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

在经过化疗和放疗的小儿脑肿瘤小鼠模型中测试癌症患者特异性 SARS-CoV-2 疫苗

• 批准号: 10202077
• 负责人: JAMES M OLSON
• 金额: $ 17.6万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-06 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202077
• 关键词: 2019-nCoV; Address; Antibody Response; Antibody-mediated protection; Biological Assay; COVID-19 vaccine; Cancer Patient; Chemotherapy and/or radiation; Chemotherapy-Oncologic Procedure; Child; Childhood Brain Neoplasm; Immune system; Immunize; Immunocompromised Host; Mus; Nature; Patients; Proteins; Serum; Tandem Repeat Sequences; Testing; Vaccines; Virus; Work; chemotherapy; cohort; design; immunogenicity; improved; in silico; mouse model; neutralizing antibody; novel; pediatric patients; scaffold; vaccine candidate; vaccine effectiveness

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.

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，可以在接受化疗的儿科患者中引发中和抗体反应。我们将用在许多领先的疫苗方法中发现的SARS-CoV-2刺突蛋白构建体以及用新型三聚体计算设计的环状串联重复蛋白（“cTRP”或“toroid”）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。我们认为，环形支架将更好地稳定三聚体刺突蛋白，以引发中和抗体应答所需的理想融合前确认，以及通过计算机模拟序列和cTRP支架的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组群中分离的血清在已建立的感染性测定中中和SARS-CoV-2假病毒的能力来评估两种构建体的抗原性。这些结果将告知接受化疗的患者疫苗有效性的可能性，并可能提供一种专门设计用于在免疫功能低下的患者中安全地引发抗体介导的保护的替代疫苗候选物。