HSV-2 Vaccine: Current Status and Insight into Factors for Developing an Efficient Vaccine

Herpes simplex virus type 2 (HSV-2), a globally sexually transmitted virus, and also one of the main causes of genital ulcer diseases, increases susceptibility to HIV-1. Effective vaccines to prevent HSV-2 infection are not yet available, but are currently being developed. To facilitate this process, the latest progress in development of these vaccines is reviewed in this paper. A summary of the most promising HSV-2 vaccines tested in animals in the last five years is presented, including the main factors, and new ideas for developing an effective vaccine from animal experiments and human clinical trials. Experimental results indicate that future HSV-2 vaccines may depend on a strategy that targets mucosal immunity. Furthermore, estradiol, which increases the effectiveness of vaccines, may be considered as an adjuvant. Therefore, this review is expected to provide possible strategies for development of future HSV-2 vaccines.

[1]  L. BenMohamed,et al.  Gender-Dependent HLA-DR-Restricted Epitopes Identified from Herpes Simplex Virus Type 1 Glycoprotein D , 2008, Clinical and Vaccine Immunology.

[2]  A. Wald,et al.  HSV-2: in pursuit of a vaccine. , 2011, The Journal of clinical investigation.

[3]  N. Bourne,et al.  Antibody-mediated protection against genital herpes simplex virus type 2 disease in mice by Fc gamma receptor-dependent and -independent mechanisms. , 2007, Journal of reproductive immunology.

[4]  A. Harandi,et al.  The Mucosal Adjuvant Effect of α-Galactosylceramide for Induction of Protective Immunity to Sexually Transmitted Viral Infection1 , 2009, The Journal of Immunology.

[5]  M. Stefanidou,et al.  Herpes Simplex Virus 2 (HSV-2) Prevents Dendritic Cell Maturation, Induces Apoptosis, and Triggers Release of Proinflammatory Cytokines: Potential Links to HSV-HIV Synergy , 2012, Journal of Virology.

[6]  R. Pyles,et al.  FSL-1, a bacterial-derived toll-like receptor 2/6 agonist, enhances resistance to experimental HSV-2 infection , 2009, Virology Journal.

[7]  Geoffrey P Garnett,et al.  .‫املقالة‬ ‫لهذه‬ ‫الكامل‬ ‫النص‬ ‫نهاية‬ ‫يف‬ ‫الخالصة‬ ‫لهذه‬ ‫العربية‬ ‫الرتجمة‬ an Estimate of the Global Prevalence and Incidence of Herpes Simplex Virus Type 2 Infection , 2022 .

[8]  T. Geijtenbeek,et al.  Herpes Simplex Virus Type 2 Enhances HIV-1 Susceptibility by Affecting Langerhans Cell Function , 2010, The Journal of Immunology.

[9]  Aston Liu,et al.  A heat shock protein based polyvalent vaccine targeting HSV-2: CD4(+) and CD8(+) cellular immunity and protective efficacy. , 2011, Vaccine.

[10]  A. Nesburn,et al.  Future of an "Asymptomatic" T-cell Epitope-Based Therapeutic Herpes Simplex Vaccine. , 2012, Future virology.

[11]  J. Cohen,et al.  A Herpes Simplex Virus 2 Glycoprotein D Mutant Generated by Bacterial Artificial Chromosome Mutagenesis Is Severely Impaired for Infecting Neuronal Cells and Infects Only Vero Cells Expressing Exogenous HVEM , 2012, Journal of Virology.

[12]  Mimi Y. Kim,et al.  ORIGINAL ARTICLE: Female Genital Tract Secretions Inhibit Herpes Simplex Virus Infection: Correlation with Soluble Mucosal Immune Mediators and Impact of Hormonal Contraception , 2009, American journal of reproductive immunology.

[13]  Takashi Kawana,et al.  [Genital herpes]. , 2009, Nihon rinsho. Japanese journal of clinical medicine.

[14]  A. Nesburn,et al.  A genital tract peptide epitope vaccine targeting TLR-2 efficiently induces local and systemic CD8+ T cells and protects against herpes simplex virus type 2 challenge , 2009, Mucosal Immunology.

[15]  Q. Sattentau,et al.  Polyethyleneimine is a potent mucosal adjuvant for viral glycoprotein antigens , 2012, Nature Biotechnology.

[16]  A. Ashkar,et al.  Prolonged Exposure to Progesterone Prevents Induction of Protective Mucosal Responses following Intravaginal Immunization with Attenuated Herpes Simplex Virus Type 2 , 2003, Journal of Virology.

