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

项目总结 为了有效管理新冠肺炎大流行及其第二波，设计和实施 采取多种干预方法至关重要。其中包括开发有效的抗病毒药物、高亲和力 SARS-CoV-2.神经化人或人源化单抗，快速诊断分析，免疫原性 和保护性疫苗，减轻病毒传播性的战略，以及加强与培训相关的能力 医疗人员、设施和用品。由于抗体依赖增强(ADE)的可能性 新冠肺炎，疫苗工作应考虑使用新的疫苗平台并设计相关抗原 策略。必须指出的是，老年人是人口中最脆弱的部分，他们处于 更高的新冠肺炎严重风险；因此，疫苗开发工作应该考虑到 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 流感保护与剂量节约，不受先前存在的人类Ad载体免疫的影响。 最近，我们发现坏疫苗平台提供了明显更高水平的表达 免疫原、先天免疫和获得性免疫相关因子与人Ad载体的比较 老鼠。这项工作表明，不良的媒介系统可以作为一种很好的传播媒介 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。我们还鉴定了一种22个氨基酸残基的自噬诱导多肽C5(AIP-C5)。 来自结核分枝杆菌CFP10蛋白，它能增强小鼠对H7N9 NP的强大T细胞免疫应答 通过腺病毒载体传播的流感病毒。它提供了对H1N1，H3N2， H5N2H7N9和H9N2型流感病毒。 这一建议是基于这样的假设，即自噬诱导复制缺陷的免疫 表达SARS-CoV-2相关抗原的BAD载体/S将增强有效的粘膜(肺)和 系统性抗新冠肺炎免疫。在目标1下，我们将评估其免疫原性和保护性 一种新型疫苗平台的有效性和动物模型中的抗原设计 新冠肺炎疫苗。而在目标2中，我们将研究疫苗诱导的抗体依赖 SARS-CoV-2感染的增强(ADE)、固有记忆质量、B和T细胞反应，以及 保护性免疫的持久性是最好的动物模型。我们相信，使用独特的 非人Ad疫苗平台和含有AIP-C5的新型抗原设计将产生有效的新冠肺炎 为所有人群接种疫苗。这一努力将对有效地平坦化COVID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.