The human papillomavirus (HPV) minor capsid protein, L2, is a good candidate for prophylactic vaccine development because L2-specific antibodies have cross-neutralizing activity against diverse HPV types. Here, we developed a HPV mucosal vaccine candidate using the poly-γ-glutamic acid synthetase A (pgsA) protein to display a partial HPV-16 L2 protein (N-terminal 1-224 amino acid) on the surface of Lactobacillus casei (L. casei). The oral immunization with L. casei-L2 induced productions of L2-specific serum IgG and vaginal IgG and IgA in Balb/c mice. To examine cross-neutralizing activity, we used a sensitive high-throughput neutralization assay based on HPV-16, -18, -45, -58, and bovine papillomavirus 1 (BPV1) pseudovirions. Our results revealed that mice vaccinated with L. casei-L2 not only generated neutralizing antibodies against HPV-16, but they also produced antibodies capable of cross-neutralizing the HPV-18, -45, and -58 pseudovirions. Consistent with previous reports, vaccination with HPV-16 L1 virus-like particles (VLPs) failed to show cross-neutralizing activity. Finally, we found that oral administration of L. casei-L2 induced significant neutralizing activities against genital infection by HPV-16, -18, -45, and -58 pseudovirions encoding a fluorescence reporter gene. These results collectively indicate that oral administration of L2 displayed on L. casei induces systemic and mucosal cross-neutralizing effects in mice.
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