title: Towards a new generation of vaccines: the cytokine IL-12 as an adjuvant to enhance cellular immune responses to pathogens during prime-booster vaccination regimens.
abstract: A main goal of the industrialized world is the development of effective vaccines to control infectious diseases with major health and socio-economic impact. Current understanding of the immune response triggered during infection with pathogens causing malaria, hepatitis C and AIDS emphasizes the importance of cytotoxic T lymphocytes (CTLs) in combating these infections. This has led to the development of new vaccination strategies, some of which are in phase I/II clinical trials. Promising strategies of vaccination are based on highly attenuated viral vectors, such as Vaccinia virus (VV) in combination with heterologous like vectors naked DNA, referred to as priming/booster vaccination. While these immunization schedules increased the production of specific CTLs, there is a need to further expand the CD8+T cell population to control an infection. Among molecules that play a significant role in the modulation of the CTL response is the cytokine IL-12. Immunoregulation by IL-12 is of central importance in cell-mediated immunity (CMI) against those pathogens and tumors that are controlled by cell-mediated mechanisms, supported by Thl cells. The use of this cytokine in combination with highly immunogenic VV-derived vectors is a promising system for development of future vaccination schedules. In this review, we summarize recent data on the use of IL-12 in vaccination procedures, as well as undesired side-effects of the cytokine that can be overcome by accurate use of dose, route and time-window administration of IL-12 encoding vectors. Results described here indicate that VV IL-12-mediated enhancement of the specific CMI response against a model antigen HIV-1 env was time- and dose-dependent and that the antigen and the cytokine could be expresed from two different rVVs modulating the doses of the vectors and allowing for enhancement of a specific CMI response. Moreover, the use of IL-12 during DNA prime/VV boost regimens enhanced the specific anti-HIV-1 env cellular response 20 times compared to that generated after a single rVVenv inoculation. Variables such as: a) dose of the cytokine applied, b) time of its administration and c) routes of inoculation play a critical role in the final outcome of the response. The findings presented here can be extended to other antigens, suggesting that immunomodulatory cytokines can be useful in the development of the future vaccines against numerous infectious diseases and tumors.
authors.affiliation: Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CSIC, Madrid, Spain.
authors.forename: M M
authors.initials: MM
authors.lastname: Gherardi
authors.forename: J C
authors.initials: JC
authors.lastname: Ramírez
authors.forename: M
authors.initials: M
authors.lastname: Esteban
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D019302:HIV Envelope Protein gp160 / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007117:Immunization, Secondary; D018664:Interleukin-12 / Q000276:immunology* / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D019444:Vaccines, DNA / Q000276:immunology*; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D019302:HIV Envelope Protein gp160; D019444:Vaccines, DNA; D014765:Viral Vaccines; D018664:Interleukin-12