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

项目摘要 尽管目前全球正在开发100多种COVID-19疫苗，以应对全球公众 在健康紧急情况下，大多数或所有人都可能遭受引发抗病毒刺突抗体（Abs）的责任， 疫苗接种者接触流行的SARS后，会增强（ADE）病毒感染或COVID-19疾病- CoV-2病毒。这种现象以前在人类呼吸道合胞病毒和人类呼吸道合胞病毒中观察到。 SARS和MERS病毒密切相关的临床前研究。值得注意的是，目前这些病毒 尽管经过15年（SARS）到60年（RSV）的努力， 科学界。这些事实提出了一种令人担忧的可能性，即所有目前的COVID-19疫苗， 旨在避免ADE的合理设计可能会失败，使当前的全球卫生紧急状况持续下去， 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学“风暴” 开始于症状出现后7-14天，这大约是抗体对病毒产生反应的时候。 正在上升或达到峰值。这表明，免疫病理学ADE的疾病增强，在人类中， 在疫苗设计中不能忽视当前的紧急情况。目前的一些候选疫苗需要少量的 通过将疫苗免疫原限制于SARS-CoV-2受体结合来避免ADE的步骤 结构域（RBD），理论上可以通过最大限度地减少免疫复合物的形成而避免ADE， 病毒中和表位。另一些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应答。我们建议开发一种独特的疫苗， 沿着这条路一直走下去，只包含一个单一的，中和的，B细胞表位， 最大限度地避免病毒感染的ADE和疾病的ADE，以及测试ALVAC明矾 我们之前已经验证了HIV的平台，可以将免疫力引导到炎症较少的保护状态。 利用已经购买的恒河猴（本项目无需购买成本），我们将 产生并测试由单一、中和、B细胞表位（Aim 1）以及 对ALVAC-明矾平台的免疫应答（Aim 2）。这些结果可能会为一场迅速的 生产疫苗，以紧急填补当前COVID-19疫苗领域的ADE缺口。

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.