The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Harvey M Friedman - One of the best experts on this subject based on the ideXlab platform.
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a trivalent gc2 GD2 ge2 vaccine for herpes simplex virus generates antibody responses that block immune evasion domains on gc2 better than natural infection
Vaccine, 2019Co-Authors: Lauren M Hook, Sita Awasthi, Jonathan Dubin, Jessica Flechtner, Deborah Long, Harvey M FriedmanAbstract:Vaccines for prevention and treatment of genital herpes are high public health priorities. Our approach towards vaccine development is to focus on blocking virus entry mediated by herpes simplex virus type 2 (HSV-2) glycoprotein D (GD2) and to prevent the virus from evading complement and antibody attack by blocking the immune evasion domains on HSV-2 glycoproteins C (gC2) and E (gE2), respectively. HSV-2 gC2 and gE2 are expressed on the virion envelope and infected cell surface where they are potential targets of antibodies that bind and block their immune evasion activities. We demonstrate that antibodies produced during natural infection in humans or intravaginal inoculation in guinea pigs bind to gC2 but generally fail to block the immune evasion domains on this glycoprotein. In contrast, immunization of naive or previously HSV-2-infected guinea pigs with gC2 subunit antigen administered with CpG and alum as adjuvants produces antibodies that block domains involved in immune evasion. These results indicate that immune evasion domains on gC2 are weak antigens during infection, yet when used as vaccine immunogens with adjuvants the antigens produce antibodies that block immune evasion domains.
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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
PLOS Pathogens, 2018Co-Authors: Lauren M Hook, Gary H Cohen, Sita Awasthi, Tina M Cairns, Roselyn J Eisenberg, Benjamin D Brooks, Noah Ditto, Harvey M FriedmanAbstract: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.
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a dual modality herpes simplex virus 2 vaccine for preventing genital herpes by using glycoprotein c and d subunit antigens to induce potent antibody responses and adenovirus vectors containing capsid and tegument proteins as t cell immunogens
Journal of Virology, 2015Co-Authors: Sita Awasthi, Carolyn E Shaw, Harvey M Friedman, Gregory G Mahairas, Meei Li Huang, David M Koelle, Christine M Posavad, Lawrence CoreyAbstract:ABSTRACT We evaluated a genital herpes prophylactic vaccine containing herpes simplex virus 2 (HSV-2) glycoproteins C (gC2) and D (GD2) to stimulate humoral immunity and U L 19 (capsid protein VP5) and U L 47 (tegument protein VP13/14) as T cell immunogens. The HSV-2 gC2 and GD2 proteins were expressed in baculovirus, while the U L 19 and U L 47 genes were expressed from replication-defective adenovirus vectors. Adenovirus vectors containing U L 19 and U L 47 stimulated human and murine CD4 + and CD8 + T cell responses. Guinea pigs were either (i) mock immunized; (ii) immunized with gC2/GD2, with CpG and alum as adjuvants; (iii) immunized with the U L 19/U L 47 adenovirus vectors; or (iv) immunized with the combination of gC2/GD2-CpG/alum and the U L 19/U L 47 adenovirus vectors. Immunization with gC2/GD2 produced potent neutralizing antibodies, while U L 19 and U L 47 also stimulated antibody responses. After intravaginal HSV-2 challenge, the mock and U L 19/U L 47 adenovirus groups developed severe acute disease, while 2/8 animals in the gC2/GD2-only group and none in the combined group developed acute disease. No animals in the gC2/GD2 or combined group developed recurrent disease; however, 5/8 animals in each group had subclinical shedding of HSV-2 DNA, on 15/168 days for the gC2/GD2 group and 13/168 days for the combined group. Lumbosacral dorsal root ganglia were positive for HSV-2 DNA and latency-associated transcripts for 5/8 animals in the gC2/GD2 group and 2/8 animals in the combined group. None of the differences comparing the gC2/GD2-only group and the combined group were statistically significant. Therefore, adding the T cell immunogens U L 19 and U L 47 to the gC2/GD2 vaccine did not significantly reduce genital disease and vaginal HSV-2 DNA shedding compared with the excellent protection provided by gC2/GD2 in the guinea pig model. IMPORTANCE HSV-2 infection is a common cause of genital ulcer disease and a significant public health concern. Genital herpes increases the risk of transmission and acquisition of HIV-1 infection 3- to 4-fold. A herpes vaccine that prevents genital lesions and asymptomatic genital shedding will have a substantial impact on two epidemics, i.e., both the HSV-2 and HIV-1 epidemics. We previously reported that a vaccine containing HSV-2 glycoprotein C (gC2) and glycoprotein D (GD2) reduced genital lesions and asymptomatic HSV-2 genital shedding in guinea pigs, yet the protection was not complete. We evaluated whether adding the T cell immunogens U L 19 (capsid protein VP5) and U L 47 (tegument protein VP13/14) would enhance the protection provided by the gC2/GD2 vaccine, which produces potent antibody responses. Here we report the efficacy of a combination vaccine containing gC2/GD2 and U L 19/U L 47 for prevention of genital disease, vaginal shedding of HSV-2 DNA, and latent infection of dorsal root ganglia in guinea pigs.
