ADE-minimized COVID-19 vaccine via epitope focusing and anti-inflammatory innate immunity

通过表位聚焦和抗炎先天免疫实现 ADE 最小化的 COVID-19 疫苗

基本信息

批准号：
10161068
负责人：
TIMOTHY J CARDOZO
金额：
$ 46.61万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161068
关键词：
2019-nCoV 3-Dimensional ALVAC Acute Lung Injury Address Adjuvant Animal Model Animals Anti-Inflammatory Agents Antibodies Antibody Response Antibody-Dependent Enhancement Antigen-Antibody Complex Antigens Antiviral Agents Antiviral Response B-Lymphocyte Epitopes Biological Blood COVID-19 COVID-19 vaccine Cardiac Cells Cholera Toxin Clinic Clinical Communities Coronavirus DNA Data Development Disease Disease Outbreaks Emergency Situation Epidemic Epitopes Escherichia coli Vaccines Event Exhibits Failure Ferrets Funding HIV Heart Human Immune response Immune system Immunity Immunize Immunoglobulin G In Vitro Individual Infection Inflammation Inflammatory Liver Lung Lung diseases Macaca Macaca mulatta Maps Mediating Medical Methods Middle East Respiratory Syndrome Middle East Respiratory Syndrome Coronavirus Modality Modeling Morbidity - disease rate Mucous Membrane Mus Natural Immunity Oryctolagus cuniculus Outcome Pathogenicity Pathway interactions Patients Phenotype Pre-Clinical Model Primates Proteins RNA RNA Splicing Respiratory Syncytial Virus Vaccines Respiratory syncytial virus SARS coronavirus Serum Severe Acute Respiratory Syndrome Subunit Vaccines Suggestion Symptoms Synthetic Vaccines Technology Testing Time Tissues Training Vaccinated Vaccine Design Vaccines Viral Viral Load result Viral Vector Virus Virus Diseases Work aluminum sulfate base coronavirus disease cost cytokine design experience global health emergency in vivo mortality neutralizing antibody nonhuman primate pandemic disease pre-clinical preclinical study public health emergency receptor binding response safety study scaffold vaccine candidate vaccine development vaccine evaluation vaccine response vector

项目摘要

Project Summary Although over 100 COVID-19 vaccines are currently in development worldwide in response to the global public health emergency, most or all may suffer from the liability of eliciting anti-viral-spike antibodies (Abs) that enhance (ADE) either viral infection or COVID-19 disease, upon exposure of vaccinees to circulating SARS- CoV-2 viruses. This phenomenon was observed previously in humans for respiratory syncytial viruses and in preclinical studies for the closely related SARS and MERS viruses. Notably, none of these viruses currently have a licensed effective and safe vaccine available despite 15 (SARS) to 60 (RSV) years of effort by the scientific community. These facts raise the alarming possibility that all current COVID-19 vaccines that are not rationally designed to avoid ADE may fail, perpetuating the current global health emergency and eroding confidence in vaccines and in the medical scientific community. Many COVID-19 patients experience near-fatal or fatal immunopathologic “storms” in lung, heart and blood starting at 7-14 days after onset of symptoms, which is approximately when the antibody response to the virus is rising or peaking. This suggests that immunopathologic ADE of disease enhancement in humans in the current emergency cannot be ignored in vaccine design. A few of the current vaccine candidates take a small step towards avoidance of ADE by restricting vaccine immunogens to the SARS-CoV-2 receptor binding domain (RBD), which is theorized to avoid ADE by minimizing immune complex formation without sacrificing virus neutralization epitopes. Others seek to steer the immune system away from harmful, pro-inflammatory vaccine responses using viral vectors and adjuvants. We propose to develop a unique vaccine in the pandemic that goes all the way down this road to incorporate only a single, neutralization, B-cell epitope, thereby maximally avoiding both ADE of viral infection and ADE of disease, as well as testing the ALVAC-alum platform we have previously validated for HIV to steer immunity towards a less inflammatory, protective state. Leveraging Rhesus macaques that are already purchased (no cost to this project for purchase), we will produce and test the protection afforded by the single, neutralization, B-cell epitope (Aim 1) as well as the immune response to the ALVAC-alum platform (Aim 2). The results may set the stage for a rapidly manufactured vaccine to emergently fill the ADE gap in the current COVID-19 vaccine landscape.

项目概要尽管目前全球有超过 100 种 COVID-19 疫苗正在开发中，以应对全球公众的需求卫生紧急情况下，大多数或所有人可能会引发抗病毒尖峰抗体（Abs），当疫苗接触到正在流行的 SARS 时，会增强 (ADE) 病毒感染或 COVID-19 疾病以前在人类呼吸道合胞病毒和 CoV-2 病毒中观察到这种现象。值得注意的是，目前还没有针对密切相关的 SARS 和 MERS 病毒的临床前研究。尽管经过 15（SARS）至 60（RSV）年的努力，仍拥有获得许可的有效且安全的疫苗这些事实提出了一个令人震惊的可能性，即当前所有的 COVID-19 疫苗都不是疫苗。旨在避免 ADE 的合理设计可能会失败，从而使当前的全球卫生紧急情况长期存在并削弱对疫苗和医学科学界的信心。许多 COVID-19 患者在肺、心脏和血液中经历了近乎致命或致命的免疫病理“风暴” 从症状出现后 7-14 天开始，大约是抗体对病毒产生反应的时间这表明人类疾病的免疫病理学 ADE 正在增强。当前的紧急情况在疫苗设计中不容忽视。通过限制疫苗免疫原与 SARS-CoV-2 受体结合来逐步避免 ADE 域（RBD），理论上可以通过在不牺牲免疫复合物形成的情况下最小化免疫复合物的形成来避免 ADE 其他病毒中和表位则试图引导免疫系统远离有害的、促炎的。使用病毒载体和佐剂的疫苗反应我们建议在大流行中开发一种独特的疫苗。沿着这条路一直走下去，只整合一个单一的中和B细胞表位，从而最大限度地避免病毒感染的 ADE 和疾病的 ADE，以及测试 ALVAC-alum 我们之前已经针对 HIV 验证了该平台，可以将免疫力引导至炎症较少的保护状态。利用已经购买的恒河猴（本项目无需支付购买费用），我们将产生并测试单一中和 B 细胞表位（目标 1）以及对 ALVAC-alum 平台的免疫反应（目标 2）可能会为快速反应奠定基础。生产疫苗以紧急填补当前 COVID-19 疫苗领域的 ADE 缺口。