Human and rhesus macaque B-cell and serum antibody repertoires

总结 项目1，穆迪 这项研究计划的总体目标是设计一种能引起广泛中和反应的免疫原 流感仍然是一个持续的全球健康威胁，需要对流行菌株进行监测。主 预防流感感染的方法是接种疫苗，在过去的二十年里， 流感疫苗接种已经扩大到几乎所有美国人。在一项研究中， 在2008年的三价流感疫苗中，我们发现对流感疫苗接种的反应有亚型 主导地位：任何特定个体的大多数反应都针对的是系统的单个组成部分。 多价疫苗，并包括对血凝素（HA）受体结合位点（RBS）的应答。我们有 现在发现，这种由B细胞产生的显性反应是由流感引起的 这些成年人是婴儿时流行的毒株，这表明早期流感暴露可能会影响 后续反应的结果（“印记”）。调查这些观察结果对公共卫生有影响， 婴儿和成人使用各种流感疫苗。项目1将测试以下假设：（i） 免疫系统的早期感染流感导致亚型优势在随后的反应， 但（ii）婴儿早期接种多价疫苗可使免疫系统产生 对多种毒株的反应在疫苗季节持续存在，即使在接种疫苗后也能保持平衡。 在生命后期感染，和（iii）用设计用于刺激RBS克隆谱系HA免疫 抗体可以改变印记反应。我们将在人类和恒河猴中调查这些假设 猕猴（RM）。

Summary Project 1, Moody The overall goal of the research program is to design immunogens that elicit a broadly neutralizing response Influenza remains a persistent global health threat requiring surveillance of circulating strains. The primary method of preventing influenza infection is vaccination, and in the last two decades, the recommendations for influenza vaccination have been expanded to include almost all people in the US. In a study of recipients of the 2008 trivalent influenza vaccine, we found that the response to influenza vaccination had subtype dominance: most of the responses in any particular individual were directed to a single component of the multivalent vaccine, and included responses to the hemagglutinin (HA) receptor binding site (RBS). We have now found that this dominant response derived from B cells descended from those elicited by the influenza strain circulating when these adults were infants, suggesting that an early influenza exposure may affect the outcome of later responses ("imprinting"). Investigating these observations has public health implications for the use of various influenza vaccines in infants and adults. Project 1 will test the hypotheses that (i) imprinting of the immune system by early infection with influenza results in subtype dominance in subsequent responses, but that (ii) early vaccination with multivalent vaccine in infants can prime the immune system to produce responses to multiple strains that persist across vaccine seasons and that can remain balanced even after an infection later in life, and (iii) that immunization with HAs designed to stimulate clonal lineages of RBS antibodies can modify an imprinted response. We will investigate these hypotheses in humans and rhesus macaques (RMs).