Project 3

DEVELOPMENT OF A PAN ONCOGENIC

HPV PREVENTIVE VACCINE

Description

Our long-term goal is to eliminate cervical cancer by development of a single prophylactic vaccine effective against all genotypes of oncogenic HPV. Papillomavirus has only two capsid proteins, L1 and L2. L2 is critical for papillomavirus infection and is a promising antigen for a pan-HPV prophylactic vaccine. Indeed, immunization of rabbits or cows with L2 protein or peptides induces neutralizing antibody and protects from experimental papillomavirus infection at both mucosal and cutaneous sites, suggesting Hypothesis I: Vaccination with L2 induces cross-neutralizing antibody that protects against infection by homologous and heterologous papillomavirus types. Specific Aim 1: Determine whether passive transfer of homologous or heterologous type L2-specific neutralizing antibodies protects rabbits from cutaneous cotton-tail rabbit papillomavirus (CRPV) infection and genital mucosal challenge with rabbit oral papillomavirus (ROPV). Furthermore, while L1 virus-like particle vaccines induce only type-specific neutralizing antibody, vaccination with HPV L2 induces antibodies that cross-neutralize diverse HPV genotypes, implying: Hypothesis II: L2 contains multiple neutralizing epitopes that are conserved amongst the genital HPV types. Specific aim 2: Identify the neutralizing epitopes in L2s of HPV16 and determine their cross-reactivity with other papillomaviruses. Patients have been vaccinated with a therapeutic vaccine containing full length L2 protein. We propose: Hypothesis III: Patients immunized with HPV16 or HPV6 L2 generate antibodies that neutralize a broad range of genital HPV types. Specific Aim 3: Determine whether patients immunized with HPV16 or HPV6 L2 fusion proteins generate antibodies that neutralize a broad range of genital HPVs. Natural history studies provide an opportunity to correlate antibody against neutralizing epitopes in L2 with a reduction in subsequent oncogenic HPV infection of both homologous and heterologous genotypes. Hypothesis IV: Patients that develop antibody to the cross-neutralizing epitopes in response to natural HPV infection are protected from subsequent infection by both the homologous and heterologous oncogenic HPVs. Specific Aim 4: Compare the natural history of acquisition of HPV16 and other oncogenic HPV types in those patients with or without antibody specific for HPV16 L2 neutralizing epitopes.