Post-hoc analysis from phase III trials of human papillomavirus vaccines: considerations on impact on non-vaccine types

ABSTRACT

Background: Substantial heterogeneity has been reported in efficacy against high-grade cervical intraepithelial neoplasia (CIN) irrespective of HPV type in phase III results for bivalent and quadrivalent human papillomavirus virus (HPV) vaccines (AS04-HPV and qHPV). Real-world data recently confirmed a very high overall impact of AS04-HPV, supporting the validity of the observed heterogeneity. To explore the reasons for heterogeneous efficacy, we assessed vaccine impact on high-grade lesions not caused by vaccine types.

Research methods: We extracted case counts of CIN lesions containing (1) at least one vaccine HPV type, (2) at least one vaccine HPV type and a high-risk non-vaccine type (co-infections) and (3) no vaccine types (non-vaccine or no high-risk HPV types). Based on these, Phase III cross-protective efficacies were estimated with exclusion (3) and with inclusion (2 and 3) of co-infections.

Results: Cross-protective efficacy of AS04-HPV against CIN3 lesions ranges from 81.3% (95%CI: 34.7;96.5) (excluding co-infections) to 88.5% (95%CI:62.4;97.8) (including co-infections). For qHPV the efficacy ranges from −58.7% (95%CI: −180.5;8.5) (excluding co-infections) to 13.1% (95%CI: −39.0;45.9) (including co-infections).

Conclusions: Heterogenous overall efficacy against CIN3 between AS04-HPV and qHPV is driven by differential efficacy against lesions that do not contain vaccine types, which may be related to the impact of different adjuvants on the immune response.

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KEYWORDS:

• AS04-adjuvanted HPV-16/18 vaccine
• cervical cancer
• cervical intraepithelial neoplasia
• cross-protection
• human papillomavirus

Article highlights

• Prophylactic HPV vaccines vary in the number of HPV types included in the vaccines and in the adjuvant added to their formulation.

• All prophylactic HPV vaccines show high efficacy against infections and precancerous lesions related to HPV types included in the vaccines. However, when comparing phase III results for the different vaccines, the point estimate for overall efficacy of precancerous lesions irrespective of the type of HPV that causes the disease largely differ.

• Through our analysis we provide evidence that these differences in overall efficacy are driven by vaccines differential impact on lesions that are not caused by the HPV types included in the vaccines.

• The observation may be explained with differences of the immunological effects of the different adjuvants on lesion clearance and progression, irrespective of the HPV type.

• We highlight that epidemiological projections based on the HPV types included in the vaccines are not sufficient to predict overall impact on advanced precancerous lesions. Benefits and associated public health relevance of adjuvant formulations in HPV vaccines, as well as underlying immunological mechanisms require further exploration

Author contributions

AM and MR were involved in the conception or the design of the study. All authors were involved in the analyses or interpretation of the data. VB and MR participated in the collection or generation of the study data. NK performed the analysis. All authors had full access to the data and gave final approval before submission.

Acknowledgments

The authors would like to thank Frank Struyf (GSK, Wavre, Belgium) for his contribution to the analysis. The authors also thank Business & Decision Life Sciences platform for editorial assistance, manuscript coordination and design support for the digital animation related to this publication, on behalf of GSK. Bruno Baudoux coordinated publication development and editorial support and Valérie Lafontaine provided design support.

Declaration of interest

All authors are employees of the GSK group of companies. M. Ryser, V. Berlaimont, A. Mihalyi and R. van der Most also hold shares in the GSK group of companies.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplemental material

Supplemental data for this article can be accessed here.

Additional information

Funding

GlaxoSmithKline Biologicals SA took in charge all costs associated with the analysis; and the development and publication of this manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.