A novel prophylactic and therapeutic vaccine for ocular herpes simplex virus infections

一种针对眼部单纯疱疹病毒感染的新型预防和治疗疫苗

基本信息

批准号：
10482237
负责人：
Edward Gershburg
金额：
$ 26.96万
依托单位：
RATIONAL VACCINES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10482237
关键词：
Adult Afferent Neurons Antiviral Agents Attenuated Attenuated Vaccines Axon Binding Biological Models Blindness Cavia Cell Culture Techniques Child Clinical Research Cornea Dermal Disease Electric Stimulation Epinephrine Eye Eye Infections Eye diseases Glycoproteins Herpes Simplex Virus Vaccines Herpesviridae Infections Herpesvirus Type 3 Herpetic Keratitis Human Human Herpesvirus 2 Immune Immune response Immunologics Immunotherapy Infection Inflammation Intramuscular Investigation Iontophoresis Keratitis Lead Lesion Mechanical Stimulation Mediating Modeling Mus Mutation Nerve Growth Factors Neurons Nicotine Oryctolagus cuniculus Outcome Pathogenesis Phase Prevention Prevention approach Preventive vaccine Production Radial Keratotomy Recurrence Rights Route SCID Mice Safety Saliva Simplexvirus Stimulus Structure of trigeminal ganglion Testing Therapeutic Intervention Therapeutic Uses Tissues Vaccination Vaccine Therapy Vaccines Viral Viral Genome Virion Virus Virus Diseases Virus Latency Virus Shedding clinically significant corneal epithelium experimental study guinea pig model human disease immunopathology neuronal cell body neurotropic novel prevent prophylactic reactivation from latency therapeutic vaccine vaccine trial

项目摘要

SUMMARY: Herpes simplex virus (HSV-1) is a neurotropic alphaherpesvirus and a major cause of ocular disease that can lead to blindness worldwide. The virus infects the corneal epithelium and subsequently establishes latency in sensory neurons of the trigeminal ganglia (TG). Recurrent reactivation of the virus causes shedding of virions in tears and herpetic stromal keratitis (HSK) that can lead to irreparable cornea damage and loss of vision. Vaccination with a safe, live- attenuated virus could induce robust humoral and cellular immune responses as it has been shown with other viruses including varicella zoster virus, which also belongs to the alphaherpesvirus subfamily. A major roadblock in the use of HSV-1, as a live-attenuated vaccine approach is that these viruses remain competent for infection of neurons and establishment of latency. Rational Vaccines, Inc has acquired the rights to the VC2 live-attenuated HSV-1 vaccine strain. VC2 is derived from HSV-1(F) and carries deletions in the amino termini of glycoprotein K (gK) and UL20, both of which bind glycoprotein B (gB). These mutations allow the virus to replicate efficiently in cell culture; however, the virus cannot enter into the axonal endings and establish latency in TG neurons after ocular infection of mouse eyes. Intramuscular vaccination with the VC2 virus produces robust humoral and cellular immune responses in mice and guinea pigs, and impressive protection against lethal intravaginal challenge with either HSV-1(McKrae) or HSV-2(G) wild-type viruses in both mouse and guinea pig models, as well as against ocular infection of mice. To explore the potential of VC2 as a vaccine approach for the prevention and treatment of ocular herpes infection, we propose a detailed vaccination study in rabbits because rabbits allow for the testing of VC2 as both a prophylactic and therapeutic vaccine. Our hypothesis is that intramuscular vaccination with the VC2 virus will generate significant immune responses to protect rabbits challenged with HSV-1 (McKrae) via the ocular route and prevent the establishment of latent viral genomes in TG neurons. In addition, therapeutic vaccination with VC2 will significantly reduce viral shedding and concomitant ocular virus-associated immunopathogenesis. Therapeutic intervention of recurrent ocular HSV-1 disease would be of great clinical significance. Positive results from the proposed experiments will pave the way for phase I clinical studies in humans.

摘要：单纯疱疹病毒 (HSV-1) 是一种嗜神经性 α 疱疹病毒，也是眼部疾病的主要原因。在全世界范围内可能导致失明的疾病。病毒感染角膜上皮，随后确定三叉神经节 (TG) 感觉神经元的潜伏期。病毒反复重新激活导致泪液中病毒颗粒脱落和疱疹性基质角膜炎 (HSK)，从而导致角膜无法修复损伤和视力丧失。接种安全的减毒活病毒疫苗可以诱导强大的体液和细胞免疫反应，正如其他病毒（包括水痘带状疱疹病毒）所显示的那样也属于α疱疹病毒亚科。使用 HSV-1 作为减毒活病毒的主要障碍疫苗方法是这些病毒仍然能够感染神经元并建立延迟。 Rational Vaccines, Inc 已获得 VC2 减毒 HSV-1 疫苗株的权利。 VC2 源自 HSV-1(F)，并在糖蛋白 K (gK) 和 UL20 的氨基末端带有缺失，两者均结合糖蛋白 B (gB)。这些突变使病毒能够在细胞培养物中有效复制；然而，病毒不能进入轴突末梢并在眼部感染后在 TG 神经元中建立潜伏期。小鼠眼睛感染。肌肉注射 VC2 病毒疫苗可产生强大的体液和细胞活性小鼠和豚鼠的免疫反应，以及对致命阴道内挑战的令人印象深刻的保护在小鼠和豚鼠模型中也使用 HSV-1(McKrae) 或 HSV-2(G) 野生型病毒对抗小鼠眼部感染。探索 VC2 作为预防疫苗方法的潜力和眼部疱疹感染的治疗，我们建议对兔子进行详细的疫苗接种研究，因为兔子允许测试 VC2 作为预防性和治疗性疫苗。我们的假设是肌肉注射 VC2 病毒疫苗将产生显着的免疫反应以保护兔子通过眼部途径受到 HSV-1 (McKrae) 攻击并阻止潜伏病毒基因组的建立在 TG 神经元中。此外，治疗性疫苗接种 VC2 将显着减少病毒脱落和伴随眼部病毒相关的免疫发病机制。复发性眼病的治疗干预 HSV-1疾病将具有重要的临床意义。拟议实验的积极结果将为人类 I 期临床研究铺平道路。