Recombinant Glycoprotein Vaccine for the Prevention of Genital HSV-2 Infection

Corey, Lawrence; Langenberg, Andria; Ashley, Rhoda; Sekulovich, Rose E.; Izu, Allen; Douglas, John M.; Handsfield, H. Hunter; Warren, Terri; Marr, Lisa; Tyring, Stephen K.; DiCarlo, Richard P.; Adimora, Adaora A.; Leone, Peter A.; Dekker, Cornelia L.; Burke, Rae Lyn; Leong, Wai Ping; Straus, Stephen E.

doi:10.1001/jama.282.4.331

Cited by 430 publications

(310 citation statements)

References 40 publications

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“…Subunit vaccines should be safer than either of these strategies but have met with mixed results in human clinical trials [6,23]. These vaccines typically generate neutralizing antibody titers, but this alone is likely insufficient to confer a high degree of protection [6]. Indeed, results presented here argue that a neutralizing antibody response is not required to protect animals from disease and cellular-mediated immunity clearly plays an important role.…”

Section: Discussionmentioning

confidence: 91%

“…Although these vaccines are safer than live attenuated vaccines, they may not be capable of generating a robust and durable immune response and the high doses of virus required might make them difficult to manufacture. Subunit vaccines should be safer than either of these strategies but have met with mixed results in human clinical trials [6,23]. These vaccines typically generate neutralizing antibody titers, but this alone is likely insufficient to confer a high degree of protection [6].…”

Section: Discussionmentioning

confidence: 99%

“…However, most of the clinical experience with HSV-2 vaccines has been with recombinant subunit vaccines consisting of one or both of the major HSV-2 surface glycoproteins (gB2 and gD2) formulated with adjuvant to increase their immunogenicity. While the subunit vaccine regimens proved to be immunogenic and generated high-titered neutralizing antibodies, a clinical trial using this approach vaccine was unable to demonstrate protection against acquisition ofHSV-2 infection suggesting that a neutralizing antibody response is insufficient to prevent infection with this virus [6]. Recent results with an engineered subunit vaccine and novel adjuvant has met with some success in clinical trials and appeared to be protective against clinically apparent disease in seronegative women, but appeared to be ineffective in men [23].…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of AD472, a live attenuated recombinant herpes simplex virus type 2 vaccine in guinea pigs

Prichard¹,

Kaiwar²,

Jackman³

et al. 2005

Vaccine

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An attenuated recombinant herpes simplex virus type 2 (HSV-2), designated as AD472, was constructed by deleting both copies of the γ 1 34.5 gene, UL55-56, UL43.5, and the US10-12 region from HSV-2 strain G. This virus was engineered to be a safe and effective live attenuated HSV-2 vaccine and was tested in the guinea pig model of genital herpes to evaluate its ability to protect from disease upon challenge with the wild type (wt) virus, HSV-2 (G). AD472 administered intramuscularly did not prevent infection or virus replication in the vaginal tract, but did reduce both lesion development and severity in a dose-dependent manner in guinea pigs challenged with the wt virus. Frequency of reactivation from latency was low compared with that of the parent virus, HSV-2 (G). Immunization with AD472 at doses of 1 × 10 5 PFU generally precluded colonization of the ganglia or establishment of latency by the challenge virus. Results presented here support the concept of a rationally engineered live attenuated vaccine for the prevention of the genital disease associated with infection by HSV-2.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Evaluation of AD472, a live attenuated recombinant herpes simplex virus type 2 vaccine in guinea pigs

Prichard¹,

Kaiwar²,

Jackman³

et al. 2005

Vaccine

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“…This opinion is bolstered by the success of other live virus vaccines, including the varicella-zoster virus vaccine. The somewhat limited effectiveness of a gD subunit vaccine, which provided only partial protection in women and no protection in men, also supports pursuing other options [13,14]. Inoculation (A) and zosteriform (B) site disease scores in mice inoculated with 5×10 5 PFU of KOS, rKOS-gDA3C or KOS-gDA3C.…”

Section: Discussionmentioning

confidence: 99%

“…Chiron Corporation and GlaxoSmithKline (GSK) performed large-scale human trials to evaluate the safety and efficacy of HSV-2 glycoprotein subunit vaccines [13,14] The Chiron vaccine formulation included HSV-2 glycoproteins B (gB) and gD in adjuvant MF59, which is an oil-in-water emulsion containing squalene, polysorbate 80, and sorbitan trioleate. The GSK vaccine contains HSV-2 gD in alum and 3-O-deacylated-monophosphoryl lipid A (MPL).…”

Section: Introductionmentioning

confidence: 99%

An HSV-1 gD mutant virus as an entry-impaired live virus vaccine

Awasthi

Lubinski

Eisenberg

et al. 2008

Vaccine

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HSV-1 glycoprotein D (gD) interacts with HVEM and nectin-1 cell receptors to initiate virus entry. We prepared an HSV-1 strain with mutations in the gD gene at amino acid residues 3 and 38 by changing alanine to cysteine and tyrosine to cysteine, respectively (A3C/Y38C). These mutations were constructed with the intent of evaluating infection in vivo when virus enters by HVEM but not nectin-1 receptors and were based on prior reports demonstrating that purified gDA3C/Y38C protein binds to HVEM but not to nectin-1. While preparing a high titered purified virus pool, the cysteine mutation at position 38 reverted to tyrosine, which occurred on two separate occasions. The resultant HSV-1 strain, KOS-gDA3C, had a single amino acid mutation at residue 3 and exhibited reduced entry into both HVEM and nectin-1 expressing cells. When tested in the murine flank model, the mutant virus was markedly attenuated for virulence and caused only mild disease, while the parental and rescued viruses produced much more severe disease. Thirty days after KOS-gDA3C infection, mice were challenged with a lethal dose of HSV-1 and were highly resistant to disease. The KOSgDA3C mutation was stable during 30 passages in vitro and was present in each of 3 isolates obtained from infected mice. Therefore, this gD mutant virus impaired in entry may represent a novel candidate for an attenuated live HSV-1 vaccine.

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