RG2-VLP: a Vaccine Designed to Broadly Protect against Anogenital and Skin Human Papillomaviruses Causing Human Cancer

The family of human papillomaviruses (HPV) includes over 400 genotypes. Genus a genotypes generally infect the anogenital mucosa, and a subset of these HPV are a necessary, but not sufficient, cause of cervical cancer. Of the 13 high-risk (HR) and 11 intermediate-risk (IR) HPV associated with cervical cancer, genotypes 16 and 18 cause 50% and 20% of cases, respectively, whereas HPV16 dominates in other anogenital and oropharyngeal cancers. A plethora of bHPVs are associated with cutaneous squamous cell carcinoma (CSCC), especially in sun-exposed skin sites of epidermodysplasia verruciformis (EV), AIDS, and immunosuppressed patients. Licensed L1 virus-like particle (VLP) vaccines, such as Gardasil 9, target a subset of aHPV but no bHPV. To comprehensively target both a- and bHPVs, we developed a two-component VLP vaccine, RG2-VLP, in which L2 protective epitopes derived from a conserved aHPV epitope (amino acids 17 to 36 of HPV16 L2) and a consensus bHPV sequence in the same region are displayed within the DE loop of HPV16 and HPV18 L1 VLP, respectively. Unlike vaccination with Gardasil 9, vaccination of wild-type and EV model mice (Tmc6^D/^D or Tmc8^D/^D) with RG2-VLP induced robust L2-specific antibody titers and protected against b-type HPV5. RG2-VLP protected rabbits against 17 aHPV, including those not covered by Gardasil 9. HPV16- and HPV18-specific neutralizing antibody responses were similar between RG2-VLP- and Gardasil 9-vaccinated animals. However, only transfer of RG2-VLP antiserum effectively protected naive mice from challenge with all bHPVs tested. Taken together, these observations suggest RG2-VLP’s potential as a broad-spectrum vaccine to prevent aHPV-driven anogenital, oropharyngeal, and bHPV-associated cutaneous cancers.