Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants

doi:10.1126/science.abh1766

GSTDTAP > 气候变化

DOI	10.1126/science.abh1766
	Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants
	Lingshu Wang; Tongqing Zhou; Yi Zhang; Eun Sung Yang; Chaim A. Schramm; Wei Shi; Amarendra Pegu; Olamide K. Oloniniyi; Amy R. Henry; Samuel Darko; Sandeep R. Narpala; Christian Hatcher; David R. Martinez; Yaroslav Tsybovsky; Emily Phung; Olubukola M. Abiona; Avan Antia; Evan M. Cale; Lauren A. Chang; Misook Choe; Kizzmekia S. Corbett; Rachel L. Davis; Anthony T. DiPiazza; Ingelise J. Gordon; Sabrina Helmold Hait; Tandile Hermanus; Prudence Kgagudi; Farida Laboune; Kwanyee Leung; Tracy Liu; Rosemarie D. Mason; Alexandra F. Nazzari; Laura Novik; Sarah O’Connell; Sijy O’Dell; Adam S. Olia; Stephen D. Schmidt; Tyler Stephens; Christopher D. Stringham; Chloe Adrienna Talana; I-Ting Teng; Danielle A. Wagner; Alicia T. Widge; Baoshan Zhang; Mario Roederer; Julie E. Ledgerwood; Tracy J. Ruckwardt; Martin R. Gaudinski; Penny L. Moore; Nicole A. Doria-Rose; Ralph S. Baric; Barney S. Graham; Adrian B. McDermott; Daniel C. Douek; Peter D. Kwong; John R. Mascola; Nancy J. Sullivan; John Misasi
	2021-08-13
发表期刊	Science
出版年	2021
英文摘要	Our key defense against the COVID-19 pandemic is neutralizing antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus elicited by natural infection or vaccination. Recent emerging viral variants have raised concern because of their potential to escape antibody neutralization. Wang et al. identified four antibodies from early-outbreak convalescent donors that are potent against 23 variants, including variants of concern, and characterized their binding to the spike protein of SARS-CoV-2. Yuan et al. examined the impact of emerging mutations in the receptor-binding domain of the spike protein on binding to the host receptor ACE2 and to a range of antibodies. These studies may be helpful for developing more broadly effective vaccines and therapeutic antibodies. Science , abh1766, this issue p. [eabh1766][1], abh1139, this issue p. [818][2] ### INTRODUCTION Worldwide appearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) with increased transmissibility and resistance to therapeutic antibodies necessitates the discovery of broadly reactive antibodies. We isolated receptor binding domain (RBD) targeting antibodies that potently neutralize 23 variants, including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, and B.1.617 VOCs. Structural and functional studies revealed the molecular basis for antibody binding and showed that antibody combinations reduce the generation of escape mutants, suggesting a potential means to mitigate development of therapeutic resistance. ### RATIONALE Investigation of antibody responses from convalescent subjects infected with the Washington-1 (WA-1) strain for reactivity against WA-1 and VOCs can inform improvements to vaccine design and therapeutics. ### RESULTS Blood from 22 convalescent subjects who recovered from SARS-CoV-2 WA-1 infection was screened for neutralizing and binding activity, and four subjects with high reactivity against the WA-1 variant were selected for antibody isolation. SARS-CoV-2 spike (S)–reactive antibodies were identified through B cell sorting with S protein–based probes. WA-1 live-virus neutralization assays identified four RBD-targeting antibodies with high potency [half-maximal inhibitory concentration (IC50) 2.1 to 4.8 ng/ml], two of which were derived from the same IGHV1-58 germline but from different donors. Antigen-binding fragments (Fabs) of these antibodies exhibited nanomolar affinity to S (2.3 to 7.3 nM). Competition assays and electron microscopy indicated that two of the most potent antibodies blocked angiotensin-converting enzyme 2 (ACE2) and bound open conformation RBD, whereas the other two bound both up and down conformations of RBD and blocked ACE2 binding. Binding and lentivirus neutralization assays against 13 circulating VOCs or variants of interest—including B.1.1.7, B.1.351, B.1.427, B.1.429, B.1.526, P.1, P.2, B.1.617.1, and B.1.617.2—indicated that these antibodies were highly potent against VOCs despite being isolated from subjects infected with early ancestral SARS-CoV-2 viruses. Cryo-EM studies of the two most potent antibodies in complex with S revealed that these antibodies target a site of vulnerability on RBD but have minimal contacts with mutational hotspots, defining the structural basis for their high effectiveness against the emerging VOCs and further delineating an IGHV1-58 antibody supersite. To investigate potential mechanisms of escape, we applied antibody selection pressure to replication-competent vesicular stomatitis virus (rcVSV) expressing the WA-1 SARS-CoV-2 S (rcVSV-SARS2) and identified S mutations that conferred in vitro resistance. We evaluated these antibodies individually or in combinations for their capacity to prevent rcVSV-SARS2 escape and discovered that antibody combinations with complementary modes of recognition to the RBD lowered the risk of resistance. ### CONCLUSION Our study demonstrates that convalescent subjects previously infected with ancestral variant SARS-CoV-2 produce antibodies that cross-neutralize emerging VOCs with high potency. Structural and functional analyses reveal that antibody breadth is mediated by targeting a site of vulnerability at the RBD tip offset from major mutational hotspots in VOCs. Selective boosting of immune responses targeting specific RBD epitopes, such as the sites defined by these antibodies, may induce breadth against current and future VOCs. ![Figure][3] Isolation and characterization of convalescent donor antibodies that effectively neutralize emerging SARS-CoV-2 VOCs. Antibodies isolated from donors infected with ancestral SARS-CoV-2 viruses showed ultrapotent neutralization of emerging VOCs. The two most potent antibodies shared usage of the IGHV1-58 gene and targeted the RBD with minimal contact to VOC mutational hotspots. Cocktails of antibodies with complementary binding modes suppressed antibody escape. The emergence of highly transmissible SARS-CoV-2 variants of concern (VOCs) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identified four receptor binding domain–targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 23 variants, including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, and B.1.617 VOCs. Two antibodies are ultrapotent, with subnanomolar neutralization titers [half-maximal inhibitory concentration (IC50) 0.3 to 11.1 nanograms per milliliter; IC80 1.5 to 34.5 nanograms per milliliter). We define the structural and functional determinants of binding for all four VOC-targeting antibodies and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting their potential in mitigating resistance development. [1]: /lookup/doi/10.1126/science.abh1766 [2]: /lookup/doi/10.1126/science.abh1139 [3]: pending:yes
领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/335876
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Lingshu Wang,Tongqing Zhou,Yi Zhang,et al. Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants[J]. Science,2021.
APA	Lingshu Wang.,Tongqing Zhou.,Yi Zhang.,Eun Sung Yang.,Chaim A. Schramm.,...&John Misasi.(2021).Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants.Science.
MLA	Lingshu Wang,et al."Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants".Science (2021).