Viral Modulation of Polysaccharide Antibody Responses and Vaccine Efficacy

 简介(申请人提供)：肺炎链球菌是肺炎、脑膜炎和败血症等危及生命的疾病的主要原因。世界卫生组织估计，每年至少有160万人死于肺炎球菌感染。然而，肺炎球菌感染可以通过诱导针对肺炎球菌多糖(PPS)胶囊的抗体(Abs)反应的疫苗显著减少。PPS特异性抗体的免疫球蛋白同种类型提供了最实质性的保护，以防止威胁生命的侵袭性疾病。因此，激发PPS特异性免疫球蛋白是疫苗接种的主要目标。目前的建议源于我们惊人的初步数据，该数据表明，在小鼠和灵长类动物中感染呼吸道病毒可以极大地减少免疫球蛋白G的数量，但增加免疫球蛋白A的产生，而免疫球蛋白A是在病毒感染前几周注射多糖抗原时产生的。因此，我们假设呼吸道病毒感染可能对基于多糖的疫苗诱导的对肺炎链球菌和其他被包裹的细菌的保护具有重要的生理后果。我们的目标是验证这一假说，并定义病毒感染诱导的信号，这些信号调节多糖特异性抗体反应。此外，我们建议检验新的假设，即病毒感染诱导Ps特异性Ig��分泌细胞进行二级类开关重组。这些研究的结果有望为病毒诱导的因素和机制提供重要线索，这些因素和机制涉及将多糖特异性的免疫球蛋白应答转移到免疫球蛋白A应答，以及这种调节可能对人类多糖基疫苗效力产生的生理影响。

 DESCRIPTION (provided by applicant): Streptococcus pneumoniae is a major cause of life‑threatening diseases such as pneumonia, meningitis and sepsis. The World Health Organization estimates that at least 1.6 million people die each year from pneumococcal infections. However, pneumococcal infections can be significantly reduced by vaccines that induce antibodies (Abs) reactive against the pneumococcal polysaccharide (PPS) capsule. PPS‑specific Abs of the IgG isotype offers the most substantial protection against life‑threatenin invasive disease. Thus, eliciting PPS‑specific IgG is a major goal of vaccination. The current proposal stems from our striking preliminary data showing that respiratory virus infections in mice and primates can dramatically reduce the quantity of IgG, but increase IgA, produced in response to polysaccharide antigens that were administered several weeks preceding viral infection. We therefore hypothesize that respiratory viral infections may have important physiological consequences for polysaccharide‑based vaccine induced‑protection against S. pneumoniae and other encapsulated bacteria. Our objectives are to test this hypothesis and define the virus infection‑induced signals that modulate polysaccharide‑specific Ab responses. In addition, we propose to test the novel hypothesis that virus infection induces Ps‑specific Ig��secreting cells to undergo secondary class switch recombination. The results obtained from these studies are expected to provide important clues regarding the viral-induced factors and mechanisms involved in shifting polysaccharide‑specific IgG responses to IgA responses, as well as the physiological impact this modulation may have on polysaccharide‑based vaccine efficacy in humans.