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      Pan-HSV-2 IgG Antibody in Vaccinated Mice and Guinea Pigs Correlates with Protection against Herpes Simplex Virus 2

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          Abstract

          We lack a correlate of immunity to herpes simplex virus 2 (HSV-2) that may be used to differentiate whether a HSV-2 vaccine elicits robust or anemic protection against genital herpes. This gap in knowledge is often attributed to a failure to measure the correct component of the adaptive immune response to HSV-2. However, efforts to identify a correlate of immunity have focused on subunit vaccines that contain less than 3% of HSV-2's 40,000-amino-acid proteome. We were interested to determine if a correlate of immunity might be more readily identified if 1. animals were immunized with a polyvalent immunogen such as a live virus and/or 2. the magnitude of the vaccine-induced immune response was gauged in terms of the IgG antibody response to all of HSV-2's antigens (pan-HSV-2 IgG). Pre-challenge pan-HSV-2 IgG levels and protection against HSV-2 were compared in mice and/or guinea pigs immunized with a gD-2 subunit vaccine, wild-type HSV-2, or one of several attenuated HSV-2 ICP0 viruses (0Δ254, 0Δ810, 0ΔRING, or 0ΔNLS). These six HSV-2 immunogens elicited a wide range of pan-HSV-2 IgG levels spanning an ∼500-fold range. For 5 of the 6 immunogens tested, pre-challenge levels of pan-HSV-2 IgG quantitatively correlated with reductions in HSV-2 challenge virus shedding and increased survival frequency following HSV-2 challenge. Collectively, the results suggest that pan-HSV-2 IgG levels may provide a simple and useful screening tool for evaluating the potential of a HSV-2 vaccine candidate to elicit protection against HSV-2 genital herpes.

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          Efficacy results of a trial of a herpes simplex vaccine.

          Two previous studies of a herpes simplex virus type 2 (HSV-2) subunit vaccine containing glycoprotein D in HSV-discordant couples revealed 73% and 74% efficacy against genital disease in women who were negative for both HSV type 1 (HSV-1) and HSV-2 antibodies. Efficacy was not observed in men or HSV-1 seropositive women. We conducted a randomized, double-blind efficacy field trial involving 8323 women 18 to 30 years of age who were negative for antibodies to HSV-1 and HSV-2. At months 0, 1, and 6, some subjects received the investigational vaccine, consisting of 20 μg of glycoprotein D from HSV-2 with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant; control subjects received the hepatitis A vaccine, at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units. The primary end point was occurrence of genital herpes disease due to either HSV-1 or HSV-2 from month 2 (1 month after dose 2) through month 20. The HSV vaccine was associated with an increased risk of local reactions as compared with the control vaccine, and it elicited ELISA and neutralizing antibodies to HSV-2. Overall, the vaccine was not efficacious; vaccine efficacy was 20% (95% confidence interval [CI], -29 to 50) against genital herpes disease. However, efficacy against HSV-1 genital disease was 58% (95% CI, 12 to 80). Vaccine efficacy against HSV-1 infection (with or without disease) was 35% (95% CI, 13 to 52), but efficacy against HSV-2 infection was not observed (-8%; 95% CI, -59 to 26). In a study population that was representative of the general population of HSV-1- and HSV-2-seronegative women, the investigational vaccine was effective in preventing HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection. (Funded by the National Institute of Allergy and Infectious Diseases and GlaxoSmithKline; ClinicalTrials.gov number, NCT00057330.).
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            Glycoprotein-D-adjuvant vaccine to prevent genital herpes.

