黑猩猩型腺病毒作为疫苗载体的免疫学研究

Since there is generally no pre-existing immunity to chimpanzee adenovirus in the population, vaccine vector originated from on chimpanzee adenovirus is superior to the common human serotype adenovirus such as AdHu5. Therefore, in recent years, chimpanzee adenovirus has become the first choice of a novel vaccine vector. Near 100 types of chimpanzee adenovirus have been isolated and identified, some of which have been used in basic research and even into clinical trials. However, due to the construction technology and other reasons, these vectors have not been systematically screened and comparative tested before their application to vaccine research and development. Up to now, we have no idea about which chimpanzee adenovirus is the best as vaccine vector, because there has no comprehensive evaluation on humoral immunity, cellular immunity and inflammatory response induced by these vectors. Therefore, it lacks the systematic and in-depth study on the immunological characteristics of these viruses as vaccine vectors, in particular the omnidirectional comparative study between the chimpanzee adenoviral vector and the common human serotype adenoviral vector, as well as a variety of chimpanzee adenoviral vectors. However, these studies are crucial for screening the ideal chimpanzee adenoviral vector or for optimizing the vaccine vector to improve the vaccine's efficacy. This grant application intends to take advantage of our technology and use influenza as a model to deeply explore the immune mechanism of chimpanzee adenovirus as a vaccine carrier and determine the screening criteria of adenoviral vectors, so as to pave the way for the developing novel and efficient vaccines.

由于人群中一般不存在针对黑猩猩型腺病毒的预存免疫，该类病毒载体的免疫效果优于常见的人血清型腺病毒如AdHu5。因此，近年来，黑猩猩型腺病毒成为新型疫苗载体的首选。黑猩猩型腺病毒分离鉴定有近100种，其中部分被应用于基础研究甚至进入临床试验。但由于构建技术等原因，该类载体在应用于疫苗研发之前并没有经过系统筛选、比较，至今尚未根据体液免疫、细胞免疫、炎症反应等综合评价来确定最佳黑猩猩型疫苗载体。因此，该类病毒作为疫苗载体的免疫学特性缺乏系统深入的研究，特别缺乏黑猩猩型腺病毒载体与常见的人血清型腺病毒载体、以及多种黑猩猩型腺病毒载体之间全方位的比较研究。这些研究对于筛选理想的黑猩猩型腺病毒载体或优化疫苗载体、提高疫苗免疫效果至关重要。本项目拟利用我们的技术优势，以流感为模型，深入探讨黑猩猩型腺病毒作为疫苗载体的免疫机理，确定腺病毒疫苗载体的筛选标准，为新型、高效疫苗研发奠定基础。

腺病毒是一种理想的疫苗载体，在疫苗研发及应用中展示了良好的发展前景，然后腺病毒种类较多，不同型腺病毒具有不同的病毒学、免疫学特性，为此，本项目比较研究了多种腺病毒作为疫苗载体的免疫原性、免疫保护性的差异，并探究了相关的免疫机制，主要研究包括：1. 探究两种黑猩猩腺病毒载体分别表达新冠病毒S蛋白全长序列（AdC68-S与AdC6-S）作为候选新冠疫苗的免疫反应、免疫保护效果及其免疫机理。结果显示：单次免疫或异源初免-加强免疫小鼠，两种候选疫苗都能诱导强烈且持久的抗体反应、T细胞反应及生发中心反应，并对SARS-CoV-2感染小鼠提供有效保护。然而，异源初免-加强免疫诱导了更高滴度的保护性抗体，和更强的特异性记忆CD8+ T细胞反应，可进一步发展为预防新冠疫情的有效措施。2.探究两种黑猩猩腺病毒载体分别表达埃博拉病毒G蛋白作为新型埃博拉疫苗（AdC7-EBOVgp、AdC68-EBOVgp）的免疫反应及免疫机理。结果显示：AdC68较AdC7载体具有更强的免疫原性，AdC7-EBOVgp/AdC68-EBOVgp初免/加强免疫在小鼠及猴子体内诱导出更高滴度、持久的特异性结合抗体、中和抗体以及T细胞免疫，并可抵御假病毒的攻击感染。3. 采用黑猩猩腺病毒载体AdC68分别表达新冠病毒S蛋白 (AdC68-19S)及RBD作为候选疫苗，通过小鼠、叙利亚金黄地鼠及非人灵长类猴子模型，证明AdC68-19S具有较强的免疫原性，对SARS-CoV-2感染具有显著的免疫保护效果。该候选疫苗转化给沃森生物，并完成Ⅰ、II期临床试验。4. 开展了基于腺病毒载体的狂犬病疫苗、人4/7型腺病毒双价疫苗、通用流感疫苗等相关研究。 .以上研究系统探究了不同腺病毒载体的免疫原性、免疫方式及相关免疫机理，为腺病毒载体及免疫程序的优化、腺病毒载体疫苗的推广应用提供了科学依据。