A Replication-Defective Herpes Simplex Virus (HSV)-2 Vaccine, HSV529, is Safe and Well-Tolerated in Adults with or without HSV Infection and Induces Significant HSV-2-Specific Antibody Responses in HSV Seronegative Individuals

Dropulic, Lesia; Wang, Kening; Oestreich, Makinna; Pietz, Harlan L.; Garabedian, Doreen; Jegaskanda, Sinthujan; Dowdell, Kennichi C.; Nguyen, Hanh; Laing, Kerry J; Koelle, David M.; Azose, Aaron; Hunsberger, Sally; Lumbard, Keith; Chen, Aiying; Chang, Lee-Jah; Phogat, Sanjay; Cohen, Jeffrey I.

doi:10.1093/ofid/ofx163.1041

Cited by 10 publications

(6 citation statements)

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“…The vaccine was safe and elicited neutralizing and gD-specific antibody responses in doubly seronegative participants. However, in contrast to the studies in guinea pigs, the vaccine did not boost neutralizing antibody responses in HSV-1 or HSV-2 seropositive participants (Dropulic et al 2017;Dropulic et al 2019). Efforts to increase the immunogenicity of this vaccine are currently being evaluated.…”

Section: Candidates That Have Been Evaluated In Clinical Trialsmentioning

confidence: 75%

Alphaherpesvirus Vaccines

Aschner¹,

Herold²

2021

Current Issues in Molecular Biology

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Prophylactic and therapeutic vaccines for the alphaherpesviruses including varicella zoster virus (VZV) and herpes simplex virus types 1 and 2 have been the focus of enormous preclinical and clinical research. A live viral vaccine for prevention of chickenpox and a subunit therapeutic vaccine to prevent zoster are highly successful. In contrast, progress towards the development of effective prophylactic or therapeutic vaccines against HSV-1 and HSV-2 has met with limited success. This review provides an overview of the successes and failures, the different types of immune responses elicited by various vaccine modalities, and the need to reconsider the preclinical models and immune correlates of protection against HSV. BackgroundThe Alphaherpesvirinae subfamily of the Herpesviridae are large, enveloped double-stranded DNA viruses that include several important human and animal pathogens. The majority of the world's population is infected with at least one or more of the three major human Alphaherpesvirinae: herpes simplex virus type 1 (HSV-1), HSV type 2 (HSV-2) and human herpesvirus 3, more commonly known as varicella zoster virus (VZV). This subfamily is caister.com/cimb 469 Curr. Issues Mol. Biol. Vol. 41

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Section: Candidates That Have Been Evaluated In Clinical Trialsmentioning

confidence: 75%

Alphaherpesvirus Vaccines

Aschner¹,

Herold²

2021

Current Issues in Molecular Biology

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“…Participants stopped valacyclovir 3 days prior to vaccination. Genital skin biopsies were performed prior to each vaccine dose on days 0, 30, and 180, and 10 days after each dose at days 10, 40, and 190 (42). Non-genital skin biopsies were obtained from the arm at days 0, 10, 40 and 190.…”

Section: Methodsmentioning

confidence: 99%

“…Isolation of PBMCs: In the initial trial of HSV529, the majority of alterations in HSV-2 specific Tcell responses in PBMCs from HSV seronegative and HSV-2 seropositive participants were in the CD4+ T-cell population (42). HSV-2-reactive CD4+ T cells were enriched from PBMCs obtained at days 0 and 10 by two methods.…”

Section: Methodsmentioning

confidence: 99%

Expansion of the HSV-2-specific T cell repertoire in skin after immunotherapeutic HSV-2 vaccine

