Abstract A138: Vaccination with HPV 16 L2E6E7 with GPI-0100 adjuvant elicits protective humoral as well as cell-mediated immune responses

A138

L1 virus-like particle (VLP) vaccines provide effective protection against Human papillomavirus (HPV) type from which the L1 was derived via the induction of neutralizing antibodies. While partial protection can occur against very closely related types, it is generally type-restricted and necessitates highly multivalent L1 VLP vaccines to obtain broad coverage. The minor capsid protein, L2, is emerging as an attractive alternative cross-protective antigen. Unfortunately, neither L1 VLP nor L2-based vaccines are effective against pre-existing disease, suggesting the need to develop therapeutic vaccines. Unlike the capsid proteins, the E6 and E7 oncoproteins are both required to maintain and expressed throughout cervical intraepithelial neoplasia (CIN) and cancer. TA-CIN, a vaccine comprising the HPV16 L2, E6 and E7 in a single tandem fusion protein, attempts to combine the advantages of broad cross-protection against HPV transmission with therapeutic responses targeting HPV16 early proteins. Here we test TA-CIN formulated along with GPI-0100, a semi-synthetic quillaja saponin analog, that was developed to promote both humoral and cellular immune responses. TA-CIN administered subcutaneously to mice three times at monthly intervals (125μg of clinical-grade protein) with 50μg GMP-grade GPI-0100 was found to elicit high titer antibodies that effectively neutralized not only HPV16 but also other oncogenic HPV types including HPV18, HPV31, HPV45, HPV58. Similarly, vaccination of pigtail macaques (Macaca nemestrina) with TA-CIN (three doses of 125μg of TA-CIN with 1000μg GMP-grade GPI-0100 at monthly intervals) was well tolerated and induced serum antibodies that neutralized HPV16, HPV18, and HPV31 in vitro. Notably, vaccination of mice with TA-CIN protected them from cutaneous HPV16 challenge as effectively as HPV16 L1 VLP. Combination of TA-CIN along with adjuvant GPI-0100 enhanced production of E7-specific, interferon gamma producing CD8+ T cell precursors by 20-fold. Vaccination with TA-CIN in adjuvant GPI-0100 completely prevented tumor growth after challenge with 5 x 10⁴ HPV16-transformed TC-1 tumor cells. Protection of the mice immunized with TA-CIN plus GPI-0100 against TC-1 in a prophylactic setting was significantly more effective than TA-CIN alone or GPI-0100 alone. Patients vaccinated with TA-CIN alone develop weak HPV neutralizing antibody and E6/E7-specific T cell responses. GPI-0100 has been used safely as an adjuvant in several human trials suggesting that the combination of TA-CIN and GPI-0100 warrants further study.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A138.