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; 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.

项目摘要/摘要 与Covid-19相关的高发病率和死亡率继续强调有效的重要性 针对SARS-COV-2的疫苗。虽然一些有前途的候选人收到了EUAS，但出现了更多 影响疫苗功效的可传播变体强调了仍然存在一些挑战的事实。一个 成功的疫苗必须：1。自然感染冠状病毒时会诱导强大的长期保护 通常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。 在老年人中提供有效的免疫力，4。鉴于过去冠状病毒观察到的疾病增强 疫苗。为了应对这些挑战，该提案旨在开发安全，有效且可以快速翻译 使用合理设计的组合佐剂来靶向阵列的SARS-COV-2疫苗辅助系统 涉及抗病毒免疫的关键先天受体途径。佐剂是快速促进的强大工具， 对特定病原体最有效的耐用和定性反应，尤其是在免疫挑战中 个人。天然病毒感染通过激活Toll-，rig-i和 点状受体（TLR，RLR，NLR）。由于适当的先天反应对于持久而言至关重要 自适应免疫和为了塑造正确类型的免疫反应类型，我们将检验以下假设 整合这些途径的激动剂的组合将导致体液和细胞反应的改善 迈向SARS-COV-2。为此，我们将结合激活的基于纳米乳液的佐剂（NE） TLRS和NLRP3具有RIG-I（IVT DI）的RNA激动剂。我们已经证明了同时激活 带有NE/IVT DI的TLR，RIG-I和NLRP3诱导协同的免疫反应，而放大的Th1偏置 细胞免疫。在强大的初步数据的指导下，证明了这种联合佐剂的有效性 改善流感病毒疫苗接种的方法，以及我们对SARS-COV-2抗原的最初研究，我们将 开发此佐剂以在两个特定目的中用于SARS-COV-2疫苗中。在AIM 1中，我们将介绍免疫 NE/IVT DI通过肠胃外和粘膜路线引起多个SARS-COV-2抗原引起的反应 优化配方和疫苗接种路线。在AIM 2中，我们将确定保护性和安全性 SARS-COV-2挑战模型中优化的铅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引起了较弱的先天反应，而关键抗病毒药的激活不佳 途径，这可能导致免疫反应的幅度和耐用性的巨大变化 康复的患者。采用这种有针对性的方法，我们希望能够以更强大和耐用的免疫力来 避免促进疫苗相关病理的免疫反应。 NE佐剂和几个Rig-i激动剂 在I期人类试验中表现出良好的安全概况。因此，我们希望成功完成 这项工作将导致与多个SARS-COV-2兼容的快速翻译和可交付的佐剂 候选疫苗，并提供急需的洞察力，了解保护性SARS-COV-2免疫的关键效应因素。