a Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences , School of Medicine, Tsinghua University , Beijing , People's Republic of China.
b Department of Microbiology and Immunology , The University of Iowa , Iowa City , IA , USA.
Emerg Microbes Infect. 2019;8(1):760-772. doi: 10.1080/22221751.2019.1620083.
The recently identified Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe and fatal acute respiratory illness in humans. However, no approved prophylactic and therapeutic interventions are currently available. The MERS-CoV envelope spike protein serves as a crucial target for neutralizing antibodies and vaccine development, as it plays a critical role in mediating viral entry through interactions with the cellular receptor, dipeptidyl peptidase 4 (DPP4). Here, we constructed a recombinant rare serotype of the chimpanzee adenovirus 68 (AdC68) that expresses full-length MERS-CoV S protein (AdC68-S). Single intranasal immunization with AdC68-S induced robust and sustained neutralizing antibody and T cell responses in BALB/c mice. In a human DPP4 knock-in (hDPP4-KI) mouse model, it completely protected against lethal challenge with a mouse-adapted MERS-CoV (MERS-CoV-MA). Passive transfer of immune sera to naïve hDPP4-KI mice also provided survival advantages from lethal MERS-CoV-MA challenge. Analysis of sera absorption and isolated monoclonal antibodies from immunized mice demonstrated that the potent and broad neutralizing activity was largely attributed to antibodies targeting the receptor binding domain (RBD) of the S protein. These results show that AdC68-S can induce protective immune responses in mice and represent a promising candidate for further development against MERS-CoV infection in both dromedaries and humans.
最近发现的中东呼吸综合征冠状病毒（MERS-CoV）可导致人类发生严重且致命的急性呼吸道疾病。然而，目前尚无批准的预防和治疗干预措施。MERS-CoV 包膜刺突蛋白是中和抗体和疫苗开发的重要靶标，因为它在通过与细胞受体二肽基肽酶 4（DPP4）相互作用介导病毒进入中起着关键作用。在这里，我们构建了表达全长 MERS-CoV S 蛋白的重组稀有血清型黑猩猩腺病毒 68（AdC68-S）。单次鼻腔免疫接种 AdC68-S 可在 BALB/c 小鼠中诱导出强大且持续的中和抗体和 T 细胞反应。在人类 DPP4 敲入（hDPP4-KI）小鼠模型中，它完全可预防致死性适应小鼠的 MERS-CoV（MERS-CoV-MA）挑战。将免疫血清被动转移给未致敏的 hDPP4-KI 小鼠，也可使其免受致死性 MERS-CoV-MA 挑战的影响。对免疫血清的吸收和分离的单克隆抗体进行分析表明，强大而广泛的中和活性主要归因于针对 S 蛋白受体结合域（RBD）的抗体。这些结果表明，AdC68-S 可在小鼠中诱导出保护性免疫反应，是针对骆驼和人类 MERS-CoV 感染的进一步开发的有前途的候选物。
