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

项目摘要 为有效管理COVID-19疫情及其第二波， 多种干预方法是至关重要的它们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克隆抗体，快速诊断测定，免疫原性 保护性疫苗、减轻病毒传播性的战略，以及加强与训练有素的 医疗人员、设施和用品。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设计相关抗原 战略必须指出，老年人是人口中最脆弱的部分， COVID-19严重程度的风险更高;因此，疫苗开发工作应考虑 老年人的免疫能力。 我们已经开发了一种新的复制缺陷型（E1和E3缺失）牛腺病毒（Ad）3型（BAd 3）， 的疫苗平台，其比目前可用的Ad载体系统更好地提供异源性 本发明的组合物具有剂量节省的流感保护作用，并且不受预先存在的人Ad载体免疫力的影响。 最近，我们已经揭示了BAd疫苗平台提供了显著更高水平的表达， 与人Ad载体相比， 小鼠这项工作表明，BAd载体系统可以作为一个很好的运载工具， 为老年人和老年人的其他群体开发针对新出现的病原体的重组疫苗 人口我们还鉴定了一种由22个氨基酸残基组成的自噬诱导肽（AIP）C5（AIP-C5）。 从M.结核病增强小鼠对H7N9 NP的强大T细胞免疫应答 当通过Ad载体递送时，流感病毒的抗体。它提供了对H1N1，H3 N2， H5 N2、H7N9和H9 N2流感病毒。 该建议是基于这样的假设，即用诱导自噬的复制缺陷的 表达SARS-CoV-2相关抗原的BAd载体将增强有效的粘膜（肺）和 全身抗COVID-19免疫。根据目标1，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用于开发有效疫苗的功效 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 增强SARS-CoV-2感染的ADE，先天记忆的质量，B和T细胞应答，以及 在最佳动物模型中保护性免疫的持久性。我们认为，使用一种独特的 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COVID-19 为所有人群提供疫苗。这一努力将对有效遏制新冠肺炎疫情具有重要价值- 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.