Recombinant Listeria monocytogenes vaccination eliminates papillomavirus-induced tumors and prevents papilloma formation from viral DNA

Abstract

Listeria monocytogenes is a gram-positive, facultative intracellular bacterium that enters the cytoplasm of infected cells and spreads directly into neighboring cells without encountering the extracellular environment. Cytoplasmic L. monocytogenes efficiently presents secreted proteins to the major histocompatibility complex class I pathway which can stimulate protective T-cell-mediated immune responses. We have used a cottontail rabbit papillomavirus (CRPV) rabbit model to test the ability of recombinant L. monocytogenes strains secreting the viral E1 protein (E1-rLm) to protect outbred rabbits against CRPV- and CRPV DNA-induced tumors. CRPV infection of outbred rabbits serves as a model for oncogenic papillomaviruses since CRPV-induced papillomas progress with high frequency to malignant carcinoma. Rabbits were vaccinated with wild-type L. monocytogenes or E1-rLm and then challenged with CRPV or viral DNA. In contrast to 0% papilloma regression in control animals, 77% of E1-rLm-vaccinated rabbits generated protective immunity that controlled and induced complete regression of tumors induced by CRPV. Latent viral DNA was not detected at 71% of the papilloma regression sites examined 4.5 months postregression. E1-rLm responder rabbits were completely resistant to papilloma formation from viral DNA. In contrast to controls, peripheral blood mononuclear cells from E1-rLm responder rabbits were able to proliferate in response to in vitro E1 stimulation. These results indicate that E1-rLm immunization generated a systemic anti-CRPV E1 cell-mediated immune response which protected outbred rabbits from tumors induced by CRPV or CRPV DNA challenge.