Efficacy of Recombinant Glycoprotein D Subunit Vaccines on the Development of Primary, Recurrent, and Latent Genital Infections with Herpes Simplex Virus Type 2 in Guinea Pigs

Berman, Phillip W.; Vogt, Peggy E.; Gregory, Timothy J.; Lasky, Laurence A.; Kern, Earl R.

doi:10.1093/infdis/157.5.897

Cited by 54 publications

(20 citation statements)

References 13 publications

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“…Numerous studies have demonstrated the efficacy of gD-based subunit vaccination for protection against HSV-2 infection and establishment of latency in female guinea pigs (34)(35)(36)(37), a model believed to closely replicate the pathology of natural HSV-2 infection in humans (38,39). The promising outcomes of these studies prompted several recent gD-based vaccine trials in humans (7-11, 40, 41).…”

Section: Discussionmentioning

confidence: 99%

Repertoire of Epitopes Recognized by Serum IgG from Humans Vaccinated with Herpes Simplex Virus 2 Glycoprotein D

Whitbeck

Huang

Cairns

et al. 2014

J Virol

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). The vaccine consisted of a soluble form of herpes simplex virus 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 enzyme-linked immunosorbent assay (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 MAbs. Importantly, IgGs 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 IgGs 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 gD2. We found that the virus-neutralizing abilities of the 10 most potent samples correlated with overall gD-binding activity and to an even greater extent with the combined content of IgGs 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. IMPORTANCESeveral herpes simplex virus 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 the 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 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.

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Section: Discussionmentioning

confidence: 99%

Repertoire of Epitopes Recognized by Serum IgG from Humans Vaccinated with Herpes Simplex Virus 2 Glycoprotein D

Whitbeck

Huang

Cairns

et al. 2014

J Virol

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“…Finally, groups of 10 guinea pigs were inoculated intravaginally with 106 pfu's of each of the four viruses (21)(22)(23). Infection was accomplished by use of virus-soaked cotton tip applicators.…”

Section: Methodsmentioning

confidence: 99%

Replication, establishment of latency, and induced reactivation of herpes simplex virus gamma 1 34.5 deletion mutants in rodent models.

Whitley

Kern²,

Chatterjee³

et al. 1993

J. Clin. Invest.

175

146

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“…Early HSV-1 vaccines against primary or recurrent ocular infection in animal models focused on the use of HSV-1/HSV-2 (HSV-1/2) glycoprotein subunits alone or in combination (12)(13)(14), likely due to the success of earlier studies that found that glycoprotein subunit vaccines were efficacious in experimental models of genital HSV-2 infection (15)(16)(17). More recent studies employing additional means to generate an immune response to viral antigens have shown that such prophylactic approaches are highly successful in terms of suppressing (i) viral replication and dissemination, (ii) establishment of latency, (iii) development of severe keratitis, and (iv) leukocyte infiltration into the cornea (18)(19)(20)(21).…”

mentioning

confidence: 99%

A Highly Efficacious Herpes Simplex Virus 1 Vaccine Blocks Viral Pathogenesis and Prevents Corneal Immunopathology via Humoral Immunity

Royer

Gurung

Jinkins

et al. 2016

J Virol

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Correlates of immunologic protection requisite for an efficacious herpes simplex virus 1 (HSV-1) vaccine remain unclear with respect to viral pathogenesis and clinical disease. In the present study, mice were vaccinated with a novel avirulent, live attenuated virus (0⌬NLS) or an adjuvanted glycoprotein D subunit (gD-2) similar to that used in several human clinical trials. Mice vaccinated with 0⌬NLS showed superior protection against early viral replication, neuroinvasion, latency, and mortality compared to that of gD-2-vaccinated or naive mice following ocular challenge with a neurovirulent clinical isolate of HSV-1. Moreover, 0⌬NLS-vaccinated mice exhibited protection against ocular immunopathology and maintained corneal mechanosensory function. Vaccinated mice also showed suppressed T cell activation in the draining lymph nodes following challenge. Vaccine efficacy correlated with serum neutralizing antibody titers. Humoral immunity was identified as the correlate of protection against corneal neovascularization, HSV-1 shedding, and latency through passive immunization. Overall, 0⌬NLS affords remarkable protection against HSV-1-associated ocular sequelae by impeding viral replication, dissemination, and establishment of latency. IMPORTANCEHSV-1 manifests in a variety of clinical presentations ranging from a rather benign "cold sore" to more severe forms of infection, including necrotizing stromal keratitis and herpes simplex encephalitis. The present study was undertaken to evaluate a novel vaccine to ocular HSV-1 infection not only for resistance to viral replication and spread but also for maintenance of the visual axis. The results underscore the necessity to reconsider strategies that utilize attenuated live virus as opposed to subunit vaccines against ocular HSV-1 infection. Herpes simplex virus 1 (HSV-1) is a highly successful human pathogen that results in approximately 40,000 new cases of severe visual impairment each year (1). In such cases, the immune response to the pathogen inadvertently mediates corneal pathology. Moreover, the morbidity associated with ocular infection results from episodic viral recrudescence (2, 3). This etiology is dependent upon reactivation of HSV-1 from latently infected neurons within the trigeminal ganglion (TG), which innervates the cornea and orofacial mucosae. Although gamma interferon (IFN-␥) and other cytokines secreted by T cells and other cornearesident cells facilitate viral clearance in the cornea, these soluble factors also recruit neutrophils and activate macrophages replete with proteases that instigate extracellular matrix remodeling and scar formation, thereby compromising visual acuity (4-10). Furthermore, protracted inflammatory responses sustained beyond clearance of the virus contribute to corneal neovascularization (1, 11). Consequently, developing HSV vaccines that elicit robust protection against infection without enhancing the risk for corneal immunopathology is an important clinical matter as no sanctioned HSV vaccine clinical trials to dat...

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Efficacy of Recombinant Glycoprotein D Subunit Vaccines on the Development of Primary, Recurrent, and Latent Genital Infections with Herpes Simplex Virus Type 2 in Guinea Pigs

Cited by 54 publications

References 13 publications

Repertoire of Epitopes Recognized by Serum IgG from Humans Vaccinated with Herpes Simplex Virus 2 Glycoprotein D

Repertoire of Epitopes Recognized by Serum IgG from Humans Vaccinated with Herpes Simplex Virus 2 Glycoprotein D

Replication, establishment of latency, and induced reactivation of herpes simplex virus gamma 1 34.5 deletion mutants in rodent models.

A Highly Efficacious Herpes Simplex Virus 1 Vaccine Blocks Viral Pathogenesis and Prevents Corneal Immunopathology via Humoral Immunity

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