A Global Syphilis Vaccine Targeting Outer Membrane Proteins of Treponema pallidum.

针对梅毒螺旋体外膜蛋白的全球梅毒疫苗。

• 批准号: 10618184
• 负责人: Michael Anthony Moody
• 金额: $ 214.82万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618184
• 关键词: Affect; Agreement; Amino Acid Substitution; Antibodies; Antibody Response; Antigenic Variation; Antigens; Architecture; B-Lymphocytes; Bacteria; Bacteriophages; Bioinformatics; Biomedical Research; Books; Case Study; Centers for Disease Control and Prevention (U.S.); Clinical; Collaborations; Communicable Diseases; Congenital Syphilis; Containment; Coupled; Cues; Data; Elements; Epidemiology; Epitopes; Extracellular Domain; Fostering; Genetic; Genomics; Goals; HIV vaccine; HIV-1; Health; Human; Humanities; Immune; Immune system; Immunity; Immunology; Individual; Infection; Infrastructure; International; Knowledge; Laboratory Research; Low income; Mediating; Membrane; Membrane Proteins; Methods; Molecular; Monoclonal Antibodies; North Carolina; Order Spirochaetales; Organism; Patients; Perinatal mortality demographics; Population; Pregnant Women; Public Health; Recombinants; Reporting; Research; Research Infrastructure; Research Personnel; Resources; Rest; Route; Serum; Structural Models; Surface; Syphilis; Techniques; Technology; Treponema pallidum; Treponema pallidum subspecies pallidum; United States; Universities; Vaccine Design; Vaccine Research; Vaccines; Variant; Work; beta barrel; biophysical analysis; biophysical techniques; deep sequencing; experimental study; extracellular; fetal loss; global health; high risk population; men who have sex with men; neutralizing antibody; novel; pathogenic bacteria; personalized approach; pressure; programs; stillbirth; structural biology; success; synergism; syphilis vaccine; vaccine candidate; vaccine development; vaccinology

The scientific premise of this CRC proposal rests upon our three decades of work defining the molecular architecture of the outer membrane (OM) of Treponema pallidum subsp. pallidum (TPA), coupled with our recent successes combining bioinformatics, biophysical techniques, and localization methods with live TPA to topologically characterize TPA outer membrane proteins (OMPs) and define the syphilis spirochete's `OMPeome'--its repertoire of OMPs. Its central hypothesis is that the principal targets for a syphilis vaccine reside within TPA's repertoire of rare outer membrane proteins (OMPs). The projects in the proposal employ three different, but closely integrated, strategies to exploit this novel application of reverse vaccinology to develop a syphilis vaccine with global efficacy. Project 1 is `immune-agnostic', selecting leading vaccine candidates based on genomic sequences, bioinformatics, biophysical analysis, and structural modeling. Project 2 takes its cue from the human immune system: since the large majority of untreated individuals do eventually control TPA infection, it stands to reason that OMPs targeted by opsonic antibodies6-9 should be excellent vaccine candidates. Project 3 borrows a page from the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) `book', using state-of-the art recombinant B cell and phage technology to generate broadly reactive, opsonic monoclonal antibodies directed against surface-exposed loops of TPA OMPs. The extraordinary deep sequencing capabilities of the Genetics and Genomics core will provide the data needed to tailor these approaches for efficacy on a global scale. This CRC, led by two senior investigators, established collaborators with complementary clinical and research backgrounds, pulls together (a) the unique capabilities of the Spirochete Research Laboratories at UConn Health; (b) the world-class B cell technology and vaccine research infrastructure of the Duke Human Vaccine Institute (DHVI); (c) the international health infrastructure and expertise of the University of North Carolina Institute for Global Health and Infectious Diseases; and (d) the unparalleled knowledge of TPA genomics at Masaryk University to achieve our long-term objective. The Administrative Core will provide the managerial oversight needed to integrate these capabilities and resources to strengthen existing collaborations and foster new ones within the Center and with other CRCs. The ultimate strength of this CRC is the diversity and complementarity of approaches, technologies, resources, and expertise it marshals to interrogate the TPA OMPeome to achieve our long-term goals. An effective syphilis vaccine would represent a triumph of biomedical research over an ailment that for more than five centuries has exacted a heavy toll on humanity4,5 and that has defied conventional public health strategies for containment. If successful, the scientific and public health impact of our approach to reverse vaccinology will extend well beyond syphilis, establishing a paradigm applicable to other recalcitrant organisms.

该CRC提案的科学前提取决于我们定义分子的三十年工作 Treponema Pallidum subsp的外膜（OM）的结构。 Pallidum（TPA），与我们的 最新的成功结合了生物信息学，生物物理技术和与实时TPA的本地化方法 拓扑表征TPA外膜蛋白（OMP）并定义梅毒螺旋体的 ``''它的中心假设是梅毒疫苗的主要靶标 驻留在TPA的稀有外膜蛋白（OMP）的曲目中。提案雇用的项目 三种不同但紧密整合的策略，以利用这种反疫苗的新颖应用来发展 具有全球疗效的梅毒疫苗。项目1是“免疫敏锐的”，选择了基于候选疫苗的领先疫苗 关于基因组序列，生物信息学，生物物理分析和结构建模。项目2采取提示 来自人类免疫系统：由于大多数未经治疗的个体最终都会控制TPA 感染，有理由认为由Opsonic抗体靶向的OMP 6-9应该是出色的候选疫苗。 项目3从艾滋病毒/艾滋病疫苗免疫学和免疫原中心借用一页 （chavi-id）“书”，使用最先进的重组B细胞和噬菌体技术来产生广泛的反应性， 针对TPA OMP表面暴露环的opsonic单克隆抗体。非凡的深处 遗传学和基因组核心的测序能力将提供定制这些所需的数据 在全球范围内提高功效的方法。这位由两名高级调查员领导的CRC成立了合作者 借助互补的临床和研究背景，将其汇集在一起​​（a） UConn Health的Spirochete研究实验室； （b）世界一流的B细胞技术和疫苗研究 公爵人疫苗研究所（DHVI）的基础设施； （c）国际卫生基础设施和 北卡罗来纳大学全球健康与传染病研究所的专业知识； （d） Masaryk University对TPA基因组学的无与伦比的知识，以实现我们的长期目标。这 行政核心将提供整合这些功能所需的管理监督 加强现有合作并与其他CRC培养新的合作的资源。这 这种CRC的最终力量是方法，技术，资源和资源的多样性和互补性 专业知识元帅可以质疑TPA竞争者以实现我们的长期目标。有效的梅毒 疫苗将代表生物医学研究的胜利，该研究已有五个世纪以上 对人类的巨大造成了巨大的损失4,5，这违反了常规公共卫生策略的遏制。如果 成功的，我们反疫苗学方法的科学和公共卫生影响将远远超出 梅毒，建立适用于其他顽固生物的范式。