Comparative Analysis of Emerging B.1.1.7+E484K SARS-CoV-2 Isolates

Moustafa, Ahmed; Bianco, Colleen; Denu, Lidiya; Ahmed, Anwar; Coffin, Susan; Neide, Brandy; Everett, J.K.; Reddy, Shantan; Rabut, Emilie; Deseignora, Jasmine; Feldman, Michael D.; Rodino, Kyle G.; Bushman, Frederic D.; Harris, Rebecca M.; Mell, Josh Chang; Planet, Paul J.

doi:10.1093/ofid/ofab300

Cited by 16 publications

(14 citation statements)

References 19 publications

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“…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 . Collier and coworkers very recently reported that the introduction of the E484K mutation in the B.1.1.7 background (to account for the new VOC B.1.1.7 + E484K found in the virus isolated both in UK and in Pennsylvania, USA) 75 led to robust loss of neutralizing activity by 19 out of 31 vaccine-elicited antibodies and mAbs if compared with the decrease in sensitivity conferred by the mutations in B.1.1.7 alone 76 . Moreover, the E484Q/V/A/G/D mutations have been just described by Chen et al as critical in promoting escape not only from Eli Lilly mAbs but also from other similar therapeutics that are currently in clinical trials 77 .…”

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

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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.

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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

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“…An additional substitution E484K was added to the original Alpha variant (Alpha+E484K) as this mutation occurred in many clinical isolates. 16 The spike genes from all recombinant viruses were sequenced to ensure no aberrant mutations. Comparable ratios of viral RNA copies versus plaque-forming units (RNA/PFU) were found for both WT and chimeric viruses when produced and analyzed on Vero E6 cells ( Extended Data Fig.…”

Section: Resultsmentioning

confidence: 99%

Distinct neutralizing kinetics and magnitudes elicited by different SARS-CoV-2 variant spikes

Liu

Zou

et al. 2021

Preprint

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The rapid evolution of SARS-CoV-2 mandates a better understanding of cross-protection between variants after vaccination or infection, but studies directly evaluating such cross-protection are lacking. Here we report that immunization with different variant spikes elicits distinct neutralizing kinetics and magnitudes against other SARS-CoV-2 variants. After immunizing hamsters with wild-type or mutant SARS-CoV-2 bearing variant spikes from Alpha, Beta, Gamma, or Epsilon, the animals developed faster and greater neutralization activities against homologous SARS-CoV-2 variants than heterologous variants, including Delta. The rank of neutralizing titers against different heterologous variants varied, depending on the immunized variant spikes. The differences in neutralizing titers between homologous and heterologous variants were as large as 62-, 15-, and 9.7-fold at days 14, 28, and 45 post-immunization, respectively. Nevertheless, all immunized hamsters were protected from challenges with all SARS-CoV-2 variants, including those exhibiting the lowest neutralizing antibody titers. The results provide insights into the COVID-19 vaccine booster strategies.

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“…Similarly, the Delta variant is represented by 47 distinct CCs. This adds granularity for investigating outbreaks, local patterns, and emerging variants within a particular lineage ( Moustafa et al 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Emerging SARS-CoV-2 Diversity Revealed by Rapid Whole-Genome Sequence Typing

Moustafa

Planet

2021

Genome Biology and Evolution

Self Cite

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Background Discrete classification of SARS-CoV-2 viral genotypes can identify emerging strains and detect geographic spread, viral diversity, and transmission events. Methods We developed a tool (GNUVID) that integrates whole genome multilocus sequence typing and a supervised machine learning random forest-based classifier. We used GNUVID to assign sequence type (ST) profiles to all high-quality genomes available from GISAID. STs were clustered into clonal complexes (CCs), and then used to train a machine learning classifier. We used this tool to detect potential introduction and exportation events, and to estimate effective viral diversity across locations and over time in 16 US states. Results GNUVID is a highly scalable tool for viral genotype classification (https://github.com/ahmedmagds/GNUVID) that can quickly classify hundreds of thousands of genomes in a way that is consistent with phylogeny. Our genotyping ST/CC analysis uncovered dynamic local changes in ST/CC prevalence and diversity with multiple replacement events in different states, an average of 20.6 putative introductions and 7.5 exportations for each state over the time period analyzed. We introduce the use of effective diversity metrics (Hill numbers) that can be used to estimate the impact of interventions (eg., travel-restrictions, vaccine uptake, mask mandates) on the variation in circulating viruses. Conclusions Our classification tool uncovered multiple introduction and exportation events, as well as waves of expansion and replacement of SARS-CoV-2 genotypes in different states. GNUVID classification lends itself to measures of ecological diversity, and, with systematic genomic sampling, it could be used to track circulating viral diversity and identify emerging clones and hotspots.

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Comparative Analysis of Emerging B.1.1.7+E484K SARS-CoV-2 Isolates

Cited by 16 publications

References 19 publications

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

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

Distinct neutralizing kinetics and magnitudes elicited by different SARS-CoV-2 variant spikes

Emerging SARS-CoV-2 Diversity Revealed by Rapid Whole-Genome Sequence Typing

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