Staphylococcus aureus interference with IsdB vaccination

金黄色葡萄球菌干扰 IsdB 疫苗接种

基本信息

批准号：
9894152
负责人：
George Y Liu
金额：
$ 55.59万
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：
2019
资助国家：
美国
起止时间：
2019-09-18 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894152
关键词：
Address Adoptive Transfer Affect Age Antibiotic Resistance Antibodies Antibody Diversity Antibody Response B-Lymphocytes BLT mice Bacterial Vaccines Binding Characteristics Clinical Trials Data Epitopes Exposure to Failure Frequencies Generations Genetic Genus staphylococcus Human Immune response Immunity Immunization Infection Infectious Skin Diseases Interleukin-10 Iron Laboratory Animals Lead Life Mediating Modification Mus Pharmacologic Substance Public Health Research Personnel Resources Rodent Specificity Staphylococcal Infections Staphylococcal Vaccines Staphylococcus aureus Staphylococcus aureus infection Surface Testing Time Vaccinated Vaccination Vaccines Viral clinically relevant combat experience experimental study exposed human population human pathogen humanized mouse methicillin resistant Staphylococcus aureus mouse model novel novel strategies phase III trial response success vaccine development vaccine efficacy vaccine evaluation vaccine response vaccine trial

项目摘要

ABSTRACT Staphylococcus aureus is a leading cause of infection worldwide and a major driver of antibiotic resistance. Although many staphylococcal vaccines have been developed, all vaccines tested to date in human trials have failed for unclear reasons. Unlike humans who are infected or colonized with S. aureus at an early age, laboratory animals are rarely exposed to the human pathogen. Therefore, we queried if prior S. aureus exposure, in the form of infection, modifies protective immunity conferred by IsdB vaccination. Strikingly, prior staphylococcal infection in mice interferes with the induction of anti-staphylococcal immunity by IsdB vaccination. The mechanism appears to be driven by IL-10 and S. aureus-experienced B cells. These findings led us to hypothesize that S. aureus infection induces an ineffective B cell response associated with IL-10 that is preferentially recalled when subsequent IsdB vaccine is administered (original antigenic sin). To address our hypothesis, in Aim 1, we will determine how S. aureus- activated B cells and IL-10 modulate the host immune response to IsdB vaccine and nullify anti-staphylococcal protection. In Aim 2, we will determine what modifications to the IsdB-specific antibodies, induced by prior S. aureus exposure, make the antibodies non- protective. In Aim 3, we will determine the broader clinical relevance of our findings by testing if vaccine interference occurs in humanized BLT mice and in various clinically relevant settings.

抽象的金黄色葡萄球菌是全球感染的主要原因，也是抗生素耐药性的主要驱动因素。尽管已经开发出许多葡萄球菌疫苗，但迄今为止在人体试验中测试的所有疫苗都因不明原因失败。与早年感染或定植金黄色葡萄球菌的人类不同，实验动物很少接触人类病原体。因此，我们询问先前是否存在金黄色葡萄球菌以感染形式出现的暴露会改变 IsdB 疫苗接种所赋予的保护性免疫力。引人注目的是，之前小鼠葡萄球菌感染干扰 IsdB 诱导抗葡萄球菌免疫疫苗接种。该机制似乎是由 IL-10 和金黄色葡萄球菌经历过的 B 细胞驱动的。这些发现使我们推测金黄色葡萄球菌感染会诱导与 IL-10 相关的无效 B 细胞反应，当随后接种 IsdB 疫苗时优先召回（原抗原罪）。致地址我们的假设，在目标 1 中，我们将确定金黄色葡萄球菌激活的 B 细胞和 IL-10 如何调节宿主 IsdB 疫苗的免疫反应并使抗葡萄球菌保护无效。在目标 2 中，我们将确定什么由之前的金黄色葡萄球菌暴露引起的 IsdB 特异性抗体的修饰使抗体非- 保护的。在目标 3 中，我们将通过测试疫苗是否有效来确定我们的研究结果更广泛的临床相关性。干扰发生在人源化 BLT 小鼠和各种临床相关环境中。