Vesicular Stomatitis Virus-Based Therapeutic Vaccination Targeted to the E1, E2, E6, and E7 Proteins of Cottontail Rabbit Papillomavirus

Abstract

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.Human papillomavirus (HPV) infections induce benign proliferative epithelial lesions (papillomas) at cutaneous and mucosal sites. Persistent lesions cause widespread morbidity and, when they progress to cancer, mortality (reviewed in references 1, 2, 7, 13, and 23). The new HPV virus-like particle (VLP) vaccine elicits strong HPV type-specific neutralizing antibodies and protects against subsequent infection with the corresponding HPV types (12). However, since it is unlikely to be immunotherapeutic, additional HPV vaccines are needed to ameliorate the severity of disease in the millions of people already infected with HPV (reviewed in reference 37).A promising new approach to vaccine development uses attenuated recombinant vesicular stomatitis viruses (VSVs) as vaccines (reviewed in reference 26). Compared to other viral vectors, the VSV vector offers several advantages. It is replication competent, like the most effective human vaccines, but is not a human pathogen. It induces strong cell-mediated and humoral immune responses compara...

Molecular Pathways: Multimodal Cancer-Killing Mechanisms Employed by Oncolytic Vesiculoviruses

“…Taking a more biologically relevant approach, others have built VSVs that express viral genes from known carcinogens, for the treatment of virus-infected tumors. For example, intradermal vaccination with VSV-expressing cottontail rabbit papillomavirus (CRPV) proteins was shown to induce complete regression of CRPV-induced papillomas in rabbits (40)(41)(42), and similar observations were made in murine papilloma models (43). However, as most tumors lack strong viral antigens, this approach, while having the potential to treat a small subset of human cancers, does not have broad therapeutic use.…”

Therapeutic vaccination of rabbits with a ubiquitin-fused papillomavirus E1, E2, E6 and E7 DNA vaccine

“…DNA vectors can be particularly useful priming agents for other vaccines based on viral vectors [24]. Future studies will assess the ability of CRPV early gene DNA vaccines to augment therapeutic immune responses induced by recombinant adenoviruses [25] and vesicular stomatitis viruses (VSVs) [10,11] encoding the same protein (s). Papilloma growth in rabbits vaccinated after papilloma formation.…”

“…The analysis of vaccine effects on papilloma volumes were based on cumulative volumes as in a previous study [10], due to the heterogeneity of the volume data. In first experiment an ANOVA model with censoring was used; censoring was used to deal with sites that did not form a papilloma.…”

“…The ANOVA model takes into consideration the similarity of volumes at the three sites at a given dose level within a rabbit. As in a previous study [10], log transformation was used before model fitting and SAS Version 9.1 was the software package for computing.…”

A Vesicular Stomatitis Virus-Based Therapeutic Vaccine Generates a Functional CD8 T Cell Response to Hepatitis B Virus in Transgenic Mice

“…The ability of VSV to generate potent CD8 T cell responses may make it better suited as a therapeutic strategy for chronic HBV infection than other immunization methods, as recovery from acute HBV infection is associated with strong, multispecific T cell responses to HBV antigens (8). Furthermore, immunization with VSV has been demonstrated to be effective as a therapeutic strategy for cervical carcinoma and other papillomavirus-associated cancers in animal models, an effect that was shown to be CD8 T cell dependent (9,10). Therefore, we sought to determine the potential of recombinant VSV expressing the HBV middle envelope surface glycoprotein (VSV-MS) as a therapeutic vaccine for chronic HBV infection.…”