重组腺病毒载体已广泛用于疫苗开发。为了克服人类5型腺病毒（Ad5）在人群中预先存在的免疫力，已经产生了一系列黑猩猩或罕见的人类腺病毒载体。然而,这些新型腺病毒载体介导宿主中的多种免疫应答。在这项研究中,我们探索了由我们先前开发的两种新型猿猴腺病毒23型（Sad23L）和人腺病毒49型（Ad49L）免疫的小鼠对SARS-CoV-2S蛋白的差异抗体应答的免疫机制，和Ad5载体COVID-19疫苗。Sad23L-nCoV-S和Ad5-nCoV-S疫苗在野生型和IFN-α/β受体缺陷型(IFNAR-/-)C57小鼠中诱导低水平的干扰素-α(IFN-α)和高水平的抗原特异性抗体应答,而Ad49L-nCoV-S疫苗在C57小鼠中诱导高IFN-α和低抗体反应，而在IFNAR-/-小鼠中诱导高抗体反应。此外,在用Ad49L-nCoV-S疫苗免疫的自然杀伤(NK)细胞阻断的C57小鼠中检测到高抗体应答,而在滤泡辅助性T(TFH)细胞阻断的C57小鼠中检测到低抗体应答.这些结果表明，Ad49L载体疫苗刺激IFN-α分泌激活NK细胞，然后减少TFH细胞的数量，生成中心（GC）B细胞和浆细胞，随后减少了抗原特异性抗体的产生。根据针对特定疾病的体液或细胞或两种免疫保护的需要,可以选择不同的新型腺病毒载体用于疫苗开发。重要性新型腺病毒载体是疫苗开发的重要抗原递送平台。了解不同腺病毒载体之间的免疫多样性对于设计针对目标疾病的适当疫苗至关重要。在这项研究中,我们描述了Sad23L和Ad49L载体疫苗在小鼠中产生同样高的特异性T细胞应答但不同水平的特异性抗体应答的免疫机制。我们发现Ad49L载体疫苗通过下调CD4+TFH细胞的数量引发高IFN-α和激活的NK细胞来抑制抗体反应，从而导致GCB细胞和浆细胞的减少。
Recombinant adenovirus vectors have been widely used in vaccine development. To overcome the preexisting immunity of human adenovirus type 5 (Ad5) in populations, a range of chimpanzee or rare human adenovirus vectors have been generated. However, these novel adenovirus vectors mediate the diverse immune responses in the hosts. In this study, we explored the immune mechanism of differential antibody responses to SARS-CoV-2 S protein in mice immunized by our previously developed two novel simian adenovirus type 23 (Sad23L) and human adenovirus type 49 (Ad49L), and Ad5 vectored COVID-19 vaccines. Sad23L-nCoV-S and Ad5-nCoV-S vaccines induced the low level of interferon-α (IFN-α) and the high level of antigen-specific antibody responses in wild-type and IFN-α/β receptor defective (IFNAR-/-) C57 mice, while Ad49L-nCoV-S vaccine induced the high IFN-α and low antibody responses in C57 mice but the high antibody response in IFNAR-/- mice. In addition, the high antibody response was detected in natural killer (NK) cells-blocked but the low in follicular helper T (TFH) cells -blocked C57 mice immunized with Ad49L-nCoV-S vaccine. These results showed that Ad49L vectored vaccine stimulated IFN-α secretion to activate NK cells, and then reduced the number of TFH cells, generation center (GC) B cells and plasma cells, and subsequently reduced antigen-specific antibody production. The different novel adenovirus vectors could be selected for vaccine development according to the need for either humoral or cellular or both immune protections against a particular disease. IMPORTANCE Novel adenovirus vectors are an important antigen delivery platform for vaccine development. Understanding the immune diversity between different adenoviral vectors is critical to design the proper vaccine against an aim disease. In this study, we described the immune mechanism of Sad23L and Ad49L vectored vaccines for raising the equally high specific T cell response but the different level of specific antibody responses in mice. We found that Ad49L-vectored vaccine initiated the high IFN-α and activated NK cells to inhibit antibody response via downregulating the number of CD4+ TFH cells leading to the decline of GC B cells and plasma cells.
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