A Herpes Simplex Virus 2 (HSV-2) gD Mutant Impaired for Neural Tropism Is Superior to an HSV-2 gD Subunit Vaccine To Protect Animals from Challenge with HSV-2

Wang, Kening; Goodman, Kyle N.; Li, Daniel Y.; Chavez, Mayra; Cohen, Jeffrey I.

doi:10.1128/jvi.01845-15

Cited by 23 publications

(13 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both attenuated viruses are being further studied in animal models and have transitioned into clinical trials (see Rational Vaccines Inc. and , respectively). Other attenuated HSV mutants that elicit protective immunity against infection with HSV in animal models are a mutant virus deleted at U L 39 which was designated ICP10ΔPK, because it has the protein kinase domain of the large subunit of HSV-2 ribonucleotide reductase (ICP10) deleted ( 40 – 43 ), an HSV-2 virus that has mutations in gD ( 44 ) which limit neuron infection, and an HSV mutant that has glycoprotein E (gE) deleted ( 45 ). Other mutant viruses tested as potential vaccines in animal models are HSV-1 VC2, which is a glycoprotein K ( U L 53 gene) and envelope protein U L 20 ( U L 20 gene)-deficient virus ( 46 ), AD 472 which has U L 55-56 (γ 1 34.5 gene), U L 43.5 , and the U S 10-12 region deleted ( 47 ) and finally RAV 9395, a mutant virus with U L 55 and U L 56 genes deleted ( 48 ).…”

Section: Hsv-2 Vaccine Approachesmentioning

confidence: 99%

A Herpes Simplex Virus Type 2 Deleted for Glycoprotein D Enables Dendritic Cells to Activate CD4+ and CD8+ T Cells

et al. 2017

View full text Add to dashboard Cite

Herpes simplex virus type 2 (HSV-2) is highly prevalent in the human population producing significant morbidity, mainly because of the generation of genital ulcers and neonatal encephalitis. Additionally, HSV-2 infection significantly increases the susceptibility of the host to acquire HIV and promotes the shedding of the latter in the coinfected. Despite numerous efforts to create a vaccine against HSV-2, no licensed vaccines are currently available. A long-standing strategy, based on few viral glycoproteins combined with adjuvants, recently displayed poor results in a Phase III clinical study fueling exploration on the development of mutant HSV viruses that are attenuated in vivo and elicit protective adaptive immune components, such as antiviral antibodies and T cells. Importantly, such specialized antiviral immune components are likely induced and modulated by dendritic cells, professional antigen presenting cells that process viral antigens and present them to T cells. However, HSV interferes with several functions of DCs and ultimately induces their death. Here, we propose that for an attenuated mutant virus to confer protective immunity against HSV in vivo based on adaptive immune components, such virus should also be attenuated in dendritic cells to promote a robust and effective antiviral response. We provide a background framework for this idea, considerations, as well as the means to assess this hypothesis. Addressing this hypothesis may provide valuable insights for the development of novel, safe, and effective vaccines against herpes simplex viruses.

show abstract

Section: Hsv-2 Vaccine Approachesmentioning

confidence: 99%

A Herpes Simplex Virus Type 2 Deleted for Glycoprotein D Enables Dendritic Cells to Activate CD4+ and CD8+ T Cells

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Thus, selective elimination of retrograde delivery to the nervous system is an attractive approach for the development of HSV vaccines 26 , 27 because it decreases concerns that a live-attenuated HSV vaccine could become latent, possibly revert or recombine, or subsequently cause complications if the immune system becomes compromised or distressed 3 , 26 . Similarly, the concerns that a persistent HSV vaccine virus could contribute to neurodegenerative diseases, such as Alzheimer’s disease, are eliminated 9 , 10 .…”

Section: Discussionmentioning

confidence: 99%

The R2 non-neuroinvasive HSV-1 vaccine affords protection from genital HSV-2 infections in a guinea pig model

