Cross-protective efficacy of two human papillomavirus vaccines: A systematic review and meta-analysis

Talía Malagón, Mélanie Drolet, Marie Claude Boily, Eduardo L. Franco, Mark Jit, Jacques Brisson, Marc Brisson*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    331 Citations (Scopus)


    Background: The extent of cross-protection is a key element in the choice of human papillomavirus (HPV) vaccine to use in vaccination programmes. We compared the cross-protective efficacy of the bivalent vaccine (HPV 16 and 18; Cervarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) and quadrivalent vaccine (HPV 6, 11, 16, and 18; Gardasil, Merck, Whitehouse Station, NJ, USA) against non-vaccine type HPVs. Methods: We searched Medline and Embase databases, conference abstracts, and manufacturers' websites for randomised clinical trials assessing the efficacy of bivalent and quadrivalent vaccines against persistent infections (lasting ≥6 months) and cervical intraepithelial neoplasia (CIN) associated with the non-vaccine type HPVs (types 31, 33, 45, 52, and 58). We included studies of participants who were HPV DNA negative before vaccination for all HPV types assessed. We assessed heterogeneity in vaccine efficacy estimates between trials with I2 and χ2 statistics. Findings: We identified two clinical trials (Females United to Unilaterally Reduce Endo/Ectocervical Disease [FUTURE] I and II) of the quadrivalent vaccine and three (Papilloma Trial Against Cancer In Young Adults [PATRICIA], HPV007, and HPV-023) of the bivalent vaccine. Analysis of the most comparable populations (pooled FUTURE I/II data vs PATRICIA) suggested that cross-protective vaccine efficacy estimates against infections and lesions associated with HPV 31, 33, and 45 were usually higher for the bivalent vaccine than the quadrivalent vaccine. Vaccine efficacy in the bivalent trial was higher than it was in the quadrivalent trial against persistent infections with HPV 31 (77·1% [95% CI 67·2 to 84·4] for bivalent vaccine vs 46·2% [15·3 to 66·4] for quadrivalent vaccine; p=0·003) and HPV 45 (79·0% [61·3 to 89·4] vs 7·8% [-67·0 to 49·3]; p=0·0003), and against CIN grade 2 or worse associated with HPV 33 (82·3% [53·4 to 94·7] vs 24·0% [-71·2 to 67·2]; p=0·02) and HPV 45 (100% [41·7 to 100] vs -51·9% [-1717·8 to 82·6]; p=0·04). We noted substantial heterogeneity between vaccine efficacy in bivalent trials against persistent infections with HPV 31 (I2=69%, p=0·04) and HPV 45 (I2=70%, p=0·04), with apparent reductions in cross-protective efficacy with increased follow-up. Interpretation: The bivalent vaccine seems more efficacious against non-vaccine HPV types 31, 33, and 45 than the quadrivalent vaccine, but the differences were not all significant and might be attributable to differences in trial design. Efficacy against persistent infections with types 31 and 45 seemed to decrease in bivalent trials with increased follow-up, suggesting a waning of cross-protection; more data are needed to establish duration of cross-protection. Funding: Public Health Agency of Canada.

    Original languageEnglish
    Pages (from-to)781-789
    Number of pages9
    JournalThe Lancet Infectious Diseases
    Issue number10
    Publication statusPublished - Oct 2012

    Bibliographical note

    Funding Information:
    This work was supported by the Public Health Agency of Canada, the Canada Research Chairs program (support for MB), a team grant from the Canadian Institutes of Health Research ( grant CRN-83320 ), and a Frederick Banting and Charles Best Canada Graduate Scholarship from the Canadian Institutes of Health Research (support for TM). We thank Lauri Markowitz and Harrell Chesson for their comments on the report.


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