Antibody escape and cryptic cross-domain stabilization in the SARS-CoV-2 Omicron spike protein

Javanmardi, Kamyab; Segall-Shapiro, Thomas H.; Chou, Chih‐Ju; Boutz, Daniel R.; Olsen, Randall J.; Xie, Xuping; Xia, Hongjie; Shi, Pei–Yong; Johnson, Connor; Annapareddy, Ankur; Weaver, Scott C.; Musser, James M.; Ellington, Andrew D.; Finkelstein, Ilya J.; Gollihar, Jimmy

doi:10.1016/j.chom.2022.07.016

Cited by 32 publications

(28 citation statements)

References 61 publications

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“…We found that Omicron BA.1 and BA.2 RBDs have reduced yeast surface expression levels relative to Wuhan-Hu-1 (S2 Data and S3C Fig. ), consistent with biochemical studies demonstrating that the Omicron RBD is less thermodynamically stable than Wuhan-Hu-1 [16,25,26]. Our maps identify candidate stabilizing mutations in the Omicron RBD core (e.g., positions 358, 363, 365, 392) and surrounding the loop containing Omicron substitutions at sites 371, 373, and 375 (e.g., positions 369, 374, 376; Fig.…”

Section: Deep Mutational Scans Of the Omicron Ba1 And Ba2 Rbdssupporting

confidence: 88%

“…Omicron emerged suddenly with a constellation of RBD substitutions that balance immune escape with the maintenance of ACE2 binding affinity [10,16,19]. We show that these substitutions also altered the potential future mutational landscape of SARS-CoV-2 evolution in several ways.…”

Section: Discussionmentioning

confidence: 99%

“…The BA.1 and BA.2 Omicron variants have 15 and 16 amino acid substitutions in the RBD alone (Fig. 1A) [11,12], many of which impact ACE2 binding or antibody recognition [5,[13][14][15][16][17]. Though it is now clear that epistatic interactions among substitutions shaped Omicron emergence [10,16,[18][19][20][21], it is unclear how the substitutions in Omicron have reshaped the impacts of all the other possible mutations that form the substrate for future viral evolution.…”

Section: Introductionmentioning

confidence: 99%

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Deep mutational scans for ACE2 binding, RBD expression, and antibody escape in the SARS-CoV-2 Omicron BA.1 and BA.2 receptor-binding domains

Starr

Greaney

Stewart

et al. 2022

Preprint

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SARS-CoV-2 continues to acquire mutations in the spike receptor-binding domain (RBD) that impact ACE2 receptor binding, folding stability, and antibody recognition. Deep mutational scanning prospectively characterizes the impacts of mutations on these biochemical properties, enabling rapid assessment of new mutations seen during viral surveillance. However, the effects of mutations can change as the virus evolves, requiring updated deep mutational scans. We determined the impacts of all amino acid mutations in the Omicron BA.1 and BA.2 RBDs on ACE2-binding affinity, RBD folding, and escape from binding by the LY-CoV1404 (bebtelovimab) monoclonal antibody. The effects of some mutations in Omicron RBDs differ from those measured in the ancestral Wuhan-Hu-1 background. These epistatic shifts largely resemble those previously seen in the Beta variant due to the convergent epistatically modifying N501Y substitution. However, Omicron variants show additional lineage-specific shifts, including examples of the epistatic phenomenon of entrenchment that causes the Q498R and N501Y substitutions present in Omicron to be more favorable in that background than in earlier viral strains. In contrast, the Omicron substitution Q493R exhibits no sign of entrenchment, with the derived state, R493, being as unfavorable for ACE2 binding in Omicron RBDs as in Wuhan-Hu- 1. Likely for this reason, the R493Q reversion has occurred in Omicron sub-variants including BA.4/BA.5 and BA.2.75, where the affinity buffer from R493Q reversion may potentiate concurrent antigenic change. Consistent with prior studies, we find that Omicron RBDs have reduced expression, and identify candidate stabilizing mutations that ameliorate this deficit. Last, our maps highlight a broadening of the sites of escape from LY-CoV1404 antibody binding in BA.1 and BA.2 compared to the ancestral Wuhan-Hu-1 background. These BA.1 and BA.2 deep mutational scanning datasets identify shifts in the RBD mutational landscape and inform ongoing efforts in viral surveillance.