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improving immunogenicity and efficacy of vaccines for genital herpes containing herpes simplex virus glycoprotein d
Expert Review of Vaccines, 2014Co-Authors: Sita Awasthi, Carolyn E Shaw, Harvey M FriedmanAbstract: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 a...
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better neutralization of herpes simplex virus type 1 hsv 1 than hsv 2 by antibody from recipients of glaxosmithkline hsv 2 glycoprotein d2 subunit vaccine
The Journal of Infectious Diseases, 2014Co-Authors: Sita Awasthi, Robert B Belshe, Harvey M FriedmanAbstract:The Herpevac Trial evaluated a herpes simplex virus type 2 (HSV-2) glycoprotein D (GD2) subunit vaccine to prevent genital herpes. Unexpectedly, the vaccine protected against genital HSV-1 infection but not genital HSV-2 infection. We evaluated sera from 30 women seronegative for HSV-1 and HSV-2 who were immunized with GD2 in the Herpevac Trial. Neutralizing antibody titers to HSV-1 were 3.5-fold higher than those to HSV-2 (P < .001). HSV-2 gC2 and gE2 on the virus blocked neutralization by GD2 antibody, while HSV-1 gC1 and gE1 did not block neutralization by GD2 antibody. The higher neutralizing antibody titers to HSV-1 offer an explanation for the Herpevac results, and shielding neutralizing domains provides a potential mechanism.
Sita Awasthi - One of the best experts on this subject based on the ideXlab platform.
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a trivalent gc2 GD2 ge2 vaccine for herpes simplex virus generates antibody responses that block immune evasion domains on gc2 better than natural infection
Vaccine, 2019Co-Authors: Lauren M Hook, Sita Awasthi, Jonathan Dubin, Jessica Flechtner, Deborah Long, Harvey M FriedmanAbstract:Vaccines for prevention and treatment of genital herpes are high public health priorities. Our approach towards vaccine development is to focus on blocking virus entry mediated by herpes simplex virus type 2 (HSV-2) glycoprotein D (GD2) and to prevent the virus from evading complement and antibody attack by blocking the immune evasion domains on HSV-2 glycoproteins C (gC2) and E (gE2), respectively. HSV-2 gC2 and gE2 are expressed on the virion envelope and infected cell surface where they are potential targets of antibodies that bind and block their immune evasion activities. We demonstrate that antibodies produced during natural infection in humans or intravaginal inoculation in guinea pigs bind to gC2 but generally fail to block the immune evasion domains on this glycoprotein. In contrast, immunization of naive or previously HSV-2-infected guinea pigs with gC2 subunit antigen administered with CpG and alum as adjuvants produces antibodies that block domains involved in immune evasion. These results indicate that immune evasion domains on gC2 are weak antigens during infection, yet when used as vaccine immunogens with adjuvants the antigens produce antibodies that block immune evasion domains.
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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
PLOS Pathogens, 2018Co-Authors: Lauren M Hook, Gary H Cohen, Sita Awasthi, Tina M Cairns, Roselyn J Eisenberg, Benjamin D Brooks, Noah Ditto, Harvey M FriedmanAbstract: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.
