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，但到目前为止在人体试验中测试的所有疫苗都 失败的原因不明。与在幼年时感染或定居金黄色葡萄球菌的人类不同， 实验动物很少接触到人类病原体。因此，我们质疑之前的金黄色葡萄球菌 暴露以感染的形式改变了ISDB疫苗接种所产生的保护性免疫。令人惊讶的是，普赖斯 小鼠葡萄球菌感染干扰ISDB诱导的抗葡萄球菌免疫 接种疫苗。这一机制似乎是由IL-10和金黄色葡萄球菌感染的B细胞驱动的。这些发现 这让我们假设金黄色葡萄球菌感染诱导了与IL-10相关的无效B细胞反应， 在随后接种ISDB疫苗时优先召回(原始抗原性SIN)。致信地址 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 对ISDB疫苗的免疫应答和无效的抗葡萄球菌保护。在目标2中，我们将确定 由先前的金黄色葡萄球菌暴露引起的对ISDB特异性抗体的修饰使抗体成为非 防护性的。在目标3中，我们将通过测试疫苗来确定我们的发现的更广泛的临床相关性 干扰发生在人源化的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.