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）是一种神经性αHERPESVIRUS，是眼部的主要原因疾病可能导致全球失明。该病毒感染角膜上皮，然后在三叉神经节（TG）的感觉神经元中建立潜伏期。病毒的复发重新激活导致病毒体在眼泪和疱疹性基质角膜炎（HSK）中脱落，可能导致无法弥补的角膜损害和视力丧失。安全，活着的病毒疫苗接种可能会引起强大的体液和细胞免疫反应已与其他病毒一起显示，包括水痘带状疱疹病毒，还属于αHERPESVIRUS亚家族。 HSV-1的使用中的主要障碍，作为活体侵蚀疫苗方法是，这些病毒仍然有能力感染神经元和建立潜伏期。 Rational Vacines，Inc已获得了VC2实时衰减的HSV-1疫苗菌株的权利。 VC2衍生自HSV-1（f），并在糖蛋白K（GK）和UL20的氨基末端中遗传。两者结合糖蛋白B（GB）。这些突变使该病毒在细胞培养中有效复制。但是，该病毒无法进入轴突末端，并在眼后建立TG神经元的潜伏期小鼠眼睛的感染。 VC2病毒的肌内疫苗接种可产生强大的体液和细胞小鼠和几内亚猪的免疫反应，以及对致命性肠内挑战的令人印象深刻的保护在小鼠和豚鼠模型中，HSV-1（McKrae）或HSV-2（G）野生型病毒也与小鼠的眼部感染相对。探索VC2作为预防疫苗方法的潜力和眼疱疹感染的治疗，我们在兔子中提出了一项详细的疫苗接种研究允许将VC2作为预防性和治疗性疫苗进行测试。我们的假设是 VC2病毒肌内疫苗接种将产生明显的免疫反应以保护兔子通过眼路线挑战HSV-1（McKrae），并防止建立潜在的病毒基因组在TG神经元中。此外，通过VC2治疗疫苗接种将显着降低病毒脱落和与眼病毒相关的免疫致病发生。复发性眼的治疗干预 HSV-1疾病将具有极大的临床意义。提出的实验的积极结果将为人类I期临床研究铺平道路。