine effectiveness (VE) as a function of number of doses, age at first dose, dosing interval, receipt of a booster or coadministration of other vaccines (in the same or different syringes). Studies were eligible if they presented VE comparing a given number of doses to another number of doses, or to no vaccination. Eligible outcomes were all-cause pneumonia, Hib pneumonia, bacteraemia/septicaemia, meningitis, invasive Hib disease, all-cause mortality, mortality due to Hib pneumonia, mortality due to invasive Hib disease and epiglottitis.

We excluded studies that reported only on polysaccharide (nonconjugate) vaccine, or PRP-D conjugate vaccine (which is no longer used). Studies that used historical (as opposed to concurrent) comparison groups were also excluded.

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Screening of Articles

Studies were initially classified as likely observational studies, intervention studies and other studies. Titles and abstracts of observational studies were searched electronically for key terms likely to be included in eligible studies (eg, describing the study design; see Appendix, Supplemental Digital Content 1,, for the full list). Papers with potentially relevant titles, and with abstracts in a language other than English, were marked for retrieval in full. Studies that passed electronic screening were manually screened and the full text retrieved where necessary. A 10% random sample of observational studies that did not pass electronic screening was also manually screened.

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Data Extraction and Analysis

Data were extracted by 1 reviewer and checked by a second. Some information is presented in a similar format to the previous review4; we also extracted data on additional schedule relevant factors. Due to the relatively small number of articles identified, we did not exclude studies based on their potential for bias, but summarize any methodological concerns in the text. Forms for screening and data extraction were created in web-based systematic review software (DistillerSR, Evidence Partners, Ottawa, Canada).

For each outcome against which dose-specific VE was reported by ≥3 studies, we performed random effects meta-analysis using the method of DerSimonian and Laird11 to calculate a pooled odds ratio (OR). The OR is related to VE by the equation VE = 100 × (1−OR). Studies were eligible for meta-analysis if they reported VE for 1, 2 or 3 vaccine doses. Studies of the polyribosyl ribitol phosphate outer membrane protein (PRP-OMP) vaccine were analyzed separately from other vaccines, as there is evidence that this vaccine is more immunogenic12–14 than other Hib vaccines, especially after a single dose. Any point estimate or confidence limit of 100% was set to 99.5% before meta-analysis (papers did not always provide sufficient information to allow modification of the point estimate based on changes to a 2 × 2 table).

Heterogeneity was assessed using the I2 statistic, which measures the percentage of variation between studies that is attributable to heterogeneity.15 Values of I2 of 25%, 50% and 75% are considered to represent low, moderate and high heterogeneity, respectively.15 We identified insufficient data to stratify further, for example, by dosing interval or age at initiation. Statistical analysis was conducted using Stata 12 (StataCorp, College Station, TX).

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After de-duplication, the literature search produced 3892 results. Our screening process identified 24 eligible papers; 7 more were identified from the previous review.4 Therefore, 31 papers (reporting 30 studies conducted in 17 countries) were included: 20 case-control studies, 6 cohort studies and 4 studies that used the screening method (Fig. 1). Manual checking of a 10% random sample of the studies that were classified as observational on initial screening but not identified by electronic screening found no additional eligible papers.

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None of the studies directly compared schedules (eg, by comparing rates of Hib disease among children initiating vaccination at different ages), although several presented VE estimates for different numbers of doses. Therefore, many of the comparisons we report are between estimates from different studies. We focus on Hib meningitis and invasive Hib disease, as these were the only outcomes with microbiological confirmation for which VE estimates were available for more than 1 schedule. We present VE estimates for 1, 2 and 3 doses in the main text and include estimates for undetermined numbers of doses (eg, ≥1) and for other outcomes (including radiologically confirmed pneumonia) in the Appendix, Supplemental Digital Content 1,

