Development of a Pre-Exposure Vaccine for Population-Level ProtectionAgainst Staphylococcus aureus Infection

项目总结 金黄色葡萄球菌是一种侵袭性的、抗药性强的人类细菌性病原体。S.aureus是一家领先的 美国传染病发病率、死亡率和医院相关感染的原因，以及一个令人敬畏的 世界范围内的健康威胁。鉴于金黄色葡萄球菌迅速获得抗药性，普遍接种疫苗已经 一直是该领域的首要目标，为金黄色葡萄球菌疾病提供持久的解决方案。在过去的20年里， 然而，多种金黄色葡萄球菌疫苗未能在临床试验中证明疗效。这些失败反映了 我们目前对人类对金黄色葡萄球菌免疫的自然发展以及如何自然发展的理解存在差距 可以通过接种疫苗来利用免疫力，以获得对疾病的保护。这份STTR提案旨在 开发一种创新的金黄色葡萄球菌疫苗，专为暴露前给药而设计，基于我们的 金黄色葡萄球菌毒素(HL A)暴露会损害抗原特异性T细胞发育 保护性免疫所需的反应。由于金黄色葡萄球菌的接触发生在生命的头几个月到一年内， 针对成年人的疫苗接种计划是“暴露后”疫苗，注定要放大现有的、免疫的 由人类白细胞抗原(Hla)的免疫调节作用形成的反应。因此，针对人类免疫缺陷病毒的保护将需要 在金黄色葡萄球菌暴露之前建立。这一第一阶段的计划旨在表征新型的人类白细胞抗原靶向疫苗 经过战略性设计的配方，在给药时可产生保护性免疫 新生儿/婴儿。在一系列的两个目标中，我们将首先比较评估每种疫苗配方 新生儿系统中的免疫原性，定义在反应中产生的免疫反应的确切性质 到利用多方面方法进行免疫接种。第二，我们将评估疫苗的预防效果。 新生小鼠免疫后感染金黄色葡萄球菌病。尽管体内研究和高- 疫苗诱导的免疫反应的维度分析，这一STTR建议将提供 在活体模型中证明这种疫苗方法的可行性、免疫原性和保护效果 新生儿免疫接种。这种完全开发的疫苗将把疾病的临床负担转移到 通过中和感染期间人类白细胞抗原的损害作用，同时中和精确的 金黄色葡萄球菌在生命早期阻碍T细胞免疫发展的机制。作为当前的 临床护理标准仅限于现有金黄色葡萄球菌感染的抗生素治疗，成功 实施暴露前疫苗将引发该领域向感染预防的根本性转变。 目前的研究对于确定单一的铅疫苗配方将是至关重要的，以在前 临床发展到第二阶段研究，在该阶段中，疫苗的生产、安全性/毒性和有效性是不同的 可以对动物模型系统进行评估。因此，这一第一阶段的STTR计划将推动一种新的金黄色葡萄球菌疫苗 朝向商业发展。

PROJECT SUMMARY Staphylococcus aureus is an aggressive antibiotic-resistant human bacterial pathogen. S. aureus is a leading cause of infectious disease morbidity, mortality, and hospital-associated infection in the U.S., and a formidable health threat worldwide. Given the rapid acquisition of drug resistance by S. aureus, universal vaccination has been a premier goal in the field to provide a durable solution to S. aureus disease. Within the past 20 years, however, multiple S. aureus vaccines have failed to demonstrate efficacy in clinical trials. These failures reflect gaps in our current understanding of the natural development of human immunity to S. aureus, and how natural immunity may be harnessed through vaccination to elicit protection against disease. This STTR proposal aims to develop an innovative S. aureus vaccine designed for pre-exposure administration, predicated on our demonstration that that exposure to S. aureus -toxin (Hla) impairs the development of antigen-specific T cell response required for protective immunity. As exposure to S. aureus occurs within the first months to year of life, vaccination programs targeting adults are ‘post-exposure’ vaccines, destined to amplify an existing, immune response shaped by the immunomodulatory action of Hla. Thus, protection against Hla will need to be established prior to S. aureus exposure. This Phase I program seeks to characterize novel Hla-targeting vaccine formulations that have been strategically designed to elicit protective immunity when administered to neonates/infants. In a series of two aims, we will first comparatively evaluate each vaccine formulation for immunogenicity in a neonatal system, defining the precise nature of the immune response generated in response to immunization utilizing a multi-faceted approach. Second, we will evaluate vaccine efficacy in protection against S. aureus disease following immunization of neonatal mice. Though a combination of in vivo studies and high- dimensionality analysis of the vaccine-elicited immune response, this STTR proposal will provide a demonstration of feasibility, immunogenicity, and protective efficacy of this vaccine approach in an in vivo model of neonatal immunization. The fully-developed vaccine will shift the clinical burden of disease within the population by neutralizing the injurious effect of Hla during infection, and simultaneously counteract the precise mechanism by which S. aureus impedes the development of T cell-mediated immunity early in life. As the current standard of clinical care is limited to antibiotic treatment of existing S. aureus infection, successful implementation of a pre-exposure vaccine would elicit a foundational shift in the field toward infection prevention. The current studies will be essential for the identification of a single lead vaccine formulation to advance in pre- clinical development to a Phase II study in which vaccine production, safety/toxicity, and efficacy in a distinct animal model system can be assessed. This Phase I STTR program will thus propel a novel S. aureus vaccine toward commercial development.