Synthetic multi-component influenza vaccines to elicit broad immunity

项目总结 季节性流感病毒会造成重大的疾病负担。虽然季节性流感疫苗已经上市， 由于与流行的病毒株不匹配，这些病毒往往效果不佳，特别是在 感染并发症的风险最大，包括老年人、婴儿和免疫功能受损的人。甲型流感 病毒(IAV)也构成大流行风险，季节性流感疫苗无法提供交叉保护。在……里面 2018年，国家过敏症和传染病研究所(NIAID)发布了发展战略规划 一种通用流感疫苗，随后发布了FOA PA-18-859，“推进研究需要 开发一种通用流感疫苗。这项提议的长期目标是发展一种普遍的流感 疫苗。 我们假设，一种由广泛交叉反应的B和T表位组成的流感疫苗与 免疫佐剂将激发强大的免疫反应，防止各种甲型流感病毒感染和 相关疾病。这一预期得到了我们之前的研究的支持，这些研究表明， 肿瘤相关糖肽B-和CTL-表位组成的CD4T细胞多肽疫苗 表位和TLR2激动剂(Pam3CysSK4)诱导强烈的免疫反应并对严格的 在小鼠癌症模型中的肿瘤挑战。我们将化学合成多组分疫苗，这些疫苗是 由来自IAV的保守多肽抗原和佐剂组成，如Pam3CysSK4或 单磷脂A(目标1)。此外，我们将采用酶促多糖重塑策略来修改 重组血凝素(RHA)，用于获得许可的流感疫苗，含有各种TLR激动剂和DC 目标部分(目标2)。为了将免疫集中到更保守的HA茎结构域，新的HAstrik蛋白 将通过免疫增强部分进行检查和修改。该疫苗的免疫原性和有效性将在 小鼠(目标1和目标2)和雪貂(目标3)疫苗接种和挑战模式，使用创新方法和 用于评估多功能T细胞反应和双生中心(GC)B细胞反应的抗原探针。这项研究 具有重要意义，因为它直接解决了NIAID在其制定普遍 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 已开发的药物应适合于发展到临床前研究。此外，佐剂和方法 本建议中开发的疫苗将适用于其他疫苗和宿主对流感反应的研究 感染，并将产生更广泛的影响，超越通用流感疫苗的开发。

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.