Mapping mutations to the SARS-CoV-2 RBD that escape binding by different classes of antibodies

Greaney, Allison J; Starr, Tyler N; Barnes, Christopher O.; Weisblum, Yiska; Schmidt, Fabian; Caskey, Marina; Gaebler, Christian; Cho, Alice; Agudelo, Marianna; Finkin, Shlomo; Wang, Zijun; Poston, Daniel; Muecksch, Frauke; Hatziioannou, Théodora; Bieniasz, Paul D.; Robbiani, Davide F.; Nussenzweig, Michel C.; Björkman, Pamela J.; Bloom, Jesse D

doi:10.1038/s41467-021-24435-8

Cited by 383 publications

(492 citation statements)

References 71 publications

(178 reference statements)

Supporting

Mentioning

472

Contrasting

Order By: Relevance

“…Despite success in identifying neutralizing S1 epitopes on SARS-CoV-2 that block ACE2 interactions 6,28-33 , even broadly neutralizing RBD antibodies may be susceptible to escape [34][35][36] which has motivated interest in the more conserved S2 domain. Over 200 S2 targeting antibodies have been reported 7 , but very few have been described in detail.…”

Section: Discussionmentioning

confidence: 99%

Identification of a conserved neutralizing epitope present on spike proteins from all highly pathogenic coronaviruses

Huang

Nguyen

Hsieh

et al. 2021

Preprint

View full text Add to dashboard Cite

Three pathogenic human coronaviruses have emerged, with SARS-CoV-2 causing a global pandemic. While therapeutic antibodies targeting the SARS-2 spike currently focus on the poorly conserved receptor-binding domain, targeting essential neutralizing epitopes on the more conserved S2 domain may provide broader protection. We report three antibodies, binding epitopes conserved on the pre-fusion MERS, SARS-1 and SARS-2 spike S2 domains. Antibody 3A3 binds a conformational epitope with ~2.5 nM affinity and neutralizes in in vitro SARS-2 cell fusion and pseudovirus assays. Hydrogen-deuterium exchange mass spectrometry identified residues 980-1006 in the flexible hinge region at the S2 apex as the 3A3 epitope, consistent with binding to natural and engineered spike variants. This location at the spike trimer interface suggests 3A3 prevents the S2 conformational rearrangements required for virus-host cell fusion. This work defines a highly conserved vulnerable site on the SARS-2 S2 domain and may help guide the design of pan-protective spike immunogens.TEASERA conserved, neutralizing epitope in the S2 domain of coronavirus spike was identified as a target for pan-coronavirus therapy and vaccination.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of a conserved neutralizing epitope present on spike proteins from all highly pathogenic coronaviruses

Huang

Nguyen

Hsieh

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…S1 , Table 2 and Tables S4 , S5 ). From a validation standpoint, the E484K mutation is present in a large number of VOC/VOI/VUM—including the lineages B.1.525 (now Eta, firstly reported in Nigeria on 12/20), P.1 (now Gamma) and P.2 (now Zeta, Brazil, 12/20), P.3 (now Theta, The Philippines, 01/21), B.1.351 (now Beta, South Africa, 09/20), B.1.621 (Colombia, 01/2021), and some strains of lineages B.1.1.7 (firstly reported in the United Kingdom on 09/20, now Alpha) and B.1.526 (reported on 11/20 in the city of New York, USA, now Iota) 51 , 52 —and it is indeed well known to confer substantial loss of sensitivity to neutralizing Abs found in sera of convalescent and vaccinated individuals 59 – 70 . Further, for all these variants there is evidence of a significant reduction in neutralization by the LY-CoV555/LY-CoV016 and other mAb treatments 56 , 70 – 74 .…”

Section: Discussionmentioning

confidence: 99%

Molecular rationale for SARS-CoV-2 spike circulating mutations able to escape bamlanivimab and etesevimab monoclonal antibodies

Laurini

Aulić

Fermeglia

et al. 2021

Sci Rep

View full text Add to dashboard Cite

The purpose of this work is to provide an in silico molecular rationale of the role eventually played by currently circulating mutations in the receptor binding domain of the SARS-CoV-2 spike protein (S-RBDCoV‑2) in evading the immune surveillance effects elicited by the two Eli Lilly LY-CoV555/bamlanivimab and LY-CoV016/etesevimab monoclonal antibodies. The main findings from this study show that, compared to the wild-type SARS-CoV-2 spike protein, mutations E484A/G/K/Q/R/V, Q493K/L/R, S494A/P/R, L452R and F490S are predicted to be markedly resistant to neutralization by LY-CoV555, while mutations K417E/N/T, D420A/G/N, N460I/K/S/T, T415P, and Y489C/S are predicted to confer LY-CoV016 escaping advantage to the viral protein. A challenge of our global in silico results against relevant experimental data resulted in an overall 90% agreement. Thus, the results presented provide a molecular-based rationale for all relative experimental findings, constitute a fast and reliable tool for identifying and prioritizing all present and newly reported circulating spike SARS-CoV-2 variants with respect to antibody neutralization, and yield substantial structural information for the development of next-generation vaccines and monoclonal antibodies more resilient to viral evolution.