et al. 2020

View full text Add to dashboard Cite

Herpes simplex virus (HSV) infections are common and can cause severe illness but no vaccine is currently available. The recent failure of subunit HSV vaccines has highlighted the need for vaccines that present a diverse array of antigens, including the development of next-generation live-attenuated vaccines. However, most attenuated HSV strains propagate poorly, limiting their ability to elicit protective immune responses. A live-attenuated vaccine that replicates in non-neural tissue but is ablated for transmission into the nervous system may elicit protective immune responses without evoking neurologic complications or establishing life-long infections. Initial studies of R2, a live-attenuated vaccine that is engineered to be unable to invade the nervous system, used the guinea pig genital HSV model to evaluate the ability of R2 to replicate at the site of inoculation, cause disease and infect neural tissues. R2 was then evaluated as a vaccine using three routes of inoculation: intramuscular (IM), intradermal (ID) and intravaginal (IVag) and compared to IM administered gD2+MPL/Alum vaccine in the same model. R2 replicated in the genital tract but did not produce acute or recurrent disease and did not infect the neural tissue. The R2 vaccine-induced neutralizing antibody and decreased the severity of acute and recurrent HSV-2 disease as well as recurrent shedding. The ID route was the most effective. ID administered R2 was more effective than gD2+MPL/Alum at inducing neutralizing antibody, suppressing acute disease, and acute vaginal virus replication. R2 was especially more effective at reducing recurrent virus shedding, the most common source of HSV transmission. The live-attenuated prophylactic HSV vaccine, R2, was effective in the guinea pig model of genital HSV-2 especially when administered by the ID route. The use of live-attenuated HSV vaccines that robustly replicate in mucosal tissues but are ablated for neuroinvasion offers a promising approach for HSV vaccines.

show abstract

“…Many vaccine trials in animal models have used gD2 as an immunogen and numerous studies have assessed protection by antibody passive transfer in mice [ 27 , 28 , 41 – 43 , 51 – 59 ]. Some animal and human studies have also evaluated epitope-specific antibody responses to gD2 immunization [ 25 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Vaccine-induced antibodies to herpes simplex virus glycoprotein D epitopes involved in virus entry and cell-to-cell spread correlate with protection against genital disease in guinea pigs

et al. 2018

View full text Add to dashboard Cite

Herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit antigen is included in many preclinical candidate vaccines. The rationale for including gD2 is to produce antibodies that block crucial gD2 epitopes involved in virus entry and cell-to-cell spread. HSV-2 gD2 was the only antigen in the Herpevac Trial for Women that protected against HSV-1 genital infection but not HSV-2. In that trial, a correlation was detected between gD2 ELISA titers and protection against HSV-1, supporting the importance of antibodies. A possible explanation for the lack of protection against HSV-2 was that HSV-2 neutralization titers were low, four-fold lower than to HSV-1. Here, we evaluated neutralization titers and epitope-specific antibody responses to crucial gD2 epitopes involved in virus entry and cell-to-cell spread as correlates of immune protection against genital lesions in immunized guinea pigs. We detected a strong correlation between neutralizing antibodies and protection against genital disease. We used a high throughput biosensor competition assay to measure epitope-specific responses to seven crucial gD2 linear and conformational epitopes involved in virus entry and spread. Some animals produced antibodies to most crucial epitopes while others produced antibodies to few. The number of epitopes recognized by guinea pig immune serum correlated with protection against genital lesions. We confirmed the importance of antibodies to each crucial epitope using monoclonal antibody passive transfer that improved survival and reduced genital disease in mice after HSV-2 genital challenge. We re-evaluated our prior study of epitope-specific antibody responses in women in the Herpevac Trial. Humans produced antibodies that blocked significantly fewer crucial gD2 epitopes than guinea pigs, and antibody responses in humans to some linear epitopes were virtually absent. Neutralizing antibody titers and epitope-specific antibody responses are important immune parameters to evaluate in future Phase I/II prophylactic human vaccine trials that contain gD2 antigen.

show abstract

A Herpes Simplex Virus 2 (HSV-2) gD Mutant Impaired for Neural Tropism Is Superior to an HSV-2 gD Subunit Vaccine To Protect Animals from Challenge with HSV-2

Cited by 23 publications

References 52 publications

A Herpes Simplex Virus Type 2 Deleted for Glycoprotein D Enables Dendritic Cells to Activate CD4+ and CD8+ T Cells

A Herpes Simplex Virus Type 2 Deleted for Glycoprotein D Enables Dendritic Cells to Activate CD4+ and CD8+ T Cells

The R2 non-neuroinvasive HSV-1 vaccine affords protection from genital HSV-2 infections in a guinea pig model

Vaccine-induced antibodies to herpes simplex virus glycoprotein D epitopes involved in virus entry and cell-to-cell spread correlate with protection against genital disease in guinea pigs

Contact Info

Product

Resources

About