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

• 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
• 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

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)是一种嗜神经性的甲型疱疹病毒，是引起眼部疾病的主要原因之一。 可能导致全世界失明的疾病。病毒感染角膜上皮，随后 建立三叉神经节(TG)感觉神经元的潜伏期。病毒的反复激活 导致泪液中的病毒粒子脱落和疱疹间质角膜炎(HSK)，可导致无法修复的角膜 损伤和失明。接种一种安全的、减毒的病毒可以诱导出强大的体液和 细胞免疫反应与其他病毒一样，包括水痘带状疱疹病毒，它 也属于甲型疱疹病毒亚科。HSV-1作为减毒活疫苗使用的主要障碍 疫苗的方法是这些病毒仍然有能力感染神经元并建立 延迟。Rational Vaccines公司已经获得了VC2减毒HSV-1疫苗株的权利。 VC2来源于HSV-1(F)并携带糖蛋白K(Gk)和UL20的氨基末端的缺失， 两者都能结合糖蛋白B(Gb)。这些突变使病毒能够在细胞培养中高效复制； 然而，病毒不能进入轴突终末，并在眼后三叉神经节神经元中建立潜伏期。 小鼠眼部感染。肌肉内接种VC2病毒可产生强大的体液和细胞 小鼠和豚鼠的免疫反应，以及对致命性阴道内攻击的出色保护 在小鼠和豚鼠模型中也可携带HSV-1(McKrae)或HSV-2(G)野生型病毒 对小鼠眼部感染有明显的保护作用。探讨VC2作为疫苗预防该病的潜力 和治疗眼疱疹感染，我们建议对兔子进行详细的疫苗接种研究，因为兔子 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 肌肉注射VC2病毒将产生显著的免疫反应以保护兔子 经眼部途径感染HSV-1(McKrae)并阻止潜伏病毒基因组的建立 在三叉神经节神经元中。此外，VC2的治疗性疫苗接种将显著减少病毒的脱落和 伴随而来的眼部病毒相关免疫病理机制。复发性眼部的治疗性干预 单纯疱疹病毒1型疾病将具有重要的临床意义。拟议中的实验的积极结果将 为人类第一阶段临床研究铺平道路。