[17]  B. Williams,et al.  RNA-Dependent Protein Kinase Is Required for Alpha-1 Interferon Transgene-Induced Resistance to Genital Herpes Simplex Virus Type 2 , 2005, Journal of Virology.

[18]  V. Ferreira,et al.  Delayed but effective induction of mucosal memory immune responses against genital HSV-2 in the absence of secondary lymphoid organs , 2012, Mucosal Immunology.

[19]  A. Wald,et al.  Phase I Study of a Herpes Simplex Virus Type 2 (HSV-2) DNA Vaccine Administered to Healthy, HSV-2-Seronegative Adults by a Needle-Free Injection System , 2008, Clinical and Vaccine Immunology.

[20]  A. Iwasaki,et al.  Dendritic cells and B cells maximize mucosal Th1 memory response to herpes simplex virus , 2008, The Journal of experimental medicine.

[21]  J. Adler-Moore,et al.  Liposomal gD ectodomain (gD1-306) vaccine protects against HSV2 genital or rectal infection of female and male mice. , 2009, Vaccine.

[22]  A. Ashkar,et al.  A critical role for IL‐15 in TLR‐mediated innate antiviral immunity against genital HSV‐2 infection , 2011, Immunology and cell biology.

[23]  Shizuo Akira,et al.  IC31, a novel adjuvant signaling via TLR9, induces potent cellular and humoral immune responses. , 2006, Vaccine.

[24]  K. Rosenthal,et al.  Estradiol Regulates Susceptibility following Primary Exposure to Genital Herpes Simplex Virus Type 2, while Progesterone Induces Inflammation , 2005, Journal of Virology.

[25]  D. Bernstein,et al.  Efficacy results of a trial of a herpes simplex vaccine. , 2012, The New England journal of medicine.

[26]  A. Rolland,et al.  Vaxfectin-adjuvanted plasmid DNA vaccine improves protection and immunogenicity in a murine model of genital herpes infection. , 2012, The Journal of general virology.

[27]  W. Halford,et al.  Herpes Simplex Virus 2 ICP0− Mutant Viruses Are Avirulent and Immunogenic: Implications for a Genital Herpes Vaccine , 2010, PloS one.

[28]  F. Eko,et al.  A recombinant multivalent combination vaccine protects against Chlamydia and genital herpes. , 2007, FEMS immunology and medical microbiology.

[29]  Lei Jin,et al.  Immune Surveillance by CD8αα+ Skin Resident T Cells in Human Herpesvirus Infection , 2013, Nature.

[30]  A. Wald,et al.  Rapidly Cleared Episodes of Oral and Anogenital Herpes Simplex Virus Shedding in HIV-Infected Adults , 2010, Journal of acquired immune deficiency syndromes.

[31]  A. Wald,et al.  A randomized controlled trial of a replication defective (gH deletion) herpes simplex virus vaccine for the treatment of recurrent genital herpes among immunocompetent subjects. , 2006, Vaccine.

[32]  K. Rosenthal,et al.  Protection against Genital Herpes Infection in Mice Immunized under Different Hormonal Conditions Correlates with Induction of Vagina-Associated Lymphoid Tissue , 2005, Journal of Virology.

[33]  S. Delagrave,et al.  High-Purity Preparation of HSV-2 Vaccine Candidate ACAM529 Is Immunogenic and Efficacious In Vivo , 2013, PloS one.

[34]  D. Marciani,et al.  Effect of an immune enhancer, GPI-0100, on vaccination with live attenuated herpes simplex virus (HSV) type 2 or glycoprotein D on genital HSV-2 infections of guinea pigs. , 2008, Antiviral research.

[35]  J. Lubinski,et al.  Live Attenuated Herpes Simplex Virus 2 Glycoprotein E Deletion Mutant as a Vaccine Candidate Defective in Neuronal Spread , 2012, Journal of Virology.

[36]  C. Kaushic,et al.  Increased prevalence of sexually transmitted viral infections in women: the role of female sex hormones in regulating susceptibility and immune responses. , 2011, Journal of reproductive immunology.

[37]  L. BenMohamed,et al.  Future viral vectors for the delivery of asymptomatic herpes epitope-based immunotherapeutic vaccines. , 2010, Future virology.

[38]  Xiliang Wang,et al.  Identification of B- and T-cell epitopes from glycoprotein B of herpes simplex virus 2 and evaluation of their immunogenicity and protection efficacy. , 2012, Vaccine.

[39]  L. BenMohamed,et al.  Immunodominant “Asymptomatic” Herpes Simplex Virus 1 and 2 Protein Antigens Identified by Probing Whole-ORFome Microarrays with Serum Antibodies from Seropositive Asymptomatic versus Symptomatic Individuals , 2012, Journal of Virology.

