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.

项目总结