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力。尽管已经开发了许多葡萄球菌疫苗，但迄今为止在人类试验中测试的所有疫苗都有由于不明确的原因而失败。与在早期被链球菌感染或殖民的人不同，实验动物很少暴露于人类病原体。因此，我们询问是否存在先验的金黄色葡萄球菌暴露于感染的形式，修饰了ISDB疫苗接种赋予的保护性免疫。令人惊讶的是，先验小鼠中的葡萄球菌感染会干扰ISDB诱导抗稳定球菌免疫疫苗接种。该机制似乎是由IL-10和金黄色葡萄球菌的B细胞驱动的。这些发现导致我们假设金黄色葡萄球菌感染引起与IL-10相关的无效B细胞反应当施用随后的ISDB疫苗（原始抗原罪）时，优先召回了。解决我们的假设在AIM 1中，我们将确定金黄色葡萄球菌活化的B细胞和IL-10如何调节宿主对ISDB疫苗的免疫反应，并无效抗稳定球菌保护。在AIM 2中，我们将确定什么先前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AIM 3中，我们将通过测试疫苗来确定发现结果的更广泛的临床相关性干涉发生在人源化的BLT小鼠和各种临床相关的环境中。