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a dual modality herpes simplex virus 2 vaccine for preventing genital herpes by using glycoprotein c and d subunit antigens to induce potent antibody responses and adenovirus vectors containing capsid and tegument proteins as t cell immunogens
Journal of Virology, 2015Co-Authors: Sita Awasthi, Carolyn E Shaw, Harvey M Friedman, Gregory G Mahairas, Meei Li Huang, David M Koelle, Christine M Posavad, Lawrence CoreyAbstract:ABSTRACT We evaluated a genital herpes prophylactic vaccine containing herpes simplex virus 2 (HSV-2) glycoproteins C (gC2) and D (GD2) to stimulate humoral immunity and U L 19 (capsid protein VP5) and U L 47 (tegument protein VP13/14) as T cell immunogens. The HSV-2 gC2 and GD2 proteins were expressed in baculovirus, while the U L 19 and U L 47 genes were expressed from replication-defective adenovirus vectors. Adenovirus vectors containing U L 19 and U L 47 stimulated human and murine CD4 + and CD8 + T cell responses. Guinea pigs were either (i) mock immunized; (ii) immunized with gC2/GD2, with CpG and alum as adjuvants; (iii) immunized with the U L 19/U L 47 adenovirus vectors; or (iv) immunized with the combination of gC2/GD2-CpG/alum and the U L 19/U L 47 adenovirus vectors. Immunization with gC2/GD2 produced potent neutralizing antibodies, while U L 19 and U L 47 also stimulated antibody responses. After intravaginal HSV-2 challenge, the mock and U L 19/U L 47 adenovirus groups developed severe acute disease, while 2/8 animals in the gC2/GD2-only group and none in the combined group developed acute disease. No animals in the gC2/GD2 or combined group developed recurrent disease; however, 5/8 animals in each group had subclinical shedding of HSV-2 DNA, on 15/168 days for the gC2/GD2 group and 13/168 days for the combined group. Lumbosacral dorsal root ganglia were positive for HSV-2 DNA and latency-associated transcripts for 5/8 animals in the gC2/GD2 group and 2/8 animals in the combined group. None of the differences comparing the gC2/GD2-only group and the combined group were statistically significant. Therefore, adding the T cell immunogens U L 19 and U L 47 to the gC2/GD2 vaccine did not significantly reduce genital disease and vaginal HSV-2 DNA shedding compared with the excellent protection provided by gC2/GD2 in the guinea pig model. IMPORTANCE HSV-2 infection is a common cause of genital ulcer disease and a significant public health concern. Genital herpes increases the risk of transmission and acquisition of HIV-1 infection 3- to 4-fold. A herpes vaccine that prevents genital lesions and asymptomatic genital shedding will have a substantial impact on two epidemics, i.e., both the HSV-2 and HIV-1 epidemics. We previously reported that a vaccine containing HSV-2 glycoprotein C (gC2) and glycoprotein D (GD2) reduced genital lesions and asymptomatic HSV-2 genital shedding in guinea pigs, yet the protection was not complete. We evaluated whether adding the T cell immunogens U L 19 (capsid protein VP5) and U L 47 (tegument protein VP13/14) would enhance the protection provided by the gC2/GD2 vaccine, which produces potent antibody responses. Here we report the efficacy of a combination vaccine containing gC2/GD2 and U L 19/U L 47 for prevention of genital disease, vaginal shedding of HSV-2 DNA, and latent infection of dorsal root ganglia in guinea pigs.
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improving immunogenicity and efficacy of vaccines for genital herpes containing herpes simplex virus glycoprotein d
Expert Review of Vaccines, 2014Co-Authors: Sita Awasthi, Carolyn E Shaw, Harvey M FriedmanAbstract: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 a...
