Potently neutralizing and protective human antibodies against SARS-CoV-2
By Seth J. Zost, P. Gilchuk, J. Case, E. Binshtein, Rita E. Chen, Joseph P. Nkolola, A. Schäfer, Joseph X. Reidy, Andrew Trivette, Rachel S. Nargi and 31 more. 2020
1,004 citations recorded by the source corpus.
The ongoing pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health1 and the medical countermeasures available so far are limited2,3. Moreover, we currently lack a thorough understanding of the mechanisms of humoral immunity to SARS-CoV-24. Here we analyse a large panel of human monoclonal antibodies that target the spike (S) glycoprotein5, and identify several that exhibit potent neutralizing activity and fully block the receptor-binding domain of the S protein (SRBD) from interacting with human angiotensin-converting enzyme 2 (ACE2). Using competition-binding, structural and functional studies, we show that the monoclonal antibodies can be clustered into classes that recognize distinct epitopes on the SRBD, as well as distinct conformational states of the S trimer. Two potently neutralizing monoclonal antibodies, COV2-2196 and COV2-2130, which recognize non-overlapping sites, bound simultaneously to the S protein and neutralized wild-type SARS-CoV-2 virus in a synergistic manner. In two mouse models of SARS-CoV-2 infection, passive transfer of COV2-2196, COV2-2130 or a combination of both of these antibodies protected mice from weight loss and reduced the viral burden and levels of inflammation in the lungs. In addition, passive transfer of either of two of the most potent ACE2-blocking monoclonal antibodies (COV2-2196 or COV2-2381) as monotherapy protected rhesus macaques from SARS-CoV-2 infection. These results identify protective epitopes on the SRBD and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutic agents. An analysis identifies human monoclonal antibodies that potently neutralize wild-type SARS-CoV-2 and protect animals from disease, including two that synergize in a cocktail, suggesting that these could be candidates for use as therapeutic agents for the treatment of COVID-19 in humans.
Subfields: Cardiology and Cardiovascular Medicine, Infectious Diseases
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In Infectious Diseases
Citations in the corpus
- Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2 (2020, neutral): “…domain (RBD) in complex with ACE2 defined key residues involved in recognition and guide surveillance studies aiming to detect the emergence of mutants with altered binding affinity for ACE2 or distinct antigenicity (Lan et al., 2020; Shang et al., 2020; Wang et al., 2020b; Yan et al., 2020).”
- COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection (2021, background): “Likewise, after screening a large panel of human mAbs that target the spike protein, two antibodies, COV2-2196 and COV2-2130, recognized the non-overlapping epitopes on RBD and bound simultaneously to the S protein inducing virus neutralization in a synergistic manner [138].”