title: A live-attenuated HSV-2 ICP0 virus elicits 10 to 100 times greater protection against genital herpes than a glycoprotein D subunit vaccine.
abstract: Glycoprotein D (gD-2) is the entry receptor of herpes simplex virus 2 (HSV-2), and is the immunogen in the pharmaceutical industry's lead HSV-2 vaccine candidate. Efforts to prevent genital herpes using gD-2 subunit vaccines have been ongoing for 20 years at a cost in excess of $100 million. To date, gD-2 vaccines have yielded equivocal protection in clinical trials. Therefore, using a small animal model, we sought to determine if a live-attenuated HSV-2 ICP0⁻ virus would elicit better protection against genital herpes than a gD-2 subunit vaccine. Mice immunized with gD-2 and a potent adjuvant (alum+monophosphoryl lipid A) produced high titers of gD-2 antibody. While gD-2-immunized mice possessed significant resistance to HSV-2, only 3 of 45 gD-2-immunized mice survived an overwhelming challenge of the vagina or eyes with wild-type HSV-2 (MS strain). In contrast, 114 of 115 mice immunized with a live HSV-2 ICP0⁻ virus, 0ΔNLS, survived the same HSV-2 MS challenges. Likewise, 0ΔNLS-immunized mice shed an average 125-fold less HSV-2 MS challenge virus per vagina relative to gD-2-immunized mice. In vivo imaging demonstrated that a luciferase-expressing HSV-2 challenge virus failed to establish a detectable infection in 0ΔNLS-immunized mice, whereas the same virus readily infected naïve and gD-2-immunized mice. Collectively, these results suggest that a HSV-2 vaccine might be more likely to prevent genital herpes if it contained a live-attenuated HSV-2 virus rather than a single HSV-2 protein.
authors.affiliation: Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America. halford@siumed.edu
authors.forename: William P
authors.initials: WP
authors.lastname: Halford
authors.forename: Ringo
authors.initials: R
authors.lastname: Püschel
authors.forename: Edward
authors.initials: E
authors.lastname: Gershburg
authors.forename: Andrew
authors.initials: A
authors.lastname: Wilber
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gershburg
authors.forename: Brandon
authors.initials: B
authors.lastname: Rakowski
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006558:Herpes Genitalis / Q000276:immunology* / Q000517:prevention & control* / Q000821:virology; D022301:Herpes Simplex Virus Vaccines / Q000276:immunology*; D018258:Herpesvirus 2, Human / Q000276:immunology* / Q000472:pathogenicity; D021621:Imaging, Three-Dimensional; D007109:Immunity / Q000276:immunology; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D019913:Nuclear Localization Signals; D017384:Sequence Deletion; D014613:Vaccines, Attenuated; D022223:Vaccines, Subunit / Q000276:immunology; D014621:Vagina / Q000821:virology; D014759:Viral Envelope Proteins / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology*; D014774:Virulence / Q000276:immunology
chemical_list: D022301:Herpes Simplex Virus Vaccines; D007074:Immunoglobulin G; D019913:Nuclear Localization Signals; D014613:Vaccines, Attenuated; D022223:Vaccines, Subunit; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C040570:glycoprotein D-herpes simplex virus type 2; D049452:Green Fluorescent Proteins; D008156:Luciferases