[40]  J. Dou,et al.  An ocular mucosal administration of nanoparticles containing DNA vaccine pRSC-gD-IL-21 confers protection against mucosal challenge with herpes simplex virus type 1 in mice. , 2011, Vaccine.

[41]  Koanhoi Kim,et al.  Modulation of protective immunity against herpes simplex virus via mucosal genetic co-transfer of DNA vaccine with β2-adrenergic agonist , 2009, Experimental & Molecular Medicine.

[42]  A. Ashkar,et al.  Differential induction of innate anti-viral responses by TLR ligands against Herpes simplex virus, type 2, infection in primary genital epithelium of women. , 2009, Antiviral research.

[43]  D. Long,et al.  An Adjuvanted Herpes Simplex Virus 2 Subunit Vaccine Elicits a T Cell Response in Mice and Is an Effective Therapeutic Vaccine in Guinea Pigs , 2013, Journal of Virology.

[44]  A. Adimora,et al.  Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: two randomized controlled trials. Chiron HSV Vaccine Study Group. , 1999, JAMA.

[45]  A. Wald,et al.  Phase I Dose-Escalation Study of a Monovalent Heat Shock Protein 70-Herpes Simplex Virus Type 2 (HSV-2) Peptide-Based Vaccine Designed To Prime or Boost CD8 T-Cell Responses in HSV-Naïve and HSV-2-Infected Subjects , 2008, Clinical and Vaccine Immunology.

[46]  A. Iwasaki,et al.  Cutting Edge: Plasmacytoid Dendritic Cells Provide Innate Immune Protection against Mucosal Viral Infection In Situ1 , 2006, The Journal of Immunology.

[47]  A. Gettie,et al.  Immunomodulatory effects of HSV-2 infection on immature macaque dendritic cells modify innate and adaptive responses. , 2005, Blood.

[48]  Ya-Wun Yang,et al.  Delivery of DNA-based cancer vaccine with polyethylenimine. , 2010, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[49]  L. BenMohamed,et al.  Asymptomatic Human CD4+ Cytotoxic T-Cell Epitopes Identified from Herpes Simplex Virus Glycoprotein B , 2008, Journal of Virology.

[50]  N. Bourne,et al.  A Vaxfectin(®)-adjuvanted HSV-2 plasmid DNA vaccine is effective for prophylactic and therapeutic use in the guinea pig model of genital herpes. , 2012, Vaccine.

[51]  J. Eyles,et al.  Single and Combination Herpes Simplex Virus Type 2 Glycoprotein Vaccines Adjuvanted with CpG Oligodeoxynucleotides or Monophosphoryl Lipid A Exhibit Differential Immunity That Is Not Correlated to Protection in Animal Models , 2011, Clinical and Vaccine Immunology.

[52]  D. Roopenian,et al.  Efficient Mucosal Delivery of Vaccine Using the FcRn-Mediated IgG Transfer Pathway , 2011, Nature Biotechnology.

[53]  J. Fuchs,et al.  Impact of Herpes Simplex Virus Type 2 on HIV-1 Acquisition and Progression in an HIV Vaccine Trial (the Step Study) , 2011, Journal of acquired immune deficiency syndromes.

[54]  A. Iwasaki,et al.  A vaccine strategy protects against genital herpes by establishing local memory T cells , 2012, Nature.

[55]  J. Banchereau,et al.  Functional diversity of human vaginal APC subsets in directing T cell responses , 2012, Mucosal Immunology.

[56]  S. Schmechel,et al.  Herpes Simplex Virus-Induced Epithelial Damage and Susceptibility to Human Immunodeficiency Virus Type 1 Infection in Human Cervical Organ Culture , 2011, PloS one.

[57]  K. Lamberth,et al.  HLA-A*0201-Restricted CD8+ Cytotoxic T Lymphocyte Epitopes Identified from Herpes Simplex Virus Glycoprotein D1 , 2008, The Journal of Immunology.

[58]  A. Wald,et al.  Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation , 2007, The Journal of experimental medicine.

[59]  L. Morrison,et al.  Virus-Encoded B7-2 Costimulation Molecules Enhance the Protective Capacity of a Replication-Defective Herpes Simplex Virus Type 2 Vaccine in Immunocompetent Mice , 2008, Journal of Virology.

[60]  W. Halford,et al.  Loss of the Type I Interferon Pathway Increases Vulnerability of Mice to Genital Herpes Simplex Virus 2 Infection , 2010, Journal of Virology.