Ford

Johnston

et al. 2022

Preprint

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The skin at the site of HSV-2 reactivation is enriched for HSV-2 specific T cells. To evaluate whether an immunotherapeutic vaccine could elicit skin-based memory T cells we studied skin biopsies and HSV-2-reactive CD4+ T cells from peripheral blood mononuclear cells (PBMCs) by T-cell receptor (TCR) sequencing before and after vaccination with a replication-incompetent whole virus HSV-2 vaccine candidate (HSV529). The representation of HSV-2-reactive CD4+ T cell sequences from PBMCs increased from a median of 0.03% (range 0-0.09%) to 0.6% (range 0-1.3%) of the total skin TCR repertoire after the first vaccine dose. We found sustained expansion after vaccination in unique, skin-based T-cell clonotypes that were not detected in HSV-2-reactive CD4+ T cells isolated from PBMCs. While detection of skin clonotypes in the blood was related to abundance in the skin it was not related to expansion after vaccination. In one participant a switch in immunodominance was observed after vaccination with the emergence of a newly dominant TCRa/b pair in skin that was not detected in blood. We confirmed that the newly dominant clonotype was derived from an HSV-specific CD4+ T cell by creation of a synthetic TCR in a Jurkat-based cell line with a NR4A1-mNeonGreen reporter system. Our data indicate that the skin in areas of HSV-2 reactivation possesses an oligoclonal TCR repertoire that is distinct from the circulation with prominent clonotypes infrequently detected in the circulation by standard methods. Defining the influence of therapeutic vaccination on the HSV-2-specific TCR repertoire requires tissue-based evaluation.

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“…Fortunately, some vaccines are continuing their clinical trials. The following vaccines are currently in clinical trials or show excellent results in preclinical trials: COR-1 ( Dutton et al., 2016 ; Chandra et al., 2019 ), NE-HSV2 ( Truong et al., 2019 ), HSV-2 trivalent vaccine ( Awasthi et al., 2014 ; Awasthi et al., 2017 ; Egan et al., 2020 ), G103 ( Odegard et al., 2016 ), HSV529 ( Bernard et al., 2015 ; Dropulic et al., 2017 ; Dropulic et al., 2019 ), RVX201 ( Halford et al., 2011 ), VC2, R2 ( Richards et al., 2017 ; Bernstein et al., 2020 ), HSV2 ΔgD2 ( Dropulic et al., 2017 ; Burn et al., 2018 ), and HSV-2 trivalent mRNA ( Egan et al., 2020 ). Hopefully, one or more of these may be developed into a successful vaccine to control HSV infection in the human population.…”

Section: Viral Glycoproteins As Antiviral Targetsmentioning

confidence: 99%

Herpes Simplex Virus Cell Entry Mechanisms: An Update

Madavaraju

Koganti

Volety

et al. 2021

Front. Cell. Infect. Microbiol.

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Herpes simplex virus (HSV) can infect a broad host range and cause mild to life threating infections in humans. The surface glycoproteins of HSV are evolutionarily conserved and show an extraordinary ability to bind more than one receptor on the host cell surface. Following attachment, the virus fuses its lipid envelope with the host cell membrane and releases its nucleocapsid along with tegument proteins into the cytosol. With the help of tegument proteins and host cell factors, the nucleocapsid is then docked into the nuclear pore. The viral double stranded DNA is then released into the host cell’s nucleus. Released viral DNA either replicates rapidly (more commonly in non-neuronal cells) or stays latent inside the nucleus (in sensory neurons). The fusion of the viral envelope with host cell membrane is a key step. Blocking this step can prevent entry of HSV into the host cell and the subsequent interactions that ultimately lead to production of viral progeny and cell death or latency. In this review, we have discussed viral entry mechanisms including the pH-independent as well as pH-dependent endocytic entry, cell to cell spread of HSV and use of viral glycoproteins as an antiviral target.

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A Replication-Defective Herpes Simplex Virus (HSV)-2 Vaccine, HSV529, is Safe and Well-Tolerated in Adults with or without HSV Infection and Induces Significant HSV-2-Specific Antibody Responses in HSV Seronegative Individuals

Cited by 10 publications

References 0 publications

Alphaherpesvirus Vaccines

Alphaherpesvirus Vaccines

Expansion of the HSV-2-specific T cell repertoire in skin after immunotherapeutic HSV-2 vaccine

Herpes Simplex Virus Cell Entry Mechanisms: An Update

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