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

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Summary

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.

Introduction

Infection with the human papillomavirus (HPV) is a key cause of cervical cancer,1 and has been associated with other anogenital (vulvar, vaginal, penile, and anal) cancers2, 3 and head and neck cancers.4 HPV types of high oncogenic risk, 16 and 18, are detected in about 70% of invasive cervical cancers5 worldwide and in most anogenital and head and neck cancers that are positive for HPV.2, 4 The most common oncogenic HPV types worldwide—16, 18, 31, 33, 45, 52, and 58—contribute to about 90% of invasive cervical cancers.5

Two prophylactic vaccines have been licensed for use in many countries: the bivalent vaccine Cervarix (against HPV 16 and 18; GlaxoSmithKline Biologicals, Rixensart, Belgium) and the quadrivalent vaccine Gardasil (against HPV 6, 11, 16, and 18; Merck, Whitehouse Station, NJ, USA). Large clinical trials have shown almost 100% vaccine efficacy against precancerous lesions associated with these vaccine HPV types.6, 7, 8 Recent trials have also reported vaccine efficacy against non-vaccine type HPVs.8, 9, 10, 11

Public health officials worldwide continue to assess which HPV vaccine should be used in their vaccination programmes. Cross-protection afforded by the HPV vaccines is a key factor of interest.12, 13 However, differences between characteristics of trial participants such as baseline prevalence and distribution of HPV infection complicate the comparison of cross-protection between bivalent and quadrivalent vaccines. Through a systematic review of published work, we aimed to summarise and compare evidence from clinical trials about the cross-protective efficacy of the bivalent and quadrivalent vaccines in HPV-naive populations (ie, individuals who are DNA negative for all tested oncogenic HPV types). We focused on vaccine efficacy in this population because such efficacy is least diluted by the presence of women who are infected or immune at baseline, which can vary between trials. Thus, trials in HPV-naive populations provide improved estimates of the true prophylactic effect of vaccination.

Section snippets

Search strategy and selection criteria

We systematically reviewed published work and report it in accordance with the PRISMA guidelines.14 We searched for randomised controlled trials assessing the efficacy of the bivalent or quadrivalent vaccines that included populations who were HPV negative for all tested oncogenic types. We included trials reporting efficacy against either cervical or genital infection or disease (cervical intraepithelial neoplasia [CIN] or cervical cancer) endpoints associated with non-vaccine type oncogenic

Results

Figure 1 shows the search strategy. We identified 12 reports, including results from five different trials (two for the quadrivalent vaccine and three for the bivalent vaccine; appendix).9, 11, 21, 22, 23, 24, 25, 26, 27, 28, 29 The table summarises participant information and study characteristics and the appendix shows potential sources of bias. Populations from two trials of the quadrivalent vaccine (Females United to Unilaterally Reduce Endo/Ectocervical Disease [FUTURE] I and FUTURE II)

Discussion

Quadrivalent and bivalent HPV vaccines offer cross-protection against some non-vaccine HPV types for individuals without previous infection. In our analysis, quadrivalent vaccine was efficacious against outcomes associated with HPV 31, and bivalent vaccine was efficacious against outcomes associated with HPV 31, 33, and 45. We noted differences in estimates between the vaccines, with the bivalent vaccine showing greater efficacy than the quadrivalent vaccine against HPV 31, 33, and 45 for

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