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

开发针对人群级别的金黄色葡萄球菌感染预防暴露前疫苗

• 批准号: 10483136
• 负责人: Juliane Bubeck Wardenburg
• 金额: $ 30万
• 依托单位: FORWARD DEFENSE, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10483136
• 关键词: Adjuvant; Adult; Affect; Animal Model; Antibiotic Resistance; Antibiotic Therapy; Antibodies; Antibody Response; Antigens; Biodistribution; Biological Assay; Biological Models; Cells; Cellular Immunity; Cessation of life; Child; Childhood; Clinical; Clinical Trials; Communicable Diseases; Community Hospitals; Cost Savings; Cytolysis; Data; Development; Disease; Drug resistance; Exposure to; FDA approved; Failure; Financial Hardship; Foundations; Goals; Health; Hospitals; Human; Immune response; Immunity; Immunization; Immunization Programs; Impairment; Individual; Infant; Infection; Infection prevention; Intellectual Property; International; Investigation; Lead; Licensing; Life; Longevity; Mediating; Methodology; Morbidity - disease rate; Mus; Natural Immunity; Nature; Neonatal; Nongovernmental Organizations; Outcome; Phase; Pneumonia; Population; Private Sector; Public Sector; Rights; Safety; Sales; Sepsis; Series; Serum; Severities; Severity of illness; Small Business Technology Transfer Research; Staphylococcus aureus; Staphylococcus aureus infection; System; T cell response; T memory cell; T-Cell Development; T-Lymphocyte; Toxic effect; Toxin; Universities; Vaccination; Vaccine Design; Vaccine Production; Vaccines; Washington; antigen-specific T cells; base; burden of illness; clinical care; clinical efficacy; cohort; commercial application; comparative; cost estimate; design; dimensional analysis; efficacy study; high dimensionality; immunogenicity; immunoregulation; in vivo; in vivo Model; in vivo evaluation; innovation; lead candidate; mortality; neonatal mice; neonate; neutralizing antibody; novel; novel vaccines; pathogenic bacteria; phase 1 study; phase 2 study; pre-clinical; preclinical development; preclinical safety; preclinical study; prevent; programs; protective efficacy; response; skin lesion; standard of care; universal vaccine; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vaccine formulation

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.

项目摘要 金黄色葡萄球菌是一种侵袭性的耐药性人类细菌病原体。S. aureus是一个领先的 美国传染病发病率、死亡率和医院相关感染的原因，一个强大的 全球健康威胁。鉴于S.金黄色葡萄球菌，普遍接种疫苗， 一直是该领域的首要目标，为S.金黄色葡萄球菌病在过去的20年里， 然而，多个S.金黄色葡萄球菌疫苗在临床试验中未能证明有效性。这些失败反映了 我们目前对人类对S.金黄色，多么自然 免疫力可以通过接种疫苗来产生对疾病的保护。STTR提案旨在 发展创新的S.金黄色葡萄球菌疫苗设计用于暴露前给药，基于我们的 证明了暴露于S.金黄色葡萄球菌毒素（Hla）损害抗原特异性T细胞的发育 保护性免疫所需的反应。由于S.金黄色葡萄球菌发生在生命的最初几个月到一年内， 针对成年人的疫苗接种计划是“暴露后”疫苗，注定要扩大现有的免疫系统， 由Hla的免疫调节作用形成的反应。因此，对Hla的保护将需要 建立在S之前。金黄色葡萄球菌暴露。该I期计划旨在表征新型Hla靶向疫苗 已经策略性设计的制剂，当施用给 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制剂， 新生儿系统中的免疫原性，定义了应答中产生的免疫应答的确切性质 利用多方面的方法进行免疫接种。第二，我们将评估疫苗在预防 S.金黄色葡萄球菌病的免疫接种后的新生小鼠。尽管结合了体内研究和高- 疫苗引起的免疫反应的维度分析，这个STTR提案将提供一个 在体内模型中证明该疫苗方法的可行性、免疫原性和保护效力 新生儿免疫。完全开发的疫苗将把疾病的临床负担转移到 通过中和Hla在感染期间的有害作用， 机制，S。金黄色葡萄球菌在生命早期阻碍T细胞介导的免疫的发展。作为当前 临床护理标准仅限于现有S.金黄色葡萄球菌感染，成功 实施暴露前疫苗将在该领域引起向感染预防的根本转变。 目前的研究对于确定一种单一的先导疫苗配方至关重要， 临床开发到II期研究，其中疫苗生产，安全性/毒性和有效性在不同的 可以评估动物模型系统。因此，第一阶段STTR计划将推动一种新的S。金黄色葡萄球菌疫苗 走向商业发展。