Comparing Haemophilus influenzae type b Conjugate Vaccine Schedules: Systematic Review and Meta-Analysis of Vaccine Trials

Background: The optimal schedule and the need for a booster dose are unclear for Haemophilus influenzae type b (Hib) conjugate vaccines. We systematically reviewed relative effects of Hib vaccine schedules. Methods: We searched 21 databases to May 2010 or June 2012 and selected randomized controlled trials (RCTs) or quasi-RCTs that compared different Hib schedules (three primary doses with no booster dose [3p+0], 3p+1 and 2p+1) or different intervals in primary schedules and between primary and booster schedules. Outcomes were clinical efficacy, nasopharyngeal carriage and immunological response. Results were combined in random-effects meta-analysis. Results: Twenty trials from 15 countries were included; 16 used vaccines conjugated to tetanus toxoid (PRP-T). No trials assessed clinical or carriage outcomes. Twenty trials examined immunological outcomes and found few relevant differences. Comparing PRP-T 3p+0 with 2p+0 there was no difference in seropositivity at the 1.0μg/ml threshold by six months after the last primary dose (combined risk difference -0.02, 95%CI -0.10, 0.06). Only small differences were seen between schedules starting at different ages, with different intervals between primary doses, or with different intervals between primary and booster doses. Individuals receiving a booster were more likely to be seropositive than those at the same age who did not. Conclusions: There is no clear evidence from trials that any 2p+1, 3p+0 or 3p+1 schedule of Hib conjugate vaccine is likely to provide better protection against Hib disease than other schedules. Until more data become available, scheduling is likely to be determined by epidemiological and programmatic considerations in individual settings.