Synthetic multi-component influenza vaccines to elicit broad immunity

项目摘要 季节性流感病毒造成重大疾病负担。虽然季节性流感疫苗是可用的， 由于与循环病毒株不匹配，这些病毒通常效果不佳，特别是在 感染并发症的风险最大，包括老年人、婴儿和免疫功能低下者。甲型流感 IAV病毒也会造成大流行的风险，而季节性流感疫苗不能提供交叉保护。在 2018年，国家过敏和传染病研究所（NIAID）发布了一项战略计划， 通用流感疫苗，并随后发布了FOA PA-18-859，“推进研究需要， 研制通用流感疫苗。”这项提案的长期目标是研制一种通用流感 疫苗 我们假设流感疫苗由广泛交叉反应的B和T表位共价连接到一个 免疫佐剂将引发有效免疫应答并保护免受多种甲型流感病毒感染， 相关疾病。这一预期得到了我们先前研究的支持，这些研究表明， 由肿瘤相关糖肽B-和CTL-表位组成的组分疫苗， 表位和TLR 2激动剂（Pam 3CysSK 4）引起了强烈的免疫应答，并保护免受严格的免疫应答。 在鼠癌症模型中的肿瘤攻击。我们将化学合成多组分疫苗， 由来自IAV的保守肽抗原和佐剂如Pam 3CysSK 4或 单磷酰脂质A（Aim 1）。此外，我们将采用酶促聚糖重塑策略来修饰 重组血凝素（rHA），其用作许可的流感疫苗，与各种TLR激动剂和DC 靶向部分（目的2）。为了将免疫力集中于HA的更保守的茎结构域， 将被免疫增强部分修饰。免疫原性和有效性将在 小鼠（目标1和2）和雪貂（目标3）疫苗接种和攻击模型，使用创新的方法， 抗原探针以评估多功能T细胞应答和生殖中心（GC）B细胞应答。本研究 这是重要的，因为它直接解决了多个NIAID优先事项，在他们的战略计划，以发展一个普遍的 流感疫苗。这些研究的结果可能会产生重大影响，因为通用流感疫苗 开发的药物应适合推进临床前研究。此外，佐剂和方法 本提案中开发的疫苗将适用于其他疫苗和研究宿主对流感的反应 感染，并将有更广泛的影响超越通用流感疫苗的发展。

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.