            An effective prophylactic vaccine would help control the spread of genital herpes. We conducted two double-blind, randomized trials of a herpes simplex virus type 2 (HSV-2) glycoprotein-D-subunit vaccine with alum and 3-O-deacylated-monophosphoryl lipid A in subjects whose regular sexual partners had a history of genital herpes. In Study 1, subjects were seronegative for herpes simplex virus type 1 (HSV-1) and HSV-2; in Study 2, subjects were of any HSV serologic status. At months 0, 1, and 6, subjects received either vaccine or a control injection and were evaluated for 19 months. The primary end point was the occurrence of genital herpes disease in all subjects in Study 1 and in HSV-2-seronegative female subjects in Study 2. A total of 847 subjects who were seronegative for both HSV-1 and HSV-2 (268 of them women, in Study 1) and 1867 subjects who were seronegative for HSV-2 (710 of them women, in Study 2) underwent randomization and received injections. Vaccination was well tolerated and elicited humoral and cellular responses. Overall, the efficacy of the vaccine was 38 percent in Study 1 (95 percent confidence interval, -18 to 68 percent; 15 cases occurred in the vaccine group and 24 in the control group), and efficacy in female subjects was 42 percent in Study 2 (95 percent confidence interval, -31 to 74 percent; 9 cases occurred in the vaccine group and 16 in the control group). In both studies, further analysis showed that the vaccine was efficacious in women who were seronegative for both HSV-1 and HSV-2: efficacy in Study 1 was 73 percent (95 percent confidence interval, 19 to 91 percent; P=0.01), and efficacy in Study 2 was 74 percent (95 percent confidence interval, 9 to 93 percent; P=0.02). It was not efficacious in women who were seropositive for HSV-1 and seronegative for HSV-2 at base line or in men. These studies suggest that the glycoprotein D vaccine has efficacy against genital herpes in women who are seronegative for both HSV-1 and HSV-2 at base line but not in those who are seropositive for HSV-1 and seronegative for HSV-2. It had no efficacy in men, regardless of their HSV serologic status. Copyright 2002 Massachusetts Medical Society
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              Herpes simplex virus-specific memory CD8+ T cells are selectively activated and retained in latently infected sensory ganglia.

              This study challenges the concept that herpes simplex virus type 1 (HSV-1) latency represents a silent infection that is ignored by the host immune system, and suggests antigen-directed retention of memory CD8(+) T cells. CD8(+) T cells specific for the immunodominant gB(498-505) HSV-1 epitope are selectively retained in the ophthalmic branch of the latently infected trigeminal ganglion, where they acquire and maintain an activation phenotype and the capacity to produce IFN-gamma. Some CD8(+) T cells showed TCR polarization to junctions with neurons. A gB(498-505) peptide-specific CD8(+) T cell clone can block HSV-1 reactivation from latency in ex vivo trigeminal ganglion cultures. We conclude that CD8(+) T cells provide active surveillance of HSV-1 gene expression in latently infected sensory neurons.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                6 June 2013
                : 8
                : 6
                : e65523
                Affiliations
                [1]Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America
                UC Irvine Medical Center, United States of America
                Author notes

                Competing Interests: William Halford is a co-author on United States Patent Application Publication US2010/0226940 A1, which describes the uses of herpes simplex virus mutant ICP0 in the design of a live-attenuated HSV-2 vaccine strain. This does not alter the authors' adherence to all PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: WPH JG. Performed the experiments: WPH JG. Analyzed the data: WPH EG. Contributed reagents/materials/analysis tools: WPH EG. Wrote the paper: WPH.

                Article
                PONE-D-12-40101
                10.1371/journal.pone.0065523
                3675040
                23755244
                8e48ec2c-7e63-41ea-b85b-1a14131aae27
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 6 December 2012
                : 29 April 2013
                Page count
                Pages: 15
                Funding
                This work was supported by the Excellence in Academic Medicine Committee of the Southern Illinois University School of Medicine, as well as a grant from the National Institutes of Health to study the Development of an Effective Genital Herpes Vaccine (R21 AI81072). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine
                Clinical Immunology
                Immunity
                Vaccination
                Vaccines
                Vaccine Development
                Immunizations
                Immunologic Techniques
                Immunoassays
                Immunofluorescence
                Immunoglobulins
                Infectious Diseases
                Viral Diseases
                Herpes Simplex

                Uncategorized
                Uncategorized

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