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略性抗生素抗生素的人类细菌病原体。 S.金黄色葡萄球菌是领先的 在美国，传染病发病率，死亡率和与医院相关的感染的原因 全球卫生威胁。鉴于金黄色葡萄球菌快速获取耐药性，普遍的疫苗接种已有 我们是该领域的首要目标，可以为金黄色葡萄球菌提供持久的解决方案。在过去的20年中， 但是，多种金黄色葡萄球菌疫苗未能证明临床试验的效率。这些失败反映了 我们目前对金黄色葡萄球菌自然发展的自然发展的理解以及自然的差距 可以通过疫苗来利用免疫力来引起疾病的保护。这个sttr提案的目的 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，以我们 证明暴露于金黄色葡萄球菌毒素（HLA）会损害抗原特异性T细胞的发展 受保护免疫所需的反应。随着对金黄色葡萄球菌的暴露发生在生命的头几个月内 针对成年人的疫苗计划是“暴露后”疫苗，注定要放大现有的免疫力 HLA的免疫调节作用形成了反应。那是对HLA的保护将需要 在金黄色葡萄球菌暴露之前建立。该阶段I计划旨在表征新颖的HLA靶向疫苗 策略性地设计以使受保护的免疫力进行策略性的公式 新生儿/婴儿。在一系列两个目标中，我们将首先对每个疫苗配方进行比较评估 新生儿系统中的免疫原性，定义了为反应产生的免疫增强响应的精确性 使用多方面的方法进行免疫接种。其次，我们将评估疫苗防止疫苗效率 新生小鼠免疫抑制后金黄色葡萄球菌。虽然体内研究和高度的结合 疫苗引起的免疫响应的维度分析，该Sttr提案将提供 在体内模型中证明这种疫苗方法的可行性，免疫原性和受保护的效率 新生儿免疫。完全发达的疫苗将改变疾病的临床燃烧 通过中和感染期间HLA的受伤作用，并仅抵消精度 金黄色葡萄球菌阻碍了T细胞介导的免疫成绩的发展的机制。作为电流 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 暴露前疫苗的实施将引起该领域的基本转变，向预防感染。 当前的研究对于鉴定单个铅疫苗配方的鉴定至关重要 临床开发到一项II期研究，其中疫苗的产生，安全/毒性和效率不同 动物模型系统可以评估。因此，I阶段I STTR程序将推动新颖的金黄色葡萄球菌疫苗 致力于商业发展。