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尽管已经报道了许多实验性葡萄球菌疫苗，但所有疫苗都存在耐药性。迄今为止，在人体试验中的测试均因不明原因而失败，与小鼠不同的是，人类接触到了金黄色葡萄球菌。金黄色葡萄球菌在生命早期就开始产生，导致初步产生针对金黄色葡萄球菌抗原的抗体。实验表明，特定的人类抗金黄色葡萄球菌抗体具有保护作用，但许多抗体都具有保护作用。在接触金黄色葡萄球菌的小鼠中，针对保护性抗原的疫苗接种可以产生针对金黄色葡萄球菌的免疫力。金黄色葡萄球菌，而针对非保护性抗原的疫苗接种则诱导非保护性免疫的回忆根据这些发现，我们进一步通过直接竞争干扰保护性抗体。生成了一个模型，展示现有抗体如何塑造疫苗反应以及如何预测新抗体开发针对金黄色葡萄球菌的有效疫苗的方法为了质疑我们模型的有效性，在目标 1 中，我们进行了研究。将招募患有侵袭性金黄色葡萄球菌感染的儿童和老年人，调查抗金黄色葡萄球菌抗体。在目标 2 中，我们将分析并定义针对金黄色葡萄球菌抗原的功能性保护性抗体反应。识别并表征候选者的保护性和非保护性抗金黄色葡萄球菌抗体。目标 1 中获取的样本，并评估了特定抗体的结构和功能特征在目标 3 中，我们将研究这些抗体及其靶标。我们将评估首次接触金黄色葡萄球菌的小鼠和先前接触过金黄色葡萄球菌的小鼠的机制。因此，非保护性记忆决定了疫苗功效和规避的测试策略总的来说，我们的目标是使用新颖的模型系统开发一个更具预测性的框架。解释葡萄球菌疫苗的失败并制定有效疫苗接种的新策略对抗金黄色葡萄球菌。