Development of prophylactic human papillomavirus vaccines

Abstract

The demonstration of the etiologic role of oncogenic type HPV infection in cervical cancer has led to the development of the prophylactic vaccines Cervarix and Gardasil. Despite their licensure, current vaccines do not elicit complete protection against all 15 oncogenic HPV genotypes, and the high cost of these vaccines is a major hurdle in access to vaccination. During my thesis, I have compared several promising technologies as candidate preventive vaccines with the potential to target a broad swath of medically significant HPV types using approaches that are simple and inexpensive to manufacture, and thus represent potential alternatives to highly multivalent L1 VLP vaccines. An initial critical step was the development of pseudovirions derived from medically significant HPV types, and examining their assembly and infectious pathway for commonalities using inhibitors and antibodies. The HPV pseudovirions were utilized for measuring the neutralizing antibody responses to candidate vaccines and for vaginal challenge studies in mice. In passive transfer studies neutralizing antibodies by all vaccines tested were sufficient to mediate protection against experimental vaginal challenge, implying their central role in effecting immunity and their relevance as a correlate of protection. We compared four L2-based HPV vaccine candidates: 1. in vivo electroporation of a DNA vector expressing a codon-optimized L1 gene, 2. HPV16 L1 capsomers linked with amino acids 13-47 of HPV18, HPV31, and HPV45 L2 in tandem (GST-HPV16L1Δ-L2x3), 3. A chimeric VLP presenting HPV16 L2 amino acids 17-36 in an immunodominant loop of HPV16 L1 (RG1-VLP), and 4. L2 multimer fusions comprising L2 protective domains (amino acids 11-88) derived from 8 or 5 different HPV subtypes (11-88×8 and 11-88×5). Electroporation of L1 DNA vector elicited type-restricted immunity but when different HPV type vectors were co-administered heterotypic L1 interactions produced interference. GST-HPV16L1Δ-L2x3 and RG1-VLP induced high titers of HPV16 L1-specific neutralizing antibody but moderate titers of L2-specific antibody, although sufficient for cross-protection against other HPV types. L2 multimers induced substantially broader protection against vaginal challenge with medically significant HPV types than either Gardasil or Cervarix in the mouse model. Our data suggest the potential of L2 multimer and RG1-VLP as next generation prophylactic HPV vaccines