Epistasis lowers the genetic barrier to SARS-CoV-2 neutralizing antibody escape

Witte, Leander; Baharani, Viren A.; Schmidt, Fabian; Wang, Zijun; Cho, Alice; Raspe, Raphael; Guzman-Cardozo, Camila; Muecksch, Frauke; Canis, Marie; Park, Debby J.; Gaebler, Christian; Caskey, Marina; Nussenzweig, Michel C.; Hatziioannou, Théodora; Bieniasz, Paul D.

doi:10.1038/s41467-023-35927-0

Cited by 53 publications

(46 citation statements)

References 40 publications

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“…2A and 2B, middle and bottom ). The broadening of the escape pathways in pre-Omicron-elicited antibody responses with Omicron VOCs compared to WH-1 has been observed in other studies (46, 65) and could provide additional flexibility for escape.…”

Section: Resultssupporting

confidence: 55%

Identification of broad, potent antibodies to functionally constrained regions of SARS-CoV-2 spike following a breakthrough infection

Guenthoer

Lilly

Starr

et al. 2022

Preprint

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The antiviral benefit of antibodies can be compromised by viral escape especially for rapidly evolving viruses. Therefore, durable, effective antibodies must be both broad and potent to counter newly emerging, diverse strains. Discovery of such antibodies is critically important for SARS-CoV-2 as the global emergence of new variants of concern (VOC) has compromised the efficacy of therapeutic antibodies and vaccines. We describe a collection of broad and potent neutralizing monoclonal antibodies (mAbs) isolated from an individual who experienced a breakthrough infection with the Delta VOC. Four mAbs potently neutralize the Wuhan-Hu-1 vaccine strain, the Delta VOC, and also retain potency against the Omicron VOCs, including recently circulating BA.4/BA.5, in both pseudovirus-based and live virus assays, and one also potently neutralizes SARS-CoV-1. The potency of these mAbs was greater against Omicron VOCs than all but one of the mAbs that had been approved for therapeutic applications. The mAbs target distinct epitopes on the spike glycoprotein, three in the receptor binding domain (RBD) and one in an invariant region downstream of the RBD in subdomain 1 (SD1). The escape pathways we defined at single amino acid resolution with deep mutational scanning show they target conserved, functionally constrained regions of the glycoprotein, suggesting escape could incur a fitness cost. Overall, these mAbs are novel in their breadth across VOCs, their epitope specificity, and include a highly potent mAb targeting a rare epitope outside of the RBD in SD1.

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Section: Resultssupporting

confidence: 55%

Identification of broad, potent antibodies to functionally constrained regions of SARS-CoV-2 spike following a breakthrough infection

Guenthoer

Lilly

Starr

et al. 2022

Preprint

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“…Epistatic interactions between mutations add substantial complexity of their adaptive landscapes are believed to play an important role in the virus evolution. The proposed in our study a network-based model for the analysis of non-additive contributions of the RBD residues indicated that some convergent Omicron mutations such as G446S (BA.2.75, BA.2.75.2, XBB), F486V (BA.4, BA.5, BQ.1, BQ.1.1), F486S, F490S (XBB.1), F486P (XBB.1.5) can display epistatic relationships with the major stability and binding affinity hotspots which may allow for the observed broad antibody resistance induced by these mutations [68]. Using atomistic simulations, the ensemble-based mutational scanning of binding/stability and network-based approaches, we showed that the binding affinity hotspots R498 and Y501 serve as central mediators of the interfacial communities in the RBD-ACE2 complexes.…”

Section: Discussionmentioning

confidence: 99%

“…A systematic mapping of the epistatic interactions between the 15 BA.1 RBD mutations relative to the Wu-Hu-1 strain showed evidence of compensatory epistasis in which immune escape BA.1 mutations can individually reduce ACE2 binding but are compensated through epistatic couplings with affinity-enhancing mutations including Q498R and N501Y [67]. Recent evolutionary and functional studies revealed strong epistasis between pre-existing substitutions in BA.1/BA.2 variants and antibody resistance mutations acquired during selection experiments, suggesting that epistasis can lower the genetic barrier for antibody escape [68].…”

Section: Introductionmentioning

confidence: 99%

Balancing Functional Tradeoffs between Protein Stability and ACE2 Binding in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB Lineages : Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic and Energetic Changes

