Optimization of novel immunogen design to elicit broadly protective immune responses against influenza viruses

优化新型免疫原设计以引发针对流感病毒的广泛保护性免疫反应

• 批准号: 10468075
• 负责人: Peter Palese
• 金额: $ 43.7万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468075
• 关键词: Adenoviruses; Adjuvant; Advanced Development; Animal Model; Antibodies; Antibody Formation; Antigenic Diversity; Antigens; Avian Influenza A Virus; Binding; Binding Sites; Biological Assay; Cells; China; Clinical Research; Collaborations; Cysteine; DNA; DNA Recombinant Proteins; Development; Disease; Effector Cell; Engineering; Epitopes; Evaluation; Ferrets; Flow Cytometry; Funding; Generations; Goals; Head; Hemagglutination; Hemagglutinin; Human; Humoral Immunities; Immune response; Individual; Influenza; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H7N9 Subtype; Influenza A virus; Influenza B Virus; Influenza vaccination; Investigation; Lead; Location; Measures; Mediating; Modeling; Monoclonal Antibodies; Mosaicism; Mus; Neuraminidase; Outcome; Pathogenicity; Phase; Phase I Clinical Trials; Positioning Attribute; Process; Program Research Project Grants; Property; Regimen; Reporter; Reporting; Role; Sialic Acids; Site; Structure; Techniques; Testing; Vaccinated; Vaccination; Vaccine Design; Vaccines; Validation; Viral; Viral Antigens; Viral Vector; Virus; Work; base; design; disulfide bond; efficacy testing; immunogenicity; improved; in vivo; influenza virus vaccine; influenzavirus; live attenuated influenza vaccine; murine monoclonal antibody; neutralizing antibody; next generation; novel; novel vaccines; pandemic disease; prevent; programs; receptor; receptor binding; response; screening; success; tool; universal influenza vaccine; universal vaccine; vaccine candidate; vaccine formulation; vaccine platform

PROJECT SUMMARY Our understanding of the properties of broadly-neutralizing antibodies (bnAbs) directed towards conserved influenza virus epitopes has rapidly evolved in the last five years and yet, we are still unraveling key features and functions of this antibody class. The overarching goal of this entire Program Project Grant is the generation of long-lived, broadly protective immune responses to influenza virus by vaccination. To this end, our group has developed novel immunogens and vaccination regimens that have yielded promising results in animal models and candidate vaccines based on chimeric hemagglutinins (cHA) are now advancing towards Phase I clinical trials. The work proposed in Project 1, seeks to advance the development of next-generation immunogens for group 2 influenza A viruses (IAVs) and influenza B viruses (IBVs), in an effort to overcome the immunodominance of the globular head domain of HA, and allow improved recognition of highly conserved, but immunosubdominant HA epitopes. The application of our prior expertise with influenza A cHA immunogens will allow us to rapidly advance new group 2 cHA constructs. However, the development of a truly universal influenza virus vaccine will require combined efforts to elicit bnAb responses against group 1 and 2 IAVs as well as IBVs. Therefore, we propose to generate new universal influenza B virus constructs, based on novel "mosaic" HA design in which major antigenic sites in the immunodominant HA head domain have been eliminated. Optimized cHA for group 2 IAVs, or mosaic immunogens for IBVs, will be tested as DNA, recombinant protein, inactivated influenza vaccine (IIV) or live attenuated influenza vaccine (LAIV) formulations in mice for their ability to elicit broad and protective humoral immune responses recognizing conserved epitopes. In parallel, we will continue to further elucidate the determinants of Fc-mediated protection using novel techniques to probe the interactions between broadly protective HA antibodies, infected target cells, and effector cells. These mechanisms will be extended to investigations of the role of antibodies recognizing additional influenza viral antigens, including the viral neuraminidase (NA), in collaboration with Project 4. This program of work will be executed through close collaborations with each of the other Projects. We will characterize human and murine monoclonal antibodies (mAb) produced by Project 4 and the mAb Core. Vaccine constructs will be formulated with adjuvants selected in Project 2 to see if we can enhance Ab responses directed towards conserved epitopes and the in vivo efficacy of lead vaccine immunogens will be evaluated in the ferret model in Project 3. Thus, the overall aim of our project is to identify unique properties of broadly protective immune responses that can be exploited to further enhance and aid in the development of universal influenza virus vaccines.

项目概要 我们对广泛中和抗体 (bnAb) 特性的理解针对保守 流感病毒表位在过去五年中迅速进化，但我们仍在揭开关键特征 以及该抗体类别的功能。整个计划项目拨款的总体目标是 通过疫苗接种产生针对流感病毒的长期、广泛保护性免疫反应。为此， 我们的小组开发了新型免疫原和疫苗接种方案，并在以下方面取得了有希望的结果 基于嵌合血凝素（CHA）的动物模型和候选疫苗目前正在朝着 I 期临床试验。 项目 1 中提出的工作旨在促进群体下一代免疫原的开发 2 甲型流感病毒（IAV）和乙型流感病毒（IBV），努力克服甲型流感病毒（IAV）和乙型流感病毒（IBV）的免疫优势 HA 的球状头结构域，并允许提高对高度保守但免疫显性的识别 HA表位。应用我们之前在甲型流感 cHA 免疫原方面的专业知识将使我们能够快速 推进新的 2 组 cHA 构建。然而，真正通用的流感病毒疫苗的开发 将需要共同努力来引发针对第 1 组和第 2 组 IAV 以及 IBV 的 bnAb 反应。所以， 我们建议基于新型“马赛克”HA 设计生成新的通用乙型流感病毒构建体 免疫显性 HA 头域中的主要抗原位点已被消除。优化的 cHA 第 2 组 IAV 或 IBV 镶嵌免疫原将作为 DNA、重组蛋白、灭活进行测试 流感疫苗（IIV）或减毒活流感疫苗（LAIV）制剂在小鼠体内的诱导能力 识别保守表位的广泛和保护性体液免疫反应。与此同时，我们将继续 使用新技术探索相互作用，进一步阐明 Fc 介导的保护的决定因素 具有广泛保护性的 HA 抗体、受感染的靶细胞和效应细胞之间的关系。这些机制将 扩展到识别其他流感病毒抗原的抗体的作用的研究，包括 病毒神经氨酸酶 (NA)，与项目 4 合作。该工作计划将通过密切合作来执行 与其他每个项目的合作。我们将表征人类和鼠单克隆抗体 (mAb) 由项目 4 和 mAb 核心生产。疫苗构建体将用选定的佐剂配制 在项目 2 中，看看我们是否可以增强针对保守表位和体内抗体的反应 将在项目 3 的雪貂模型中评估先导疫苗免疫原的功效。因此，总体目标 我们的项目是确定广泛保护性免疫反应的独特特性，可用于 进一步加强和协助通用流感病毒疫苗的开发。