Interrogating human anti-staphylococcal antibody responses for S. aureus vaccine insights

探究人类抗葡萄球菌抗体反应以获得金黄色葡萄球菌疫苗见解

基本信息

批准号：
10826874
负责人：
Clarence Buddy Creech
金额：
$ 81.88万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10826874
关键词：
Accounting Active Immunization Address Age Animal Model Antibiotic Resistance Antibodies Antibody Response Antibody-mediated protection Antigen Targeting Antigens Bacterial Infections Biological Assay Biological Models Child Clinical Clinical assessments Coupled Development Disease Elderly Environment Exposure to Generations Genes Genus staphylococcus Goals Human Human Characteristics Immune Immune response Immunity Impairment In Vitro Infection Infrastructure Intervention Kinetics Life Membrane Proteins Memory Modeling Mus Passive Immunization Patients Prospective cohort Reporting Sampling Sepsis Series Serology Serum Shapes Staphylococcal Infections Staphylococcal Vaccines Staphylococcus aureus Staphylococcus aureus infection Surveys Vaccination Vaccines alpha Toxin clinically relevant cohort cytotoxicity experimental study exposed human population human pathogen humanized mouse imprint in vivo in vivo Model insight mouse model novel novel strategies predictive modeling prevent prototype rational design recruit response success vaccination strategy vaccine candidate vaccine development vaccine efficacy vaccine evaluation vaccine failure vaccine response

项目摘要

Abstract Staphylococcus aureus is a leading cause of infection worldwide and a major driver of antibiotic resistance. Although many experimental staphylococcal vaccines have been reported, all vaccines tested to date in human trials have failed for unclear reasons. Unlike mice, humans are exposed to S. aureus beginning early in life, leading to generation of antibodies to S. aureus antigens. In preliminary experiments, we have shown that select human anti-S. aureus antibodies are protective, but many are not. In mice exposed to S. aureus, vaccination against protective antigens leads to immunity against S. aureus whereas vaccination against non-protective antigens induced recall of non-protective immunity which further interferes with protective antibodies by direct competition. Based on these findings, we generated a model of how pre-existing antibodies shape vaccine responses and how this predicts novel ways to develop effective vaccines against S. aureus. To query the validity of our model, in Aim 1, we will recruit children and old adults with invasive S. aureus infections, survey the anti-S. aureus antibody profile and define functionally protective antibody responses to S. aureus antigens. In Aim 2, we will identify and characterize protective and non-protective anti-S. aureus antibodies from candidate samples acquired in Aim 1, and assess structural and functional features of the specific antibodies that confer protection or non-protection. In Aim 3, we will study these antibodies and their target in the context of naïve mice and mice previously exposed to S. aureus. We will evaluate mechanisms whereby non-protective memory shapes vaccine efficacy and test strategies that circumvent interference. Overall, using the novel model systems, we aim to develop a more predictive framework for explaining staphylococcal vaccine failures and developing novel strategies for effective vaccination against S. aureus.

抽象的金黄色葡萄球菌是全球感染的主要原因，也是抗生素的主要驱动因素抗药性。尽管已经报道了许多实验性葡萄球菌疫苗，但所有疫苗迄今为止在人类试验中进行的测试由于不清楚的原因未能通过。与小鼠不同，人类暴露于S。金黄色葡萄球菌从生命的早期开始，导致抗原抗原的抗体产生。在初步实验，我们已经表明选择了人类抗S。金黄色元素受到保护，但许多是不是。在暴露于金黄色葡萄球菌的小鼠中，针对受保护抗原的疫苗接种可导致对S.的免疫力金黄色这进一步干扰了直接竞争的保护性抗体。基于这些发现，我们生成了一个模型，该模型是如何抗离存抗体塑造疫苗反应以及这种预测如何新颖开发针对金黄色葡萄球菌的有效疫苗的方法。要查询我们的模型的有效性，在AIM 1中，我们将招募具有侵入性金黄色葡萄球菌感染的儿童和老年人，调查抗S。金黄色抗体轮廓并定义了对金黄色葡萄球菌抗原的功能保护抗体反应。在AIM 2中，我们将识别并表征受保护和非保护抗S。候选人的金黄色抗体在AIM 1中获取的样品，并评估特定抗体的结构和功能特征会议保护或非保护。在AIM 3中，我们将研究这些抗体及其靶标我们将评估先前暴露于金黄色葡萄球菌的幼稚小鼠和小鼠的机制。非保护记忆会塑造疫苗效率和测试策略干涉。总体而言，使用新型模型系统，我们旨在开发一个更具预测性的框架用于解释葡萄球菌疫苗失败并制定有效疫苗的新型策略对抗金黄色葡萄球菌。