Development of broadly-protective vaccines for influenza B viruses

开发针对乙型流感病毒的广泛保护性疫苗

• 批准号: 10359831
• 负责人: YOSHIHIRO KAWAOKA
• 金额: $ 19.69万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-25 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359831
• 关键词: Address; Adjuvant; Affect; Alhydrogel; Animals; Antibodies; Antibody titer measurement; Antigens; Attenuated Vaccines; Bacteriophages; Biological Assay; CD8-Positive T-Lymphocytes; Cells; Complement; Control Animal; Data; Development; Epidemic; Epitopes; Ferrets; Future; Hemagglutinin; Human; Immune response; Immunity; Immunization; Immunize; Immunology; Infection; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A virus; Influenza B Virus; Lead; Libraries; Maps; Morbidity - disease rate; Mutagenesis; Mutation; Organ; Peptides; Phage Display; Pharmaceutical Preparations; Phase; Population; Property; Proteins; Recombinants; Research; Respiratory Disease; Saint Jude Children' s Research Hospital; Serum; Spleen; Testing; Update; Vaccinated; Vaccination; Vaccines; Variant; Viral Antigens; Viral Proteins; Virus; base; cross reactivity; cytokine; design; experimental study; immunogenicity; improved; influenza virus strain; influenza virus vaccine; influenzavirus; lymph nodes; mortality; mutant; nanoparticle; novel; novel strategies; protective efficacy; respiratory; response; stem; universal vaccine; vaccine access; vaccine candidate; vaccine efficacy

PROJECT SUMMARY Influenza B viruses (IBV) cause annual epidemics with appreciable morbidity and mortality, but have been understudied compared to influenza A viruses (IAV). Currently available vaccines for IBV and IAV are sub- optimal and must be updated frequently due to the emergence of novel antigenic variants. To date, efforts to develop broadly protective, potentially ‘universal’ vaccines have almost exclusively focused on IAV. RFA-AI-20- 003 therefore calls for the “development and/or characterization of IBV vaccine components that complement existing lead IAV vaccine candidates”. In Aim 1 (R21 phase), we plan to develop broadly reactive influenza B candidate vaccine viruses. Using mutagenesis approaches, we have already generated mutant IBV hemagglutinins (HA, the major viral antigen) whose antigenic properties are in-between those of the two major lineages of IBV. Thus, these antigens may elicit immune responses that confer protection against viruses of both IBV lineages. Here, we plan to develop additional IBV HA mutants with potentially higher cross-reactivity than that of our current candidates. In addition, we will establish an antigenic map for IBV HA to analyze the antigenic properties of IBV HAs (antigenic maps are now widely used for IAV HAs, but have not been developed for IBV HA). In Aim 2 (R33 phase), we will assess the immunogenicity of influenza B candidate vaccine viruses. Briefly, the top 5 candidates from Aim 1 will be used to immunize ferrets. Immunization will be carried out with adjuvanted, secreted IBV HA (sHA) mutants (thus eliminating the contribution of other IBV proteins to immune responses), or with adjuvanted IBV HA presented on nanoparticles composed of a self-assembling phage protein (generated by Dr. R. Kane, Georgia Tech). The sera from vaccinated ferrets will be tested for reactivity with IBV HA antigens, and these data will be integrated into the antigenic map. Using an established phage display approach, Dr. S. Khurana (Federal Drug Administration) will identify the epitopes targeted by the antibodies elicited by our HA mutants. This analysis will allow us to identify antigens that elicit broadly reactive antibodies that target conserved epitopes. Immunology studies will be carried out by Dr. P. Thomas, St. Jude Children’s Research Hospital. On the basis of the data obtained in Aim 2, the top 2 IBV HA immunogens will be used to assess the protective efficacy of influenza B candidate vaccine viruses (Aim 3, R33 phase). Ferrets will be immunized as established in Aim 2 and challenged with IBVs representing both current lineages and an ancestral virus (isolated before the separation of the lineages). Virus titers and immune responses will be compared with those of control animals. We expect that a single immunization with the IBV HA mutants will elicit more broadly protective immunity than a single immunization with wild-type IBV HA. In summary, upon completion of both phases, we expect to have developed a novel strategy for the design of broadly protective IBV vaccines, and to have demonstrated their broadly protective efficacy in ferrets.

项目摘要 流感B病毒（IBV）引起年度发作，具有可观的发病率和死亡率，但已有 与影响力病毒（IAV）相比，研究了。目前可用于IBV和IAV的疫苗是 由于新型抗原变体的出现，因此必须经常更新，并且必须经常更新。迄今为止，努力 开发广泛保护的，潜在的“通用”疫苗几乎完全集中在IAV上。 rfa-ai-20- 003因此要求“开发和/或表征IBV疫苗成分的表征 补充现有的铅IAV疫苗候选者”。在AIM 1（R21阶段）中，我们计划开发广泛反应 流感B候选疫苗病毒。使用诱变方法，我们已经产生了突变体 IBV血凝素（HA，主要病毒抗原）的抗原特性与两者之间 IBV的主要血统。这是这些抗原可能会引起免疫反应，以防止病毒保护 两种IBV谱系。在这里，我们计划开发具有潜在较高交叉反应性的其他IBV HA突变体 比我们目前的候选人。此外，我们还将为IBV HA建立一个抗原图来分析 IBV的抗原特性具有（抗原图现已广泛用于IAV，但尚未开发 对于IBV HA）。在AIM 2（R33阶段）中，我们将评估造成影响的候选疫苗的免疫原性 病毒。简而言之，AIM 1的前5名候选人将用于免疫雪貂。免疫将被携带 用调整后的，分泌的IBV HA（SHA）突变体（从而消除了其他IBV蛋白对 免疫反应），或在由自组装组成的纳米颗粒上提出的调整后的IBV HA 噬菌体蛋白（由佐治亚理工学院R. Kane博士生成）。接种雪貂的血清将进行测试 与IBV HA抗原的反应性，这些数据将集成到抗原图中。使用已建立的 噬菌体显示方法，S。Khurana博士（联邦药物管理局）将确定 我们的HA突变体引起的抗体。该分析将使我们能够识别引起广泛反应性的抗原 靶向表位的抗体。免疫学研究将由圣裘德的P. Thomas博士进行 儿童研究医院。根据在AIM 2中获得的数据，前2个IBV HA免疫原子将是 用于评估造影症B候选疫苗病毒的受保护效率（AIM 3，R33期）。雪貂 将在AIM 2中建立的疫苗接种，并受到代表当前血统和一个的IBV挑战 祖先病毒（在谱系分离之前分离）。病毒滴度和免疫反应将是 与对照动物的动物相比。我们希望通过IBV HA突变体进行一次免疫 与具有野生型IBV HA的单个免疫抑制相比，更广泛地保护免疫培养。总而言之 这两个阶段的完成，我们希望已经制定了一种新颖的策略，以设计广泛保护 IBV疫苗，并在雪貂中证明了它们广泛保护的效率。