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Case-control Studies

Six of the 20 case-control studies16–21 (Appendix Table 1, Supplemental Digital Content 1, were not included in the previous review.4 Among 15 case-control studies that reported the intended vaccination schedule, 6 (from Malawi,22 Bangladesh,23 Uganda,24,25 Senegal20 and Rwanda26) used the basic Expanded Programme on Immunization schedule of 6, 10, 14 weeks. In the Dominican Republic,27 Brazil28 and Colombia,29 the intended schedule was 2, 4, 6 months. Studies from the United Kingdom18,19 and The Gambia30 used a 2-, 3-, 4-month schedule. In a US study, the schedules were 2, 4, 12 months for PRP-OMP and 2, 4, 6, 15 months for Hib oligosaccharide conjugate vaccine.31 The latter was the only schedule reported in a case-control study that included a booster dose. Two other US studies reported intended schedules of 2, 4, 6 months.17,32 One case-control study was nested within a nonrandomized intervention study (the primary analysis included children who were not offered the vaccine and those whose parents refused vaccination).17 We report only results from the nested case-control study.

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Potential Biases in Included Case-control Studies

The case-control studies appeared to be at low risk of bias. Most (17/20) used community controls, for example, children identified from electronic registers or door-to-door canvassing,16–21,23,24,27–35 who are likely to have come from the same population as the cases.

Five studies used hospital controls22–26 (2 also included community controls).23,24 In 3 of these, the controls for estimating VE against Hib meningitis were children hospitalized with pneumococcal meningitis22,25,26 (the studies were conducted before pneumococcal vaccine was introduced in the respective countries). It is unclear whether these hospital controls came from the same population as the cases; however, the VE estimates against Hib meningitis from these studies were similar to those from other studies.

Two studies recruited hospital controls with conditions other than pneumonia and meningitis23 or conditions unlikely to be caused by Hib.24 Both studies reported similar VE estimates based on hospital and community controls.23,24

All of the case-control studies considered 1 or more confounders, except for 1 study of purulent meningitis26 (Appendix Table 1, Supplemental Digital Content 1, The remainder either matched on or adjusted for age, and most took account of confounding by socioeconomic status.

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Number of Doses in Primary Schedule
1 Dose Versus 0 Doses.

Estimates of effectiveness of 1 dose of Hib vaccine ranged from 11% (95% confidence interval [CI]: −151 to 66%) against Hib meningitis in Malawi22 to 100% (95% CI: 39–100%) against invasive Hib disease in a US study using PRP-OMP.31 (In the latter study, the authors interpreted the result cautiously, choosing not to present a point estimate of 100% given the limited use of PRP-OMP, the small numbers of cases and the complete absence of cases in vaccinated children.)

Meta-analysis produced estimates of 1-dose VE against Hib meningitis of 55% (95% CI: 2–80%) and 53% (95% CI: −14 to 81%), based on studies using community and hospital controls, respectively (Fig. 2); all of these studies used PRP-T vaccine. There was moderate heterogeneity in the estimate using hospital controls (I2 = 35.8%) but not that using community controls (I2 = 7.9%). All of the case-control studies of invasive Hib disease used community controls. Excluding studies that used only or mainly PRP-OMP, VE of 1 dose against invasive Hib disease was estimated as 59% (95% CI: 30–76%), with little heterogeneity (I2 = 0%, Fig. 3). For PRP-OMP, VE appeared to be high (>90%) even after a single dose, but meta-analysis was not performed as estimates were available from only 2 studies (Fig. 3).

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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).

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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).

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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,

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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

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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

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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]).

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Cohort Studies

Six eligible cohort studies were identified (reported in 7 papers; Appendix Tables 4 and 5, Supplemental Digital Content 1, 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.

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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,

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).

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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

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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.

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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

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Other Numbers of Doses Versus 0 Doses.

Appendix Table 6, Supplemental Digital Content 1,, summarizes estimates of VE following unspecified numbers of doses.

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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

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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

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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.

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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.

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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, 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.

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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.

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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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