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better neutralization of herpes simplex virus type 1 hsv 1 than hsv 2 by antibody from recipients of glaxosmithkline hsv 2 glycoprotein d2 subunit vaccine
The Journal of Infectious Diseases, 2014Co-Authors: Sita Awasthi, Robert B Belshe, Harvey M FriedmanAbstract:The Herpevac Trial evaluated a herpes simplex virus type 2 (HSV-2) glycoprotein D (GD2) subunit vaccine to prevent genital herpes. Unexpectedly, the vaccine protected against genital HSV-1 infection but not genital HSV-2 infection. We evaluated sera from 30 women seronegative for HSV-1 and HSV-2 who were immunized with GD2 in the Herpevac Trial. Neutralizing antibody titers to HSV-1 were 3.5-fold higher than those to HSV-2 (P < .001). HSV-2 gC2 and gE2 on the virus blocked neutralization by GD2 antibody, while HSV-1 gC1 and gE1 did not block neutralization by GD2 antibody. The higher neutralizing antibody titers to HSV-1 offer an explanation for the Herpevac results, and shielding neutralizing domains provides a potential mechanism.
David I Bernstein - One of the best experts on this subject based on the ideXlab platform.
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intranasal nanoemulsion adjuvanted hsv 2 subunit vaccine is effective as a prophylactic and therapeutic vaccine using the guinea pig model of genital herpes
Vaccine, 2019Co-Authors: David I Bernstein, Rhonda D Cardin, Fernando J Bravo, Tarek Hamouda, Derek A Pullum, Gary H Cohen, Vira Bitko, Ali Ibrahim FattomAbstract:Genital herpes is a sexually transmitted disease representing a major global health concern. Currently, there is no approved vaccine and existing antiviral therapies exhibit limited efficacy. Herein, we describe an intranasal (IN) vaccine comprised of HSV-2 surface glycoproteins GD2 and gB2 formulated in a nanoemulsion adjuvant (NE01-GD2/gB2). Using the HSV-2 genital herpes guinea pig model, we demonstrate that IN NE01-GD2/gB2 induces higher levels of neutralizing antibody compared to a monovalent IN NE01-GD2 vaccine, but less than an intramuscular (IM) Alum/MPL-GD2 vaccine. Following intravaginal (IVag) challenge with HSV-2, the group immunized with IN NE01-GD2/gB2 exhibited significantly reduced acute and recurrent disease scores compared to placebo recipients. Significantly, latent virus was only detected in the dorsal root ganglia of 1 of 12 IN NE01-GD2/gB2-vaccinated animals compared to 11 of 12 placebo recipient. In the therapeutic model, IN NE01-GD2/gB2 immunized guinea pigs exhibited a significant reduction in the recurrent lesions scores (64%, p < 0.01), number of animal days with disease (64%, p < 0.01), number of animals with viral shedding (50%, p < 0.04) and reduction in virus positive vaginal swabs (56%, p < 0.04), These data suggests that the treatment may be effective in treating chronic disease and minimizing virus transmission. These results warrant advancing the development of IN NE01-GD2/gB2 as both a prophylactic and therapeutic vaccine against HSV-2.
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the adjuvant cldc increases protection of a herpes simplex type 2 glycoprotein d vaccine in guinea pigs
Vaccine, 2010Co-Authors: David I Bernstein, Fernando J Bravo, Nicholas Farley, Julie Earwood, Monica M Mcneal, Jeff Fairman, Rhonda D CardinAbstract:Herpes simplex virus (HSV) infections are common but there is no vaccine available. We evaluated cationic liposome-DNA complexes (CLDC) as an adjuvant for an HSV GD2 vaccine and compared it to an MPL/Alum adjuvant in a guinea pig model of genital herpes. The addition of CLDC to the GD2 vaccine significantly decreased acute and recurrent disease and most importantly the number of days with recurrent virus shedding compared to GD2 alone. Reductions in these outcomes were also detected when GD2+CLDC was compared to GD2+MPL/Alum. When the vaccine and adjuvants were evaluated as therapeutic vaccines, they were ineffective. CLDC enhanced protection compared to MPL/Alum and is the first vaccine to reduce recurrent virus shedding, a key to decreasing the spread of HSV-2.
