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

基本信息

批准号：
10361957
负责人：
Michael Schotsaert
金额：
$ 74.46万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/10361957
关键词：
2019-nCoV Address Adenovirus Vector Adjuvant Agonist Animals Antibodies Antibody Avidity Antibody Response Antibody-Dependent Enhancement Antigens Antiviral Response Automobile Driving COVID-19 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 Interferons 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 Severe Acute Respiratory Syndrome Shapes Sterility System T cell response T memory cell Technology Testing Tissues Transgenic Mice Vaccination Vaccines Variant Viral Virulence Virus Virus Diseases Work adaptive immune response adaptive immunity aged antiviral immunity base coronavirus vaccine immunopathology improved influenzavirus insight lead optimization medical schools mortality mouse model nanoemulsion neutralizing antibody novel pathogen protective efficacy rational design receptor response safety study senescence tool vaccine candidate vaccine development vaccine efficacy vaccine platform virus envelope

项目摘要

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.

项目概要/摘要与 Covid-19 相关的高发病率和死亡率继续强调了有效控制的重要性针对 SARS-CoV-2 的疫苗。虽然一些有前途的候选者已获得 EUA，但更多的候选者的出现影响疫苗功效的传染性变异突显了仍然存在一些挑战的事实。一个成功的疫苗必须： 1. 在自然感染冠状病毒时产生强大的持久保护通常会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. 为老年人提供强大的免疫力，并且 4. 鉴于过去冠状病毒观察到的疾病增强，因此是安全的疫苗。为了应对这些挑战，该提案旨在开发一种安全、有效且可快速翻译的方法 SARS-CoV-2 疫苗佐剂系统，使用合理设计的组合佐剂来靶向阵列参与抗病毒免疫的关键先天受体途径。佐剂是快速促进的有力工具，对特定病原体最有效的持久和定性反应，特别是在免疫缺陷的情况下个人。自然病毒感染通过激活 Toll-、RIG-I- 和 NOD 样受体（TLR、RLR、NLR）。由于适当的先天反应的诱导对于持久至关重要适应性免疫并为了塑造正确的免疫反应类型，我们将测试以下假设：整合这些途径的激动剂组合将改善体液和细胞反应针对 SARS-CoV-2。为了实现这一目标，我们将结合一种基于纳米乳剂的佐剂（NE）来激活 TLR 和 NLRP3 与 RIG-I (IVT DI) 的 RNA 激动剂。我们已经证明，同时激活 TLR、RIG-I 和 NLRP3 与 NE/IVT DI 诱导协同免疫反应，并放大 TH1 偏向性细胞免疫。以强有力的初步数据为指导，证明了这种组合佐剂的有效性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 疫苗有两个具体目标。在目标 1 中，我们将分析免疫 NE/IVT DI 通过肠胃外和粘膜途径用多种 SARS-CoV-2 抗原引起的反应优化配方和疫苗接种途径。在目标 2 中，我们将确定以下药物的保护功效和安全性： SARS-CoV-2 挑战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 引起的先天反应较弱，关键抗病毒药物的激活较差途径，这可能导致免疫反应的强度和持久性存在巨大差异康复的患者。通过这种有针对性的方法，我们希望能够带来更强大和持久的免疫力，同时避免促进疫苗相关病理的免疫反应。 NE佐剂和几种RIG-I激动剂在第一阶段人体试验中表现出良好的安全性。因此，我们期望顺利完成这项工作将产生一种与多种 SARS-CoV-2 兼容的快速可翻译和可递送的佐剂候选疫苗，并提供对保护性 SARS-CoV-2 免疫的关键效应物急需的见解。