title: Inactivated HSV-2 in MPL/alum adjuvant provides nearly complete protection against genital infection and shedding following long term challenge and rechallenge.
abstract: Herpes Simplex Virus Type 2 (HSV-2) infection can result in life-long recurrent genital disease, asymptomatic virus shedding, and transmission. No vaccine to date has shown significant protection clinically. Here, we used a mouse model of genital HSV-2 infection to test the efficacy of a vaccine consisting of whole, formalin-inactivated HSV-2 (FI-HSV2) formulated with monophosphoryl lipid A (MPL) and alum adjuvants. Vaccine components were administered alone or as a prime-boost immunization together with DNA vaccines encoding a truncated glycoprotein D2 (gD2t) and two conserved HSV-2 genes necessary for virus replication, UL5 (DNA helicase) and UL30 (DNA polymerase). Our results show: (1) compared with mock immunized controls, mice immunized with FI-HSV2 plus MPL/alum consistently showed protection against disease burden and total viral shedding while the mice immunized with gD2t protein with MPL/alum did not; (2) protection against genital disease and viral replication correlated with the type of boost in a prime-boost immunization with little advantage afforded by a DNA prime; (3) intramuscular (i.m.) immunization with FI-HSV2 in MPL/Alhydrogel adjuvant provided nearly complete protection against vaginal HSV-2 shedding after a lethal intravaginal (i.vag.) short-term challenge and long-term rechallenge; (4) single formulation immunization with DNA vaccines, FI-HSV2, and MPL in an aluminum phosphate (Adju-Phos) adjuvant did not increase protection relative to FI-HSV2/MPL/Adju-Phos alone; and (5) addition of MPL/alum to the FI-HSV2 was required for optimal protection against disease, viral replication, and latent virus load in the dorsal root ganglia (DRG). Most notably, an optimized vaccine formulation of FI-HSV2 MPL/Alhydrogel given i.m. completely protected against detectable vaginal HSV-2 shedding in the majority of animals and HSV-2 latent DNA in the DRG of all animals.
authors.affiliation: Department of Cellular and Molecular Medicine University of California, San Diego, La Jolla, CA 92093-0712.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Morello
authors.affiliation: Department of Cellular and Molecular Medicine University of California, San Diego, La Jolla, CA 92093-0712.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Kraynyak
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0712.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Levinson
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Zhijiang
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Kuo-Fen
authors.initials: KF
authors.lastname: Lee
authors.affiliation: Department of Cellular and Molecular Medicine University of California, San Diego, La Jolla, CA 92093-0712.|Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0712.
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Spector
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000534:Alum Compounds / Q000008:administration & dosage*; D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000821:virology; D006558:Herpes Genitalis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D018258:Herpesvirus 2, Human / Q000235:genetics / Q000276:immunology*; D022283:Herpesvirus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051379:Mice; D008807:Mice, Inbred BALB C; D016019:Survival Analysis; D014611:Vaccination / Q000379:methods; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology; D014621:Vagina / Q000821:virology; D017201:Virus Shedding
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000956:Antigens, Viral; D022283:Herpesvirus Vaccines; D008050:Lipid A; D019444:Vaccines, DNA; C041524:aluminum sulfate; C048436:monophosphoryl lipid A