Synthetic multi-component influenza vaccines to elicit broad immunity

合成多成分流感疫苗可引发广泛免疫力

基本信息

批准号：
10458316
负责人：
Geert-Jan Boons
金额：
$ 56.26万
依托单位：
UNIVERSITY OF GEORGIA
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：
2021-08-13 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10458316
关键词：
Address Adjuvant Agonist Animal Model Antibodies Antigens Area B-Lymphocytes Biological Assay CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cancer Model Cells Cellular Immunity Cessation of life Chemicals Disease Elderly Engineering Epitopes Ferrets Glycoconjugates Glycopeptides Goals Gold Health Hemagglutinin Human Humoral Immunities Immune Immune response Immunity Immunocompromised Host Immunologic Adjuvants Immunologics Individual Infant Infection Influenza Influenza A virus Influenza vaccination Link Lipid A Measures Mediating Methods Modeling Mus National Institute of Allergy and Infectious Disease Obesity Peptides Polysaccharides Population Pre-Clinical Model Proteins Recombinants Research Risk Self Efficacy Serology test Strategic Planning Subunit Vaccines Surface Antigens Synthetic Vaccines T cell response T-Lymphocyte T-Lymphocyte Epitopes TLR2 gene Testing Update Vaccinated Vaccination Vaccine Adjuvant Vaccine Design Vaccines Virus Virus Diseases Zoonoses base burden of illness cost effective measures cross reactivity design expectation experience human model immunogenic immunogenicity influenza infection influenza virus vaccine influenzavirus innovation interest new technology next generation novel novel vaccines pandemic disease preclinical study prevent response seasonal influenza skills stem success tumor universal influenza vaccine universal vaccine vaccination strategy vaccine access vaccine candidate vaccine development vaccine trial

项目摘要

PROJECT SUMMARY Seasonal influenza viruses cause significant disease burden. While seasonal influenza vaccines are available, these are often poorly efficacious due to mismatch with circulating virus strains, particularly in the populations at greatest risk of complications from infection, including the elderly, infant, and immunocompromised. Influenza A viruses (IAV) also pose a pandemic risk for which seasonal influenza vaccines provide no cross protection. In 2018, the National Institute of Allergy and Infectious Diseases (NIAID) released a strategic plan for developing a universal influenza vaccine and subsequently released the FOA PA-18-859, “Advancing Research Needed to Develop a Universal Influenza Vaccine.” The long-term goal of this proposal is to develop a universal influenza vaccine. We hypothesize that a flu vaccine composed of broadly cross-reactive B-and T-epitopes covalently linked to an immune adjuvant will elicit potent immune responses and protect against diverse influenza A virus infections and associated disease. This expectation is supported by our prior studies which demonstrated a fully multi- component vaccine composed of tumor associated glycopeptide B- and CTL-epitope, a peptide CD4 T cell epitope and a TLR2 agonist (Pam3CysSK4) elicited robust immune responses and protected against a stringent tumor challenge in a murine cancer model. We will chemically synthesize multi-component vaccines that are composed of conserved peptide antigens derived from IAV and an adjuvant such as Pam3CysSK4 or monophosphoryl lipid A (Aim 1). In addition, we will employ an enzymatic glycan remodeling strategy to modify recombinant hemagglutinin (rHA), which is used as a licensed flu vaccine, with various TLR agonists and DC targeting moieties (Aim 2). To focus immunity to the more conserved stalk domain of HA, novel HAstalk proteins will be examine modified by immune-potentiating moieties. The immunogenicity and efficacy will be evaluated in murine (Aims 1 and 2) and ferret (Aim 3) vaccination and challenge models, using innovative approaches and antigen probes to assess polyfunctional T cell responses and geminal center (GC) B cell response. This research is significant as it directly addresses multiple NIAID priorities in their strategic plan for developing a universal influenza vaccine. The results of these studies could have a significant impact as the universal influenza vaccines developed should be suitable for advancement to pre-clinical studies. Moreover, the adjuvants and approaches developed in this proposal will be applicable to other vaccines and study of the host response to influenza infection, and will have broader impacts beyond universal influenza vaccine development.

项目概要尽管有季节性流感疫苗，但季节性流感病毒会造成严重的疾病负担。由于与流行病毒株不匹配，这些药物通常效果不佳，特别是在以下人群中：感染并发症的风险最大，包括老年人、婴儿和免疫功能低下的人。病毒（IAV）也会造成大流行风险，而季节性流感疫苗无法提供交叉保护。 2018年，美国国家过敏和传染病研究所（NIAID）发布了发展战略计划通用流感疫苗，随后发布了 FOA PA-18-859，“需要推进研究开发通用流感疫苗。该提案的长期目标是开发通用流感疫苗。” 疫苗。我们追求的是一种由广泛交叉反应的 B 和 T 表位组成的流感疫苗，这些表位与免疫佐剂将引发有效的免疫反应并预防多种甲型流感病毒感染和我们之前的研究证明了这种预期与多种相关疾病有关。成分疫苗由肿瘤相关糖肽 B 和 CTL 表位（一种肽 CD4 T 细胞）组成表位和 TLR2 激动剂 (Pam3CysSK4) 引发强大的免疫反应并免受严格的免疫反应。我们将在小鼠癌症模型中化学合成多组分疫苗。由源自 IAV 的保守肽抗原和佐剂（例如 Pam3CysSK4 或）组成单磷酰脂质 A（目标 1）。此外，我们将采用酶促聚糖重塑策略来修改。重组血凝素 (rHA)，用作许可的流感疫苗，与各种 TLR 激动剂和 DC 目标部分（目标 2）将免疫集中于 HA 更保守的茎结构域，即新型 HAstalk 蛋白。将检查免疫增强部分的修饰，并评估免疫原性和功效。鼠类（目标 1 和 2）和雪貂（目标 3）疫苗接种和挑战模型，使用创新方法和本研究使用抗原探针评估多功能 T 细胞反应和芽胞中心 (GC) B 细胞反应。意义重大，因为它直接解决了 NIAID 制定通用药物的战略计划中的多个优先事项这些研究结果可能对通用流感疫苗产生重大影响。此外，所开发的佐剂和方法应适合推进临床前研究。该提案中开发的内容将适用于其他疫苗和宿主对流感反应的研究感染，并将产生比通用流感疫苗开发更广泛的影响。