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Principal Investigator: Jeffrey Cohen
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2020
Award: $947,827
Funding agency: National Institute of Allergy and Infectious Diseases
Herpes simplex virus 2 (HSV-2) causes genital herpes and increases the risk of transmission and infection with HIV. Thus a vaccine for HSV-2 would not only reduce the rate of genital herpes, but also might reduce spread of HIV. Several HSV-2 vaccines have been tested in humans for prevention or reduction of genital herpes disease, but none has been licensed for use in humans.
Previously we performed a randomized, double blind, placebo-controlled clinical trial of a replication-defective vaccine for HSV2 termed HSV529. This vaccine can infect cells, but not replicate in the cells. We vaccinated three groups of 20 subjects with three doses (at 0, 1, and 6 months) of HSV529 (15 subjects per group) or saline placebo injection (5 subjects per group). The groups were a) subjects who were infected with HSV2 in the past but may or may not have been infected with HSV-1 (HSV2+), (b) subjects who were infected only with HSV1 (HSV1+/HSV2-), and (c) subjects who were not infected with HSV1 or HSV2 (HSV1-/HSV2-). Each subject was followed after vaccination, and safety, the primary endpoint, and immune responses to the vaccine were studied. Eighty-nine percent of vaccine recipients experienced mild to moderate solicited injection site reactions compared with 47% of placebo recipients. Sixty-four percent of vaccine recipients experienced systemic reactions compared with 53% of placebo recipients. Seventy-eight percent of HSV1-/HSV2- vaccine recipients had > 4-fold rises in neutralizing antibody titer after three doses of vaccine, whereas none of the participants in the other serogroups had such responses. HSV2-specific CD4+ T-cell responses were detected in 36% 46%, and 27%, of HSV1-/HSV2-, HSV2+, and HSV1+/HSV2- participants, respectively, one month after the third dose of vaccine, and CD8+ T-cell responses were detected in 14%, 8%, and 18% of participants in each group, respectively. Thus, the HSV529 vaccine was safe and elicited neutralizing antibody and modest CD4+ T-cell responses in HSV seronegative vaccine recipients.
This year we collaborated with Jay Chung in NHLBI to study how the innate immune system is important for protection against HSV. Under oxidative stress, mitochondria release short mitochondrial DNA fragments through pores formed by voltage-dependent anion channel (VDAC) oligomers in the outer membrane of the mitochondria. VDAC is the most abundant protein in mitochondria outer membrane and regulates calcium flux, metabolism, and inflammasome activation. There are three isoforms of VDAC, VDAC1, VDAC2, and VDAC3. Mouse embryo fibroblasts knocked-out for VDAC1 and VDAC3 have lower levels of cytosolic mitochondrial DNA and interferon-stimulated gene mRNA than wild-type cells. We found that mouse embryo fibroblasts knocked-out for VDAC1 and VDAC3 are less resistant to HSV-1 than wild-type cells. These experiments identify a host factor important for the interferon response to HSV-1 infection and important for control of HSV-1. Thus, we have identified proteins (VDAC1 and VDAC3) in the innate immune response that may contribute to the host response against HSV-1.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Animal Model><Animal Models and Related Studies><Antibodies><Antibody titer measurement><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cavia><Cell Body><Cells><Controlled Clinical Trials><Disease><Disorder><Dose><Double-Blind Method><Double-Blind Study><Double-Blinded><Double-Masked Method><Double-Masked Study><Early-Stage Clinical Trials><Embryo><Embryonic><Fibroblasts><Genes><Genital Herpes Simplex><Goals><Guinea Pigs><Guinea Pigs Mammals><HHV-2><HHV2><HIV><HSV><HSV Vaccines><HSV-1><HSV-2><HSV1><HSV2><Herpes Genitalis><Herpes Simplex><Herpes Simplex Infections><Herpes Simplex Virus><Herpes Simplex Virus 1><Herpes Simplex Virus 2><Herpes Simplex Virus Type 1><Herpes Simplex Virus Type 2><Herpes Simplex Virus Vaccines><Herpes labialis Virus><Herpes simplex disease><Herpesvirus 1><Herpesvirus 2 (alpha), Human><Herpesvirus hominis disease><Herpesvirus progenitalis><Host Factor><Host Factor Protein><Human><Human (alpha) herpes virus 2><Human Herpesvirus 2><Human Immunodeficiency Viruses><Human herpes simplex virus type 2><IFN><Immune response><Immunological response><Infection><Inflammasome><Injection Site Reaction><Injections><Innate Immune Response><Innate Immune System><Innate Immunity><Integration Host Factors><Interferons><Intermediary Metabolism><Isoforms><Knock-out><Knockout><LAV-HTLV-III><Lymphadenopathy-Associated Virus><Messenger RNA><Metabolic Processes><Metabolism><Mice><Mice Mammals><Mitochondria><Mitochondrial DNA><Mitochondrial Porin><Modern Man><Monkeys><Murine><Mus><NHLBI><NIH><National Heart, Lung, and Blood Institute><National Institutes of Health><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Outer Mitochondrial Membrane><Oxidative Stress><Participant><Phase 1 Clinical Trials><Phase I Clinical Trials><Placebos><Prevention><Protein Isoforms><Proteins><Randomized><Reaction><Resistance><Risk><Safety><Saline><Saline Solution><Sham Treatment><Simplexvirus><Simplexvirus Vaccines><T cell response><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Testing><Transmission><United States National Institutes of Health><VDAC mitochondrial porin><VDAC proteins><VDAC1><VDAC1 gene><VDAC2><VDAC2 gene><VDAC3><VDAC3 gene><Vaccinated><Vaccination><Vaccines><Viral Diseases><Virus Diseases><Virus-Genital Herpes><Virus-HIV><Voltage-Dependent Anion Channel><anion-selective channels voltage-dependent><antibody titering><calcium flux><calcium mobilization><cell type><clinical center><develop a vaccine><development of a vaccine><experience><experiment><experimental research><experimental study><genital herpes><herpes genitalia><herpes simplex i><herpes simplex ii><host response><human alphaherpesvirus 2><immunoresponse><mRNA><mitochondria porins><mitochondrial><mitochondrial pore protein><model of animal><model organism><mtDNA><neutralizing antibody><phase I protocol><pore forming protein><pore forming protein VDAC><porin><primary end point><primary endpoint><randomisation><randomization><randomly assigned><release of sequestered calcium ion into cytoplasm><resistant><response><sham therapy><transmission process><vaccine development><vaccine formulation><venereal herpes><viral infection><virus infection><virus-induced disease><voltage-dependent, anion-selective, channel forming protein, mitochondrial>