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Herpes Simplex Virus (HSV) Type 2 Glycoprotein D Subunit Vaccines and Protection against Genital HSV-1 or HSV-2 Disease in Guinea Pigs
The Journal of infectious diseases, 2003Co-Authors: Nigel Bourne, David I Bernstein, Fernando J Bravo, Francotte Myriam, Martin G. Myers, Moncef Mohamed Slaoui, Lawrence R. StanberryAbstract:In two recent clinical trials, a vaccine containing herpes simplex virus (HSV) type 2 glycoprotein D (GD2) and a novel adjuvant AS04 comprising alum (Al) and 3-deactylated monophosphoryl lipid A (3-dMPL) afforded HSV-seronegative women significant protection against HSV-2 genital disease (vaccine efficacy, 73% in study 1 and 74% in study 2) and limited protection against infection (46% in study 1 and 39% in study 2). In the present report, studies in the guinea pig model investigated the protection afforded by GD2/AS04 against HSV-1 and HSV-2 genital herpes and investigated whether immunization could prevent or reduce recurrent disease in guinea pigs that developed mucosal infection. Immunization with GD2/AS04 conveyed nearly complete protection against primary disease with either virus but did not prevent mucosal infection. Guinea pigs immunized with GD2/AS04 were significantly better protected against recurrent disease than were guinea pigs immunized with a GD2/Al vaccine, which suggests that inclusion of 3-dMPL improved protection against latent infection.
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herpes simplex virus dna vaccine efficacy effect of glycoprotein d plasmid constructs
The Journal of Infectious Diseases, 2000Co-Authors: J E Strasser, Renee L Arnold, Catherine J Pachuk, Terry J Higgins, David I BernsteinAbstract:The impact of vaccination with plasmid DNA encoding full-length glycoprotein D (gD) from herpes simplex virus (HSV) type 2 (GD2), secreted GD2, or cytosolic GD2 was evaluated in mice and guinea pigs. Immunization with plasmids encoding full-length GD2 or secreted GD2 produced high antibody levels, whereas immunization with DNA encoding cytosolic GD2 resulted in significantly lower antibody titers in both species (P <.001). Vaccination with DNA encoding full-length or secreted GD2 significantly reduced acute disease in mice and guinea pigs (both P <.001) and subsequent recurrent disease in guinea pigs (P <.05). In guinea pigs, immunization with DNA encoding cytosolic GD2 did not protect from acute or recurrent disease, whereas in mice it did protect, but not as well as DNA encoding full-length or secreted GD2. None of the vaccines resulted in improved virus clearance from the inoculation site, and none significantly reduced recurrent disease when used as a therapeutic vaccine in HSV-2-infected guinea pigs.
Feng Yao - One of the best experts on this subject based on the ideXlab platform.
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a herpes simplex virus 2 hsv 2 glycoprotein d expressing nonreplicating dominant negative hsv 2 virus vaccine is superior to a GD2 subunit vaccine against hsv 2 genital infection in guinea pigs
PLOS ONE, 2014Co-Authors: Pengwei Zhang, Lining Xie, John W Balliet, Danilo R Casimiro, Feng YaoAbstract:We recently constructed a novel non-replicating dominant-negative HSV-2 recombinant viral vaccine (CJ2-GD2) capable of expressing various HSV-2 antigens that are dominant targets of HSV-2-specific CD8 T-cell response. Importantly, CJ2-GD2 expresses GD2, the HSV-2 major antigen glycoprotein D, as efficiently as wild-type HSV-2 infection and can lead to a nearly 500-fold reduction in wild-type HSV-2 viral replication in cells co-infected with CJ2-GD2 and wild-type HSV-2. In this report, we show that CJ2-GD2 elicits a strong antibody response to various HSV-2 antigens and is highly effective in the prevention of primary and recurrent HSV-2 genital infection and disease in the immunized guinea pigs. The direct comparison study between CJ2-GD2 and a GD2 subunit vaccine (GD2-alum/MPL) with a formulation akin to a vaccine tested in phase III clinical trials shows that CJ2-GD2 is 8 times more effective than the GD2-alum/MPL subunit vaccine in eliciting an anti-HSV-2 specific neutralizing antibody response and offers significantly superior protection against primary and recurrent HSV-2 genital infections. Importantly, no challenge wild-type HSV-2 viral DNA was detectable in dorsal root ganglia DNA isolated from CJ2-GD2-immunized guinea pigs on day 60 post-challenge. CJ2-GD2 should be an excellent HSV-2 vaccine candidate for protection against HSV-2 genital infection and disease in humans.
