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

项目摘要 尽管目前全球有100多种新冠肺炎疫苗正在开发中，以回应全球公众 健康紧急情况下，大多数或全部可能会诱发抗病毒尖峰抗体(Abs)，从而 增强(ADE)病毒感染或新冠肺炎病，当接种者暴露于正在传播的SARS时- CoV-2病毒。这一现象以前曾在人类呼吸道合胞病毒和 密切相关的SARS和MERS病毒的临床前研究。值得注意的是，目前没有一种病毒 尽管经过15年(SARS)至60年(RSV)的努力，仍有经过许可的有效和安全的疫苗可用 科学界。这些事实引发了一种令人担忧的可能性，即所有当前未接种的新冠肺炎疫苗 合理设计以避免ADE可能会失败，使当前的全球卫生紧急情况永久化并受到侵蚀 对疫苗和医学科学界的信心。 许多新冠肺炎患者在肺、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，这大约是抗体对病毒产生反应的时候 是在上升还是在见顶。这表明免疫病理ADE在人类疾病中的增强 当前的紧急情况在疫苗设计中不容忽视。目前的几个候选疫苗接种了一小部分 通过限制疫苗免疫原与SARS-CoV-2受体结合来避免ADE 区域(RBD)，理论上是通过在不牺牲的情况下最大限度地减少免疫复合体的形成来避免ADE 病毒中和表位。其他人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。我们建议开发一种针对大流行的独特疫苗。 这条路一直走到只有一个中和的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，以及检测ALVAC-明矾 我们之前已经验证过的HIV平台可以将免疫引导到炎症较少的保护状态。 利用已经购买的恒河猴(这个项目没有购买成本)，我们将 生产和测试单个中和B细胞表位(目标1)以及 对ALVAC-明矾平台的免疫应答(目标2)。这一结果可能会为迅速 制造的疫苗紧急填补了当前新冠肺炎疫苗领域的ADE空白。

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.