title: A Dual-Modality Herpes Simplex Virus 2 Vaccine for Preventing Genital Herpes by Using Glycoprotein C and D Subunit Antigens To Induce Potent Antibody Responses and Adenovirus Vectors Containing Capsid and Tegument Proteins as T Cell Immunogens.
abstract: We evaluated a genital herpes prophylactic vaccine containing herpes simplex virus 2 (HSV-2) glycoproteins C (gC2) and D (gD2) to stimulate humoral immunity and UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) as T cell immunogens. The HSV-2 gC2 and gD2 proteins were expressed in baculovirus, while the UL19 and UL47 genes were expressed from replication-defective adenovirus vectors. Adenovirus vectors containing UL19 and UL47 stimulated human and murine CD4(+) and CD8(+) T cell responses. Guinea pigs were either (i) mock immunized; (ii) immunized with gC2/gD2, with CpG and alum as adjuvants; (iii) immunized with the UL19/UL47 adenovirus vectors; or (iv) immunized with the combination of gC2/gD2-CpG/alum and the UL19/UL47 adenovirus vectors. Immunization with gC2/gD2 produced potent neutralizing antibodies, while UL19 and UL47 also stimulated antibody responses. After intravaginal HSV-2 challenge, the mock and UL19/UL47 adenovirus groups developed severe acute disease, while 2/8 animals in the gC2/gD2-only group and none in the combined group developed acute disease. No animals in the gC2/gD2 or combined group developed recurrent disease; however, 5/8 animals in each group had subclinical shedding of HSV-2 DNA, on 15/168 days for the gC2/gD2 group and 13/168 days for the combined group. Lumbosacral dorsal root ganglia were positive for HSV-2 DNA and latency-associated transcripts for 5/8 animals in the gC2/gD2 group and 2/8 animals in the combined group. None of the differences comparing the gC2/gD2-only group and the combined group were statistically significant. Therefore, adding the T cell immunogens UL19 and UL47 to the gC2/gD2 vaccine did not significantly reduce genital disease and vaginal HSV-2 DNA shedding compared with the excellent protection provided by gC2/gD2 in the guinea pig model.
  
  
  OBJECTIVE
  HSV-2 infection is a common cause of genital ulcer disease and a significant public health concern. Genital herpes increases the risk of transmission and acquisition of HIV-1 infection 3- to 4-fold. A herpes vaccine that prevents genital lesions and asymptomatic genital shedding will have a substantial impact on two epidemics, i.e., both the HSV-2 and HIV-1 epidemics. We previously reported that a vaccine containing HSV-2 glycoprotein C (gC2) and glycoprotein D (gD2) reduced genital lesions and asymptomatic HSV-2 genital shedding in guinea pigs, yet the protection was not complete. We evaluated whether adding the T cell immunogens UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) would enhance the protection provided by the gC2/gD2 vaccine, which produces potent antibody responses. Here we report the efficacy of a combination vaccine containing gC2/gD2 and UL19/UL47 for prevention of genital disease, vaginal shedding of HSV-2 DNA, and latent infection of dorsal root ganglia in guinea pigs.
authors.affiliation: Infectious Disease Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA sawasthi@mail.med.upenn.edu.
authors.forename: Sita
authors.initials: S
authors.lastname: Awasthi
authors.affiliation: Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Mahairas
authors.affiliation: Infectious Disease Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Carolyn E
authors.initials: CE
authors.lastname: Shaw
authors.affiliation: Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Meei-Li
authors.initials: ML
authors.lastname: Huang
authors.affiliation: Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, Washington, USA Department of Medicine, School of Medicine, University of Washington, Seattle, Washington, USA Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Koelle
authors.affiliation: Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, Washington, USA Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Posavad
authors.affiliation: Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, Washington, USA Department of Medicine, School of Medicine, University of Washington, Seattle, Washington, USA Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
authors.affiliation: Infectious Disease Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Harvey M
authors.initials: HM
authors.lastname: Friedman
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology*; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D036022:Capsid Proteins / Q000276:immunology; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors / Q000276:immunology; D006168:Guinea Pigs; D006558:Herpes Genitalis / Q000517:prevention & control*; D018258:Herpesvirus 2, Human / Q000276:immunology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D014759:Viral Envelope Proteins / Q000276:immunology*; D014765:Viral Vaccines / Q000096:biosynthesis*
chemical_list: D000914:Antibodies, Viral; D000956:Antigens, Viral; D036022:Capsid Proteins; D017931:DNA Primers; D014759:Viral Envelope Proteins; D014765:Viral Vaccines; C048232:glycoprotein C, herpes simplex virus type 2; C040570:glycoprotein D-herpes simplex virus type 2