Testing a cancer patient-specific SARS-CoV-2 vaccine in chemotherapy- and radiation-treated pediatric brain tumor mouse models

我们提出的工作将解决以下根本问题：SARS-CoV-2刺突蛋白是许多领先的COVID19疫苗方法的基础，它是否具有足够的抗原性，能够在接受化疗的儿科患者中引发中和抗体反应。我们将用在许多主要疫苗方法中发现的SARS-CoV-2刺突蛋白构建，以及由一种新的三聚体计算设计的环形串联重复蛋白(‘cTRP’或‘torid’)稳定的SARS-CoV-2刺突蛋白免疫对照小鼠和接受相关化疗方案的小鼠。我们相信，环状支架将在理想的灌流确认中更好地稳定三聚体Spike蛋白，这是诱导中和抗体反应所必需的，并通过cTRP支架的硅内序列和重复性质提供必要的免疫原性增强。我们将通过检测从免疫队列中分离的血清中和SARS-CoV-2假病毒的能力来评估这两个构建体的抗原性。这一结果将为正在接受化疗的患者提供疫苗有效性的可能性，并可能提供一种专门设计的替代疫苗候选，以安全地在免疫受损患者中诱导抗体介导的保护。

We are proposing work that will address the fundamental question of whether or not the SARS-CoV-2 Spike protein, the basis of many leading COVID19 vaccine approaches, is sufficiently antigenic to elicit neutralizing antibody responses in pediatric patients undergoing chemotherapy. We will immunize control mice and mice undergoing relevant regimens of chemotherapy with a SARS-CoV-2 Spike protein construct found in many leading vaccine approaches, as well as a SARS-CoV-2 Spike protein stabilized with a novel trimeric computationally designed circular tandem repeat protein (a ‘cTRP’ or ‘toroid’). We believe that the toroid scaffold will better stabilize the trimeric Spike protein in the ideal prefusion confirmation necessary for eliciting neutralizing antibody responses, as well as provide a necessary boost of immunogenicity through the in-silico sequence and repetitive nature of the cTRP scaffold. We will assess the antigenicity of the two constructs by examining the ability of serum isolated from the immunized cohort to neutralize a SARS-CoV-2 pseudo virus in a well-established infectivity assay. The results will inform the likelihood of vaccine effectiveness in patients undergoing chemotherapy and potentially provide an alternative vaccine candidate specifically designed to safely elicit antibody mediated protection in the immunocompromised.