Development of a single-dose self-amplifying RNA vaccine for boosting pre-existing influenza virus immunity, driving B and T cell responses to conserved targets

开发单剂量自扩增 RNA 疫苗，用于增强已有的流感病毒免疫力，驱动 B 和 T 细胞对保守靶点的反应

• 批准号: 10484741
• 负责人: Jesse Hong-Sae Erasmus
• 金额: $ 10.47万
• 依托单位: HDT BIO CORPORATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-10 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10484741
• 关键词: Adopted; Antibodies; Antibody Response; Antibody Specificity; Antibody titer measurement; Antigens; Automobile Driving; B-Lymphocytes; Birds; COVID-19; COVID-19 pandemic; Cessation of life; Clinic; Clinical; Coupled; Custom; Data; Development; Disease; Dose; Epidemiology; Epitopes; Event; Exposure to; Ferrets; Formulation; Future; Hemagglutinin; Human; Immune; Immune response; Immunity; Inactivated Vaccines; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Influenza B Virus; Influenza vaccination; Investigational Drugs; Lead; Learning; Life; Lipids; Maintenance; Modeling; Morbidity - disease rate; Mus; Mutation; Nonstructural Protein; Nucleic Acid Vaccines; Nucleoproteins; Pharmaceutical Preparations; Phase; Population; Population Heterogeneity; Problem Solving; Process; RNA; RNA amplification; RNA vaccine; Reaction Time; Recording of previous events; Role; Safety; Secondary Immunization; Small Business Innovation Research Grant; Specificity; Speed; T cell response; Technology; Time; Update; Vaccination; Vaccinee; Vaccines; Variant; Virus; antigen-specific T cells; base; booster vaccine; design; flexibility; immunogenicity; improved; influenza infection; influenza virus strain; influenza virus vaccine; influenzavirus; interest; manufacturing process; mortality; nanoparticle; neutralizing antibody; nonhuman primate; pandemic disease; pandemic influenza; pandemic preparedness; personalized approach; personalized medicine; protective efficacy; public trust; respiratory infection virus; respiratory pathogen; respiratory virus; response; stem; universal influenza vaccine; vaccination outcome; vaccine acceptance; vaccine development; vaccine distribution; vaccine efficacy; vaccine platform; zoonotic spillover

Project Summary While a universal influenza vaccine, providing life-long protective immunity against all current and future drifted and shifted subtypes of influenza virus after 2 or 3 doses, would be a game-changing solution to reducing the global burden of influenza and its associated morbidity and mortality, other approaches to solving this problem are urgently needed. There is still much to learn about immune responses to respiratory pathogens, such as influenza virus, and vaccine approaches that drive life-long immunity to respiratory viruses have yet to be demonstrated in humans. Therefore, we propose to develop a broadly protective influenza booster vaccine that can be administered, either seasonally or during pandemics, to individuals with prior exposures to either natural infection or seasonal vaccination. Given the non-uniform influenza immune history in a given population of individuals, it is likely that booster vaccines will need to be customized either at the individual or regional level, based on local influenza virus epidemiology or vaccine uptake. Nucleic acid vaccine platforms provide the ideal framework for such personalized-medicine approaches, due to the flexibility of development, as typified by the ongoing COVID-19 pandemic. As proof-of-concept, here we propose to apply our clinical-stage replicating RNA vaccine platform to develop a booster vaccine targeting the conserved hemagglutinin stem and nucleoprotein of group 1 influenza viruses and evaluating immunogenicity and efficacy against heterologous group 1 influenza virus infections in mouse and ferret models of pre-existing influenza virus immunity. These data will inform the feasibility of such an approach and characterize what types of pre-existing immunity, in terms of anti-hemagglutinin antibody specificity and magnitude, are required for booster vaccine efficacy. As these pre-existing antibody criteria are easily assessed in humans, it is likely that a personalized approach to influenza booster vaccination is achievable.

项目摘要 虽然一种普遍的流感疫苗，可为所有当前和未来提供终身保护性免疫 2或3剂后，流感病毒的漂移和转移的亚型将是一种改变游戏规则的解决方案 减轻流感的全球负担及其相关的发病率和死亡率，其他方法 迫切需要解决此问题。关于呼吸道免疫反应仍然有很多要学习的 病原体，例如流感病毒和疫苗方法，可驱动终生对呼吸道病毒的免疫力 在人类中尚未证明。因此，我们建议开发广泛的保护性流感 可以季节性或大流行期间对具有先验的人进行的促进疫苗 暴露于自然感染或季节性疫苗接种。鉴于不均匀的流感免疫病史 在给定的个人人群中，可能需要在 基于局部流感病毒流行病学或疫苗摄取的个人或区域水平。核酸疫苗 平台为这种个性化医学方法提供了理想的框架，因为 开发，如持续的共同19-大流行。作为概念证明，我们在这里建议申请 我们的临床阶段复制RNA疫苗平台，以开发针对保守的增强疫苗 1组流感病毒的血凝素茎和核蛋白，并评估免疫原性和 针对异源的第1组流感病毒感染的疗效和现有的雪貂模型 流感病毒免疫。这些数据将告知这种方法的可行性，并表征什么 在抗凝血素抗体的特异性方面，先前存在的免疫类型是 加强疫苗功效所需。由于这些先前存在的抗体标准在人类中很容易评估，因此 可以实现一种个性化流感促进疫苗接种的个性化方法。