Next generation L2-based HPV vaccines cross-protect against cutaneous papillomavirus infection and tumor development.

Licensed L1-VLP-based immunizations against high-risk mucosal human papillomavirus (HPV) types have been a great success in reducing anogenital cancers, although they are limited in their cross-protection against HPV types not covered by the vaccine. Further, their utility in protection against cutaneous HPV types, of which some contribute to non-melanoma skin cancer (NMSC) development, is rather low. Next generation vaccines achieve broadly cross-protective immunity against highly conserved sequences of L2. In this exploratory study, we tested two novel HPV vaccine candidates, HPV16 RG1-VLP and CUT-PANHPVAX, in the preclinical natural infection model Mastomys coucha . After immunization with either vaccines, a mock control or MnPV L1-VLPs, the animals were experimentally infected and monitored. Besides vaccine-specific seroconversion against HPV L2 peptides, the animals also developed cross-reactive antibodies against the cutaneous Mastomys natalensis papillomavirus (MnPV) L2, which were cross-neutralizing MnPV pseudovirions in vitro . Further, both L2-based vaccines also conferred in vivo protection as the viral loads in plucked hair after experimental infection were lower compared to mock-vaccinated control animals. Importantly, the formation of neutralizing antibodies, whether directed against L1-VLPs or L2, was able to prevent skin tumor formation and even microscopical signs of MnPV infection in the skin. For the first time, our study shows the proof-of-principle of next generation L2-based vaccines even across different PV genera in an infection animal model with its genuine PV. It provides fundamental insights into the humoral immunity elicited by L2-based vaccines against PV-induced skin tumors, with important implications to the design of next generation HPV vaccines.
Competing Interests: RK is member of Pathovax LLC and its Scientific Advisory Board. Under a licensing agreement between PathoVax LLC and Medical University of Vienna, the University and Dr. Kirnbauer are entitled to royalties associated with an invention (RG1-VLP) described in this publication. These arrangements have been reviewed and approved by the Medical University of Vienna in accordance with its conflict-of-interest policies. MM is a co-inventor of PANHPVAX, a vaccine against low- and high-risk mucosal HPV types currently entering phase-I clinical trial. MM and FCM are co-inventors on a patent related to a cutaneous papillomavirus vaccine (WO2019063841). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.
(Copyright © 2022 Ahmels, Mariz, Braspenning-Wesch, Stephan, Huber, Schmidt, Cao, Müller, Kirnbauer, Rösl and Hasche.)