title: Single and combination herpes simplex virus type 2 glycoprotein vaccines adjuvanted with CpG oligodeoxynucleotides or monophosphoryl lipid A exhibit differential immunity that is not correlated to protection in animal models.
abstract: Despite several attempts to develop an effective prophylactic vaccine for HSV-2, all have failed to show efficacy in the clinic. The most recent of these failures was the GlaxoSmithKline (GSK) subunit vaccine based on the glycoprotein gD with the adjuvant monophosphoryl lipid A (MPL). In a phase 3 clinical trial, this vaccine failed to protect from HSV-2 disease, even though good neutralizing antibody responses were elicited. We aimed to develop a superior, novel HSV-2 vaccine containing either gD or gB alone or in combination, together with the potent adjuvant CpG oligodeoxynucleotides (CPG). The immunogenic properties of these vaccines were compared in mice. We show that gB/CPG/alum elicited a neutralizing antibody response similar to that elicited by gD/CPG/alum vaccine but a significantly greater gamma interferon (IFN-γ) T cell response. Furthermore, the combined gB-gD/CPG/alum vaccine elicited significantly greater neutralizing antibody and T cell responses than gD/MPL/alum. The efficacies of these candidate vaccines were compared in the mouse and guinea pig disease models, including a novel male guinea pig genital disease model. These studies demonstrated that increased immune response did not correlate to improved protection. First, despite a lower IFN-γ T cell response, the gD/CPG/alum vaccine was more effective than gB/CPG/alum in mice. Furthermore, the gB-gD/CPG/alum vaccine was no more effective than gD/MPL/alum in mice or male guinea pigs. We conclude that difficulties in correlating immune responses to efficacy in animal models will act as a deterrent to researchers attempting to develop effective HSV vaccines.
authors.affiliation: Internal Medicine Research Unit, Pfizer Research and Development, Sandwich, UK.
authors.forename: Tansi
authors.initials: T
authors.lastname: Khodai
authors.forename: Debbie
authors.initials: D
authors.lastname: Chappell
authors.forename: Clare
authors.initials: C
authors.lastname: Christy
authors.forename: Paul
authors.initials: P
authors.lastname: Cockle
authors.forename: Jim
authors.initials: J
authors.lastname: Eyles
authors.forename: Daisy
authors.initials: D
authors.lastname: Hammond
authors.forename: Katrina
authors.initials: K
authors.lastname: Gore
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McCluskie
authors.forename: Dana M
authors.initials: DM
authors.lastname: Evans
authors.forename: Susanne
authors.initials: S
authors.lastname: Lang
authors.forename: Peter T
authors.initials: PT
authors.lastname: Loudon
authors.forename: Tim
authors.initials: T
authors.lastname: Townend
authors.forename: Paul
authors.initials: P
authors.lastname: Wright
authors.forename: Kate
authors.initials: K
authors.lastname: West
authors.forename: Helen
authors.initials: H
authors.lastname: Bright
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000534:Alum Compounds / Q000008:administration & dosage; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006558:Herpes Genitalis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D018258:Herpesvirus 2, Human / Q000276:immunology*; D022283:Herpesvirus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000276:immunology; D014759:Viral Envelope Proteins / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C408982:CPG-oligonucleotide; D022283:Herpesvirus Vaccines; D008050:Lipid A; D009838:Oligodeoxyribonucleotides; D014759:Viral Envelope Proteins; C044525:glycoprotein B, herpes simplex virus type 2; C040570:glycoprotein D-herpes simplex virus type 2; C041524:aluminum sulfate; D007371:Interferon-gamma; C048436:monophosphoryl lipid A