Abstract A143: Vaccination of a concatenated L2 fusion protein with L1 VLP or capsomeres for broad protection against HPV infection

Abstract

Abstract Background: Immunization with L1 major capsid protein in the form of the pentavalent capsomeres or 360mer virus-like particles (VLPs) generates high and long-lived titers of neutralizing antibodies and protection primarily against the human papillomavirus (HPV) type from which the vaccine was derived. Consequently, multivalent L1 VLP vaccines have been developed to expand the breadth of coverage, e.g. Cervarix which contains L1 VLPs that are derived from HPV16 and HPV18 and formulated in alum and monophosphoryl lipid A (MPL) adjuvant. Vaccination with L2 minor capsid protein induces lower titer, but more broadly neutralizing and protective antibody responses in animals. To enhance cross-protection we generated multi-type L2 proteins by fusing cross-neutralizing epitopes of divergent HPV types, e.g. 11-88×5 that is a concatamer of L2 residues 11–88 of HPV1, HPV5, HPV6, HPV16 and HPV18. Objectives: A low cost HPV vaccine that yields cross-protective antibodies and broad protection against more than a dozen oncogenic HPV types is urgently needed. We sought to combine the advantages of each protective antigen by immunization with titrated doses of multi-type L2 11-88×5 in alum+MPL, or with either HPV16 L1 capsomeres or Cervarix and to assess the importance of adjuvant for L2 dose sparing. Methods: Mice were vaccinated three times every alternate week and bled two weeks later. Serum antibody titers were determined by ELISA using HPV16 L1 VLP or L2 11-88×5antigen, as well as in vitro HPV pseudovirion neutralization assays. Results: The absolute titers and dose response to 11-88×5 were similar in mice vaccinated with 11-88×5 alone or in combination with either L1 capsomeres or VLPs. HPV16 L1 VLP generated significantly higher HPV16 neutralization titers than L1 capsomeres, and the capsomeres induce higher titers than 11-88×5. Importantly, the serum IgG titers specific to HPV16 L1 VLP were not influenced by vaccination with L1 capsomeres or VLP in the presence of L2 11-88×5. The in vitro neutralization titers elicited by vaccination with 11-88×5 in the combinations tested were not significantly different at two weeks after immunization but there was a trend at four months for reduced cross-neutralization when 11-88×5 was combined with L1 VLP but not capsomeres. Conclusions: There is no evidence of interference between the L1 and L2 serum antibody response to co-administration of L1 capsomeres, but not VLP, with multi-type L2 vaccines based on neutralization titers. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A143.