[61]  A. Ashkar,et al.  Progesterone Increases Susceptibility and Decreases Immune Responses to Genital Herpes Infection , 2003, Journal of Virology.

[62]  M. Parrington,et al.  Immunogenicity and Efficacy of Intramuscular Replication-Defective and Subunit Vaccines against Herpes Simplex Virus Type 2 in the Mouse Genital Model , 2012, PloS one.

[63]  R. Eisenberg,et al.  Three classes of cell surface receptors for alphaherpesvirus entry. , 2000, Virology.

[64]  P. Spear,et al.  Functional Interaction between Herpes Simplex Virus Type 2 gD and HVEM Transiently Dampens Local Chemokine Production after Murine Mucosal Infection , 2011, PloS one.

[65]  Z. Cui,et al.  Construction of, and T‐helper (Th)1/Th2 immune responses to, a herpes simplex virus type 2 glycoprotein D–cytotoxic T‐lymphocyte epitope DNA vaccine , 2009, Clinical and experimental dermatology.

[66]  A. Wald,et al.  Rapidly cleared episodes of herpes simplex virus reactivation in immunocompetent adults. , 2008, The Journal of infectious diseases.

[67]  A. Iwasaki Mucosal dendritic cells. , 2007, Annual review of immunology.

[68]  Jon Cohen Immunology. Painful failure of promising genital herpes vaccine. , 2010, Science.

[69]  A. Harandi,et al.  Rectal immunization generates protective immunity in the female genital tract against herpes simplex virus type 2 infection: relative importance of myeloid differentiation factor 88. , 2008, Antiviral research.

[70]  Richard J Hayes,et al.  Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies , 2006, AIDS.

[71]  S. Paludan,et al.  Expression of Type III Interferon (IFN) in the Vaginal Mucosa Is Mediated Primarily by Dendritic Cells and Displays Stronger Dependence on NF-κB than Type I IFNs , 2010, Journal of Virology.

[72]  R. Bronson,et al.  Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[73]  M. Motamedi,et al.  Estradiol improves genital herpes vaccine efficacy in mice. , 2009, Vaccine.

[74]  R. Stout,et al.  Evaluation of a needle-free delivery platform for prime-boost immunization with DNA and modified vaccinia virus ankara vectors expressing herpes simplex virus 2 glycoprotein D. , 2006, Viral immunology.

[75]  C. Kaushic,et al.  Intranasal and subcutaneous immunization under the effect of estradiol leads to better protection against genital HSV-2 challenge compared to progesterone. , 2008, Vaccine.

[76]  Sarah S. Wilson,et al.  Herpes Simplex Virus Downregulates Secretory Leukocyte Protease Inhibitor: a Novel Immune Evasion Mechanism , 2008, Journal of Virology.

[77]  D. Spector,et al.  Inactivated HSV-2 in MPL/alum adjuvant provides nearly complete protection against genital infection and shedding following long term challenge and rechallenge. , 2012, Vaccine.

[78]  J. Burnett,et al.  A double-blind study of the efficacy and safety of the ICP10deltaPK vaccine against recurrent genital HSV-2 infections. , 2002, Cutis.

[79]  Stephen T. C. Wong,et al.  Coordination of Early Protective Immunity to Viral Infection by Regulatory T Cells , 2022 .

[80]  D. Carr,et al.  Herpes Simplex Virus Type 2-Induced Mortality following Genital Infection Is Blocked by Anti-Tumor Necrosis Factor Alpha Antibody in CXCL10-Deficient Mice , 2008, Journal of Virology.

[81]  N. Pakravan,et al.  Comparison of intramuscular and footpad subcutaneous immunization with DNA vaccine encoding HSV-gD2 in mice. , 2009, Comparative immunology, microbiology and infectious diseases.

[82]  L. Brabin Interactions of the female hormonal environment, susceptibility to viral infections, and disease progression. , 2002, AIDS patient care and STDs.

[83]  S. Harrison,et al.  Long-COVID Symptoms in Individuals Infected with Different SARS-CoV-2 Variants of Concern: A Systematic Review of the Literature , 2022, Viruses.

[84]  S. Behar,et al.  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 , 2011, Journal of Virology.

[85]  Larry R. Smith,et al.  Phase 1 clinical trials of the safety and immunogenicity of adjuvanted plasmid DNA vaccines encoding influenza A virus H5 hemagglutinin. , 2010, Vaccine.

[86]  P. Srivastava,et al.  Safety and immunogenicity of long HSV-2 peptides complexed with rhHsc70 in HSV-2 seropositive persons. , 2011, Vaccine.

