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

• 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
• 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

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 季节性流感病毒造成严重的疾病负担。虽然有季节性流感疫苗， 由于与流行的病毒株不匹配，这些药物往往效果不佳，特别是在人群中 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。甲型流感 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。在 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一种通用的流感病毒 疫苗。 我们假设流感疫苗由广泛交叉反应的 B 和 T 表位组成，共价连接到 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 相关疾病。这一期望得到了我们之前的研究的支持，该研究证明了完全多 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。 小鼠癌症模型中的肿瘤挑战。我们将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 靶向部分（目标 2）。为了将免疫集中于 HA 更保守的茎结构域，新型 HAstalk 蛋白 将通过免疫增强部分进行修饰检查。免疫原性和功效将在 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 抗原探针可评估多功能 T 细胞反应和芽胞中心 (GC) B 细胞反应。这项研究 意义重大，因为它直接解决了 NIAID 制定通用疫苗战略计划中的多个优先事项 流感疫苗。这些研究结果可能会对通用流感疫苗产生重大影响 开发的应适合推进临床前研究。此外，佐剂和方法 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。