An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer

Suryadevara, Naveenchandra; Shiakolas, Andrea R; VanBlargan, Laura A.; Binshtein, Elad; Chen, Rita; Case, James Brett; Kramer, Kevin J.; Armstrong, Erica; Myers, Luke; Trivette, Andrew; Gainza, Christopher; Nargi, Rachel S.; Selverian, Christopher N; Davidson, Edgar; Doranz, Benjamin J.; Diaz, Summer M; Handal, Laura S; Carnahan, Robert H.; Diamond, Michael S.; Georgiev, Ivelin S.; Crowe, James E.

doi:10.1101/2022.01.12.476120

Cited by 3 publications

(2 citation statements)

References 61 publications

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“…S1D). It should be noted that several NTD-binding neutralizing antibodies have been identified in the past (34,35), indicating that mutations in this domain may indeed interfere with the immune system's capacity to recognize the virus. Even more interestingly, we show that the deletion of the MPLF insertion at position 16 or reinsertion of Y at position 144 increases neutralization efficiency after the adapted XBB.1.5 vaccination to BA.2 levels.…”

Section: Discussionmentioning

confidence: 99%

Reverse mutational scanning of spike BA.2.86 identifies epitopes contributing to immune escape from polyclonal sera

Bdeir,

Lüddecke,

Maaß

et al. 2024

Preprint

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SUMMARYThe recently detected Omicron BA.2.86 lineage contains more than 30 amino acid mutations relative to BA.2. Here, we identify the epitopes driving immune escape of BA.2.86 and its derivative JN.1 (BA.2.86 + S455L) lineage. We investigated the cross-reactive humoral immunity within a cohort of health care workers against Omicron BA.2.86 and JN.1 by employing pseudo-viral mutants. We demonstrate that BA.2.86 and especially JN.1 evaded neutralization by serum antibodies of fully vaccinated individuals. To discern the contribution of individual epitope mutations to immune escape, we constructed a library of 33 BA.2.86 mutants, each of which harbored a single revertant mutation going back to BA.2. This library was used in a reverse mutational scanning approach to define serum neutralization titers against each epitope separately. The mutations within the receptor binding domain (RBD) at position K356T and to a lesser extent the mutations N460K, V483Δ, A484K, and F486P enhanced the immune escape. More surprisingly, the mutation 16insMPLF within the spike N-terminal domain (NTD) and the mutation P621S in S1/S2 significantly contributed to antibody escape of BA.2.86. Upon XBB.1.5 booster vaccination, neutralization titers against JN.1 and BA.2.86 improved relative to all ancestral strains, and the residual immune escape was driven by mutations at positions 16insMPLF, Δ144Y, E544K, P621S, and A484K.

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Section: Discussionmentioning

confidence: 99%

Reverse mutational scanning of spike BA.2.86 identifies epitopes contributing to immune escape from polyclonal sera

Bdeir,

Lüddecke,

Maaß

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…The S trimer residue F43 lies at an interface between adjacent monomers and plays an important role in modulating inter-protomer packing and antibody binding. In fact, the recent experimental studies that employed alanine-scanning loss-of-binding experiments for COV2-3434 and COV2-3439 antibodies identified the primary residues F43, F175, L176, and L226 as critical for binding of COV2-3434 [96]. Despite the presence of commonly shared stability clusters, the results revealed denser distributions for the BA.…”

Section: Sars-cov-2 S Omicron Subvariantsmentioning

confidence: 99%

Coarse-Grained Molecular Simulations and Ensemble-Based Mutational Profiling of Protein Stability in the Different Functional Forms of the SARS-CoV-2 Spike Trimers : Balancing Stability and Adaptability in BA.1, BA.2 and BA.2.75 Variants

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, conformational plasticity, protein stability and allosteric modulation. In this study, we embarked on a systematic comparative analysis of the conformational dynamics, electrostatics, protein stability and allostery in the different functional states of spike trimers for BA.1, BA.2, and BA.2.75 variants. Using efficient and accurate coarse-grained simulations and atomistic reconstruction of the ensembles, we examined conformational dynamics of the spike trimers that agrees with the recent functional studies, suggesting that BA.2.75 trimers are the most stable among these variants. A systematic mutational scanning of the inter-protomer interfaces in the spike trimers revealed a group of conserved structural stability hotspots that play a key role in modulation of functional dynamics and are also involved in the inter-protomer couplings through local contacts and interaction networks with the Omicron mutational sites. The results of mutational scanning provided evidence that BA.2.75 trimers are more stable than BA.2 and comparable in stability to BA.1 variant. Using dynamic network modeling of the S Omicron BA.1, BA.2 and BA.2.75 trimers we showed that the key network positions driving long-range signaling are associated with the major stability hotspots that are inter-connected along potential communication pathways, while sites of Omicron mutations may often correspond to weak spots of stability and allostery but are coupled to the major stability hotspots through interaction networks. The presented analysis of the BA.1, BA.2 and BA.2.75 trimers suggested that thermodynamic stability of BA.1 and BA.2.75 variants may be intimately linked with the residue interaction network organization that allows for a broad ensemble of allosteric communications in which signaling between structural stability hotspots may be modulated by the Omicron mutational sites. The findings provided plausible rationale for mechanisms in which Omicron mutations can evolve to balance thermodynamic stability and conformational adaptability in order to ensure proper tradeoff between stability, binding and immune escape.

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High resolution cryo-EM structures of two potently SARS-CoV-2 neutralizing monoclonal antibodies of same donor origin that vary in neutralizing Omicron variants

Rencilin

Ansari

Chatterjee

et al. 2022

Preprint

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While vaccines have by large been found to effective against the evolving SARS-CoV-2 variants, the profound and rapid effectivity of monoclonal antibodies (mAbs) in significantly reducing hospitalization to severe disease outcomes have also been demonstrated. In the present study, by high resolution cryo-electron microscopy (cryo-EM), we examined the structural insights of two trimeric spike (S) protein bound mAbs isolated from an Indian convalescent individual infected with ancestral SARS-CoV-2 which we recently reported to potently neutralize SARS-CoV-2 from its ancestral form through highly virulent Delta form however different in their ability to neutralize Omicron variants. Our findings showed binding and conformational heterogeneities of both the mAbs (THSC20.HVTR04 and THSC20.HVTR26) bound to S trimer in its apo and hACE-2 bound forms. Additionally, cryo-EM resolved structure assisted modeling highlighted key residues associated with the ability of these two mAbs to neutralize Omicron variants. Our findings highlighted key interacting features modulating antigen-antibody interacting that can further aid in structure guided antibody engineering to enhance their breadth and potency.

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An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer

Cited by 3 publications

References 61 publications

Reverse mutational scanning of spike BA.2.86 identifies epitopes contributing to immune escape from polyclonal sera

Reverse mutational scanning of spike BA.2.86 identifies epitopes contributing to immune escape from polyclonal sera

Coarse-Grained Molecular Simulations and Ensemble-Based Mutational Profiling of Protein Stability in the Different Functional Forms of the SARS-CoV-2 Spike Trimers : Balancing Stability and Adaptability in BA.1, BA.2 and BA.2.75 Variants

High resolution cryo-EM structures of two potently SARS-CoV-2 neutralizing monoclonal antibodies of same donor origin that vary in neutralizing Omicron variants

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