Persistent human papillomavirus (HPV)-associated benign and malignant lesions are a major cause of morbidity and mortality worldwide. Vaccination against HPV early
proteins could provide an effective means of treating individuals with established
infections. Recombinant
vesicular stomatitis virus (VSV) vectors have been used previously to elicit strong humoral and cellular immune responses and develop prophylactic
vaccines. We have shown that VSV vectors also can be used to elicit therapeutic immunity in the cottontail rabbit papillomavirus (CRPV)-rabbit model of high-risk
HPV infection. In the present study, three new VSV vectors expressing the CRPV E1, E2, or E7
protein were produced and compared to the previously generated VSV-E6 vector for therapeutic efficacy. To determine whether
vaccine efficacy could be augmented by simultaneous vaccination against two CRPV
proteins, the four
vaccines were delivered individually and in all possible pairings to rabbits 1 week after CRPV
infection. Control rabbits received the recombinant wild-type VSV vector or medium only. Cumulative
papilloma volumes were computed for analysis of the data. The analyses showed that VSV-based vaccination against the E1, E2, E6, or E7
protein significantly reduced
papilloma volumes relative to those of the controls. Furthermore, VSV-based CRPV vaccination cured all of the
papillomas in 5 of 30 rabbits. Of the individual
vaccines, VSV-E7 was the most effective. The VSV-E7
vaccine alone was the most effective, as it reduced cumulative
papilloma volumes by 96.9% overall, relative to those of the controls, and ultimately eliminated all of the disease in all of the vaccinees.
Vaccine pairing was not, however, found to be beneficial, suggesting antigenic competition between the coexpressed CRPV
proteins. These preclinical results, obtained in a physiologically relevant animal model of
HPV infection, demonstrate that VSV vectors deserve serious consideration for further development as therapeutic antitumor
vaccines.