Better neutralization of HSV-1 than HSV-2 by antibody from subjects immunized with the GlaxoSmithKline gD2 vaccine.
ABSTRACT The Herpevac Trial evaluated an HSV-2 glycoprotein D (gD2) subunit vaccine to prevent genital herpes. Unexpectedly, the vaccine protected against genital HSV-1 but not HSV-2. We evaluated sera from 30 HSV-1 and HSV-2 seronegative women immunized with gD2 in the Herpevac Trial. Neutralizing antibody titers were 3.5-fold higher to HSV-1 than HSV-2 (P<0.001). HSV-2 glycoproteins C (gC2) and E (gE2) on the virus blocked neutralization of gD2, while HSV-1 gC1 and gE1 did not block neutralization of HSV-1. The higher neutralizing antibody titers to HSV-1 offer an explanation for the Herpevac results and shielding neutralizing domains provides a potential mechanism.
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ABSTRACT: The results of a clinical trial of a subunit vaccine against genital herpes were recently reported (1). The vaccine consisted of a soluble form of herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) with adjuvant. The goal of the current study was to examine the composition of the humoral response to gD2 within a selected subset of vaccinated individuals. Serum samples from 30 vaccine recipients were selected based upon relative ELISA titers against gD2; 10 samples had high titers, 10 had medium titers and the remaining 10 had low ELISA titers. We employed a novel, biosensor-based monoclonal antibody (MAb) blocking assay to determine whether gD2 vaccination elicited IgG responses against epitopes overlapping those of well-characterized monoclonal antibodies (MAb). Importantly, IgG from the majority of gD2-immunized subjects competed for gD binding with four antigenically-distinct, virus-neutralizing MAbs (MC2, MC5, MC23 and DL11). Screening of patient IgG against overlapping peptides spanning the gD2 ectodomain revealed that about half of the samples contained antibodies against linear epitopes within the N- and C-termini of gD-2. We found that the virus-neutralizing ability of the 10 most potent samples correlated with overall gD-binding activity and to an even greater extent with the combined content of IgG against the epitopes of MAbs, MC2, MC5, MC23 and DL11. This suggests that optimal virus neutralizing activity is achieved by strong and balanced responses to the four major discontinuous neutralizing epitopes of gD2. Several herpes simplex virus type 2 (HSV-2) subunit vaccine studies have been conducted in human subjects using a recombinant form of HSV-2 glycoprotein D (gD2). Although several distinct, well-characterized, virus-neutralizing epitopes on gD2 are targeted by murine monoclonal antibodies, it is not known whether these same epitopes are targeted by the humoral response to gD2 in humans. We have developed a novel, biosensor-based competition assay to directly address this important question. Using this approach, we have identified epitopes that elicit strong humoral responses in humans as well as other epitopes that elicit much weaker responses. These data provide new insight into the human response to known neutralizing gD2 epitopes and reveal characteristics of this response that may guide future vaccine development.Journal of Virology 04/2014; 88(14). DOI:10.1128/JVI.00544-14 · 4.65 Impact Factor
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ABSTRACT: Herpes simplex virus type 2 (HSV-2) subunit antigen vaccines targeting virus entry molecules have failed to prevent genital herpes in human trials. Our approach is to include a virus entry molecule and add antigens that block HSV-2 immune evasion. HSV-2 glycoprotein C (gC2) is an immune evasion molecule that inhibits complement. We previously reported that adding gC2 to gD2 improved vaccine efficacy compared to either antigen alone in mice and guinea pigs. Here we demonstrate that HSV-2 glycoprotein E (gE2) functions as an immune evasion molecule by binding the IgG Fc domain. HSV-2 gE2 is synergistic with gC2 in protecting the virus from antibody and complement neutralization. Antibodies produced by immunizing with gE2 blocked gE2-mediated IgG Fc binding and cell-to-cell spread. Mice immunized with gE2 were only partially protected against HSV-2 vaginal challenge in mice; however, when gE2 was added to gC2/gD2 to form a trivalent vaccine, neutralizing antibody titers with and without complement were significantly higher than produced by gD2 alone. Importantly, the trivalent vaccine protected the DRG of 32/33 (97%) mice between days 2 and 7 post-challenge compared with 27/33 (82%) in the gD2 group. HSV-2 DNA copy number was significantly lower in mice immunized with the trivalent vaccine than gD2 alone. The extent of DRG protection using the trivalent vaccine was better than we previously reported with gC2/gD2 immunization. Therefore, gE2 is a candidate antigen for inclusion in a multivalent subunit vaccine that attempts to block HSV-2 immune evasion. Herpes simplex virus is the most common cause of genital ulcer disease worldwide. Infection results in emotional distress for infected individuals and their partners, is life threatening for infants exposed to herpes during childbirth, and greatly increases the risk of individuals acquiring and transmitting HIV infection. A vaccine that prevents genital herpes infection will have major public health benefits. Our vaccine approach includes strategies to prevent the virus from evading immune attack. Mice were immunized with a trivalent vaccine containing an antigen that induces antibodies to block virus entry and two antigens that induce antibodies that block immune evasion from antibody and complement. Immunized mice demonstrated no genital disease and 32/33 (97%) animals had no evidence of infection of dorsal root ganglia, suggesting that the vaccine may prevent the establishment of latency and recurrent infections.Journal of Virology 05/2014; 88(15). DOI:10.1128/JVI.01130-14 · 4.65 Impact Factor
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ABSTRACT: No vaccines are approved for prevention or treatment of genital herpes. The focus of genital herpes vaccine trials has been on prevention using herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) alone or combined with glycoprotein B. These prevention trials did not achieve their primary end points. However, subset analyses reported some positive outcomes in each study. The most recent trial was the Herpevac Trial for Women that used gD2 with monophosphoryl lipid A and alum as adjuvants in herpes simplex virus type 1 (HSV-1) and HSV-2 seronegative women. Unexpectedly, the vaccine prevented genital disease by HSV-1 but not HSV-2. Currently, HSV-1 causes more first episodes of genital herpes than HSV-2, highlighting the importance of protecting against HSV-1. The scientific community is conflicted between abandoning vaccine efforts that include gD2 and building upon the partial successes of previous trials. We favor building upon success and present approaches to improve outcomes of gD2-based subunit antigen vaccines.Expert Review of Vaccines 08/2014; 13(12):1-14. DOI:10.1586/14760584.2014.951336 · 4.22 Impact Factor