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Infect. Immun. doi:10.1128/IAI.01484-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Intra-vaginal immunization of mice with recombinant Salmonellae expressing human papillomavirus type 16 antigens as a potential route of vaccination against cervical cancer

Institute of Microbiology and Institute of Pathology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH1011 Lausanne, Switzerland

^* To whom correspondence should be addressed. Email: dnardell{at}hospvd.ch.

	Abstract

Cervical cancer, the second leading cause of cancer deaths in women, is the consequence of high-risk human papillomavirus (HPV) infections. Towards the development of therapeutic vaccines that can induce both innate and adaptive mucosal immune responses, we analyzed intra-vaginal (ivag) vaccine delivery of live attenuated Salmonella enterica serovar Typhimurium expressing HPV16L1 as a model antigen. Innate immune responses were examined in cervico-vaginal tissues by determining gene expression patterns by microarray analysis using nylon membranes imprinted with cDNA fragments encoding for inflammation-associated genes. At 24 h, a wide range of genes including chemokines, Th1-and Th2-type cytokine and chemokine receptors were upregulated in mice ivag immunized with Salmonella as compared to control mice. However, the majority of transcripts returned to their steady-state levels one week after immunization, suggesting a transient inflammatory response. Indeed, cervico-vaginal histology of immunized mice showed a massive, but transient, infiltration of macrophages and neutrophils, while T cells were still increased after 7 days. Ivag immunization also induced humoral and anti-tumor immune responses i.e. serum and vaginal anti-HPV16VLP antibody titers similar to oral immunization and a significant protection in tumor protection experiments using HPV16-expressing C3 tumor cells. These results show that ivag immunization with live attenuated Salmonella-expressing HPV16 antigens modulates the local mucosal gene expression pattern into a transient pro-inflammatory profile, elicits strong systemic and mucosal immunity against HPV16 and confers tumor protection against HPV16-tumor cells subcutaneously implanted in mice. Examination of the efficacy of ivag HPV16E7E6-Salmonella to induce regression of tumors located in the cervico-vaginal tissue is warranted.

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