Combined adjuvant approaches for enhancement of SARS-CoV-2 vaccine efficacy

增强 SARS-CoV-2 疫苗功效的联合佐剂方法

• 批准号: 10631993
• 负责人: Michael Schotsaert
• 金额: $ 72.53万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631993
• 关键词: 2019-nCoV; Acceleration; Address; Adenovirus Vector; Adjuvant; Agonist; Animals; Antibodies; Antibody Avidity; Antibody Response; Antibody-Dependent Enhancement; Antigens; Antiviral Response; Automobile Driving; COVID-19; COVID-19 patient; COVID-19 vaccine; Cellular Immunity; Chemicals; Clinical; Coronavirus; Data; Disease; Dose; Effectiveness; Elderly; Ensure; Environment; Epitopes; Exhibits; Formulation; Future; Generations; Hamsters; Health; Human; Immune; Immune response; Immunity; Individual; Infection; Influenza; Influenza vaccination; Innate Immune Response; Interferon Type I; Intramuscular; Ligands; Light; Longevity; Lung; Mesocricetus auratus; Modeling; Morbidity - disease rate; Mucosal Immunity; Mucous Membrane; Mus; Mutation; Pathology; Pathway interactions; Patients; Phase; Population; Positioning Attribute; Prevalence; Prevention; RNA; Respiratory syncytial virus; Role; Route; SARS coronavirus; SARS-CoV-2 antigen; SARS-CoV-2 immunity; SARS-CoV-2 infection; Safety; Selection Criteria; Sendai virus; Shapes; Sterility; System; T cell response; Technology; Testing; Transgenic Mice; Vaccination; Vaccines; Variant; Viral; Virulence; Virus; Virus Diseases; Work; adaptive immune response; adaptive immunity; aged; antiviral immunity; coronavirus vaccine; immunopathology; improved; influenzavirus; insight; lead optimization; medical schools; mortality; mouse model; nanoemulsion; neutralizing antibody; novel; pathogen; permissiveness; protective efficacy; rational design; receptor; response; safety study; senescence; tissue resident memory T cell; tool; vaccine candidate; vaccine development; vaccine efficacy; vaccine platform

PROJECT SUMMARY/ABSTRACT The high morbidity and mortality associated with Covid-19 continues to underscore the importance of effective vaccines against SARS-CoV-2. While a few promising candidates have received EUAs, the emergence of more transmissible variants which have impacted vaccine efficacy highlight the fact that several challenges remain. A successful vaccine must: 1. induce robust long-lasting protection when natural infection with coronaviruses generally leads to relatively short-lived immunity, 2. impart broad immunity as viral mutations accumulate, 3. provide potent immunity in the elderly, and 4. be safe in light of enhanced disease observed with past coronavirus vaccines. To address these challenges, this proposal aims to develop a safe, effective, and rapidly translatable adjuvant system for SARS-CoV-2 vaccines using a rationally designed combination adjuvant to target an array of key innate receptor pathways involved in antiviral immunity. Adjuvants are powerful tools for promoting fast, durable and qualitative responses most effective for a particular pathogen, especially in immune-challenged individuals. Natural viral infection stimulates strong immune responses through activation of Toll-, RIG-I-, and NOD-like receptors (TLRs, RLRs, NLRs). As induction of appropriate innate responses is crucial for long-lasting adaptive immunity and for shaping the correct types of immune responses, we will test the hypothesis that using a combination of agonists that integrate these pathways will lead to improved humoral and cellular responses towards SARS-CoV-2. To achieve this, we will combine a nanoemulsion-based adjuvant (NE) that activates TLRs and NLRP3 with an RNA agonist of RIG-I (IVT DI). We have demonstrated that simultaneous activation of TLRs, RIG-I, and NLRP3 with NE/IVT DI induces a synergistic immune response with magnified TH1-biased cellular immunity. Guided by strong preliminary data demonstrating the effectiveness of this combined adjuvant approach for improving influenza virus vaccination, and our initial studies with SARS-CoV-2 antigens, we will develop this adjuvant for use in a SARS-CoV-2 vaccine in two specific aims. In Aim 1, we will profile the immune responses elicited by NE/IVT DI with multiple SARS-CoV-2 antigens through parenteral and mucosal routes to optimize formulations and vaccination routes. In Aim 2, we will determine the protective efficacy and safety of the optimized lead vaccine platforms in challenge models of SARS-CoV-2 and define key correlates of protection. Increasing data suggests that SARS-CoV-2 elicits a weak innate response, with poor activation of critical antiviral pathways, which likely contributes to the large variability in magnitude and durability of immune responses in recovered patients. With this targeted approach, we expect to drive more robust and durable immunity while avoiding immune responses promoting vaccine related pathology. The NE adjuvant and several RIG-I agonists have demonstrated good safety profiles in phase I human trials. Thus, we expect that successful completion of this work will lead to a rapidly translatable and deliverable adjuvant compatible with multiple SARS-CoV-2 vaccine candidates, and provide much needed insight on the key effectors of protective SARS-CoV-2 immunity.

