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一个基本问题，即SARS-CoV-2刺突蛋白（许多领先的covid - 19疫苗方法的基础）是否具有足够的抗原性，从而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刺突蛋白构建物，以及用新型三聚体计算设计的环状串联重复蛋白（cTRP）稳定的SARS-CoV-2刺突蛋白，对对照小鼠和接受相关化疗方案的小鼠进行免疫。我们认为，环形支架将更好地稳定三聚体Spike蛋白在理想的预融合确认中，这是引发中和抗体反应所必需的，并通过cTRP支架的硅序列和重复特性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在建立的感染性试验中中和SARS-CoV-2伪病毒的能力来评估这两种结构的抗原性。该结果将告知疫苗在接受化疗的患者中有效性的可能性，并可能提供一种专门设计的替代候选疫苗，以安全地在免疫功能低下的患者中引发抗体介导的保护。

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.