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development of a glycoprotein d expressing dominant negative and replication defective herpes simplex virus 2 hsv 2 recombinant viral vaccine against hsv 2 infection in mice
Journal of Virology, 2011Co-Authors: Natalie V Akhrameyeva, Pengwei Zhang, Nao Sugiyama, Samuel M Behar, Feng YaoAbstract:Using the T-REx (Invitrogen, California) gene switch technology and a dominant-negative mutant polypeptide of herpes simplex virus 1 (HSV-1)-origin binding protein UL9, we previously constructed a glycoprotein D-expressing replication-defective and dominant-negative HSV-1 recombinant viral vaccine, CJ9-gD, for protection against HSV infection and disease. It was demonstrated that CJ9-gD is avirulent following intracerebral inoculation in mice, cannot establish detectable latent infection following different routes of infection, and offers highly effective protective immunity against primary HSV-1 and HSV-2 infection and disease in mouse and guinea pig models of HSV infections. Given these favorable safety and immunological profiles of CJ9-gD, aiming to maximize levels of HSV-2 glycoprotein D (GD2) expression, we have constructed an ICP0 null mutant-based dominant-negative and replication-defective HSV-2 recombinant, CJ2-GD2, that contains 2 copies of the GD2 gene driven by the tetracycline operator (tetO)-bearing HSV-1 major immediate-early ICP4 promoter. CJ2-GD2 expresses GD2 as efficiently as wild-type HSV-2 infection and can lead to a 150-fold reduction in wild-type HSV-2 viral replication in cells coinfected with CJ2-GD2 and wild-type HSV-2 at the same multiplicity of infection. CJ2-GD2 is avirulent following intracerebral injection and cannot establish a detectable latent infection following subcutaneous (s.c.) immunization. CJ2-GD2 is a more effective vaccine than HSV-1 CJ9-gD and a non-GD2-expressing dominant-negative and replication-defective HSV-2 recombinant in protection against wild-type HSV-2 genital disease. Using recall response, we showed that immunization with CJ2-GD2 elicited strong HSV-2-specific memory CD4+ and CD8+ T-cell responses. Collectively, given the demonstrated preclinical immunogenicity and its unique safety profiles, CJ2-GD2 represents a new class of HSV-2 replication-defective recombinant viral vaccines in protection against HSV-2 genital infection and disease.
Carolyn E Shaw - One of the best experts on this subject based on the ideXlab platform.
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a dual modality herpes simplex virus 2 vaccine for preventing genital herpes by using glycoprotein c and d subunit antigens to induce potent antibody responses and adenovirus vectors containing capsid and tegument proteins as t cell immunogens
Journal of Virology, 2015Co-Authors: Sita Awasthi, Carolyn E Shaw, Harvey M Friedman, Gregory G Mahairas, Meei Li Huang, David M Koelle, Christine M Posavad, Lawrence CoreyAbstract:ABSTRACT We evaluated a genital herpes prophylactic vaccine containing herpes simplex virus 2 (HSV-2) glycoproteins C (gC2) and D (GD2) to stimulate humoral immunity and U L 19 (capsid protein VP5) and U L 47 (tegument protein VP13/14) as T cell immunogens. The HSV-2 gC2 and GD2 proteins were expressed in baculovirus, while the U L 19 and U L 47 genes were expressed from replication-defective adenovirus vectors. Adenovirus vectors containing U L 19 and U L 47 stimulated human and murine CD4 + and CD8 + T cell responses. Guinea pigs were either (i) mock immunized; (ii) immunized with gC2/GD2, with CpG and alum as adjuvants; (iii) immunized with the U L 19/U L 47 adenovirus vectors; or (iv) immunized with the combination of gC2/GD2-CpG/alum and the U L 19/U L 47 adenovirus vectors. Immunization with gC2/GD2 produced potent neutralizing antibodies, while U L 19 and U L 47 also stimulated antibody responses. After intravaginal HSV-2 challenge, the mock and U L 19/U L 47 adenovirus groups developed severe acute disease, while 2/8 animals in the gC2/GD2-only group and none in the combined group developed acute disease. No animals in the gC2/GD2 or combined group developed recurrent disease; however, 5/8 animals in each group had