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：
8745313
负责人：
Jeffrey Cohen
金额：
$ 49.08万
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/8745313
关键词：
Animal Model Animals Attenuated Bacterial Artificial Chromosomes Cavia Cell Culture Techniques Cells Clinical Clinical Protocols Development Disease Engineering Enrollment Epithelial Cells Ganglia Genome Glycoproteins Goals HIV Herpes Simplex Infections Human Human Herpesvirus 2 Immune response Infection Institutional Review Boards International Intramuscular Life Lymphocyte Mus Mutation Nervous system structure Neurologic Neurons PVRL1 Patients Phase Phase I Clinical Trials Plasmids Prevention Randomized Controlled Trials Reporting Risk Simplexvirus Testing United States National Institutes of Health Vaccines Viral Viral Proteins Virus Woman Work genital herpes high voltage electron microscopy immunogenicity mutant neuroblastoma cell neutralizing antibody pre-clinical receptor safety testing screening transmission process

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. A vaccine containing a single viral protein (HSV-2 glycoprotein D) recently showed no evidence for protection against genital herpes in a large international, phase three, randomized controlled trial in HSV-2 seronegative women. We postulate that the limited efficacy of the HSV-2 glycoprotein D vaccine is likely due to inadequate induction of broadly neutralizing antibody and cellular immune responses. Last year we reported that we cloned the entire HSV-2 genome into a plasmid containing a bacterial artificial chromosome (BAC). We showed that virus derived from the HSV-2 BAC replicated in cell culture at the same rate as wild-type virus and that mice infected with the HSV-2 BAC developed disease as well as latent HSV-2 infection at a similar rate as animals infected with wild-type virus. This year, we engineered mutations in the HSV-2 BAC and obtained HSV-2 with mutations in the viral glycoprotein D (gD) that are critical for the ability of gD to interact with one of its receptors, nectin-1, but not with another receptor, HVEM. Since HVEM is expressed on epithelial cells and lymphocytes, while nectin-1 is expressed on neurons and epithelial cells, the HSV-2 gD mutant would be predicted to be impaired for infecting neurons, but not epithelial cells and therefore might induce a potent immune response, but not cause neurologic disease in animals. The HSV-2 mutant was able to infect cells expressing HVEM (epithelial cells), but not cells only expressing nectin-1 (neuroblastoma cells). The mutant did not productively infect ganglia in the nervous system of mice. The inability of the HSV mutant to productively infect neuronal cells in culture or ganglia in mice after intramuscular inoculation suggests that the HSV-2 mutant might be an attractive candidate as a live attenuated HSV-2 vaccine. We are also planning to initiate a phase 1 clinical trial to test the safety and immunogenicity of a different vaccine- a replication-defective HSV-2 vaccine in humans. This vaccine was developed by Dr. David Knipe at Harvard, and our lab performed much of the preclinical work in mice and guinea pigs. The clinical protocol has been approved by our IRB and we are currently screening patients to identify those who will be eligible to enroll in the vaccine trial.

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。已经在人类中测试了几种HSV-2疫苗，以预防或减少生殖器疱疹疾病。最近在HSV-2血清神经女性中，含有单个病毒蛋白（HSV-2糖蛋白D）的疫苗（HSV-2糖蛋白D）最近没有任何证据表明可以保护防止生殖器疱疹。我们假设HSV-2糖蛋白D疫苗的有限疗效可能是由于诱导不足的广泛中和抗体和细胞免疫反应。去年，我们报告说，我们将整个HSV-2基因组克隆到含有细菌人造染色体（BAC）的质粒中。我们表明，源自在细胞培养中以与野生型病毒相同的速率复制的HSV-2 BAC的病毒，并以与野生型病毒感染的动物相似的速度感染了HSV-2 BAC感染的小鼠以及潜在的HSV-2感染。今年，我们在HSV-2 BAC中设计了突变，并在病毒糖蛋白D（GD）中获得了HSV-2，这对于GD与其一种受体Nectin-1相互作用至关重要，但与其他受体HVEM相互作用至关重要。由于HVEM在上皮细胞和淋巴细胞上表达，而在神经元和上皮细胞上表达了nectin-1，因此预计HSV-2 GD突变体将被预测会受损神经元，但不会引起上皮细胞，因此可能会诱导有效的免疫反应，但不会引起动物神经系统疾病。 HSV-2突变体能够感染表达HVEM（上皮细胞）的细胞，而不仅仅是表达nectin-1（神经母细胞瘤细胞）的细胞。突变体没有在小鼠神经系统中有效地感染神经节。肌肉接种后，HSV突变体无法在小鼠中有效地感染培养或神经节神经元细胞，这表明HSV-2突变体可能是一种有吸引力的候选者，作为活衰减的HSV-2疫苗。我们还计划启动1期临床试验，以测试其他疫苗的安全性和免疫原性 - 一种复制缺陷性的HSV-2疫苗。这种疫苗是由哈佛大学的David Knipe博士开发的，我们的实验室在小鼠和豚鼠中进行了许多临床前工作。临床方案已得到我们的IRB批准，我们目前正在筛选患者，以确定有资格参加疫苗试验的患者。