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.

项目摘要 我们对针对保守的广泛中和抗体（BNAB）的特性的理解 流感病毒表位在过去五年中迅速发展，但是，我们仍在揭示关键特征 和该抗体类的功能。整个计划项目赠款的总体目标是 通过疫苗接种产生对流感病毒的长期保护性免疫反应。为此， 我们的小组已经开发了新型免疫原和疫苗接种方案，在 基于嵌合血凝素（CHA）的动物模型和候选疫苗现在正在前进 I期临床试验。 项目1中提出的工作旨在推动小组的下一代免疫原子的开发 2流感病毒（IAVS）和流感B病毒（IBV），以克服免疫力优势 HA的球状头部结构域，并允许改善对高度保守但免疫抑制剂的识别 HA表位。我们先前在流感的专业知识的应用CHA免疫剂将使我们能够迅速 推进新组2 CHA结构。但是，开发真正普遍的流感病毒疫苗 将需要合并的努力，以引起针对第1组和第2组IAV以及IBV的BNAB响应。所以， 我们建议根据新颖的“马赛克” HA设计生成新的通用流感B病毒构建 已经消除了免疫主导HA头域中哪些主要的抗原位点。优化的cha IBV的第2组IAV或镶嵌性免疫原子将被测试为DNA，重组蛋白，灭活 小鼠的流感疫苗（IIV）或活衰减的流感疫苗（LAIV）表达 识别保守的表位的广泛而保护性的体液免疫反应。同时，我们将继续 进一步阐明了使用新技术来探测相互作用的FC介导保护的决定因素 在广泛的保护性HA抗体，感染的靶细胞和效应细胞之间。这些机制将是 扩展到研究抗体的作用，以识别其他流感病毒抗原，包括 病毒神经氨酸酶（NA），与项目4合作。该工作计划将通过近距离执行 与其他每个项目的合作。我们将表征人和鼠单克隆抗体 （mab）由项目4和mAb核心产生。疫苗构建体将与选择的佐剂配制 在项目2中，查看我们是否可以增强针对保守表位和体内的AB反应 铅疫苗免疫原子的功效将在项目3的雪貂模型中进行评估。因此， 我们的项目是确定可以利用的广泛保护性免疫反应的独特特性 进一步增强和帮助开发普遍流感病毒疫苗。