Evaluation of iDMV-1.0: A Single Dose Self-Amplifying Vaccine for SARS-CoV-2

iDMV-1.0 的评估：针对 SARS-CoV-2 的单剂量自放大疫苗

• 批准号: 10808286
• 负责人: Devdoot Majumdar
• 金额: $ 11.09万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-13 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10808286
• 关键词: Evaluation; iDMV; 1.0; Single; Dose

The mRNA vaccines against SARS-CoV-2 proved unexpectedly efficacious, but also require a series of booster immunizations to remain protective. Global deployment of these vaccines has been slow, particularly in low- and middle-income countries (LMIC), in part due to the logistical complications associated with multiple vaccinations. We therefore propose a new RNA vaccine design: a single-dose self-amplifying mRNA vaccine based on the SARS-CoV-2 coronavirus. Our long-term goal is to develop of a novel vaccine modality that consists of an RNA vaccine that feasibly delivers durable humoral and cellular immunity to SARS-CoV-2 in a single dose. Our novel design, named iDMV-1.0, utilizes RNA encoding the coronavirus replication machinery in order to produce Spike mRNA within double membrane vesicles (DMV). iDMV-1.0, a 20 kB RNA derived from the SARS-CoV-2 genome, consists of NSP1-16 of SARS CoV-2, mutations to stabilize the prefusion conformation of Spike protein (19), ORF6-10, M protein, and N protein, GFP and Luciferase for detection, and all non-coding 5’ and 3’ sequences of the SARS-CoV-2 genome. Because iDMV-1.0 permits self-amplification of Spike mRNA, this lipid nanoparticles-encapsulated RNA vaccine exhibits increased protein expression in tissue culture systems as compared to single round mRNA controls. The objective of this grant is to assess iDMV-1.0 in preclinical studies in mice. In Aim 1, the humoral immune response to the vaccine will be studied by assessing epitope choice of iDMV-1.0 as compared to mRNA-1273 (Moderna SARS-CoV-2 mRNA vaccine) using deep mutational scanning and traditional serology. We will assess durability of antigen expression and durability of humoral immune response for iDMV-1.0 as compared to conventional mRNA vaccination in mice. In Aim 2, the cellular immune response will be compared between both vaccine modalities to determine whether T cells specific to the SARS-CoV-2 proteome are generated by iDMV-1.0. Together, these studies will provide the foundation to understand durability and specificity of a potential single-shot SARS-CoV-2 mRNA vaccine, providing a paradigm that may facilitate greater vaccine uptake, particularly in LMIC settings.

针对SARS-CoV-2的mRNA疫苗被证明是出乎意料的有效，但也需要一系列的加强免疫来保持保护性。这些疫苗的全球部署一直很缓慢，特别是在低收入和中等收入国家，部分原因是与多种疫苗接种相关的后勤复杂性。因此，我们提出了一种新的RNA疫苗设计：基于SARS-CoV-2冠状病毒的单剂量自扩增mRNA疫苗。我们的长期目标是开发一种新的疫苗模式，该模式由RNA疫苗组成，该疫苗可在单剂量中提供对SARS-CoV-2的持久体液和细胞免疫。我们的新设计，命名为iDMV-1.0，利用编码冠状病毒复制机制的RNA，以在双膜囊泡（DMV）内产生Spike mRNA。iDMV-1.0是来自SARS-CoV-2基因组的20 kB RNA，由SARS-CoV-2的NSP 1 -16、稳定刺突蛋白（19）、ORF 6 -10、M蛋白和N蛋白的融合前构象的突变、用于检测的GFP和荧光素酶以及SARS-CoV-2基因组的所有非编码5'和3'序列组成。由于iDMV-1.0允许刺突mRNA的自扩增，因此与单轮mRNA对照相比，这种脂质纳米颗粒包封的RNA疫苗在组织培养系统中表现出增加的蛋白质表达。 该资助的目的是评估iDMV-1.0在小鼠临床前研究中的应用。在目的1中，将通过使用深度突变扫描和传统血清学评估iDMV-1.0与mRNA-1273（Moderna SARS-CoV-2 mRNA疫苗）相比的表位选择来研究对疫苗的体液免疫应答。我们将在小鼠中评估iDMV-1.0与常规mRNA疫苗接种相比抗原表达的持久性和体液免疫应答的持久性。在目标2中，将比较两种疫苗模式之间的细胞免疫应答，以确定iDMV-1.0是否产生对SARS-CoV-2蛋白质组特异性的T细胞。总之，这些研究将为了解潜在的单次注射SARS-CoV-2 mRNA疫苗的持久性和特异性提供基础，提供一种可能促进更大疫苗吸收的范例，特别是在LMIC环境中。