Malewana R Dilshan, Stalls Victoria, May Aaron, Lu Xiaozhi, Martinez David R, Schäfer Alexandra, Li Dapeng, Barr Maggie, Sutherland Laura L, Lee Esther, Parks Robert, Beck Whitney Edwards, Newman Amanda, Bock Kevin W, Minai Mahnaz, Nagata Bianca M, DeMarco C Todd, Denny Thomas N, Oguin Thomas H, Rountree Wes, Wang Yunfei, Mansouri Katayoun, Edwards Robert J, Sempowski Gregory D, Eaton Amanda, Muramatsu Hiromi, Henderson Rory, Tam Ying, Barbosa Christopher, Tang Juanjie, Cain Derek W, Santra Sampa, Moore Ian N, Andersen Hanne, Lewis Mark G, Golding Hana, Seder Robert, Khurana Surender, Montefiori David C, Pardi Norbert, Weissman Drew, Baric Ralph S, Acharya Priyamvada, Haynes Barton F, Saunders Kevin O
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA.
bioRxiv. 2023 Dec 19:2023.12.18.572191. doi: 10.1101/2023.12.18.572191.
Immunization with mRNA or viral vectors encoding spike with diproline substitutions (S-2P) has provided protective immunity against severe COVID-19 disease. How immunization with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike elicits neutralizing antibodies (nAbs) against difficult-to-neutralize variants of concern (VOCs) remains an area of great interest. Here, we compare immunization of macaques with mRNA vaccines expressing ancestral spike either including or lacking diproline substitutions, and show the diproline substitutions were not required for protection against SARS-CoV-2 challenge or induction of broadly neutralizing B cell lineages. One group of nAbs elicited by the ancestral spike lacking diproline substitutions targeted the outer face of the receptor binding domain (RBD), neutralized all tested SARS-CoV-2 VOCs including Omicron XBB.1.5, but lacked cross-Sarbecovirus neutralization. Structural analysis showed that the macaque broad SARS-CoV-2 VOC nAbs bound to the same epitope as a human broad SARS-CoV-2 VOC nAb, DH1193. Vaccine-induced antibodies that targeted the RBD inner face neutralized multiple Sarbecoviruses, protected mice from bat CoV RsSHC014 challenge, but lacked Omicron variant neutralization. Thus, ancestral SARS-CoV-2 spike lacking proline substitutions encoded by nucleoside-modified mRNA can induce B cell lineages binding to distinct RBD sites that either broadly neutralize animal and human Sarbecoviruses or recent Omicron VOCs.
用编码含二脯氨酸替代的刺突蛋白（S-2P）的mRNA或病毒载体进行免疫接种，已提供针对重症COVID-19疾病的保护性免疫。严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突蛋白的免疫接种如何引发针对难以中和的关注变体（VOCs）的中和抗体（nAbs），仍然是一个备受关注的领域。在这里，我们比较了用表达野生型刺突蛋白（无论是否包含二脯氨酸替代）的mRNA疫苗对猕猴进行免疫接种的情况，并表明二脯氨酸替代对于抵抗SARS-CoV-2攻击或诱导广泛中和的B细胞谱系并非必需。一组由缺乏二脯氨酸替代的野生型刺突蛋白引发的nAbs靶向受体结合域（RBD）的外表面，中和了所有测试的SARS-CoV-2 VOCs，包括奥密克戎XBB.1.5，但缺乏跨沙贝病毒属的中和作用。结构分析表明，猕猴广泛的SARS-CoV-2 VOC nAbs与人类广泛的SARS-CoV-2 VOC nAb DH1193结合相同的表位。靶向RBD内表面的疫苗诱导抗体中和了多种沙贝病毒，保护小鼠免受蝙蝠冠状病毒RsSHC014攻击，但缺乏对奥密克戎变体的中和作用。因此，由核苷修饰的mRNA编码的缺乏脯氨酸替代的野生型SARS-CoV-2刺突蛋白可以诱导B细胞谱系结合到不同的RBD位点，这些位点要么广泛中和动物和人类沙贝病毒，要么中和最近的奥密克戎VOCs。
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