Engineering Protein Antigens and their Presentation from Multivalent Scaffolds

工程蛋白质抗原及其从多价支架的呈现

• 批准号: 10582942
• 负责人: Ravi S. Kane
• 金额: $ 85.2万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-07 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582942
• 关键词: Address; Antibodies; Antibody Response; Antigens; Avian Influenza A Virus; B-Cell Antigen Receptor; Coronavirus; Development; Economic Burden; Engineering; Ensure; Epidemic; Epitopes; Female; Ferrets; Flavivirus; Glycoproteins; Head; Health; Hemagglutinin; Human; Immune response; Immunize; Immunodominant Epitopes; Immunology; Infection; Influenza; Influenza A virus; Influenza vaccination; Licensing; Ligands; Location; Longevity; Membrane; Modeling; Mus; Mutation; Play; Protein Engineering; Proteins; Public Health; Research; Research Project Grants; Role; Testing; Therapeutic; Vaccination; Vaccine Design; Vaccines; Viral; Virion; Virus; Virus-like particle; Work; design; endosome membrane; experience; global health; immunogenicity; in vivo; influenza infection; influenza virus vaccine; influenzavirus; male; nanoscale; neutralizing antibody; novel; pandemic disease; pandemic influenza; pandemic potential; pandemic virus; pathogen; prophylactic; response; scaffold; seasonal influenza; universal influenza vaccine; vaccine access; vaccine development; vaccine efficacy

The objective of the proposed work is to develop a vaccine that provides broad protection against group 1 influenza A viruses – a group that includes the 1918, 1957-1958, and 2009 pandemic viruses, as well as avian influenza “viruses of concern” – by eliciting a robust and durable immune response targeting the highly conserved membrane-proximal stalk domain of hemagglutinin (HA). The project will test the hypothesis that the combination of shielding the variable head domain of HA, refocusing the immune response to the highly conserved stalk domain by controlling the orientation of HA, and multivalent presentation, will provide broad, durable, and robust protection against group 1 influenza A viruses. Influenza represents a serious global health problem, with seasonal influenza virus infections imposing significant health and economic burdens, and pandemics caused by novel influenza viruses representing an even more serious threat. Licensed vaccines induce an immune response that primarily targets the head domain of HA, which is highly variable in sequence. As a result, the immune response to influenza vaccination is narrow and strain-specific and would provide little protection against potential pandemic influenza viruses. While “broadly neutralizing” antibodies targeting the highly conserved stalk domain of HA are prophylactically and therapeutically protective against influenza virus challenges in vivo, such antibodies are not elicited effectively in natural infections or by licensed influenza vaccines. The immunosubdominance of the HA stalk domain may result from its membrane-proximal location, with interactions of B-cell receptors with conserved stalk epitopes being blocked by steric hindrance on virions which are densely packed with glycoproteins. Indeed, we have recently shown that tuning the orientation of HA to enhance the accessibility of stalk epitopes results in an enhanced protective stalk-directed immune response. Furthermore, we have demonstrated an approach (tethered antigenic suppression) for suppressing the immune response to the head domain of HA and refocusing the immune response on desired epitopes (such as the stalk). We have also designed vaccines that elicit a robust protective antibody response against a variety of antigens, including HA, by displaying them multivalently from virus-like particles. The first aim of the proposed work is to engineer and test novel HA antigen designs to provide an enhanced stalk- directed immune response. We will shield the head domain of HA to suppress its immunogenicity and will tune the orientation of the head-shielded HA to increase the accessibility of the stalk domain and enhance its immunogenicity. We will also investigate the ability to further increase the breadth of protection by using engineered HA antigens that incorporate stalk domains from different viral subtypes. The second aim is to characterize the breadth and the longevity of the anti-stalk response induced by vaccination in mice. The third aim is to characterize immunogenicity and vaccine efficacy in naïve and pre-immunized, male and female ferrets.

拟议工作的目的是开发一种疫苗，可为1组提供广泛的保护 影响力病毒 - 包括1918、1957-1958和2009年大流行病毒的组以及鸟类 影响力的“关注病毒” - 通过引起对高度针对的稳健耐用的免疫反应 血凝素（HA）的保守膜 - 核茎结构域。该项目将检验以下假设 屏蔽HA的可变头域的组合，将免疫反应重新聚焦于高度 通过控制HA的方向和多价表示，保守的茎域将提供广泛的， 耐用，并强大的保护1组影响病毒。流感代表着严重的全球健康 问题，季节性影响病毒感染施加了巨大的健康和经济伯恩根，以及 由新型影响病毒引起的大流行，代表了更严重的威胁。许可疫苗 诱导一种主要针对HA的头域的免疫反应，这在高度变化 顺序。结果，对影响力疫苗接种的免疫响应是狭窄且特异性的，将 几乎没有保护潜在的大流行影响病毒。而“广泛中和”抗体 靶向HA的高度保守的茎结构域在预防性和治疗中受到保护 流感病毒在体内挑战，这种抗体并未在自然感染中有效或获得许可。 流感疫苗。 HA茎结构域的免疫接管可能是由其膜透明带来的 位置，B细胞接收器与组成的茎表位的相互作用被空间障碍阻塞 关于含有糖蛋白的不足的病毒。确实，我们最近表明，调整 HA的方向增强了茎表位的可及性导致受保护的茎导向增强 免疫反应。此外，我们已经证明了一种方法（束带抗原抑制） 抑制对HA的头域的免疫反应并根据所需的重新聚焦免疫反应 表位（例如茎）。我们还设计了引起强大保护性抗体反应的疫苗 通过各种抗原（包括HA）来表现出来自病毒样颗粒的数量显示。第一个 拟议工作的目的是设计和测试新型HA抗原设计，以提供增强的茎 - 定向免疫反应。我们将屏蔽HA的头部域以抑制其免疫原性，并将调整 头部屏蔽HA的方向增加了茎域的可及性并增强其 免疫原性。我们还将研究通过使用的能力进一步提高保护广度 设计的HA抗原，结合了来自不同病毒亚型的茎域。第二个目标是 表征小鼠疫苗接种引起的抗stalk反应的宽度和寿命。第三 目的是表征幼稚和预释的男性和女性的免疫原性和疫苗效率 雪貂。