show abstract

“…Due to its occurrence in several highly transmissible variants, the RBD mutation L452R/Q has recently gained much attention. It was reported to increase viral infectivity and spread and to confer partial immune escape [44,[64][65][66]69,72,73]. Substitution of the adjacent position Y453F was previously observed in a virus cluster from minks in mid-2020 (lineage B.1.1.298) and displayed increased interaction with both mink and human ACE2 receptors [35,56,74,75].…”

Section: Origin and Evolution Of Sars-cov-2 In Humansmentioning

confidence: 93%

“…Besides affecting the interaction with ACE2, RBD mutations K417N, N439K and F490S also contribute to immune escape (Figure 1, upper right panel) [44,45,57,[61][62][63][64][65][66][67]. Interestingly, as in case of the K417N mutation, the substitution of Y449 to a histidine, which recently emerged on the RBD surface of C. 1.2 variants has also been reported to reduce ACE2 receptor binding but confers immune escape to certain class 1 and class 3 antibodies [56,64,65,67]. However, the best characterized immune escape mutation resides at position E484K/Q.…”

Section: Origin and Evolution Of Sars-cov-2 In Humansmentioning

confidence: 99%

“…This mutation independently emerged worldwide and is prevalent in most variants, including Beta, Gamma, Delta, Zeta, Eta, Iota, C.1.2 and also in several isolates of the B.1.1.7 lineage (denoted as B.1.1.7+E484K) [68,69]. E484K is majorly responsible for reduced neutralization by either infection-induced antibodies or commercially available mAbs, such as Bamlanivimab that is used for COVID-19 treatments in immune suppressed patients and known to induce the emergence of E484K [40][41][42][43][44][45][46]48,[64][65][66][67]70,71].…”

Section: Origin and Evolution Of Sars-cov-2 In Humansmentioning

confidence: 99%

See 1 more Smart Citation

Shooting at a Moving Target—Effectiveness and Emerging Challenges for SARS-CoV-2 Vaccine Development

et al. 2021

View full text Add to dashboard Cite

Since late 2019 the newly emerged pandemic SARS-CoV-2, the causative agent of COVID‑19, has hit the world with recurring waves of infections necessitating the global implementation of non-pharmaceutical interventions, including strict social distancing rules, the wearing of masks and the isolation of infected individuals in order to restrict virus transmissions and prevent the breakdown of our healthcare systems. These measures are not only challenging on an economic level but also have a strong impact on social lifestyles. Using traditional and novel technologies, highly efficient vaccines against SARS-CoV-2 were developed and underwent rapid clinical evaluation and approval to accelerate the immunization of the world population, aiming to end the pandemic and return to normality. However, the emergence of virus variants with improved transmission, enhanced fitness and partial immune escape from the first generation of vaccines poses new challenges, which are currently being addressed by scientists and pharmaceutical companies all over the world. In this ongoing pandemic, the evaluation of SARS-CoV-2 vaccines underlies diverse unpredictable dynamics, posed by the first broad application of the mRNA vaccine technology and their compliance, the occurrence of unexpected side effects and the rapid emergence of variations in the viral antigen. However, despite these hurdles, we conclude that the available SARS-CoV-2 vaccines are very safe and efficiently protect from severe COVID-19 and are thereby the most powerful tools to prevent further harm to our healthcare systems, economics and individual lives. This review summarizes the unprecedented pathways of vaccine development and approval during the ongoing SARS-CoV-2 pandemic. We focus on the real-world effectiveness and unexpected positive and negative side effects of the available vaccines and summarize the timeline of the applied adaptations to the recommended vaccination strategies in the light of emerging virus variants. Finally, we highlight upcoming strategies to improve the next generations of SARS-CoV-2 vaccines.

show abstract

Mapping mutations to the SARS-CoV-2 RBD that escape binding by different classes of antibodies

Cited by 383 publications

References 71 publications

Identification of a conserved neutralizing epitope present on spike proteins from all highly pathogenic coronaviruses

Identification of a conserved neutralizing epitope present on spike proteins from all highly pathogenic coronaviruses

Molecular rationale for SARS-CoV-2 spike circulating mutations able to escape bamlanivimab and etesevimab monoclonal antibodies

Shooting at a Moving Target—Effectiveness and Emerging Challenges for SARS-CoV-2 Vaccine Development

Contact Info

Product

Resources

About