A chimeric L1-L2 virus-like particle (VLP) vaccine targeting common cutaneous human papillomavirus type 1 (HPV1)

Licensed Human Papillomavirus (HPV) vaccines are comprised of Virus-like Particles (VLP) assembled from the major capsid protein L1 and provide type-restricted protection against the incorporated vaccine types. However, they do not target cutaneous HPV types causing common, palmo-plantar and plane skin warts, which are a frequent nuisance in children and immunosuppressed individuals. Although benign, cutaneous warts can be painful, aesthetically unpleasant, recalcitrant to treatment and are a common cause of medical consultations burdening health care systems. Timely vaccination targeting cutaneous HPV types might greatly reduce incidence of cutaneous warts. HPV1 and HPV63 are closely related cutaneous types frequently found in plantar warts. Previous attempts to generate self-assembled HPV1 and HPV63 VLP as vaccine antigens by expressing L1 have been unsuccessful, contrary to many other cutaneous types. As an alternative strategy, the highly conserved N-terminus of minor capsid protein L2 can induce (cross-)neutralizing antisera that protect against experimental challenge. Thus, VLP assembled from HPV16 L1 (16 L1) were utilized as scaffold to repetitively present a L2 cross-neutralization epitope ('RG1') of HPV1 or HPV63 on 16 L1 VLP surface loops. Both chimeric 16 L1-1RG1 and 16 L1-63RG1 fusion proteins assembled into VLP. Immunizations of mice induced a functional antibody response, reacting with and (cross-)neutralizing both HPV1 and HPV63 by ELISA and Pseudovirion (PsV) neutralization assays, respectively. Immune sera also neutralized HPV16 PsV, indicating retained ability of chimeric 16 L1 VLP to induce a functional L1-mediated response despite epitope insertion. Immune sera also sterilized native HPV1 virions isolated from children's foot warts, preventing infection of keratinocytes in vitro. In an in vivo challenge model, immune sera to 16 L1-1RG1 protected mice against HPV1 hybrid PsV challenge, while sera to 16 L1-63RG1 conferred partial protection. In conclusion, chimeric VLP appear as promising vaccine candidates to target prevalent cutaneous HPV1, and possibly HPV63, with the potential to reduce the burden of HPV-induced skin warts.