title: Immunization with a vaccine combining herpes simplex virus 2 (HSV-2) glycoprotein C (gC) and gD subunits improves the protection of dorsal root ganglia in mice and reduces the frequency of recurrent vaginal shedding of HSV-2 DNA in guinea pigs compared to immunization with gD alone.
abstract: Attempts to develop a vaccine to prevent genital herpes simplex virus 2 (HSV-2) disease have been only marginally successful, suggesting that novel strategies are needed. Immunization with HSV-2 glycoprotein C (gC-2) and gD-2 was evaluated in mice and guinea pigs to determine whether adding gC-2 to a gD-2 subunit vaccine would improve protection by producing antibodies that block gC-2 immune evasion from complement. Antibodies produced by gC-2 immunization blocked the interaction between gC-2 and complement C3b, and passive transfer of gC-2 antibody protected complement-intact mice but not C3 knockout mice against HSV-2 challenge, indicating that gC-2 antibody is effective, at least in part, because it prevents HSV-2 evasion from complement. Immunization with gC-2 also produced neutralizing antibodies that were active in the absence of complement; however, the neutralizing titers were higher when complement was present, with the highest titers in animals immunized with both antigens. Animals immunized with the gC-2-plus-gD-2 combination had robust CD4+ T-cell responses to each immunogen. Multiple disease parameters were evaluated in mice and guinea pigs immunized with gC-2 alone, gD-2 alone, or both antigens. In general, gD-2 outperformed gC-2; however, the gC-2-plus-gD-2 combination outperformed gD-2 alone, particularly in protecting dorsal root ganglia in mice and reducing recurrent vaginal shedding of HSV-2 DNA in guinea pigs. Therefore, the gC-2 subunit antigen enhances a gD-2 subunit vaccine by stimulating a CD4+ T-cell response, by producing neutralizing antibodies that are effective in the absence and presence of complement, and by blocking immune evasion domains that inhibit complement activation.
authors.affiliation: Infectious Disease Division, Department of Medicine, School of Medicine, University of Pennsylvania, 502 Johnson Pavilion, Philadelphia, PA 19104-6073, USA. sawasthi@mail.med.upenn.edu
authors.forename: Sita
authors.initials: S
authors.lastname: Awasthi
authors.forename: John M
authors.initials: JM
authors.lastname: Lubinski
authors.forename: Carolyn E
authors.initials: CE
authors.lastname: Shaw
authors.forename: Shana M
authors.initials: SM
authors.lastname: Barrett
authors.forename: Michael
authors.initials: M
authors.lastname: Cai
authors.forename: Fushan
authors.initials: F
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Betts
authors.forename: Susan
authors.initials: S
authors.lastname: Kingsley
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Distefano
authors.forename: John W
authors.initials: JW
authors.lastname: Balliet
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Flynn
authors.forename: Danilo R
authors.initials: DR
authors.lastname: Casimiro
authors.forename: Janine T
authors.initials: JT
authors.lastname: Bryan
authors.forename: Harvey M
authors.initials: HM
authors.lastname: Friedman
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005727:Ganglia, Spinal / Q000276:immunology*; D006168:Guinea Pigs; D006558:Herpes Genitalis / Q000276:immunology / Q000517:prevention & control*; D006562:Herpes Zoster / Q000276:immunology / Q000517:prevention & control*; D053061:Herpes Zoster Vaccine / Q000008:administration & dosage / Q000276:immunology*; D018258:Herpesvirus 2, Human / Q000276:immunology*; D007114:Immunization / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055502:Secondary Prevention; D014621:Vagina / Q000821:virology; D014759:Viral Envelope Proteins / Q000276:immunology*; D017201:Virus Shedding
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D053061:Herpes Zoster Vaccine; D014759:Viral Envelope Proteins; C048232:glycoprotein C, herpes simplex virus type 2; C040570:glycoprotein D-herpes simplex virus type 2