• Studies of natural papilloma virus infections in the dog, rabbit, and cow showed serum induction of antibody responses to viral capsid proteins. Sero-positive animals were protected for life against challenge with high virus inocula. • Neutralizing serum antibody responses are directed against the L1 capsid protein. These responses depended on L1 in the native configuration, that is, correctly folded. • It was shown that the major capsid protein L1 of HPV 16, either with L2 or alone, when expressed via eukaryotic recombinant expression vectors self-assembled into empty protein shells or...

• Studies of natural papilloma virus infections in the dog, rabbit, and cow showed serum induction of antibody responses to viral capsid proteins. Sero-positive animals were protected for life against challenge with high virus inocula. • Neutralizing serum antibody responses are directed against the L1 capsid protein. These responses depended on L1 in the native configuration, that is, correctly folded. • It was shown that the major capsid protein L1 of HPV 16, either with L2 or alone, when expressed via eukaryotic recombinant expression vectors self-assembled into empty protein shells or virus-like particles (VLPs); these were morphologically and antigenically comparable to wild-type papilloma virus virions. • Rabbits, cows, and dogs immunized with the relevant species-specific VLPs were protected against high-dose viral challenge. • Proof of principle phase I trials in human subjects showed HPV 16, 11, 6, and 18 VLPs were well tolerated and highly immunogenic, generating HPV L1 type-specific antibody responses at least 100-fold higher than those observed in natural infections with these genital HPV types. • A proof of principle phase II trial of a monovalent HPV 16 L1 VLP vaccine in HPV 16 naïve women 16–23 years of age demonstrated 100% efficacy against persistent HPV 16 infection and 100% against HPV 16 associated CIN.