Structure-function analysis of infection- and vaccine-induced B-cell repertoires

摘要 疫苗的一个基本目标是防止病毒不断进化， 宿主免疫--流感和艾滋病毒是目前最主要的人类病原体， 在这方面感兴趣的是靶向选定的保守表位，并了解和 预测病毒逃逸机制。该计划项目赠款的基本前提是， 流感病毒疫苗接种或感染后B细胞个体发育分析可以促进设计 免疫原来引发“广泛中和”反应我们试图回答关键问题 关于免疫应答机制，免疫策略和B细胞免疫原设计， 定量术语，从而提供更安全的结构和生物物理基础， 疫苗研发。拟议的研究策略侧重于识别抗体的抗体， 流感病毒HA上的受体结合位点（RBS）--显示广泛 中和抗体（bnAb）靶标。我们将结合联合收割机对人类剧目的分析， 流感疫苗接种与实验后的库分析相似 小鼠和恒河猴的免疫。我们将测试关于印记的假设， 通过初次感染或接种疫苗的免疫反应，确定如何再感染或 用呈现突变表位的HA再接种影响应答的扩大 通过进一步的亲和力成熟，并将我们所学到的整合到测试中， 免疫原设计

Abstract An essential objective for vaccines to protect against viruses that continually evolve to escape host immunity -- influenza and HIV being the most prominent human pathogens of current interest in this regard -- is to target selected, conserved epitopes and to understand and anticipate viral escape mechanisms. An underlying premise of this Program Project grant is that analysis of B-cell ontogeny following influenza-virus vaccination or infection can facilitate design of immunogens to elicit a "broadly neutralizing" response. We seek to answer critical questions about immune-response mechanisms, immunization strategies and B-cell immunogen design in quantitative terms and hence to provide a more secure structural and biophysical foundation for vaccine development. The proposed research strategy focuses on antibodies that recognize the receptor-binding site (RBS) on influenza HA -- one of two conserved sites shown to be broadly neutralizing antibody (bnAb) targets. We will combine analysis of human repertoires in response to influenza vaccination with similar analyses of repertoires following experimental immunizations of mice and rhesus macaques. We will test hypotheses concerning imprinting of the immune response by initial infection or vaccination, establish how reinfection or revaccination with HA presenting a mutated epitope influences broadening of the response through further affinity maturation, and integrate what we learn into tests in of proposals for immunogen design