subclinical shedding of HSV-2 DNA, on 15/168 days for the gC2/GD2 group and 13/168 days for the combined group. Lumbosacral dorsal root ganglia were positive for HSV-2 DNA and latency-associated transcripts for 5/8 animals in the gC2/GD2 group and 2/8 animals in the combined group. None of the differences comparing the gC2/GD2-only group and the combined group were statistically significant. Therefore, adding the T cell immunogens U L 19 and U L 47 to the gC2/GD2 vaccine did not significantly reduce genital disease and vaginal HSV-2 DNA shedding compared with the excellent protection provided by gC2/GD2 in the guinea pig model. IMPORTANCE HSV-2 infection is a common cause of genital ulcer disease and a significant public health concern. Genital herpes increases the risk of transmission and acquisition of HIV-1 infection 3- to 4-fold. A herpes vaccine that prevents genital lesions and asymptomatic genital shedding will have a substantial impact on two epidemics, i.e., both the HSV-2 and HIV-1 epidemics. We previously reported that a vaccine containing HSV-2 glycoprotein C (gC2) and glycoprotein D (GD2) reduced genital lesions and asymptomatic HSV-2 genital shedding in guinea pigs, yet the protection was not complete. We evaluated whether adding the T cell immunogens U L 19 (capsid protein VP5) and U L 47 (tegument protein VP13/14) would enhance the protection provided by the gC2/GD2 vaccine, which produces potent antibody responses. Here we report the efficacy of a combination vaccine containing gC2/GD2 and U L 19/U L 47 for prevention of genital disease, vaginal shedding of HSV-2 DNA, and latent infection of dorsal root ganglia in guinea pigs.
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improving immunogenicity and efficacy of vaccines for genital herpes containing herpes simplex virus glycoprotein d
Expert Review of Vaccines, 2014Co-Authors: Sita Awasthi, Carolyn E Shaw, Harvey M FriedmanAbstract: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 a...
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protection provided by a herpes simplex virus 2 hsv 2 glycoprotein c and d subunit antigen vaccine against genital hsv 2 infection in hsv 1 seropositive guinea pigs
Journal of Virology, 2014Co-Authors: Sita Awasthi, Carolyn E Shaw, John W Balliet, Jessica A Flynn, John M Lubinski, Daniel J Distefano, Michael Cai, Martha Brown, Judith F Smith, Rose KowalskiAbstract:A prophylactic vaccine for genital herpes disease remains an elusive goal. We report the results of two studies performed collaboratively in different laboratories that assessed immunogenicity and vaccine efficacy in herpes simplex virus 1 (HSV-1)-seropositive guinea pigs immunized and subsequently challenged intravaginally with HSV-2. In study 1, HSV-2 glycoproteins C (gC2) and D (GD2) were produced in baculovirus and administered intramuscularly as monovalent or bivalent vaccines with CpG and alum. In study 2, GD2 was produced in CHO cells and given intramuscularly with monophosphoryl lipid A (MPL) and alum, or gC2 and GD2 were produced in glycoengineered Pichia pastoris and administered intramuscularly as a bivalent vaccine with Iscomatrix and alum to HSV-1-naive or -seropositive guinea pigs. In both studies, immunization boosted neutralizing antibody responses to HSV-1 and HSV-2. In study 1, immunization with gC2, GD2, or both immunogens significantly reduced the frequency of genital lesions, with the bivalent vaccine showing the greatest protection. In study 2, both vaccines were highly protective against genital disease in naive and HSV-1-seropositive animals. Comparisons between GD2 and gC2/GD2 in study 2 must be interpreted cautiously, because different adjuvants, GD2 doses, and antigen production methods were used; however, significant differences invariably favored the bivalent vaccine. Immunization of naive animals with gC2/GD2 significantly reduced the number of days of vaginal shedding of HSV-2 DNA compared with that for mock-immunized animals. Surprisingly, in both studies, immunization of HSV-1-seropositive animals had little effect on recurrent vaginal shedding of HSV-2 DNA, despite significantly reducing genital disease.
