Broad-Spectrum HPV Vaccine Based on Recombinant Measles

• Applicant: Privatdozent Dr. Michael D. Mühlebach
• Subject Area: Virology ; Immunology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 452172111

Human Papillomaviruses (HPV) induce generally benign papillomas of skin and mucosa. Persistent infection with ‘high-risk’ types causes carcinomas of the ano-genital tract (in particular cervical cancer) and the oro-pharynx, and has been implicated in development of non-melanoma skin cancer (NMSC). Licensed vaccines are based on virus-like particles (VLP) self-assembled from the major capsid protein L1. Vaccinations protect against mucosal HPV infection and thereby induced neoplasia limited to the respective vaccine genotypes requiring continued cervical screening in vaccinated women, and do not target skin types.RG1-VLP is a vaccine candidate composed of fusion protein of HPV16 L1 displaying the cross-neutralization epitope ‚RG1’ of the HPV16 L2 minor capsid protein on the assembled VLP surface. Vaccinations provide low-titer cross-type immunity and protection to a broad spectrum of high-risk and low-risk mucosal and cutaneous HPV types in vitro and in animal challenge models. However, duration and breadth of protection in vivo are unknown.Live attenuated replicating measles vaccine induces long lasting humoral and cellular immune responses. Recombinant measles virus (MV) has been developed as vaccine platform against foreign pathogens (West Nile, Dengue, etc).We propose to generate an economic next generation HPV vaccine to protect against all genital oncogenic and low-risk HPV, which may overcome the burden of continued cervical PAP screening despite licensed vaccines and yield further significant reduction of cervical cancers and other neoplasias induced by HPV. Implementation in routine measles vaccination campaigns could particularly benefit low- and middle-income countries, which carry the major burden of cervical cancers, and immunosuppressed patients, who are particularly prone to HPV infections and induced neoplasias including NMSC.In addition, we will determine crucial features for induction of memory B-cells, long-lived plasma cells, and plateau antibody titers, which are the main effectors for sterilizing immunity in the genital tract. We will also examine whether the MV vaccine platform and closely spaced HPV antigen-display act synergistically together for provoking robust and long-lasting cross-protective humoral immunity against HPV, and evaluate mechanisms for induction of cell-mediated immunity and its contribution to protection in novel animal disease models. Reinhard Kirnbauer is a co-inventor of licensed HPV vaccines and has developed HPV16 RG1-VLP, which is in clinical development as next generation broad-spectrum HPV vaccine candidate. Michael Mühlebach has used the MV vaccine platform for development of modern vaccines, in particular for a vaccine targeting MERS-CoV infections or CLDN6-positive tumors by inducing both effective humoral and cellular immune responses. Their laboratories have synergistic and complementing expertise, that provide critical additional value required for a cross-border DACH project.

• DFG Programme: Research Grants
• International Connection: Austria
• Cooperation Partner: Professor Dr. Reinhard Kirnbauer