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

• 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
• 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

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.

项目摘要 尽管目前在全球范围内开发了100多种Covid-19疫苗，以回应全球公众 健康紧急情况，大多数或全部可能遭受引起抗病毒尖峰抗体（ABS）的责任 增强（ADE）病毒感染或Covid-19疾病，在接种疫苗接触到循环SARS- COV-2病毒。以前在人类中观察到这种现象的呼吸综合病毒和 密切相关的SARS和MERS病毒的临床前研究。值得注意的是，这些病毒目前都没有 拥有有效且安全的疫苗可用目的地15（SARS）至60（RSV）的努力 科学界。这些事实引起了令人震惊的可能性，即所有目前的共同疫苗不是 理性旨在避免ADE的理性可能会失败，使当前的全球健康紧急情况永存 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致命或致命的免疫病理“风暴” 从症状发作后7-14天开始，大约是抗体对病毒的反应 正在上升或峰值。这表明，人类疾病增强的免疫病理学ADE 在疫苗设计中，当前的紧急情况不能忽略。当前候选疫苗的一些 通过将疫苗免疫量限制为SARS-COV-2受体结合，迈向避免ADE 域（RBD），理论上是为了避免通过不牺牲的免疫复合物形成而避免ADE的 病毒神经化表位。其他人则试图使免疫系统远离有害的，促炎症 使用病毒载体和调节器进行疫苗反应。我们建议在大流行中开发独特的疫苗 一直沿着这条道路，只包含一个中和，B细胞表位，从而 最大程度地避免了病毒感染和疾病的ADE，并测试了ALVAC-ALUM 我们以前已经证实了HIV的验证，可以将免疫学转向炎症，受保护的状态较少。 利用已经购买的恒河猕猴（该项目不需要购买），我们将 产生和测试单个中和，B细胞表位（AIM 1）提供的保护 对ALVAC-ALUM平台的免疫反应（AIM 2）。结果可能会迅速为阶段奠定 在当前的Covid-19疫苗景观中，制造的疫苗到紧急情况填补了ADE间隙。