Multi-epitope transplantation enables cross-type neutralization of phylogenetically distant HPV11/6/53 in mice.

In the post-vaccine era, non-vaccine human papillomavirus (HPV) types necessitate broader-spectrum HPV vaccines. This study explores epitope transplantation to bridge the phylogenetic gaps between distant related types. Using the H11-6HI molecule, originally designed to cross-neutralize HPV11 and HPV6, we replaced its DE and FG loops with critical neutralizing epitopes from HPV53, generating the chimeric virus-like particle H11-6HI-53DE-FG. Cryo-electron microscopy confirmed a well-assembled T=7 virus-like structure. Pseudovirus-based neutralization assays revealed balanced neutralizing antibody titers against HPV11, HPV6, and HPV53, with ED values of 0.528, 0.544, and 0.374 μg, respectively, in mice. This approach demonstrates that multi-epitope transplantation can overcome the phylogenetic barriers between α10 and α6 HPV types, enabling cross-neutralization between high-risk and low-risk types. These findings provide a promising foundation for designing next-generation HPV vaccines with expanded coverage.