Once-Daily Valacyclovir to Reduce the Risk of Transmission of Genital Herpes

Corey, Lawrence; Wald, Anna; Patel, Raj; Sacks, Stephen L.; Tyring, Stephen K.; Warren, Terri; Douglas, John M.; Paavonen, Jorma; Morrow, Rhoda Ashley; Beutner, Karl R.; Stratchounsky, Leonid S.; Mertz, Grégory; Keene, Oliver N.; Watson, Helen; Tait, Dereck; Vargas‐Cortes, Mauricio

doi:10.1056/nejmoa035144

Cited by 644 publications

(304 citation statements)

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“…Prevention of genital HSV infection and transmission is an important target for vaccine development because of the psychosocial and medical complications of genital herpes and because genital herpes is a significant risk factor for HIV acquisition and transmission (10)(11)(12)(13). Antiviral therapy reduces the duration of HSV-2 symptomatic disease, and daily suppressive therapy decreases symptomatic recurrences and asymptomatic viral shedding (14); however, the protection is incomplete, since antiviral therapy does not totally prevent viral shedding or eliminate latency (15)(16)(17).…”

mentioning

confidence: 99%

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

Awasthi

Balliet

Flynn

et al. 2014

J Virol

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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.

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mentioning

confidence: 99%

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

Awasthi

Balliet

Flynn

et al. 2014

J Virol

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“…The expression of gD2 on the surface of epithelial cells upon infection will make these cells susceptible to the gD2-binding R33ExoA immunotoxin. Given its efficacy at very low concentrations, application prior to intercourse or through continuous secretion from genetically engineered commensal genital flora could provide sufficient levels of the immunotoxin to achieve a level of protection not observed with the use of antivirals alone (49). Similar delivery methods for other antivirals have been used successfully to prevent STI transmission in various model systems (50,51).…”

Section: Discussionmentioning

confidence: 99%

“…Because shedding episodes are frequent and subclinical shedding accounts for 80% of shedding, it is unrealistic to rely on avoidance of sexual contact during times of shedding as a means to prevent transmission (55). While oral antiviral drugs such as valacyclovir decrease viral shedding, they do not completely eliminate viral shedding or prevent transmission (49). Daily application of this immunotoxin formulated as a microbicide could help suppress the amount of virus shed by the infected partner and therefore decrease the chance of transmission to the uninfected partner.…”

Section: Discussionmentioning

confidence: 99%

Antiviral Activity of a Single-Domain Antibody Immunotoxin Binding to Glycoprotein D of Herpes Simplex Virus 2

Geoghegan

Zhang

Desai

et al. 2015

Antimicrob Agents Chemother

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c Despite years of research dedicated to preventing the sexual transmission of herpes simplex virus 2 (HSV-2), there is still no protective vaccine or microbicide against one of the most common sexually transmitted infections in the world. Using a phage display library constructed from a llama immunized with recombinant HSV-2 glycoprotein D, we identified a single-domain antibody VHH, R33, which binds to the viral surface glycoprotein D. Although R33 does not demonstrate any HSV-2 neutralization activity in vitro, when expressed with the cytotoxic domain of exotoxin A, the resulting immunotoxin (R33ExoA) specifically and potently kills HSV-2-infected cells, with a 50% neutralizing dilution (IC 50 ) of 6.7 nM. We propose that R33ExoA could be used clinically to prevent transmission of HSV-2 through killing of virus-producing epithelial cells during virus reactivation. R33 could also potentially be used to deliver other cytotoxic effectors to HSV-2-infected cells.

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“…Infection with HSV-2 is lifelong and is characterized by periods of symptomatic disease or asymptomatic viral shedding (2), and roughly 80% of HSV-2-seropositive people are unaware of their infection (3). While antiviral therapies are available, daily use cannot eliminate the viral reservoir or completely prevent transmission in serodiscordant couples (4). With the lack of additional therapeutic options, an efficacious vaccine is necessary to control the continued spread of HSV-2 infections around the world.…”

Section: Importancementioning

confidence: 99%

Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir

Hensel¹,

Marshall²,

Dorwart³

et al. 2017

J Virol

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Several prophylactic vaccines targeting herpes simplex virus 2 (HSV-2) have failed in the clinic to demonstrate sustained depression of viral shedding or protection from recurrences. Although these vaccines have generated high titers of neutralizing antibodies (NAbs), their induction of robust CD8 T cells has largely been unreported, even though evidence for the importance of HSV-2 antigen-specific CD8 T cells is mounting in animal models and in translational studies involving subjects with active HSV-2-specific immune responses. We developed a subunit vaccine composed of the NAb targets gD and gB and the novel T cell antigen and tegument protein UL40, and we compared this vaccine to a whole-inactivated-virus vaccine (formaldehyde-inactivated HSV-2 [FI-HSV-2]). We evaluated different formulations in combination with several Th1-inducing Toll-like receptor (TLR) agonists in vivo. In mice, the TLR9 agonist cytosine-phosphate-guanine (CpG) oligodeoxynucleotide formulated in a squalene-based oil-in-water emulsion promoted most robust, functional HSV-2 antigen-specific CD8 T cell responses and high titers of neutralizing antibodies, demonstrating its superiority to vaccines adjuvanted by monophosphoryl lipid A (MPL)-alum. We further established that FI-HSV-2 alone or in combination with adjuvants as well as adjuvanted subunit vaccines were successful in the induction of NAbs and T cell responses in guinea pigs. These immunological responses were coincident with a suppression of vaginal HSV-2 shedding, low lesion scores, and a reduction in latent HSV-2 DNA in dorsal root ganglia to undetectable levels. These data support the further preclinical and clinical development of prophylactic HSV-2 vaccines that contain appropriate antigen and adjuvant components responsible for programming elevated CD8 T cell responses.IMPORTANCE Millions of people worldwide are infected with herpes simplex virus 2 (HSV-2), and to date, an efficacious prophylactic vaccine has not met the rigors of clinical trials. Attempts to develop a vaccine have focused primarily on glycoproteins necessary for HSV-2 entry as target antigens and to which the dominant neutralizing antibody response is directed during natural infection. Individuals with asymptom- Citation Hensel MT, Marshall JD, Dorwart MR, Heeke DS, Rao E, Tummala P, Yu L, Cohen GH, Eisenberg RJ, Sloan DD. 2017. Prophylactic herpes simplex virus 2 (HSV-2) vaccines adjuvanted with stable emulsion and Toll-like receptor 9 agonist induce a robust HSV-2-specific cell-mediated immune response, protect against symptomatic disease, and reduce the latent viral reservoir.

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Once-Daily Valacyclovir to Reduce the Risk of Transmission of Genital Herpes

Abstract: Once-daily suppressive therapy with valacyclovir significantly reduces the risk of transmission of genital herpes among heterosexual, HSV-2-discordant couples.

Cited by 644 publications

References 31 publications

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

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

Antiviral Activity of a Single-Domain Antibody Immunotoxin Binding to Glycoprotein D of Herpes Simplex Virus 2

Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir

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