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: 10772345
• 负责人: Anna Wald
• 金额: $ 15.4万
• 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/10772345
• 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; 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; Productivity; 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; Treponema pallidum subspecies pallidum; United States; Universities; Vaccinated; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Vertical Disease Transmission; Viral; Washington; clinical infrastructure; clinical trial readiness; 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.

抽象的 性传播感染合作研究中心 (STI CRC) 的总体目标 建议开发一种候选疫苗，对梅毒螺旋体感染提供显着保护， 引起梅毒的病原体。尽管对青霉素敏感，梅毒仍然是一个公共卫生威胁 全球每年估计有 1100 万新感染病例，全球负担为 3600 万感染病例。 在过去十年中，梅毒死灰复燃，男性梅毒感染率几乎翻了一番。 男男性行为和母婴传播导致的先天性梅毒发病率。因此，一个 除了标准公共卫生措施外，还需要有效的预防性疫苗来进行控制。 华盛顿大学拥有杰出梅毒研究的悠久传统：研究团队 为此提案而聚集的开发人员已开发出临床前候选疫苗，这些候选疫苗可在以下方面提供实质性保护： 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。 梅毒螺旋体 Tp0751 蛋白，对于梅毒螺旋体通过血流传播至关重要，可用作 通过优化蛋白质配方和疫苗原的递送方式来获得疫苗原。在项目2中， 我们将优化用于疫苗用途的 TprK 和 TprC/D2 蛋白，就像在对这些蛋白免疫的动物模型中一样 抗原可防止下疳形成；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，我们将测试组合 由这些蛋白质组成的疫苗混合物在梅毒兔模型中的保护能力。项目中 3，我们检查了自然环境中针对 Tp0751 和 Tpr 疫苗原引起的 B 和 T 细胞反应。 人类和接种疫苗的动物感染。由于激发兔子免疫力的佐剂不同于 人用佐剂，我们还将在中测试以人轨佐剂为佐剂的候选疫苗 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 统计核心、基因组学和分离核心；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 我们建议在 5 年的资助期限内开发出一种可供人体试验的候选疫苗。

项目成果

Whole Genome Sequence of a Treponema pallidum Strain From a Formalin-Fixed, Paraffin-Embedded Fine Needle Aspirate of a Cervical Lymph Node.

• DOI: 10.1097/olq.0000000000001827
• 发表时间: 2023-08-01
• 期刊: Sexually transmitted diseases
• 影响因子: 3.1

In Vitro Transformation and Selection of Treponema pallidum subsp. pallidum.

• DOI: 10.1002/cpz1.507
• 发表时间: 2022-08
• 期刊: Current protocols
• 作者: Phan, Amber;Romeis, Emily;Tantalo, Lauren;Giacani, Lorenzo
• 通讯作者: Giacani, Lorenzo

Genetic engineering of Treponema pallidum subsp. pallidum, the Syphilis Spirochete.

• DOI: 10.1371/journal.ppat.1009612
• 发表时间: 2021-07
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Romeis E;Tantalo L;Lieberman N;Phung Q;Greninger A;Giacani L
• 通讯作者: Giacani L

Transcriptional and immunological analysis of the putative outer membrane protein and vaccine candidate TprL of Treponema pallidum.

假定的外膜蛋白和疫苗候选tprl的转录和免疫学分析。

• DOI: 10.1371/journal.pntd.0008812
• 发表时间: 2021-01
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Haynes AM;Fernandez M;Romeis E;Mitjà O;Konda KA;Vargas SK;Eguiluz M;Caceres CF;Klausner JD;Giacani L
• 通讯作者: Giacani L

Evaluation of a minimal array of Treponema pallidum antigens as biomarkers for syphilis diagnosis, infection staging, and response to treatment.

• DOI: 10.1128/spectrum.03466-23
• 发表时间: 2024-01-11
• 期刊: MICROBIOLOGY SPECTRUM
• 影响因子: 3.7
• 作者: Haynes, Austin M.;Konda, Kelika A.;Romeis, Emily;Siebert, Janet;Vargas, Silver K.;Reyes Diaz, Michael;Phan, Amber;Caceres, Carlos F.;Giacani, Lorenzo;Klausner, Jeffrey D.
• 通讯作者: Klausner, Jeffrey D.