Design and function of flagellin-based immunogens for broadly neutralizing immuni

用于广泛中和免疫的基于鞭毛蛋白的免疫原的设计和功能

• 批准号: 7761183
• 负责人: Kelly D Smith
• 金额: $ 56.95万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-04 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7761183
• 关键词: Address; Adjuvant; Animals; Antibodies; Antibody Formation; Antigenic Variation; Antigens; Applications Grants; Bacteria; Binding; Caspase-1; Cell surface; Characteristics; Communicable Diseases; Disease; Engineering; Epitopes; Flagella; Flagellin; HIV; HIV vaccine; Human; Immune; Immune response; Immune system; Individual; Knowledge; Mediating; Molecular; Nature; Pathway interactions; Polymers; RNA-Directed DNA Polymerase; Source; Structure; TLR5 gene; Testing; Translating; Vaccination; Vaccines; Variant; Viral; base; design; immunogenicity; neutralizing antibody; vaccine development

DESCRIPTION (provided by applicant): Immune defense against HIV is usually ineffective. Viral escape due to error prone RNA-dependent DNA polymerase mediated replication is a constant source of variants that can evade existing defenses. Despite this antigenic variability, a small fraction of HIV-infected individuals make broadly neutralizing antibodies, and are protected from disease. Recently, we and others have defined the structures of epitopes recognized by some of the broadly neutralizing antibodies. Despite our understanding of the structural nature of these epitopes, this knowledge has not translated into effective vaccines that elicit broadly neutralizing antibodies. We hypothesize that inefficient epitope display and insufficient adjuvancy are major hurdles to overcome in HIV vaccine development. To address this hypothesis we propose to engineer flagellin molecules that will display HIV epitopes and posses potent adjuvant activity, and thus transform bacterial flagellin into an HIV vaccine. Flagellin possesses unique characteristics that promote its antigenicity. Flagellin is exposed on the cell surface as a polymer (the flagellum), and flagellin is recognized by the innate immune system through multiple pathways, including TLR5 and caspase-1. We hypothesize that HIV epitopes that are appropriately incorporated into bacterial flagellin will be potent immunogens and elicit broadly neutralizing antibody responses. To test this hypothesis, we propose to perform a detailed analysis of the structural components of flagellin that are required for antibody responses, and to define strategies to incorporate antigenically intact HIV epitopes into bacterial flagellin. The three specific aims of this grant application are: 1) define components of flagellin and innate immune pathways required for potent immune responses, 2) design HIV epitope-flagellin fusions that retain innate immune stimulatory capacity and bind broadly cross-reacting antibodies, and 3) analyze immunogenicity of HIV epitope-flagellin fusions. Immune defense against human immunodeficiency virus (HIV) is usually ineffective due to tremendous variability. However, a small fraction of HIV-infected individuals make protective antibodies to conserved structures, and these antibodies recognize the majority of the HIV strains. We propose to engineer bacterial flagellin molecules that will display conserved HIV epitopes for use as potent immunogens that elicit broadly neutralizing antibody responses to HIV.

描述（由申请人提供）：针对艾滋病毒的免疫防御通常无效。因误差依赖RNA依赖性DNA聚合酶介导的复制而导致的病毒逃逸是可以逃避现有防御措施的变体的恒定来源。尽管存在这种抗原性变异性，但一小部分HIV感染的个体会大致中和抗体，并受到疾病的保护。最近，我们和其他人定义了某些广泛中和抗体所识别的表位结构。尽管我们了解了这些表位的结构性，但这些知识并未转化为引起广泛中和抗体的有效疫苗。我们假设表现效率低下和佐剂不足是克服HIV疫苗发育中的主要障碍。为了解决这一假设，我们建议设计将显示HIV表位并具有有效辅助活性的鞭毛蛋白分子，从而将细菌鞭毛蛋白转化为HIV疫苗。鞭毛蛋白具有促进其抗原性的独特特征。鞭毛蛋白作为聚合物（鞭毛）暴露在细胞表面上，鞭毛蛋白通过包括TLR5和caspase-1在内的多种途径被先天免疫系统识别。我们假设适当掺入细菌鞭毛蛋白的HIV表位将是有效的免疫原子，并引起广泛中和抗体反应。为了检验这一假设，我们建议对抗体反应所需的鞭毛蛋白结构成分进行详细分析，并定义将抗原上完整的HIV表位掺入细菌鞭毛蛋白中的策略。该赠款应用的三个具体目的是：1）定义有效免疫反应所需的鞭毛蛋白和先天免疫途径的组成部分，2）设计HIV Epitope-Flagellin融合量，以保持先天免疫刺激能力并结合广泛交叉反应抗体，以及3）分析HIV HIV Eptipepipe-epitope-epitope-Fagellagellian fustions的免疫原理。免疫防御人类免疫缺陷病毒（HIV）通常由于巨大的可变性而无效。但是，一小部分HIV感染的个体可以对保守结构产生保护性抗体，这些抗体识别大多数HIV菌株。我们建议设计将显示保守的HIV表位的细菌鞭毛蛋白分子作为有效的免疫原子，从而广泛中和对HIV的抗体反应。