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

1960-1990 年出生者的 1918 年流感病毒中和抗体

• 批准号: 8039984
• 负责人: Christopher F Basler
• 金额: $ 25.17万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-10 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039984
• 关键词: American; Antibodies; Antibody Formation; B-Lymphocytes; Cessation of life; Collaborations; Data; Development; Drug resistance; Elderly; Epitopes; Event; Evolution; Exhibits; Exposure to; Generations; Goals; Hemagglutinin; Human; Immune response; Immunoglobulin Genes; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Label; Membrane Glycoproteins; Methods; Monoclonal Antibodies; Morbidity - disease rate; Pharmaceutical Preparations; Population; Property; Public Health; Research Infrastructure; Serum; Specificity; Survivors; System; Time; United States; Universities; Vaccination; Vaccine Production; Vaccines; Virus; Virus-like particle; anti-influenza; cross reactivity; human monoclonal antibodies; immunogenic; influenza virus strain; influenzavirus; insight; mortality; neutralizing antibody; pandemic disease; pandemic influenza; public health relevance; resistant strain; response; seasonal influenza; vaccine development

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.

描述（由申请人提供）：目前的疫苗诱导产生B细胞，这些B细胞分泌针对流感病毒血凝素（HA）的中和抗体，但这些抗体反应具有很强的毒株特异性。然而，一些单克隆抗体已经被描述为表现出相对广泛的交叉中和活性。我们最近与James Crowe博士（范德比尔特大学）合作，描述了一种来自1918年大流行幸存者的人单克隆抗体，它不仅中和了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，对这些表位的反应显然并不主导人类对感染或疫苗接种的免疫反应。我们的长期目标是了解是什么决定了人抗体对毒株特异性和广泛中和的HA表位的反应的大小和特异性，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年以后出生的人身上鉴定单克隆抗体的特征，这些抗体可以中和1918年大流行性流感病毒。我们还分别在1918年以后出生的大约13%的人的血清中检测到高滴度的1918中和抗体。鉴于这些人没有接触过1918年流感病毒，这些抗1918年流感抗体的来源尚不清楚，但可能是由于接触过其他流感病毒株而引起的。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，我们希望从这些个体中确定1918-中性单克隆抗体的特异性，从而提出引发广泛的h1 -中性抗体的策略。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年血凝素特异性人B细胞，并产生抗1918年人单克隆抗体；(2)从1918年流感大流行后出生的个体中鉴定1918年特异性人单克隆抗体。