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Comparing Haemophilus influenzae Type b Conjugate Vaccine Schedules: A Systematic Review and Meta-analysis of Vaccine Trials

Low, Nicola MD*; Redmond, Shelagh M. PhD*; Rutjes, Anne W. S. PhD*†; Martínez-González, Nahara A. MSc*‡; Egger, Matthias MD*; di Nisio, Marcello PhD§¶; Scott, Pippa PhD*

The Pediatric Infectious Disease Journal: November 2013 - Volume 32 - Issue 11 - p 1245–1256
doi: 10.1097/INF.0b013e31829f0a7e
Vaccine Reports

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 or quasi-randomized controlled trials that compared different Hib schedules (3 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 (polyribosylribitol phosphate conjugated to tetanus toxoid). No trials assessed clinical or carriage outcomes. Twenty trials examined immunological outcomes and found few relevant differences. 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). 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.

Supplemental Digital Content is available in the text.

From the *Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Center for Aging Sciences (Ce.S.I.), G. d’Annunzio University, Chieti, Italy; Institute of General Practice and Health Services Research, University of Zürich, Zürich, Switzerland; §Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University Foundation, Chieti, Italy; and Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.

Accepted for publication May 28, 2013

N.L. and S.M.R. contributed equally.

The authors alone are responsible for the views expressed in this publication, and they do not necessarily represent the decisions, policy or views of the World Health Organization.

Address for correspondence: Pippa Scott, PhD, Institute of Social and Preventive Medicine, University of Bern, Finkenhubelweg 11, CH-3012 Bern, Switzerland. E-mail:

This project received funding from the World Health Organization and from the Swiss National Science Foundation (grant no. 138490). 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 (

© 2013 by Lippincott Williams & Wilkins, Inc.