University of Washington (UW) Sexually Transmitted Infections (STI) Cooperative Research Center (CRC) - Syphilis Vaccine to Protect against Local and Disseminated T. pallidum Infection

华盛顿大学 (UW) 性传播感染 (STI) 合作研究中心 (CRC) - 梅毒疫苗可预防局部和播散性梅毒螺旋体感染

• 批准号: 10461735
• 负责人: Anna Wald
• 金额: $ 203.89万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461735
• 关键词: Adjuvant; Animal Model; Animals; Antibody Response; Antigens; Award; B-Lymphocytes; Basic Science; Biopsy; Blood - brain barrier anatomy; Blood Circulation; Clinic; Clinical; Clinical Trials; Communicable Diseases; Congenital Syphilis; Development; Disease; Endothelium; Epitope Mapping; Epitopes; Failure; Formulation; Fred Hutchinson Cancer Research Center; Genomics; Globus Pallidus; Goals; Grant; Human; Human papillomavirus HPV L1 protein; Immune response; Immunity; Immunization; Immunization Programs; Immunologist; Incidence; Infection; Investigation; Laboratories; Leadership; Lesion; Measures; Mediating; Membrane Proteins; Mentors; Modeling; Mucous Membrane; Mus; Neurosyphilis; Oryctolagus cuniculus; Patients; Penicillins; Persons; Phase; Play; Positioning Attribute; Predisposition; Preventive vaccine; Program Research Project Grants; Protein Family; Proteins; Public Health; Recombinant Proteins; Research; Research Personnel; Research Project Grants; Role; Sampling; Sanitation; Sexually Transmitted Diseases; Skin; Surface; Surface Antigens; Syphilis; Syphilitic chancre; T cell response; T-Lymphocyte; Testing; Training; Translational Research; Treponema pallidum; United States; Universities; Vaccinated; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Vertical Disease Transmission; Viral; Washington; base; clinical infrastructure; combat; design; experience; immunogenicity; improved; member; men who have sex with men; novel strategies; particle; pre-clinical; preclinical study; prevent; recruit; response; syphilis vaccine; vaccine candidate; vaccine development; vaccine trial

ABSTRACT The overarching goal of this Sexually Transmitted Infection Cooperative Research Center (STI CRC) proposal is to develop a candidate vaccine that provides significant protection against T. pallidum infection, the agent that causes syphilis. Despite susceptibility to penicillin, syphilis remains a public health threat worldwide, with an estimated 11 million new infections per year and a global burden of 36 million infections. In the last decade, there has been a resurgence of syphilis, with near doubling of rates among men who have sex with men and rates of congenital syphilis, resulting from mother to child transmission. As such, an effective prophylactic vaccine is required for control in addition to standard public health measures. The University of Washington has a long tradition of outstanding syphilis research: the research team assembled for this proposal has developed preclinical vaccine candidates that have substantial protection in the rabbit model. We propose three inter-related Scientific Projects. In Project 1, we will further refine the T. pallidum Tp0751 protein, which is essential for spread of T. pallidum through the bloodstream, for use as a vaccinogen by optimizing the protein formulation and the mode of delivery of this vaccinogen. In Project 2, we will optimize the TprK, and TprC/D2 proteins for vaccine use, as in animal models immunity to these antigens prevents chancre formation; optimization of these proteins will encompass protective epitope identification as well as optimal delivery of these epitopes. Subsequently, we will test the combined protective capacity of a vaccine cocktail comprised of these proteins in the syphilis rabbit model. In Project 3, we examine the B and T cell responses raised against the Tp0751 and Tpr vaccinogens in natural infection in humans and in vaccinated animals. As adjuvants that evoke immunity in rabbits differ from human-use adjuvants, we will also test the candidate vaccine adjuvanted with human track adjuvants in mouse immunogenicity studies as a prelude to human trials. The Scientific Projects will be supported by three Cores comprised of the Administrative Core, the Clinical and Statistical Core, and the Genomics and Isolation Core; the Developmental Research Project Program will provide mentoring and training to outstanding new investigators in the STI research field. By the end of the 5 year grant timeframe we propose to have a candidate vaccine that is ready for human trials.

摘要 性传播感染合作研究中心（STI CRC）的总体目标是 一项建议是开发一种候选疫苗，提供针对T.苍白球感染， 引起梅毒的物质。尽管对青霉素敏感，梅毒仍然是一个公共卫生威胁 在世界范围内，估计每年有1 100万新感染病例，全球负担为3 600万感染病例。 在过去的十年里，梅毒的发病率有所回升， 与男子发生性行为和先天性梅毒的发病率，这是由母婴传播造成的。因此， 除了标准的公共卫生措施外，还需要有效的预防性疫苗进行控制。 华盛顿大学在梅毒研究方面有着悠久的传统： 为这项提议而聚集的科学家们已经开发出了临床前候选疫苗，这些疫苗在以下方面具有实质性保护作用： 兔子模型我们提出了三个相互关联的科学项目。在项目1中，我们将进一步完善T。 pallidum Tp 0751蛋白是T.苍白球通过血液，用于作为一个 通过优化该疫苗原的蛋白质制剂和递送模式，来制备疫苗原。在项目2中， 我们将优化TprK和TprC/D2蛋白用于疫苗，如在对这些蛋白免疫的动物模型中， 抗原防止下疳形成;这些蛋白质的优化将包括保护性表位 鉴定以及这些表位的最佳递送。随后，我们将测试组合 由这些蛋白组成的疫苗混合物在梅毒兔模型中的保护能力。在项目 3、我们检测了在自然条件下针对Tp 0751和Tpr疫苗原引起的B和T细胞应答。 在人类和接种疫苗的动物中的感染。作为在兔子中引起免疫的佐剂， 人类使用的佐剂，我们还将测试候选疫苗佐剂与人类轨道佐剂， 小鼠免疫原性研究作为人体试验的前奏。 科学项目将得到三个核心的支持，包括行政核心、临床核心、 和统计核心，基因组学和隔离核心;发展研究项目计划 将为STI研究领域杰出的新研究人员提供指导和培训。年底前 我们建议在5年的拨款时间内，研制出一种可供人体试验的候选疫苗。