[87]  V. Ferreira,et al.  HSV-2 vaccine: current state and insights into development of a vaccine that targets genital mucosal protection. , 2013, Microbial pathogenesis.

[88]  Taku Sato,et al.  Interleukin 15–dependent crosstalk between conventional and plasmacytoid dendritic cells is essential for CpG-induced immune activation , 2006, Nature Immunology.

[89]  Taku Sato,et al.  Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo , 2006, The Journal of experimental medicine.

[90]  K. Lingnau,et al.  IC31® and IC30, novel types of vaccine adjuvant based on peptide delivery systems , 2007, Expert review of vaccines.

[91]  L. Stanberry,et al.  Impact of immunization with glycoprotein D2/AS04 on herpes simplex virus type 2 shedding into the genital tract in guinea pigs that become infected. , 2005, The Journal of infectious diseases.

[92]  T. Bergström,et al.  Glycoprotein G of Herpes Simplex Virus 2 as a Novel Vaccine Antigen for Immunity to Genital and Neurological Disease , 2012, Journal of Virology.

[93]  M. Bäckström,et al.  Intranasal immunization with a proteoliposome-derived cochleate containing recombinant gD protein confers protective immunity against genital herpes in mice. , 2010, Vaccine.

[94]  R. Eisenberg,et al.  Herpes Simplex Virus Glycoprotein D Interferes with Binding of Herpesvirus Entry Mediator to Its Ligands through Downregulation and Direct Competition , 2010, Journal of Virology.

[95]  A. Wald,et al.  Evasion of the Mucosal Innate Immune System by Herpes Simplex Virus Type 2 , 2009, Journal of Virology.

[96]  A. Harandi,et al.  Nasal and skin delivery of IC31(®)-adjuvanted recombinant HSV-2 gD protein confers protection against genital herpes. , 2012, Vaccine.

[97]  W. Muller,et al.  Herpes Simplex Virus-2 Glycoprotein Interaction with HVEM Influences Virus-Specific Recall Cellular Responses at the Mucosa , 2012, Clinical & developmental immunology.

[98]  D. Scholl,et al.  HSV IgG antibody inhibits virus detection in CSF. , 2012, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[99]  P. Srivastava,et al.  Peptides chaperoned by heat-shock proteins are a necessary and sufficient source of antigen in the cross-priming of CD8+ T cells , 2005, Nature Immunology.

[100]  W. Halford,et al.  Pan-HSV-2 IgG Antibody in Vaccinated Mice and Guinea Pigs Correlates with Protection against Herpes Simplex Virus 2 , 2013, PloS one.

[101]  W. Halford,et al.  A Live-Attenuated HSV-2 ICP0 − Virus Elicits 10 to 100 Times Greater Protection against Genital Herpes than a Glycoprotein D Subunit Vaccine , 2011, PloS one.

[102]  A. Smahi,et al.  TLR3 Deficiency in Patients with Herpes Simplex Encephalitis , 2007, Science.

[103]  E. Erbelding Glycoprotein D-adjuvant vaccine to prevent genital herpes. , 2003, Current infectious disease reports.

[104]  G. Doncel,et al.  Herpes simplex virus and HIV: genital infection synergy and novel approaches to dual prevention , 2012, International journal of STD & AIDS.

[105]  Amanda J. Lee,et al.  Herpes simplex virus-2 in the genital mucosa: insights into the mucosal host response and vaccine development , 2012, Current opinion in infectious diseases.

[106]  A. Ashkar,et al.  NK and NKT Cell-Independent Contribution of Interleukin-15 to Innate Protection against Mucosal Viral Infection , 2005, Journal of Virology.

[107]  A. Gettie,et al.  HSV-2 Infection of Dendritic Cells Amplifies a Highly Susceptible HIV-1 Cell Target , 2011, PLoS pathogens.

[108]  D. Bernstein,et al.  Potent Adjuvant Activity of Cationic Liposome-DNA Complexes for Genital Herpes Vaccines , 2009, Clinical and Vaccine Immunology.

[109]  D. Bernstein,et al.  The adjuvant CLDC increases protection of a herpes simplex type 2 glycoprotein D vaccine in guinea pigs. , 2010, Vaccine.

[110]  K. Rosenthal,et al.  Intravaginal infection with herpes simplex virus type-2 (HSV-2) generates a functional effector memory T cell population that persists in the murine genital tract. , 2010, Journal of reproductive immunology.

[111]  D. Roopenian,et al.  Transfer of IgG in the female genital tract by MHC class I-related neonatal Fc receptor (FcRn) confers protective immunity to vaginal infection , 2011, Proceedings of the National Academy of Sciences.