Effects of herpes simplex virus type 2 glycoprotein vaccines and CLDC adjuvant on genital herpes infection in the guinea pig

Bernstein, David I.; Earwood, Julie; Bravo, Fernando; Cohen, Gary H.; Eisenberg, Roselyn J.; Clark, Jennifer; Fairman, Jeffrey; Cardin, Rhonda D.

doi:10.1016/j.vaccine.2011.01.005

Cited by 29 publications

(27 citation statements)

References 42 publications

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“…Several candidate vaccines appear to reduce the quantity of HSV in the guinea pig DRG. However, once DRG are infected, shedding still occurs at a rate similar to that of nonimmunized animals (96,97). These data suggest that once neuronal infection in the DRG is established, the pathobiology of frequent reactivation may not be affected by a therapeutic vaccine, although clinical recurrences and quantity of virus shed may be diminished.…”

Section: Animal Models Of Hsv Vaccinationmentioning

confidence: 86%

HSV-2: in pursuit of a vaccine

Johnston

Koelle²,

Wald³

2011

J. Clin. Invest.

127

111

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Herpes simplex virus type 2 (HSV-2) is one of the most prevalent sexually transmitted infections worldwide. In addition to recurrent genital ulcers, HSV-2 causes neonatal herpes, and it is associated with a 3-fold increased risk for HIV acquisition. Although many HSV-2 vaccines have been studied in animal models, few have reached clinical trials, and those that have been tested in humans were not consistently effective. Here, we review HSV-2 pathogenesis, with a focus on novel understanding of mucosal immunobiology of HSV-2, and vaccine efforts to date, in an attempt to stimulate thinking about future directions for development of effective prophylactic and therapeutic HSV-2 vaccines.

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Section: Animal Models Of Hsv Vaccinationmentioning

confidence: 86%

HSV-2: in pursuit of a vaccine

Johnston

Koelle²,

Wald³

2011

J. Clin. Invest.

127

111

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“…Immunization with multiple antigens involved in virus entry failed to improve the protection provided by gD2 alone (31). We base our vaccine approach on the observation that most viral vaccines effective against mucosal infection, such as HSV-2, depend on antibodies for protection (32,33).…”

mentioning

confidence: 99%

Blocking Herpes Simplex Virus 2 Glycoprotein E Immune Evasion as an Approach To Enhance Efficacy of a Trivalent Subunit Antigen Vaccine for Genital Herpes

Awasthi

Huang

Shaw

et al. 2014

J Virol

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Herpes simplex virus 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 the efficacy of 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 immunization 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 those produced by gD2 alone. Importantly, the trivalent vaccine protected the dorsal root ganglia (DRG) of 32/33 (97%) mice between days 2 and 7 postchallenge, compared with 27/33 (82%) in the gD2 group. The HSV-2 DNA copy number was significantly lower in mice immunized with the trivalent vaccine than in those immunized with gD2 alone. The extent of DRG protection using the trivalent vaccine was better than what we previously reported for gC2/gD2 immunization. Therefore, gE2 is a candidate antigen for inclusion in a multivalent subunit vaccine that attempts to block HSV-2 immune evasion. IMPORTANCEHerpes 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. T he efficacy of the herpes simplex virus 2 (HSV-2) glycoprotein D (gD2) subunit antigen vaccine for prevention of genital herpes was evaluated in three large human trials (1, 2). In 2002, the first two trials reported that the gD2 vaccine prevented HSV-2 genital disease in HSV-1/HSV-2-seronegative women; however, this result was not reproduced in the 2012 Herpevac trial for women that showed gD2 vaccine efficacy in preventing genital disease caused by HSV-1 but n...

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“…Some subjects immunized with the GSK gD2 vaccine produced only low levels of neutralizing antibodies, including antibodies to key domains on gD2 involved in entry, or no neutralizing antibody at all [71,72]. HSV-2 gB2 was used in combination with gD2 in a prior human trial, and gB2, gD2 and gH2/ gL2 were used in combination in guinea pig prophylactic vaccine trials [10,73]. Domains have been defined on gB that mediate fusion with cell membranes for virus entry or that are targets of neutralizing antibodies; however, no information is available regarding domains on gB2 recognized by the antibodies produced by immunization in the human vaccine trial or by the subunit antigens used in the guinea pig study [73,74].…”

Section: Blocking Entry Novel Strategies To Prevent Virus Entrymentioning

confidence: 99%

“…HSV-2 gB2 was used in combination with gD2 in a prior human trial, and gB2, gD2 and gH2/ gL2 were used in combination in guinea pig prophylactic vaccine trials [10,73]. Domains have been defined on gB that mediate fusion with cell membranes for virus entry or that are targets of neutralizing antibodies; however, no information is available regarding domains on gB2 recognized by the antibodies produced by immunization in the human vaccine trial or by the subunit antigens used in the guinea pig study [73,74]. An interesting direction for future vaccine research will be to design candidate gD2, gB2 or gH2/gL2 antigens that produce antibodies to domains essential for virus entry or cell-to-cell spread.…”

Section: Blocking Entry Novel Strategies To Prevent Virus Entrymentioning

confidence: 99%

“…Immunization strategies that include mucosal delivery of antigen and adjuvants may be required for optimal protection [100][101][102][103]. Some of the newer adjuvants used with gD2 subunit antigens include CpG oligodeoxynucleotides and cationic lipid DNA complexes that contain CpG motifs within liposomes [68,71,73]. CpG oligodeoxynucleotides induce potent antibody responses, expand long-lived memory B cells to produce protective antibodies on exposure to a pathogen even after antibody titers have declined below therapeutic levels, and if directly conjugated with the antigen, CpG oligonucleotides enhance CD8 + T-cell responses [95,[104][105][106].…”

Section: Novel Adjuvantsmentioning

confidence: 99%

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Improving immunogenicity and efficacy of vaccines for genital herpes containing herpes simplex virus glycoprotein D

Awasthi

Shaw

Friedman

2014

Expert Review of Vaccines

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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.

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Effects of herpes simplex virus type 2 glycoprotein vaccines and CLDC adjuvant on genital herpes infection in the guinea pig

Cited by 29 publications

References 42 publications

HSV-2: in pursuit of a vaccine

HSV-2: in pursuit of a vaccine

Blocking Herpes Simplex Virus 2 Glycoprotein E Immune Evasion as an Approach To Enhance Efficacy of a Trivalent Subunit Antigen Vaccine for Genital Herpes

Improving immunogenicity and efficacy of vaccines for genital herpes containing herpes simplex virus glycoprotein D

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