Advancing a Mucosal HSV-2 Vaccine Towards Clinical Trials

推进粘膜 HSV-2 疫苗的临床试验

• 批准号: 8784739
• 负责人: Kejian Yang
• 金额: $ 99.98万
• 依托单位: BIOMEDICAL RESEARCH MODELS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8784739
• 关键词: Acute; Adult; American; Animal Model; Antibody Formation; Antiviral Agents; B-Lymphocytes; Biological Assay; Cavia; Childhood; Clinical; Clinical Trials; Consensus; Cyclic GMP; DNA; DNA Vaccines; Data; Development Plans; Diagnosis; Disease; Dose; Drug Formulations; Educational workshop; Encapsulated; FDA approved; Failure; Female; Frequencies; Funding; Genital system; Goals; Grant; HIV; Healthy People 2010; Herpesviridae; Herpesvirus 1; Human; Human Herpesvirus 2; Human Papillomavirus; Immune response; Immunity; Immunoglobulin A; Immunologic Surveillance; Immunology; Infant Mortality; Infection; Laboratories; Legal patent; Liposomes; Medical; Mucous Membrane; Mus; National Institute of Allergy and Infectious Disease; Neonatal; Pain; Pichia; Population; Preparation; Production; Proteins; Protocols documentation; Puberty; Public Health; Publications; Qualifying; Recurrence; Regimen; Regulatory Affairs; Request for Proposals; Research; Risk; Running; Safety; Severities; Sexually Transmitted Diseases; Simplexvirus; System; T cell response; T-Lymphocyte; Technology; Testing; Therapeutic; Toxicology; Treatment Efficacy; United States Public Health Service; Vaccine Clinical Trial; Vaccine Research; Vaccines; Vagina; Viral; Virus; Virus Diseases; Virus Shedding; Work; cell bank; cost; disease transmission; genital herpes; immunogenicity; male; meetings; member; mortality; mucosal vaccine; prevent; product development; prophylactic; protective efficacy; public health relevance; response; scale up; success; therapeutic vaccine; transmission process; vaccine candidate; vaccine development

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.

描述（由申请人提供）：在全球范围内，估计16.2%的人群感染HSV-2，包括>17%的美国成年人群。生殖器疱疹与艾滋病毒感染和传播的风险增加有关，HSV-2感染可引起新生儿疱疹，婴儿死亡率高。在过去的二十年中，尽管抗病毒药物的可用性，但成年人群中的HSV-2感染大幅增加。虽然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HSV特异性免疫应答的潜在降低是有问题的。抗病毒药物未能阻止HSV-2的传播以及与HSV-2感染相关的公共卫生问题的严重性表明需要安全有效的疫苗。参加HSV研讨会（Bethesda，2012年10月）的专家一致认为，仅抗体应答不足以产生保护性免疫;粘膜和T细胞应答被认为非常重要。HSV-2是一种非常独特的病毒，能够逃避免疫监视，并抑制免疫反应，以成功感染宿主并建立潜伏期。我们在我们的初步数据中发现了一个重要的发现，即HSV-2感染和/或参考疫苗免疫的豚鼠不能引起阴道伊加。与其他技术不同，我们的技术采用了专利的异源初免-加强策略，包括肌内（i.m.）和蛋白质封装的脂质体（Lip）疫苗加强鼻内递送。我们开发的粘膜疫苗方案的两步方案导致广泛和有效的Th 1细胞和体液免疫应答，包括关键的CTL保护性应答和粘膜伊加。为了推进本提案中的候选疫苗进行临床试验，我们申请资金以完成以下具体研究目标，最终IND填写所需的监管事务活动，以及通过最终确定临床试验团队、计划和试验来准备临床试验。 “GMP生产关键的粘膜HSV-2疫苗成分。 “开发一个细胞库，使用先进的糖开关表达系统生产gD蛋白。 “进行HSV-2 gD蛋白的GMP生产，用于稳定性和脂质体制剂目的。 “将脂质体疫苗的生产从研究级扩大到GMP级“进行确定性毒理学研究，从而评价DNA初免和蛋白质-脂质体加强疫苗制剂的安全性。 “研究粘膜HSV-2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力。这些研究工作的最终结果将是减轻3500万至4000万患有生殖器疱疹的美国人的疼痛风险和痛苦。