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

基本信息

批准号：
10206685
负责人：
YOSHIHIRO KAWAOKA
金额：
$ 22.78万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-25 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206685
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 Lung diseases Maps Morbidity - disease rate Mutagenesis Mutation Organ Peptides Phage Display Pharmaceutical Preparations Phase Population Property Proteins Recombinants Research Saint Jude Children&apos 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

项目摘要

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.

项目概要乙型流感病毒 (IBV) 每年都会引起流行病，发病率和死亡率相当高，但与甲型流感病毒 (IAV) 相比，目前可用的 IBV 和 IAV 疫苗尚未得到充分研究。由于新抗原变体的出现，必须经常更新。开发具有广泛保护性的、潜在的“通用”疫苗几乎完全集中在 RFA-AI-20-上。因此，003 呼吁“开发和/或鉴定 IBV 疫苗成分，在目标 1（R21 阶段）中，我们计划开发具有广泛反应性的候选 IAV 补体疫苗。使用诱变方法，我们已经产生了突变型乙型流感疫苗病毒。 IBV 血凝素（HA，主要病毒抗原），其抗原特性介于两者之间因此，这些抗原可能会引发免疫反应，从而提供针对病毒的保护。在这里，我们计划开发具有潜在更高交叉反应性的其他 IBV HA 突变体。此外，我们将建立 IBV HA 的抗原图谱来分析。 IBV HA 的抗原特性（抗原图谱现已广泛用于 IAV HA，但尚未开发在目标 2（R33 阶段）中，我们将评估乙型流感候选疫苗的免疫原性。简而言之，目标 1 中的前 5 名候选病毒将用于对雪貂进行免疫。与佐剂、分泌型 IBV HA (sHA) 突变体一起使用（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粒子上呈现佐剂 IBV HA 噬菌体蛋白（由佐治亚理工学院的 R. Kane 博士生成）将对肺炎雪貂的血清进行检测。与 IBV HA 抗原的反应性，并且这些数据将使用已建立的抗原图谱进行整合。通过噬菌体展示方法，S. Khurana 博士（联邦药物管理局）将鉴定噬菌体靶向的表位由我们的 HA 突变体引发的抗体该分析将使我们能够识别引发广泛反应的抗原。针对保守表位的抗体的免疫学研究将由 St. Jude 的 P. Thomas 博士进行。根据目标 2 中获得的数据，排名前 2 的 IBV HA 免疫原将是儿童研究医院。用于评估乙型流感候选疫苗病毒的保护功效（Aim 3，R33阶段）。将按照目标 2 中规定的方式进行免疫，并接受代表当前谱系和新谱系的 IBV 的挑战祖先病毒（在谱系分离之前分离）。病毒滴度和免疫反应将是。与对照动物相比，我们预计用 IBV HA 突变体进行单次免疫即可引发。与野生型 IBV HA 的单次免疫相比，具有更广泛的保护性免疫。完成这两个阶段后，我们期望能够制定出一种新颖的策略来设计广泛的保护性 IBV 疫苗，并已在雪貂中证明了其广泛的保护功效。