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

这个CRC提案的科学前提建立在我们三十年来定义分子的工作基础上 梅毒螺旋体亚种外膜的构筑梅毒(TPA)，加上我们的 最近成功地将生物信息学、生物物理技术和定位方法与活的TPA相结合 TPA外膜蛋白的拓扑学特征及梅毒螺旋体的鉴定 《OMPeome》--OMPS曲目。它的中心假设是梅毒疫苗的主要目标是 存在于TPA的稀有外膜蛋白(OMP)库中。建议书中的项目采用 三种不同但紧密结合的战略，以开发这一反向疫苗学的新应用 一种具有全球效力的梅毒疫苗。项目1是“免疫不可知的”，选择领先的候选疫苗基于 基因组序列、生物信息学、生物物理分析和结构建模。项目2得到了它的提示 来自人类免疫系统：因为绝大多数未经治疗的人最终确实控制了TPA 因此，以光学抗体6-9为靶点的OMP应该是很好的候选疫苗。 项目3借用了艾滋病毒/艾滋病疫苗免疫学和免疫原发现中心的一页 使用最先进的重组B细胞和噬菌体技术产生广泛的活性， 针对TPA OMPS表面暴露环的调理单抗。非凡的深渊 遗传学和基因组学核心的测序能力将提供定制这些数据所需的数据 在全球范围内提高药效的方法。在两名高级调查人员的领导下，该中心建立了合作伙伴 具有互补的临床和研究背景，汇集了(A) 康涅狄格州大学健康中心螺旋体研究实验室；(B)世界级B细胞技术和疫苗研究 杜克人类疫苗研究所的基础设施；(C)国际卫生基础设施和 北卡罗来纳大学全球卫生和传染病研究所的专门知识；和(D) 马萨里克大学无与伦比的TPA基因组学知识，以实现我们的长期目标。这个 管理核心将提供整合这些能力所需的管理监督，并 资源，以加强现有的合作，并在中心内和与其他社区合作中心培育新的合作。这个 这种合作伙伴关系的终极优势是方法、技术、资源和 它汇集专业知识来审问TPA OMPeome，以实现我们的长期目标。一种有效的梅毒 疫苗将代表着生物医学研究对一种疾病的胜利，这种疾病已经存在了500多个世纪 这给人类造成了沉重的代价，4，5这违背了遏制的传统公共卫生战略。如果 如果成功，我们的反向疫苗接种方法对科学和公共卫生的影响将远远超出 梅毒，建立了一个适用于其他顽固生物的范例。

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.