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.

拟议工作的目标是开发一种针对第 1 类疾病提供广泛保护的疫苗 甲型流感病毒——包括 1918 年、1957-1958 年和 2009 年大流行病毒以及禽流感病毒 流感“令人关注的病毒”——通过引发针对高度流感病毒的强大而持久的免疫反应 该项目将检验以下假设： 结合屏蔽 HA 的可变头结构域，将免疫反应重新集中到高度 通过控制 HA 的方向和多价呈现，保守的茎结构域将提供广泛的、 针对 1 类 A 型流感病毒的持久、强大的保护 流感代表着严重的全球健康问题。 问题，季节性流感病毒感染造成严重的健康和经济负担，以及 由新型流感病毒引起的大流行代表着更严重的威胁。 诱导主要针对 HA 头域的免疫反应，HA 头域在 因此，对流感疫苗接种的免疫反应是狭窄的且具有毒株特异性，并且会产生毒株特异性。 在“广泛中和”抗体的同时，对潜在的大流行性流感病毒几乎没有提供保护。 靶向HA高度保守的茎结构域可预防和治疗 流感病毒在体内挑战，这种抗体在自然感染或许可的情况下不能有效引发 HA 茎结构域的免疫亚优势可能是由于其近膜。 位置，B 细胞受体与保守茎表位的相互作用被空间位阻阻断 事实上，我们最近已经证明，在富含糖蛋白的病毒体上，可以调整 HA 的方向增强了茎表位的可及性，从而增强了茎导向的保护性 此外，我们还展示了一种方法（系留抗原抑制）。 抑制对 HA 头域的免疫反应，并将免疫反应重新集中在所需的区域 我们还设计了能引起强烈保护性抗体反应的疫苗。 通过从病毒样颗粒中多价展示它们来对抗包括 HA 在内的多种抗原。 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 stalk- 我们将屏蔽HA的头部结构域以抑制其免疫原性并调整。 头部屏蔽 HA 的方向，以增加茎域的可及性并增强其 我们还将研究通过使用进一步增加保护范围的能力。 工程化 HA 抗原包含来自不同病毒亚型的茎结构域。 表征小鼠疫苗接种诱导的抗茎反应的广度和持续时间。 目的是表征初次免疫和预免疫的男性和女性的免疫原性和疫苗功效 雪貂。