Mechanisms and Duration of Immunity to SARS-CoV-2

在美国，每2000人中就有1人患有原发免疫缺陷疾病，是非霍奇金淋巴瘤患病率的两倍。PID患者有严重新冠肺炎和疫苗接种反应受损的风险。对这些人加强疫苗接种的研究显然对公共卫生具有重要意义。对这些患者的研究，其中许多患者的表型是单基因先天原因，提供了宝贵的机会来将人类的基因表型与免疫表型联系起来。Boyd博士将与纽约西奈山医学院的PID世界专家Charlotte Cunningham-Rundles博士合作，使用以前从142名PID患者的队列中收集的血浆和外周血单核细胞，分析接种和加强疫苗后的血清学以及B和T淋巴细胞反应，这些患者的疾病会影响一系列严重的适应性免疫反应，这些患者的免疫学表型除了保护性免疫受损外，还包括自身反应。这个队列中最常见的诊断是共同变量免疫缺陷(CVID)。这些患者产生的疫苗反应不太理想，但一些人在接种疫苗后仍能产生特定的抗体滴度。我们将对这些患者的血清学反应和B细胞和T细胞群进行深入的系统免疫学表征，利用一组14种不同的DNA标记的SARS-CoV-2变异抗原四聚体来表征频率、细胞表型、B细胞和T细胞受体序列以及抗原特异性B细胞靶向的抗原表位。PID患者的T细胞反应检查将包括分析疫苗抗原刺激的T细胞频率和TCR序列，以及详细的流式细胞仪免疫表型分析。这些数据将提供有关SARS-CoV-2疫苗接种和增强PID患者反应的临床相关信息，以潜在地为临床指导，因为新的包含Omicron变体的疫苗增强剂的实施，并将提供对免疫基因、途径和细胞群体的洞察，这些免疫基因、途径和细胞群有助于人类患者在mRNA接种后的适应性免疫反应和记忆形成。

Primary immune deficiency disorders (PID) affect 1 in 2,000 individuals in the U.S., twice the prevalence of non-Hodgkin lymphoma. PID patients are at risk for severe COVID-19 and impaired responses to vaccination. Research into vaccine boosting in these individuals is clearly of importance for public health. Study of these patients, many of which have single-gene inborn causes for their phenotype, offers the valuable opportunity to correlate genotypes with immunological phenotypes in humans. Dr. Boyd will collaborate with Dr. Charlotte Cunningham-Rundles, a world expert in PID at the Mount Sinai School of Medicine in New York, to analyze the serological and B and T lymphocyte responses to vaccination and boosting using previously-collected plasma and peripheral blood mononuclear cells from a cohort of 142 PID patients whose disorders affect adaptive immune responses with a range of severity, and whose immunological phenotypes can include autoreactivity in addition to impaired protective immunity. The most common diagnosis in this cohort is Common Variable Immune Deficiency, (CVID). These patients generate suboptimal vaccine responses, but some can still mount specific antibody titers after vaccination. We will carry out an in-depth systemsimmunology characterization of serological responses and B cell and T cell populations in these patients, characterizing the frequencies, cellular phenotypes, B cell and T cell receptor sequences, and antigen epitopes targeted by antigen-specific B cells, using a panel of 14 different DNA-tagged SARS-CoV-2 variant antigen tetramers. Examination of T cell responses in the PID patients will include analysis of vaccine antigen-stimulated T cell frequencies and TCR sequences, and detailed flow cytometric immunophenotyping. These data will provide clinically relevant information about SARS-CoV-2 vaccination and boosting responses in PID patients to potentially contribute to clinical guidance as new Omicron variant-containing vaccine boosters are implemented, and should provide insights into the immunological genes, pathways and cell populations that contribute to adaptive immune responses and memory formation after mRNA vaccination in human patients.