title: An Interleukin 12 Adjuvanted Herpes Simplex Virus 2 DNA Vaccine Is More Protective Than a Glycoprotein D Subunit Vaccine in a High-Dose Murine Challenge Model.
abstract: Vaccination is a proven intervention against human viral diseases; however, success against Herpes Simplex Virus 2 (HSV-2) remains elusive. Most HSV-2 vaccines tested in humans to date contained just one or two immunogens, such as the virion attachment receptor glycoprotein D (gD) and/or the envelope fusion protein, glycoprotein B (gB). At least three factors may have contributed to the failures of subunit-based HSV-2 vaccines. First, immune responses directed against one or two viral antigens may lack sufficient antigenic breadth for efficacy. Second, the antibody responses elicited by these vaccines may have lacked necessary Fc-mediated effector functions. Third, these subunit vaccines may not have generated necessary protective cellular immune responses. We hypothesized that a polyvalent combination of HSV-2 antigens expressed from a DNA vaccine with an adjuvant that polarizes immune responses toward a T helper 1 (Th1) phenotype would compose a more effective vaccine. We demonstrate that delivery of DNA expressing full-length HSV-2 glycoprotein immunogens by electroporation with the adjuvant interleukin 12 (IL-12) generates substantially greater protection against a high-dose HSV-2 vaginal challenge than a recombinant gD subunit vaccine adjuvanted with alum and monophosphoryl lipid A (MPL). Our results further show that DNA vaccines targeting optimal combinations of surface glycoproteins provide better protection than gD alone and provide similar survival benefits and disease symptom reductions compared with a potent live attenuated HSV-2 0ΔNLS vaccine, but that mice vaccinated with HSV-2 0ΔNLS clear the virus much faster. Together, our data indicate that adjuvanted multivalent DNA vaccines hold promise for an effective HSV-2 vaccine, but that further improvements may be required.
authors.affiliation: 1 Profectus Biosciences , Baltimore Maryland.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Bagley
authors.affiliation: 1 Profectus Biosciences , Baltimore Maryland.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Schwartz
authors.affiliation: 2 BIOQUAL, Inc. , Rockville, Maryland.
authors.forename: Hanne
authors.initials: H
authors.lastname: Andersen
authors.affiliation: 3 Profectus Biosciences , Tarrytown, New York.
authors.forename: John H
authors.initials: JH
authors.lastname: Eldridge
authors.affiliation: 3 Profectus Biosciences , Tarrytown, New York.
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.affiliation: 3 Profectus Biosciences , Tarrytown, New York.
authors.forename: Ayuko
authors.initials: A
authors.lastname: Ota-Setlik
authors.affiliation: 4 Department of Microbiology and Immunology, Southern Illinois University School of Medicine , Springfield, Illinois.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Geltz
authors.affiliation: 4 Department of Microbiology and Immunology, Southern Illinois University School of Medicine , Springfield, Illinois.
authors.forename: William P
authors.initials: WP
authors.lastname: Halford
authors.affiliation: 1 Profectus Biosciences , Baltimore Maryland.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Fouts
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000276:immunology; D006558:Herpes Genitalis / Q000517:prevention & control*; D018258:Herpesvirus 2, Human / Q000276:immunology*; D022283:Herpesvirus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D018664:Interleukin-12 / Q000008:administration & dosage*; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D016019:Survival Analysis; D016896:Treatment Outcome; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D006023:Glycoproteins; D022283:Herpesvirus Vaccines; D008565:Membrane Proteins; D019444:Vaccines, DNA; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; D018664:Interleukin-12
keywords: DNA vaccine; HSV-2; adjuvant; herpes; virus