Combination Treatment with Intralesional Cidofovir and Viral-DNA Vaccination Cures Large Cottontail Rabbit Papillomavirus-Induced Papillomas and Reduces Recurrences

Abstract

. However, recurrences at periods from 1 to 8 weeks after treatment cessation were observed at approximately 50% of cured sites. DNA vaccinations with CRPV E1, E2, E6, and E7 were initiated either after or at the time of intralesional treatments, and the recurrence rates were observed. When DNA vaccinations were started after intralesional cures, recurrence rates were similar to those of vector-vaccinated rabbits. A small proportion of recurrent sites subsequently regressed (4 out of 10, or 40%) in the vaccinated group versus no regression of recurrences in the vectorimmunized group (0 out of 19, or 0%), indicating partial effectiveness. In contrast, when DNA vaccinations were conducted during intralesional treatments, a significant reduction of recurrences (from 10 out of 19, or 53%, of sites in vector-immunized rabbits to 3 out of 20, or 15%, of sites in viral-DNA-immunized rabbits) was observed. DNA vaccination without intralesional treatments had a minimal effect on preexisting papillomas. These data indicated that treatment with a combination of antiviral compounds and specific immune stimulation may lead to long-term cures of lesions without the ensuing problem of papilloma recurrence.Treatment of persistent papillomas with intralesional and topical antiviral compounds and immunomodulators often leads to effective cure of treated lesions in clinical trials with human papillomavirus (HPV) disease (4,5,16,56). However, recurrences are common after treatment cessation (5,6,16,20,56). The reasons for clinical recurrences are unclear, but possible mechanisms include (i) reinfection at adjacent sites, (ii) incomplete destruction of the entire area of active clinical disease, (iii) reactivation of subclinical HPV disease in wounded areas within and adjacent to treated sites, (iv) incomplete activation or induced anergy of antigen-specific cell-mediated immunity to HPV-infected papilloma cells, and (v) genetic factors associated with ineffective host immunity together with antigenic differences between variants of the same HPV type (2,3,9,23,31,46,47,58).There is strong evidence that host immunity to papillomavirus antigens can clear the bulk of HPV and animal papillomavirus infections (reviewed in references 22 and 39). Spontaneous regression of papillomas induced by cottontail rabbit papillomavirus (CRPV), rabbit oral papillomavirus, bovine papillomavirus type 4, and canine oral papillomavirus in rabbits, cattle, and beagles have been observed (8,10,12,34,38,41). The regressions are associated with a heavy infiltrate of T cells of both CD4 and CD8 phenotypes (1,33,40), and regressions of all lesions occur systemically. Immunosuppression of animals during the periods of papilloma growth has been shown to prolong lesion persistence (29,37,48). HPV-infected lesion regression with an associated immune infiltrate and in situ detectable cytokines has been reported also (17,57). The precise effector mechanisms leading to lesion destruction in these clinical infections, however, are unknown. Additional evidence for immu...

Long-peptide therapeutic vaccination against CRPV-induced papillomas in HLA-A2.1 transgenic rabbits

“…Improved preventive and therapeutic endpoints have been found in previous studies using combinations of topical treatments and DNA vaccination [45], peptide and DNA vaccines [42], DNA vaccines based on recombinant VSV [44,46] and combinations of multiple antigens [26,35,47]. Adjuvants such as Toll-like receptor agonists and CpG have been included in tumor therapeutic studies to enhance the specific adaptive immunity in hosts [48,49].…”

Clinical Potential of the Acyclic Nucleoside Phosphonates Cidofovir, Adefovir, and Tenofovir in Treatment of DNA Virus and Retrovirus Infections

“…If cidofovir treatment was combined with viral DNA vaccination, recurrence rates could be further reduced (45).…”

Vaccines and Immunization against Human Papillomavirus

“…One such improvement in outcome can be achieved by combination treatments that have proven successful in the management of HIV and HCV infections. For example, preclinical papillomavirus models have shown improved efficacy using combination immunotherapy and antiviral treatments [51], low-dose irradiation [52] and monoclonal antibody therapy [53]. Recent clinical trials using low-dose cyclophosphamide improved the clinical outcome of condylomatous disease [54] and paved the way for combination immunotherapy against HPV disease.…”