Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages have escaped most receptor-binding domain (RBD)-targeting therapeutic neutralizing antibodies (NAbs), which proves that previous NAb drug screening strategies are deficient against the fast-evolving SARS-CoV-2. Better b...
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Published in | Cell reports (Cambridge) Vol. 41; no. 12; p. 111845 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
20.12.2022
Cell Press |
Subjects | |
Online Access | Get full text |
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Summary: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages have escaped most receptor-binding domain (RBD)-targeting therapeutic neutralizing antibodies (NAbs), which proves that previous NAb drug screening strategies are deficient against the fast-evolving SARS-CoV-2. Better broad NAb drug candidate selection methods are needed. Here, we describe a rational approach for identifying RBD-targeting broad SARS-CoV-2 NAb cocktails. Based on high-throughput epitope determination, we propose that broad NAb drugs should target non-immunodominant RBD epitopes to avoid herd-immunity-directed escape mutations. Also, their interacting antigen residues should focus on sarbecovirus conserved sites and associate with critical viral functions, making the antibody-escaping mutations less likely to appear. Following these criteria, a featured non-competing antibody cocktail, SA55+SA58, is identified from a large collection of broad sarbecovirus NAbs isolated from SARS-CoV-2-vaccinated SARS convalescents. SA55+SA58 potently neutralizes ACE2-utilizing sarbecoviruses, including circulating Omicron variants, and could serve as broad SARS-CoV-2 prophylactics to offer long-term protection, especially for individuals who are immunocompromised or with high-risk comorbidities.
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•A rational strategy helps identify broad SARS-CoV-2 NAbs that are hard to evade•Broad NAbs from SARS-CoV-2-vaccinated SARS convalescents form non-competing cocktail•SA55+SA58 broadly and potently neutralizes SARS-CoV-2 variants and sarbecoviruses•SA55+SA58 tolerates escape mutations and protects mice from BA.1 and BA.5 infection
Cao et al. describe a strategy to identify a broad sarbecovirus-neutralizing antibody cocktail that would be hard to escape for future SARS-CoV-2 variants using high-throughput epitope mapping. The resulting antibody cocktail, named SA55+SA58, exhibits high neutralizing potency and breadth against ACE2-utilizing sarbecoviruses and efficiently protects mice from BA.1 and BA.5 infection. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally. |
ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2022.111845 |