Correlation between mouse potency and in vitro relative potency for human papillomavirus Type 16 virus-like particles and Gardasil vaccine samples.
An in vitro relative potency (IVRP) assay has been developed as an alternative to the mouse potency assay used to release Merck's human papillomavirus (HPV) vaccine, Gardasil, for early phase clinical trials. The mouse potency assay is a classical, in vivo assay, which requires 4-6 weeks to complete and exhibits variability on the order of 40% relative standard deviation (RSD). The IVRP assay is a sandwich-type immunoassay that is used to measure relative antigenicity of the vaccine product. The IVRP assay can be completed in three days, has a variability of approximately 10% RSD and does not require the sacrifice of live animals. Because antigen detection is achieved using H16.V5, a neutralizing monoclonal antibody, which binds to a clinically-relevant epitope, the relative antigenicity measured by the IVRP assay is believed to be a good predictor of in vivo potency. In this study, the relationship between immunogenicity, as measured by the mouse potency assay and antigenicity as measured by the IVRP assay, is demonstrated. Freshly manufactured and aged samples produced using two different manufacturing processes were tested using both methods. The results demonstrate that there is an inverse correlation between the IVRP and mouse potency assays. Additionally, clinical results indicate IVRP is predictive of human immunogenicity. Thus, antigenicity, as defined by the H16.V5 epitope, can be used as a surrogate for immunogenicity and the IVRP assay is suitable for use as the sole potency test for Gardasil samples.
Shank-Retzlaff
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M
Merck Research Laboratories Department of Bioprocess & Bioanalytical Research, West Point, Pennsylvania, USA. Mary_Retzlaff@merck.com
Wang
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Morley
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T
Anderson
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C
Hamm
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Brown
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M
Rowland
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Pancari
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Zorman
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J
Lowe
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Schultz
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Teyral
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Capen
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Oswald
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Wang
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Washabaugh
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Jansen
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Sitrin
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D000826:Animal Testing Alternatives / Q000379:methods*; D000818:Animals; D002986:Clinical Trials as Topic; D004229:Dithiothreitol / Q000494:pharmacology; D005260:Female; D000068857:Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18; D052162:Human papillomavirus 16 / Q000235:genetics / Q000276:immunology* / Q000648:ultrastructure; D006801:Humans; D007118:Immunoassay; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D051379:Mice; D046529:Microscopy, Electron, Transmission; D015588:Observer Variation; D030361:Papillomavirus Infections / Q000276:immunology / Q000517:prevention & control; D053918:Papillomavirus Vaccines / Q000008:administration & dosage* / Q000276:immunology; D010316:Particle Size; D012044:Regression Analysis; D015203:Reproducibility of Results; D013997:Time Factors; D022701:Virosomes
D000068857:Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18; D016056:Immunodominant Epitopes; D053918:Papillomavirus Vaccines; D022701:Virosomes; D004229:Dithiothreitol