Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine

Background: Studies in animal models have shown that systemic immunization with a papillomavirus virus-like particle (VLP) vaccine composed of L1, a m ajor structural viral protein, can confer protection against subsequent exp erimental challenge with the homologous virus. Here we report results of a double-blind, placebo-controlled, dose-escalation trial to evaluate the saf ety and immunogenicity of a human papillomavirus (HPV) type 16 (HPV16) L1 V LP vaccine in healthy adults. Methods: Volunteers were given intramuscular injections with placebo or with 10- or 50-mug doses of HPV16 L1 VLP vaccine given without adjuvant or with alum or MF59 as adjuvants at 0, 1, and 4 mo nths. All vaccine recipients were monitored for clinical signs and symptoms for 7 days after each inoculation. Immune responses were measured by an HP V16 L1 VLP-based enzyme-linked immunosorbent assay (ELISA) and by an HPV16 pseudovirion neutralization assay. The antibody titers were given as the re ciprocals of the highest dilution showing positive reactivity in each assay . All statistical tests were two-sided. Results: The prevaccination geometr ic mean ELISA titer for six seropositive individuals was 202 (range, 40-640 ), All vaccine formulations were well tolerated, and all subjects receiving vaccine seroconverted. Serum antibody responses at 1 month after the third injection were dose dependent in recipients of vaccine without adjuvant or with MF59 but were similar at both doses when alum was the adjuvant, With the higher dose, the geometric means of serum ELISA antibody titers (95% co nfidence intervals) to purified VLP 1 month after the third injection were as follows: 10240 (1499 to 69938) without adjuvant, 10 240 (1114 to 94 145) with MF59, and 2190 (838 to 5723) with alum, Responses of subjects within each group were similar. Neutralizing and ELISA antibody titers were highly correlated (Spearman correlation = .85), confirming that ELISA titers are valid proxies for neutralizing antibodies. Conclusions: The HPV16 L1 VLP va ccine is well tolerated and is highly immunogenic even without adjuvant, wi th the majority of the recipients achieving serum antibody titers that were approximately 40-fold higher than what is observed in natural infection.