Novel delivery platform and antigen design for an effective COVID-19 vaccine

项目概要 为了有效管理 COVID-19 大流行及其第二波，设计和实施 多种干预方法至关重要。它们包括开发有效的抗病毒药物、高亲和力药物 SARS-CoV-2-神经化人或人源化单克隆抗体、快速诊断测定、免疫原性 和保护性疫苗、减轻病毒传播性的策略以及增强受过训练的相关能力 医疗人员、设施和物资。由于抗体依赖性增强（ADE）的可能性 COVID-19，疫苗工作应考虑使用新型疫苗平台和相关抗原的设计 策略。值得注意的是，老年人是人口中最脆弱的群体。 COVID-19 严重程度的风险较高；因此，疫苗开发工作应考虑到感染率下降的情况 老年人的免疫能力。 我们开发了一种新型复制缺陷型（E1 和 E3 缺失）牛腺病毒 (Ad) 3 型 (BAd3)- 基于疫苗平台，比目前可用的Ad载体系统更好地提供异源 通过节省剂量提供流感保护，并且不受预先存在的人类 Ad 载体免疫力的影响。 最近，我们发现BAd疫苗平台提供了显着更高水平的表达 与人类 Ad 载体相比，免疫原以及先天性和适应性免疫相关因素的差异 老鼠。这项工作表明 BAd 载体系统可以作为一种优秀的递送工具 为老年人和其他人群开发针对新出现病原体的重组疫苗 人口。我们还鉴定了一个 22 个氨基酸残基的自噬诱导肽 (AIP) C5 (AIP-C5) 来自结核分枝杆菌的 CFP10 蛋白，可增强小鼠对 H7N9 NP 的强大 T 细胞免疫反应 流感病毒通过 Ad 载体传递。它提供针对 H1N1、H3N2、 H5N2、H7N9 和 H9N2 流感病毒。 该提议基于这样的假设：用自噬诱导复制缺陷的疫苗进行免疫 表达 SARS-CoV-2 相关抗原的 BAd 载体将增强有效的粘膜（肺）和 系统性抗 COVID-19 免疫力。在目标 1 下，我们将评估免疫原性和保护性 新型疫苗平台和抗原设计在动物模型中的功效，以开发有效的疫苗 COVID-19 疫苗。而在目标 2 下，我们将研究疫苗诱导的抗体依赖性 SARS-CoV-2 感染的增强 (ADE)、先天记忆质量、B 和 T 细胞反应，以及 最佳动物模型中保护性免疫力的持久性。我们相信，使用独特的 非人类 Ad 疫苗平台和包含 AIP-C5 的新型抗原设计将产生有效的 COVID-19 为所有人群提供疫苗。这项努力对于有效遏制新冠疫情具有重要价值 19 大流行的轨迹及其第二波。

PROJECT SUMMARY For effective management of the COVID-19 pandemic and its second wave, the design and implementation of multiple intervention approaches are crucial. They include the development of effective antivirals, high-affinity SARS-CoV-2-neuralizing human or humanized monoclonal antibodies, rapid diagnostic assays, immunogenic and protective vaccines, strategies to mitigate virus transmissibility, and enhancing capacity related to trained medical personnel, facilities, and supplies. Due to the possibility of antibody-dependent enhancement (ADE) of COVID-19, vaccine efforts should consider the use of a novel vaccine platform and design of a relevant antigen strategy. It is essential to note that the elderly are the most vulnerable segment of the population that is at a higher risk of COVID-19 severity; the vaccine development efforts should, therefore, consider the decline in the immune competence in the elderly. We have developed a novel replication-defective (E1 & E3 deleted) bovine adenovirus (Ad) type 3 (BAd3)- based vaccine platform, which is better than the currently available Ad vector systems for providing heterologous influenza protection with dose sparing and is not impacted by the pre-existing human Ad vector immunity. Recently, we have revealed that the BAd vaccine platform provides the expression of significantly higher levels of the immunogen and innate and adaptive immunity-related factors compared to that of human Ad vectors in mice. This work suggests that the BAd vector system could serve as an excellent delivery vehicle for the development of recombinant vaccines against emerging pathogens for the elderly and other segments of the population. We have also identified a 22 amino acid residues Autophagy-Inducing Peptide (AIP) C5 (AIP-C5) from the CFP10 protein of M. tuberculosis that enhances robust T cell immune responses in mice to NP of H7N9 influenza virus when delivered through an Ad vector. It conferred complete protection against H1N1, H3N2, H5N2, H7N9, and H9N2 influenza viruses. The proposal is based on the hypothesis that immunization with the autophagy-inducing replication-deficient BAd vector expressing relevant antigen/s of SARS-CoV-2 will strengthen an effective mucosal (lung) and systemic anti-COVID-19 immunity. Under Aim 1, we will evaluate the immunogenicity and protective efficacy of a novel vaccine platform and antigen design in animal models for developing an effective COVID-19 vaccine. Whereas under Aim 2, we will investigate the vaccine-induced antibody-dependent enhancement (ADE) of SARS-CoV-2 infection, the quality of memory innate, B and T cell responses, and the durability of protective immunity in the best animal model. We believe that the use of a unique nonhuman Ad vaccine platform and novel antigen design containing AIP-C5 will yield an effective COVID-19 vaccine for all segments of the population. This effort will be of significant value to effectively flatten the COVID- 19 pandemic's trajectory and its second wave.