Correlates of Protection
The FDA defines a correlate of protection as a laboratory parameter that has been shown, from adequate and well-controlled clinical trials, to be associated with protection from clinical disease, Dr. Esser continued.
Correlates of protection exist for some older vaccines such as Recombivax™ and Energix® for heptatitis B, for which the internationally agreed upon correlate of protection is 10 ml of anti-Hep B surface antigen antibodies. For newer vaccines, such as Gardasil™ for the prevention of cervical cancer, and Rotateq™ for the prevention of rotavirus-induced diarrhea, correlates of protection have not yet been determined, he noted.
Several different biomarker assays were used in the development of Gardisil™. Virus neutralization assays, multiplexed Luminex-based antibody assays, T cell immunology assays, and molecular assays for detecting HPV type-specific infections were all developed to support both pre-clinical animal studies and Phase I–III clinical trials, Dr. Esser explained.
Early in development, serology assays showed that a quadrivalent HPV type 6, 11, 16, and 18 VLP vaccine formulated on Merck’s aluminum adjuvant was immunogenic and elicited T cell responses and both serum and mucosal antibodies in animal models. In clinical development, an HPV 6, 11, 16, and 18 multiplexed, competitive Luminex® Immunoassay was used to select the optimal formulation in dose ranging studies, to show the long-term duration of antibodies following vaccination and the presence of immune memory.
Molecular HPV genotyping assays were also used in clinical development to determine whether cervical or genital lesions were caused by HPV 6, 11, 16, 18, or nonvaccine HPV types. More importantly, the immunology assay was used in an immunobridging study in 9–15 year-old females. The results indicated that Gardasil was safe and immunogenic in this population. The antibody biomarker data were included in the new drug application for Gardasil in adolescent females.