项目总结/摘要 与Covid-19相关的高发病率和死亡率继续强调了有效预防的重要性。 SARS-CoV-2疫苗。虽然有几个有希望的候选人获得了欧盟授权， 影响疫苗效力的传染性变异突出表明，仍然存在若干挑战。一 成功的疫苗必须：1.在自然感染冠状病毒时诱导强大持久保护 一般导致相对短暂的免疫力，2.随着病毒突变的积累，赋予广泛的免疫力，3. 为老年人提供强有力的免疫力，以及4.鉴于过去的冠状病毒所观察到的疾病增强， 疫苗。为了应对这些挑战，本提案旨在开发一种安全、有效、可快速翻译的 使用合理设计的组合佐剂靶向阵列的SARS-CoV-2疫苗的佐剂系统 参与抗病毒免疫的关键先天受体途径。佐剂是促进快速， 对特定病原体最有效的持久和定性反应，特别是在免疫挑战的 个体天然病毒感染通过激活Toll-、RIG-I-和 NOD样受体（TLR、RLR、NLR）。由于诱导适当的先天反应对于持久的 适应性免疫和塑造正确类型的免疫反应，我们将测试假设，使用 整合这些途径的激动剂的组合将导致改善的体液和细胞应答 SARS-CoV-2。为了实现这一目标，我们将联合收割机结合一种基于纳米乳液的佐剂（NE）， TLR和NLRP 3与RIG-I的RNA激动剂（IVT DI）。我们已经证明，同时激活 TLR、RIG-I和NLRP 3与NE/IVT DI诱导具有放大的TH 1偏向性的协同免疫应答。 细胞免疫以证明这种联合佐剂有效性的有力初步数据为指导 改进流感病毒疫苗接种的方法，以及我们对SARS-CoV-2抗原的初步研究，我们将 开发这种佐剂用于SARS-CoV-2疫苗有两个具体目的。在目标1中，我们将分析免疫 通过胃肠外和粘膜途径用多种SARS-CoV-2抗原进行NE/IVT DI引起的应答， 优化配方和疫苗接种途径。在目标2中，我们将确定 在SARS-CoV-2的攻击模型中优化的先导疫苗平台，并定义了保护的关键相关性。 越来越多的数据表明，SARS-CoV-2激发了弱的先天性反应，关键的抗病毒活性很差， 途径，这可能有助于免疫应答的幅度和持久性的巨大变化， 康复患者通过这种有针对性的方法，我们希望能够驱动更强大和持久的免疫力， 避免促进疫苗相关病理学的免疫应答。NE佐剂和几种RIG-I激动剂 在I期人体试验中表现出良好的安全性。因此，我们期望， 这项工作将导致一种与多种SARS-CoV-2兼容的可快速翻译和可交付的佐剂 候选疫苗，并提供急需的洞察力的关键效应的保护性SARS-CoV-2免疫。