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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.

单纯疱疹病毒（HSV-1）是一种嗜神经性α疱疹病毒，是引起眼部病变的主要原因。这种疾病可以导致全世界的失明。病毒感染角膜上皮，建立三叉神经节（TG）感觉神经元的潜伏期。病毒反复激活导致泪液中病毒粒子脱落和疱疹性角膜基质炎（HSK），可导致无法修复的角膜损伤和视力丧失。用一种安全的减毒活病毒接种疫苗，细胞免疫应答，如其它病毒，包括水痘带状疱疹病毒，也属于α疱疹病毒亚科。使用HSV-1作为减毒活疫苗的主要障碍是疫苗的方法是，这些病毒仍然有能力感染神经元和建立延迟。Rational Vaccines，Inc已获得VC 2 HSV-1减毒活疫苗株的权利。 VC 2来源于HSV-1（F），并在糖蛋白K（gK）和UL 20的氨基末端携带缺失，两者都结合糖蛋白B（gB）。这些突变使病毒能够在细胞培养中有效复制; 然而，病毒不能进入轴突末梢，并在TG神经元中建立潜伏期，感染小鼠眼睛。用VC 2病毒进行肌内接种产生了强有力的体液和细胞免疫应答。小鼠和豚鼠的免疫应答，以及对致死性阴道内攻击的显著保护小鼠和豚鼠模型中的HSV-1（McKrae）或HSV-2（G）野生型病毒，以及抗小鼠眼部感染。探索VC 2作为预防疾病的疫苗方法的潜力和治疗眼部疱疹感染，我们建议在兔子中进行详细的疫苗接种研究，允许测试VC 2作为预防性和治疗性疫苗。我们的假设是用VC 2病毒肌肉内接种将产生显著的免疫应答以保护兔子通过眼部途径用HSV-1（McKrae）攻击，并防止潜伏病毒基因组的建立在TG神经元中。此外，用VC 2进行治疗性疫苗接种将显著减少病毒脱落，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感染具有重要的临床意义。从拟议的实验的积极结果将为人类I期临床研究铺平道路。