Development Of Vaccines For Genital Herpes Simplex Infection

生殖器单纯疱疹感染疫苗的开发

基本信息

批准号：
10272036
负责人：
Jeffrey Cohen
金额：
$ 94.78万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10272036
关键词：
Animal Model Antibodies Antibody titer measurement CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cavia Cells Controlled Clinical Trials Disease Dose Double-Blind Method Embryo Fibroblasts Genes Goals HIV Herpes Simplex Infections Herpes Simplex Virus Vaccines Herpesvirus 1 Human Human Herpesvirus 2 Immune response Infection Inflammasome Injection Site Reaction Injections Innate Immune Response Innate Immune System Integration Host Factors Interferons Knock-out Messenger RNA Metabolism Mitochondria Mitochondrial DNA Monkeys Mus National Heart, Lung, and Blood Institute Natural Immunity Outer Mitochondrial Membrane Oxidative Stress Participant Phase I Clinical Trials Placebos Prevention Protein Isoforms Proteins Randomized Reaction Resistance Risk Safety Saline Simplexvirus T cell response Testing United States National Institutes of Health VDAC1 gene VDAC2 gene VDAC3 gene Vaccinated Vaccination Vaccines Virus Diseases Voltage-Dependent Anion Channel cell type clinical center experience experimental study genital herpes neutralizing antibody primary endpoint release of sequestered calcium ion into cytoplasm response transmission process vaccine development

项目摘要

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.

单纯疱疹病毒2（HSV-2）引起生殖器疱疹，并增加艾滋病毒传播和感染的风险。因此，用于HSV-2的疫苗不仅会降低生殖器疱疹的速度，而且可能会降低HIV的传播。几种HSV-2疫苗已在人类中进行了预防或减少生殖器疱疹疾病的测试，但没有人获得许可用于人类。以前，我们对称为HSV529的HSV2进行了复制缺陷疫苗的随机，双盲，安慰剂对照试验。该疫苗可以感染细胞，但不能在细胞中复制。我们为HSV529（每组15名受试者）或盐水安慰剂注射（每组5名受试者）的三个剂量（0、1和6个月）的20名受试者接种了三组。这些小组是a）过去感染了HSV2的受试者，但可能不会感染HSV-1（HSV2+），（b）仅感染HSV1（HSV1+/HSV2-）和（C）受试者的受试者，以及未感染HSV1或HSV1或HSV1或HSV1或HSV2（HSV1或HSV2）（HSV1-HSV1-V1-V2---HSV1-/HSV2-2-）。疫苗接种后跟踪每个受试者，安全，主要终点和对疫苗的免疫反应。百分之八十九的疫苗接收者经历了轻度至中度的注射部位反应，而安慰剂接受者中有47％。 64％的疫苗接收者经历了全身反应，而安慰剂接受者中有53％。 HSV1-/HSV2-疫苗接种者中有78％的疫苗在中和抗体滴度的上和三剂疫苗后的升高> 4倍，而其他血清群的参与者都没有这种反应。在36％的46％和27％的HSV1-/HSV2-，HSV2+和HSV1+/HSV2-参与者中，在14％和8％的参与者中，分别检测到HSV2特异性CD4+ T细胞响应的HSV1-/HSV2-，HSV2+和HSV1+/HSV2-参与者中，分别在36％46％和27％的HSV1-/HSV2-，HSV2+和HSV1+/HSV2-参与者中分别检测到HSV2。因此，HSV529疫苗是安全的，并引起中和抗体和中和CD4+ T细胞反应在HSV血清染色疫苗受体中。今年，我们与NHLBI的Jay Chung合作研究了先天免疫系统对于防止HSV的保护至关重要。在氧化应激下，线粒体通过线粒体外膜中的电压依赖性阴离子通道（VDAC）寡聚物形成的孔释放出短线粒体DNA片段。 VDAC是线粒体外膜中最丰富的蛋白质，可调节钙通量，代谢和炎性体激活。 VDAC，VDAC1，VDAC2和VDAC3有三种同工型。与野生型细胞相比，对VDAC1和VDAC3脱离的小鼠胚胎成纤维细胞的胞质线粒体DNA和干扰素刺激的基因mRNA的水平较低。我们发现，与野生型细胞相比，对VDAC1和VDAC3敲除的小鼠胚胎成纤维细胞对HSV-1的耐药性较小。这些实验确定了对干扰素对HSV-1感染的反应重要的宿主因素，对HSV-1的控制很重要。因此，我们在先天免疫反应中确定了蛋白质（VDAC1和VDAC3），可能有助于对HSV-1的宿主反应。