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 虽然是一种通用流感疫苗，提供终身保护性免疫力， 在2或3次剂量后，流感病毒的亚型发生漂移和转移，这将是一个改变游戏规则的解决方案， 减少流感及其相关发病率和死亡率的全球负担， 解决这个问题是迫切需要的。关于呼吸道感染的免疫反应， 病原体，如流感病毒，和疫苗的方法，驱动终身免疫呼吸道病毒 尚未在人类身上得到证实。因此，我们建议研制一种广泛保护性的流感疫苗， 加强疫苗，可以在季节性或大流行期间给予先前患有 自然感染或季节性疫苗接种。鉴于流感免疫史的不一致性 在特定的人群中，很可能需要在 根据当地流感病毒流行病学或疫苗接种情况，在个人或区域一级进行评估。核酸疫苗 平台为这种个性化医疗方法提供了理想的框架，因为它具有灵活性， 发展，以持续的COVID-19疫情为代表。作为概念验证，我们建议在此应用 我们的临床阶段复制RNA疫苗平台，以开发针对保守的 组1流感病毒的血凝素干细胞和核蛋白并评价免疫原性， 在预先存在的小鼠和雪貂模型中抗异源1型流感病毒感染的效力 流感病毒免疫。这些数据将为这种方法的可行性提供信息，并描述 就抗血凝素抗体的特异性和强度而言，预先存在的免疫力的类型如下： 增强疫苗效力所需的。由于这些预先存在的抗体标准很容易在人体中进行评估， 个性化的流感加强疫苗接种方法可能是可以实现的。