Advancing a Mucosal HSV-2 Vaccine Towards Clinical Trials

描述（由申请人提供）：在全球范围内，估计有16.2%的人口感染HSV-2，其中包括约17%的美国成年人。生殖器疱疹与艾滋病毒感染和传播风险增加有关，2型单纯疱疹病毒感染可导致新生儿疱疹，婴儿死亡率高。尽管有抗病毒药物，但在过去二十年中，成人人群中的2型单纯疱疹病毒感染已大幅增加。尽管长期抗病毒药物治疗可以降低病毒脱落的频率和复发的严重程度，但依从性和单纯疱疹病毒特异性免疫反应的潜在降低是有问题的。抗病毒药物未能预防2型单纯疱疹病毒的传播，以及与2型单纯疱疹病毒感染相关的公共卫生问题的严重程度表明，需要一种安全有效的疫苗。参加HSV研讨会（贝塞斯达，2012年10月）的专家一致认为，抗体反应本身不足以产生保护性免疫；粘膜和T细胞反应被认为是非常重要的。HSV-2是一种非常独特的病毒，能够逃避免疫监视，抑制免疫反应，从而成功感染宿主并建立潜伏期。我们在初步数据中有一个重要发现，即hsv -2感染和/或参比疫苗免疫的豚鼠不能引发阴道IgA。与其他技术不同的是，我们的技术采用了一种获得专利的异源启动-增强策略，包括肌肉注射（i.m）的DNA疫苗启动物和鼻内注射的蛋白质包封脂质体（Lip）疫苗增强剂。我们开发的两步方案作为粘膜疫苗方案导致广泛而有效的Th1细胞和体液免疫反应，包括关键的ctl保护反应和粘膜IgA和。为了在本提案中推进候选疫苗的临床试验，我们请求资金来完成以下具体的研究目标，必要的监管事务活动，最终的IND填充和临床试验准备，最终确定临床试验团队，计划和分析。”生产关键的HSV-2粘膜疫苗成分。”利用先进的Glyco-Switch表达系统开发一个细胞库来生产gD蛋白。”执行HSV-2 gD蛋白的GMP生产，用于稳定性和脂质体配方。将脂质体疫苗的生产规模从研究级提高到GMP级“进行明确的毒理学研究，从而评估DNA引物和蛋白质脂质体增强疫苗配方的安全性。”研究HSV-2粘膜疫苗在雄性和HSV-1血清阳性雌性豚鼠中的免疫原性和预防效果。这些研究努力的最终结果将是减轻美国3500万至4000万生殖器疱疹患者的疼痛风险和痛苦。

DESCRIPTION (provided by applicant): Globally, an estimated 16.2% of the human population is infected with HSV-2 including >17% of the U.S. adult population. Genital herpes is associated with an increased risk of HIV acquisition and transmission and HSV-2 infection can cause neonatal herpes with high infant mortality. HSV-2 infection in the adult population has increased substantially in the past two decades despite the availability of antiviral drugs. Although long-term antiviral drug treatment can lower the frequency of viral shedding and severity of recurrences, compliance and potential decreases in HSV-specific immune responses are problematic. The failure of antiviral drugs to prevent the spread of HSV-2 and the sheer magnitude of the public health problem associated with HSV-2 infection indicates a need for a safe and effective vaccine. The consensus of experts who attended the HSV workshop (Bethesda, October 2012) is that antibody response alone is not sufficient for protective immunity; mucosal and T cell responses are considered very important. HSV-2 is a very unique virus able to escape from immune surveillance, and inhibit immune responses in order to successfully infect host and establish latency. We made a significant finding in our preliminary data that HSV-2-infected and/or reference vaccine-immunized guinea pigs are not able to elicit vaginal IgA. Unlike others, our technology employs a patented heterologous prime-boost strategy consisting of a DNA vaccine prime given intramuscularly (i.m.) and a protein- encapsulated liposome (Lip) vaccine boost delivered intranasally. The two step protocol that we have developed as a mucosal vaccine regimen results in a broad and potent Th1 cellular and humoral immune response that includes critical CTLs protective responses and mucosal IgA and. To advance the vaccine candidate to clinical trials in this proposal, we request funding to accomplish these following specific research aims, necessary regulatory affair activities for ultimate IND filling and preparation for clinical trial by finalizing a clinical trial team, plan ad assays. " GMPManufacture key mucosal HSV-2 vaccine components. " Develop a cell bank to produce the gD protein using an advanced Glyco-Switch expression system. " Perform GMP manufacturing of HSV-2 gD protein for stability and liposome formulation purposes. " Scale up the production of liposome vaccine from research grade to GMP grade " Conduct a definitive toxicology study and thereby evaluate the safety of the DNA prime and protein- liposome boost vaccine formulations. " Study the immunogenicity and prophylactic efficacy of the mucosal HSV-2 vaccine in both male and HSV-1 sero-positive female guinea pigs. The net result of these research efforts will be to alleviate pain risk and suffering in the 35-40 million Americans with genital Herpes.