Early Drivers of Humoral Immunity to SARS-CoV-2 Infections

对SARS-CoV-2（CoV 2）感染的体液免疫的持续时间和性质知之甚少。最 研究主要集中在临床疾病患者的免疫反应，但对抗体的了解很少。 关于暴露后立即和发病前的最早免疫学事件的CoV 2应答 疾病或无症状个体以及这如何影响长期免疫记忆。这项建议 通过前瞻性地跟踪与临床病例的家庭接触， CoV 2，以确定28天内与这种早期病毒暴露相关的先天性和适应性免疫事件 期来自这些患者的样品的详细评价，包括外周血细胞的RNAseq和 口腔分泌物的蛋白质组学分析，初始CoV 2复制的位点。我们将决定是否有可能 交叉反应性T细胞和分泌型伊加可能有助于这种早期保护性免疫反应， 它们是否通过向B细胞提供更大的T细胞帮助来增强随后的体液免疫应答。这些 研究还将提供对CoV 2的先天免疫反应的详细知识，以及这种免疫反应如何影响免疫系统。 体液免疫的性质和持续时间。我们的中心假设是外周血淋巴细胞和 在病毒暴露时和发病前从个体收集的口咽分泌物 症状将显示与病毒清除相关的先天性和适应性免疫应答， 预测是否有效的体液免疫和长期免疫记忆的发展。 这一假设将通过探索以下目标来解决：i）评估早期免疫体液和免疫细胞因子。 诊断为COVID-19的个体的密切接触者对CoV 2的细胞免疫反应; ii）评估 诊断为COVID-19的密切接触者的早期先天免疫反应，并评估其 与体液免疫应答和病毒血症的关系;以及iii）检查体液免疫的早期驱动因素 免疫记忆和疫苗反应的持久性。这一全面评价 早期感染与先天性和获得性免疫对长期记忆和免疫力的影响 为开发高信息量和可扩展的血清学检测提供了严格的基础。我们的方法 因此，通过开发和验证新的检测方法， 同时测量来自早期感染的对CoV 2的先天性和适应性免疫应答;这种方法 将有助于定义与无症状与有症状相关的免疫参数和血清学标志物 感染和疾病严重程度。

The duration and nature of humoral immunity to SARS-CoV-2 (CoV2) infection is poorly understood. Most studies have focused on the immune response in patients with clinical illness, but little is known about antibody response to CoV2 regarding the earliest immunological events immediately after exposure and prior to onset of illness or in asymptomatic individuals and how this impacts long-term immunological memory. This proposal addresses these gaps in our knowledge by prospectively following household contacts with clinical cases of CoV2 to determine innate and adaptive immune events associated with this early viral exposure over a 28 day period. Detailed evaluation of samples from these patients including RNAseq of peripheral blood cells and proteomic analysis of oral secretions, the site of initial CoV2 replication. We will determine whether potentially cross-reactive T cells and secretory IgA may contribute to this early protective immune response and if present do they enhance the subsequent humoral immune responses by providing greater T cell help to B cells. These studies will also provide a detailed knowledge of innate immune responses to CoV2 and how this shapes the nature and duration humoral immunity. Our central hypothesis is that peripheral blood lymphocytes and oropharyngeal secretions collected from individuals at the time of viral exposure and prior to onset of symptoms will show innate and adaptive immune responses that correlate with viral clearance and predict whether or not effective humoral immunity and long-term immunological memory develops. This hypothesis will be addressed by exploring the following aims; i) evaluating the early immune humoral and cellular immune responses to CoV2 in close contacts of individuals diagnosed with COVID-19; ii) to assess early innate immune responses in close contacts of individuals diagnosed with COVID-19 and assess their relationship with humoral immune responses and viremia; and iii) to examine early drivers of humoral immunity on the durability of immunological memory and responses to vaccines. This comprehensive evaluation of the relationships between early infection with innate and adaptive immune on long-term memory and immunity will provide a rigorous basis for the development of highly informative and scalable serological tests. Our approach is therefore highly responsive to RFA-CA-20-039, through the development and validation of novel assays that simultaneously measure innate and adaptive immune responses to CoV2 from early infection; this approach will help define immune parameters and serological markers associated with asymptomatic vs. symptomatic infection and disease severity.