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 这个性传播感染合作研究中心的首要目标是 一项提议是开发一种候选疫苗，对梅毒螺旋体感染提供显著保护， 导致梅毒的药剂。尽管对青霉素敏感，梅毒仍然是公共健康的威胁。 据估计，全世界每年新增感染1100万人，全球感染人数为3600万人。 在过去的十年里，梅毒卷土重来，男性梅毒发病率几乎翻了一番 与男性发生性行为和因母婴传播而导致的先天性梅毒发病率。因此，一个 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：研究团队 为这项提案而聚集的已经开发出临床前候选疫苗，这些候选疫苗在 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，我们将进一步细化T。 梅毒Tp0751蛋白，对梅毒螺旋体通过血液传播是必不可少的，用作 通过优化这种疫苗原的蛋白质配方和递送方式，获得了一种新型的疫苗原。在项目2中， 我们将优化TprK和TprC/D2蛋白用于疫苗，就像在动物模型中对这些免疫 抗原可防止下巴形成；这些蛋白质的优化将包括保护性表位。 这些表位的鉴定以及最佳递送。随后，我们将测试合并后的 由这些蛋白质组成的疫苗鸡尾酒在梅毒兔模型中的保护能力。在项目中 3，我们检测了在自然条件下对Tp0751和Tpr疫苗原产生的B和T细胞反应。 在人类和接种疫苗的动物中的感染。作为激发兔免疫的佐剂不同于 人用佐剂，我们还将测试用人用佐剂佐剂的候选疫苗在 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 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研究领域的杰出新研究者提供指导和培训。到年底的时候 在5年的拨款时间框架内，我们建议拥有一种可用于人体试验的候选疫苗。