Staphylococcus aureus interference with IsdB vaccination

摘要 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。 尽管已经开发了许多葡萄球菌疫苗，但迄今为止在人体试验中测试的所有疫苗都 失败原因不明。不像人类感染或殖民与S。金黄色葡萄球菌在早期， 实验室动物很少接触人类病原体。因此，我们质疑是否先验S。金黄色 以感染形式的暴露改变了由IsdB疫苗接种赋予的保护性免疫。引人注目的是，副院长 小鼠葡萄球菌感染干扰IsdB诱导抗葡萄球菌免疫 预防针该机制似乎是由IL-10和S.金黄色感受性B细胞。这些发现 使我们假设S.金黄色葡萄球菌感染诱导与IL-10相关的无效B细胞应答， 当随后施用IsdB疫苗时优先回忆（原始抗原sin）。解决 我们的假设，在目标1中，我们将确定S如何。金黄色葡萄球菌激活的B细胞和IL-10调节宿主 对IsdB疫苗免疫应答并使抗葡萄球菌保护无效。在目标2中，我们将确定 对Isdb特异性抗体的修饰，由先前的S.金黄色葡萄球菌暴露，使抗体非- 保护性的在目标3中，我们将通过测试疫苗是否 干扰发生在人源化BLT小鼠和各种临床相关环境中。

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.