Verkhivker

Alshahrani

Gupta

2023

Preprint

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The evolutionary and functional studies suggested that the emergence of the Omicron variants can be determined by multiple fitness trade-offs including the immune escape, binding affinity for ACE2, conformational plasticity, protein stability and allosteric modulation. In this study, we systematically characterize conformational dynamics, protein stability and binding affinities of the SARS-CoV-2 Spike Omicron complexes with the host receptor ACE2 for BA.2 , BA.2.75, XBB.1 and XBB.1.5 variants. We combined multiscale molecular simulations and dynamic analysis of allosteric interactions together with the ensemble-based mutational scanning of the protein residues and network modeling of epistatic interactions. This multifaceted computational study characterized molecular mechanisms and identified energetic hotspots that can mediate the predicted increased stability and the enhanced binding affinity of the BA.2.75 and XBB.1.5 complexes. The results suggested a mechanism driven by the stability hotspots and a spatially localized group of the Omicron binding affinity centers, while allowing for functionally beneficial neutral Omicron mutations in other binding interface positions. A network-based community model for the analysis of non-additive epistatic contributions in the Omicron complexes is proposed revealing the key role of the binding hotspots R498 and Y501 in mediating community-based epistatic couplings with other Omicron sites and allowing for compensatory dynamics and binding energetic changes. The results also showed that mutations in the convergent evolutionary hotspot F486 can modulate not only local interactions but also rewire the global network of local communities in this region allowing the F486P mutation to restore both the stability and binding affinity of the XBB.1.5 variant which may explain the growth advantages over the XBB.1 variant. The results of this study are consistent with a broad range of functional studies rationalizing functional roles of the Omicron mutation sites that form a coordinated network of hotspots enabling balance of multiple fitness tradeoffs and shaping up a complex functional landscape of virus transmissibility.

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“…The latest variant B.1.1.529 (Omicron) and its newer sub-lineages (BA.2, BA.4, BA.5, BQ.1, and XBB.1) have acquired resistance to vaccine-induced immunity and has been infecting large population worldwide (11)(12)(13)(14)(15). It is highly plausible that there is still much more genetic space that SARS-CoV-2 can explore to navigate through host immunity without compromising transmissibility (16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Mutations in S2 subunit of SARS-CoV-2 Omicron spike strongly influence its conformation, fusogenicity and neutralization sensitivity

Kumar

Delipan

Chakraborty

et al. 2023

Preprint

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SARS-CoV-2 has remarkable ability to respond to and evolve against the selection pressure by host immunity exemplified by emergence of Omicron lineage. Here, we characterized the functional significance of mutations in Omicron spike. By systematic transfer of mutations in WT spike we assessed neutralization sensitivity, fusogenicity, and TMPRSS2-dependence for entry. The data revealed that the mutations in both S1 and S2 complement to make Omicron highly resistant. Strikingly, the mutations in Omicron S2 modulated the neutralization sensitivity to NTD- and RBD-antibodies, but not to S2 specific neutralizing antibodies, suggesting that the mutations in S2 were primarily acquired to gain resistance to S1-antibodies. Although all six mutations in S2 appeared to act in concert, D796Y showed greatest impact on neutralization sensitivity and rendered WT virus >100-fold resistant to S309, COVA2-17, and 4A8. S2 mutations greatly reduced the antigenicity for NAbs due to reduced exposure of epitopes. In terms of the entry pathway, S1 or S2 mutations only partially altered the entry phenotype of WT and required both sets of mutations for complete switch to endosomal route and loss of syncytia formation. In particular, N856K and L981F in Omicron reduced fusion capacity and explain why subsequent Omicron variants lost them to regain fusogenicity.

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Epistasis lowers the genetic barrier to SARS-CoV-2 neutralizing antibody escape

Cited by 53 publications

References 40 publications

Identification of broad, potent antibodies to functionally constrained regions of SARS-CoV-2 spike following a breakthrough infection

Identification of broad, potent antibodies to functionally constrained regions of SARS-CoV-2 spike following a breakthrough infection

Balancing Functional Tradeoffs between Protein Stability and ACE2 Binding in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB Lineages : Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic and Energetic Changes

Mutations in S2 subunit of SARS-CoV-2 Omicron spike strongly influence its conformation, fusogenicity and neutralization sensitivity

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