IMMUNOLOGY AND VACCINOLOGY OF HUMAN PAPILLOMAVIRUS MINOR CAPSID PROTEIN L2
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Date
2015-03-24
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Johns Hopkins University
Abstract
Human papillomavirus (HPV) minor capsid protein L2 has potential in being a broad spectrum protective yet low cost vaccine that is needed to eliminate HPV-related cancer as a global health problem. Several L2-based vaccines designed to induce broadly neutralizing serum antibodies are nearing phase 1 clinical trials to assess their safety and immunogenicity. Therefore, robust tools for serological assessment of L2-specific antibody responses to infection and vaccination are required. Presently, HPV neutralizing antibodies are measured in vitro using HPV Pseudovirions that deliver a reporter plasmid rather than an infectious genome. However the current assays are either cumbersome or lack sensitivity for L2-specific neutralizing antibodies because they do not fully replicate in vitro the slow but critical cleavage of L2 by furin observed in vivo. To address this issue, we developed a high-throughput in vitro neutralization assay based on a furin-cleaved infectious intermediate and validated it as sensitive measure for both HPV L1 and L2-specific neutralizing antibodies of both human and animal origin. We also generated two human chimeric antibodies for use as a standard and/or positive control necessary for validation of immunogenicity studies of planned clinical trials of L2-based vaccines. Further mechanistic studies of L2-antibody mediated protection against experimental viral challenge demonstrated the importance of the Fc region of the antibody in mediating phagocyte recognition of virions. Finally, because vaccination against L2 alone does not provide therapeutic benefit against established infection, L2 was fused with early viral antigens as an approach to combine therapy and protective immunity. Orthotopic tumor lines, such as the TC-1 cell line generated by ectopic expression of HPV16 E6 and E7 and mutant ras in C57BL6 mouse lung fibroblasts, have been utilized to assay therapeutic immunity. However, these lines do not emulate the viral life cycle or papilloma development. Given the tractability of mouse models and a plethora of reagents, we have exploited a recently identified laboratory mouse papillomavirus model (MusPV1) and pseudovirion challenge studies to demonstrate the potential of E6E7L2 fusion vaccines to prevent new infections and for the treatment of established papillomavirus infection or disease.
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Keywords
Papillomavirus, Vaccines