Broad-spectrum human papillomavirus (HPV) vaccine

Cervical cancer remains a leading cause of death for women in the developing world (more than 300.000 deaths per year worldwide) and less so in developed countries (5000 deaths per year in the US; 150 deaths per year in Austria). Indeed $6 billion is spent annually on PAP screening and intervention in the USA alone. There is unambiguous proof that HR HPV infections trigger the development of cervical and other anogenital malignancies. Prophylactic VLP vaccines have proven effective in preventing homologous HPV16 and 18 HPV infections and associated pre-neoplastic lesions, and may eventually prevent up to 70% of cervical and other anogenital neoplasias, However, the challenge of protecting against the additional 13 oncogenic HPV types causing genital cancers remains. This study aims to identify type-common peptides of the minor capid protein L2 and to develop L2-based HPV vaccines that are broadly protective against genital-mucosal types. To increase immunogenicity of the L2 peptides, we will develop chimeric L1-virus-like particles that display the L2 epitopes on capsid surface loops in a repetitive and closely spaced manner. In addition, bacterially derived L1 capsomers will be generated in E. coli that display L2 peptides in an analogous manner to L1 VLP. The latter formulation may substitute VLP as an affordable vaccine for developing countries, which carry 83% of the worldwide burden of cervical cancer

Infections with the more than 120 known human papillomavirus (HPV) types induce benign skin and genital warts (condylomata) worldwide. Certain cancer-inducing (oncogenic) mucosal types are the necessary cause of all cervical cancers in women, most anal cancers, and a subset of penile, vaginal, vulvar and oro-pharyngeal cancers (in summary about 5% of all human cancers worldwide are caused by HPV). In addition, infections with certain skin HPV types have been implicated in the development of non-melanoma skin cancer, the most frequent cancer in caucasian populations. The two licensed HPV vaccines are directed against the most important oncogenic types HPV16 and HPV18, which cause 70% of cervical cancers worldwide. One vaccine also targets HPV6 and HPV11, which cause 90% of condylomata. These subunit vaccines consist of the L1 major capsid protein of HPV, that spontaneously self- assembles into empty viral shells called virus-like particles (VLP). When given prophylactically (before viral infection occurs) vaccination prevents infection and disease with high efficacy; yet protection is limited to the (2 or 4) HPV types included in the vaccines. Vaccination with the second shell protein of the virus, the L2 minor capsid protein, has been shown to induce antisera that cross-protect against infection with other (heterologous) papillomavirus types. However L2 vaccination alone has proven not very immunogenic and thus less effective than L1 VLP vaccines. Using a molecular biological approach, we have generated a combined (chimeric) vaccine that consists of HPV16 L1 VLP carrying L2 peptides in a multimeric and repetitive array on the VLP surface. Vaccination of animals induced antisera that cross-neutralized (inactivated) a broad array of HPV including oncogenic mucosal and skin types. If proven effective in animal challenge models, this experimental vaccine could provide the basis for the development of a second generation vaccine to protect against infection with a broad spectrum of mucosal and cutaneous HPV types causing tumorous disease in humans.