1918 Influenza Virus-Neutralizing Antibodies from Individuals Born 1960-1990

描述（由申请方提供）：目前的疫苗诱导产生B细胞，该细胞分泌靶向流感病毒血凝素（HA）的中和抗体，但这些抗体应答具有很强的毒株特异性。然而，已经描述了几种表现出相对广泛的交叉中和活性的单克隆抗体。在与James Crowe博士（范德比尔特大学）的合作中，我们最近描述了一种来自1918年大流行幸存者的人单克隆抗体，该抗体不仅中和了1918年的病毒，还中和了1943年和1977年的人H1N1病毒。这些数据表明，在不同的HA分子上存在交叉反应性表位;然而，对这些表位的应答显然并不主导对感染或疫苗接种的人免疫应答。我们的长期目标是了解是什么决定了人类抗体对菌株特异性HA表位与广泛中和HA表位的反应的幅度和特异性，因为这可能有助于开发更广泛的保护性疫苗。为了实现这一目标，我们试图从1918年以后出生的个体中鉴定出中和1918年大流行性流感病毒的单克隆抗体。另外，我们在1918年以后出生的大约13%的人的血清中分别检测到高滴度的1918中和抗体。鉴于这些人没有接触过1918年病毒，这些抗1918抗体的来源尚不清楚，但推测它们是通过接触其他流感病毒株引起的。我们假设这些1918-中和抗体中的一些将对不同的H1分子表现出不寻常的交叉反应性。因此，我们希望确定这些个体的单克隆1918中和抗体的特异性将建议引发广泛的H1中和抗体的策略。我们将（1）开发有效的方法，从1918年流感大流行后出生的个体中分离1918血凝素特异性人B细胞，并产生抗1918人单克隆抗体;（2）表征1918年流感大流行后出生的个体中1918特异性人单克隆抗体。 公共卫生相关性：在美国，季节性流感每年继续导致大量的发病率和死亡率，并且新的大流行性流感病毒的可能出现是一个持续的问题。该项目的完成将确定1918年大流行性流感病毒HA上的表位，这些表位可被相对年轻的个体的抗体识别。希望这些信息将为新的、更有效的疫苗策略提供见解。

DESCRIPTION (provided by applicant): Current vaccines induce the generation of B cells that secrete neutralizing antibodies targeting the influenza virus hemagglutinin (HA), but these antibody responses are quite strain-specific. However, several monoclonal antibodies have been described that exhibit relatively broad cross-neutralizing activity. In collaboration with Dr. James Crowe (Vanderbilt University), we recently described a human monoclonal antibody from a 1918 pandemic survivor which neutralized not only the 1918 virus but also human H1N1 viruses from 1943 and 1977. These data suggest that cross-reactive epitopes on different HA molecules exist; however, responses to such epitopes clearly do not predominate the human immune response to infection or vaccination. Our long term goal is to understand what determines the magnitude and specificity of human antibody responses to strain-specific versus broadly neutralizing HA epitopes, as this may facilitate development of more broadly protective vaccines. Toward this goal, we seek to characterize monoclonal antibodies from individuals born well after 1918 that neutralize the 1918 pandemic influenza virus. We other have separately detected high titer 1918-neutralizing antibodies in the sera of approximately 13 percent of individuals born well after 1918. Given that these individuals have not been exposed to the 1918 virus, the origin of these anti-1918 antibodies is unclear, but presumably they were elicited by exposure to other influenza virus strains. We hypothesize that some of these 1918-neutralzing antibodies will exhibit unusual cross-reactivity towards different H1 molecules. Therefore, we hope that defining the specificity of monoclonal 1918-neutralizing antibodies from these individuals will suggest strategies to elicit broad H1-neutralizing antibodies. We will (1) Develop efficient methods to isolate, from individuals born well after the 1918 influenza pandemic, 1918 hemagglutinin-specific human B cells and produce anti-1918 human monoclonal antibodies; and (2) Characterize 1918-specific human monoclonal antibodies from individuals born well after the 1918 influenza pandemic.. PUBLIC HEALTH RELEVANCE: Seasonal influenza continues to cause substantial morbidity and mortality annually in the United States, and the possible emergence of a new, pandemic influenza virus is a continuing concern. Completion of this project will identify the epitopes on the 1918 pandemic influenza virus HA recognized by antibodies from relatively young individuals. It is hoped this information will provide insight into new, more effective vaccine strategies.