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

这项CRC提案的科学前提是基于我们三十年来定义分子生物学的工作。 梅毒螺旋体（Treponema pallidum subsp.）苍白球（TPA），再加上我们的 最近成功地将生物信息学、生物物理学技术和定位方法与活TPA相结合， 拓扑特征TPA外膜蛋白（OMP）和定义梅毒螺旋体的 “OMPeome”-其OMP的全部剧目。其中心假设是梅毒疫苗的主要靶点 存在于TPA的稀有外膜蛋白（OMP）库中。提案中的项目采用 三种不同但紧密结合的策略来利用反向疫苗学的这种新应用， 一种全球有效的梅毒疫苗项目1是“免疫不可知”的， 基因组序列、生物信息学、生物物理分析和结构建模。项目2采取其线索 从人类免疫系统：因为绝大多数未经治疗的个体最终控制TPA 感染，它的理由是，OMPs的调理抗体6 -9的目标应该是优秀的疫苗候选者。 项目3借用了艾滋病疫苗免疫学和免疫原发现中心的一页 （CHAVI-ID）“书”，使用最先进的重组B细胞和噬菌体技术产生广泛反应性， 针对TPA OMP的表面暴露环的调理素单克隆抗体。非凡的深海 遗传学和基因组学核心的测序能力将提供定制这些所需的数据 在全球范围内提高效率。该CRC由两名高级研究人员领导， 具有互补的临床和研究背景，汇集了（a） 康州大学卫生部的螺旋体研究实验室;（B）世界一流的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， 北卡罗来纳州大学全球健康和传染病研究所的专业知识;以及（d） 马萨里克大学的TPA基因组学无与伦比的知识，以实现我们的长期目标。的 行政核心将提供整合这些能力所需的管理监督， 加强现有的合作，并在中心内部和与其他CRC之间建立新的合作。的 该CRC的最终优势在于方法、技术、资源和 专业知识，它编组审问TPA OMPeome，以实现我们的长期目标。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五个多世纪。 对人类造成了沉重的代价4，5，并且无视传统的公共卫生遏制战略。如果 如果成功，我们逆转疫苗学方法的科学和公共卫生影响将远远超出 梅毒，建立了一个适用于其他寄生虫生物的范例。

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.