Phase II studies to select the formulation of a multivalent HPV L1 virus-like particle (VLP) vaccine

Abstract

Our objective was to develop a multivalent prophylactic HPV vaccine that protects against infection and disease caused by HPV16/18 (oncogenic types in existing prophylactic vaccines) plus additional oncogenic types by conducting 3 Phase II studies comparing the immunogenicity (i.e., anti-HPV6/11/16/18 geometric mean titers [GMT]) and safety of 7 vaccine candidates with the licensed quadrivalent HPV6/11/16/18 vaccine (qHPV vaccine) in young women ages 16–26. In the first study (Study 1), subjects received one of 3 dose formulations of an 8-valent HPV6/11/16/18/31/45/52/58 vaccine or qHPV vaccine (control). In Study 2, subjects received one of 3 dose formulations (termed low-, mid-, and high-dose formulations, respectively) of a 9-valent HPV6/11/16/18/31/33/45/52/58 vaccine (9vHPV vaccine) or qHPV vaccine (control). In Study 3, subjects concomitantly received qHPV vaccine plus 5-valent HPV31/33/45/52/58 or qHPV vaccine plus placebo (control). All vaccines were administered at day 1/month 2/month 6. In studies 1 and 3, anti-HPV6/11/16/18 GMTs at month 7 were non-inferior in the experimental arms compared with the control arm; however, there was a trend for lower antibody responses for all 4 HPV types. In Study 2, this immune interference was overcome with the mid- and high-dose formulations of the 9vHPV vaccine by increasing antigen and adjuvant doses. In all 3 studies, all vaccine candidates were strongly immunogenic with respect to HPV31/33/45/52/58 and were well tolerated. Based on the totality of the results, the middle dose formulation of the 9vHPV vaccine was selected for Phase III evaluation. Each 0.5mL dose contains 30μg/40μg/60μg/40μg/20μg/20μg/20μg/20μg/20μg of HPV6/11/16/18/31/33/45/52/58 virus-like particles, and 500μg of amorphous aluminum hydroxyphosphate sulfate adjuvant.ClinicalTrials.gov numbers NCT00260039, NCT00543543, and NCT00551187.

Keywords:

• dose selection
• formulation
• HPV
• immunogenicity
• vaccine

Abbreviations:

• cLIA, competitive Luminex Immunoassay
• CI, confidence interval
• GMTs, geometric mean titers
• HPV, human papillomavirus vaccine
• IVRS, Interactive Voice Response System
• PPI, per-protocol immunogenicity
• VLP, virus-like particle

Disclosure of Potential Conflicts of Interest

Alain Luxembourg, Roger Maansson, Erin Moeller, Michael Ritter, and Joshua Chen are current or former employees of Merck and Co., Inc. and may hold stock/stock options. Celine Bouchard reports honoraria for lectures and travel from GlaxoSmithKline and Merck and Co., Inc. Anna R. Giuliano reports receiving grants from Merck and Co., Inc. and membership in Merck and Co., Inc. advisory boards and speakers bureaus. Ole-Erik Iversen reports honoraria through his institution for the conduct of clinical trials and compensation from GlaxoSmithKline and Merck and Co., Inc. for performing vaccine clinical trials. Elmar A. Joura reports grants, personal fees and non-financial support from Merck and Co., Inc., grants, personal fees and non-financial support from Sanofi Pasteur MSD and GlaxoSmithKline and personal fees from Roche Diagnostics. Mary E. Penny reports receiving grant support from MSD and has received grant support from Sanofi Pasteur MSD, Glaxo and Novartis. Jaime A. Restrepo has nothing to disclose. Darron Brown has served on an Advisory Board at Merck and Co., Inc. and has lectured on the quadrivalent HPV vaccine (honoraria received from Merck and Co., Inc. are donated to charities). His laboratory has received research funding from Merck and Co., Inc. Indiana University and Merck and Co., Inc. have an agreement that pays the University, based on certain landmarks related to vaccine development. DB receives a portion of these funds as income. Josefina Romaguera reports participating in vaccine trials for Merck and Co., Inc., Inovio and Hoffmann La Roche Inc., and other clinical trials for AbbVie as faculty of the University of Puerto Rico, as well as being a speaker for Merck and Pfizer.

Acknowledgments

The authors thank Heather L. Sings and Karyn Davis (Merck and Co., Inc.) for assistance in the preparation of this manuscript.

Funding

Funding for this study was provided by Merck & Co., Inc., Kenilworth, NJ USA.