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Section: Deep Mutational Scans Of the Omicron Ba1 And Ba2 Rbdssupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deep mutational scans for ACE2 binding, RBD expression, and antibody escape in the SARS-CoV-2 Omicron BA.1 and BA.2 receptor-binding domains

Starr

Greaney

Stewart

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Omicron marks the largest evolutionary jump in SARS-CoV-2 RBD sequence evolution seen to date. The BA.1 and BA.2 Omicron variants have 15 and 16 amino acid substitutions in the RBD alone (Fig 1A) [11,12], many of which impact ACE2 binding or antibody recognition [5,[13][14][15][16][17]. Though it is now clear that epistatic interactions among substitutions shaped Omicron emergence [10,16,[18][19][20][21], it is unclear how the substitutions in Omicron have reshaped the impacts of all the other possible mutations that form the substrate for future viral evolution.…”

Section: Introductionmentioning

confidence: 99%

Deep mutational scans for ACE2 binding, RBD expression, and antibody escape in the SARS-CoV-2 Omicron BA.1 and BA.2 receptor-binding domains

et al. 2022

View full text Add to dashboard Cite

SARS-CoV-2 continues to acquire mutations in the spike receptor-binding domain (RBD) that impact ACE2 receptor binding, folding stability, and antibody recognition. Deep mutational scanning prospectively characterizes the impacts of mutations on these biochemical properties, enabling rapid assessment of new mutations seen during viral surveillance. However, the effects of mutations can change as the virus evolves, requiring updated deep mutational scans. We determined the impacts of all single amino acid mutations in the Omicron BA.1 and BA.2 RBDs on ACE2-binding affinity, RBD folding, and escape from binding by the LY-CoV1404 (bebtelovimab) monoclonal antibody. The effects of some mutations in Omicron RBDs differ from those measured in the ancestral Wuhan-Hu-1 background. These epistatic shifts largely resemble those previously seen in the Alpha variant due to the convergent epistatically modifying N501Y substitution. However, Omicron variants show additional lineage-specific shifts, including examples of the epistatic phenomenon of entrenchment that causes the Q498R and N501Y substitutions present in Omicron to be more favorable in that background than in earlier viral strains. In contrast, the Omicron substitution Q493R exhibits no sign of entrenchment, with the derived state, R493, being as unfavorable for ACE2 binding in Omicron RBDs as in Wuhan-Hu-1. Likely for this reason, the R493Q reversion has occurred in Omicron sub-variants including BA.4/BA.5 and BA.2.75, where the affinity buffer from R493Q reversion may potentiate concurrent antigenic change. Consistent with prior studies, we find that Omicron RBDs have reduced expression, and identify candidate stabilizing mutations that ameliorate this deficit. Last, our maps highlight a broadening of the sites of escape from LY-CoV1404 antibody binding in BA.1 and BA.2 compared to the ancestral Wuhan-Hu-1 background. These BA.1 and BA.2 deep mutational scanning datasets identify shifts in the RBD mutational landscape and inform ongoing efforts in viral surveillance.

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“…While the mutations with a small effect on antibody escape are mostly uncorrelated to ACE2 affinity, the strong-effect mutations substantially reduce ACE2 affinity. Thus, ACE2 affinity is lower for variants that escape a larger number of antibodies, unless compensatory mutations are acquired, suggesting that these compensatory mutations potentiated the establishment of the antibody escape mutations 23,30 . We also find that epistatic interactions are important in determining antibody affinity.…”

Section: Tradeoffs Between Antibody and Ace2 Affinitiesmentioning

confidence: 99%

The landscape of antibody binding affinity in SARS-CoV-2 Omicron BA.1 evolution

Moulana

Dupic

Phillips

et al. 2022

Preprint

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The Omicron BA.1 variant of SARS-CoV-2 escapes convalescent sera and monoclonal antibodies that are effective against earlier strains of the virus. This immune evasion is largely a consequence of mutations in the BA.1 receptor binding domain (RBD), the major antigenic target of SARS-CoV-2. Previous studies have identified several key RBD mutations leading to escape from most antibodies. However, little is known about how these escape mutations interact with each other and with other mutations in the RBD. Here, we systematically map these interactions by measuring the binding affinity of all possible combinations of these 15 RBD mutations (215 = 32,768 genotypes) to four monoclonal antibodies (LY-CoV016, LY-CoV555, REGN10987, and S309) with distinct epitopes. We find that BA.1 can lose affinity to diverse antibodies by acquiring a few large-effect mutations and can reduce affinity to others through several small-effect mutations. However, our results also reveal alternative pathways to antibody escape that do not include every large-effect mutation. Moreover, epistatic interactions are shown to constrain affinity decline in S309 but only modestly shape the affinity landscapes of other antibodies. Together with previous work on the ACE2 affinity landscape, our results suggest that escape of each antibody is mediated by distinct groups of mutations, whose deleterious effects on ACE2 affinity are compensated by another distinct group of mutations (most notably Q498R and N501Y).

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Antibody escape and cryptic cross-domain stabilization in the SARS-CoV-2 Omicron spike protein

Cited by 32 publications

References 61 publications

Deep mutational scans for ACE2 binding, RBD expression, and antibody escape in the SARS-CoV-2 Omicron BA.1 and BA.2 receptor-binding domains

Deep mutational scans for ACE2 binding, RBD expression, and antibody escape in the SARS-CoV-2 Omicron BA.1 and BA.2 receptor-binding domains

Deep mutational scans for ACE2 binding, RBD expression, and antibody escape in the SARS-CoV-2 Omicron BA.1 and BA.2 receptor-binding domains

The landscape of antibody binding affinity in SARS-CoV-2 Omicron BA.1 evolution

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