ACE2 receptor binding affinity
- Reported moderate increase in affinity compared to wild-type RBD on the cell surface (Kd = 38.5nM vs 56.9nM).
(Tian et al. (2021))
- Among the first selected variants in an in vitro evolution experiment for ACE2 binding.
(Zahradnik et al. (2021))
- Experimentally, ACE2 binding affinity increased 0.06 fold (Starr et al. (2020))
T cell evasion
- Analyzing responses to the E484K mutation seen in B.1.351 and P.1 variants, we noted that it did not fall in a region predicted to bind the HLAII alleles tested (table S4). The mutation appeared to have no substantial or differential impact on T cell responses.
(Reynolds et al. (2021))
Antibody epitope effects
- Multiple individuals in two related households were infected with a newly acquired E484K mutation within the B.1.311 lineage.
The timing and patterns of subsequent spread were consistent with de novo emergence of this E484K variant in the initially affected individual who had been treated with bamlanivimab monotherapy.
The subsequent transmission to close contacts occurred several days after the resolution of symptoms and the end of this patient's quarantine period. (Sabin et al. (2021))
- Complete loss of binding in ELISA by the variant against monoclonal antibody VH-Fc ab8 (Sun et al. (2021))
- Of 50 mAbs tested, major loss of neutralization observed for S2N28, S2X615, S2N12, S2X192, S2H7, S2X16, S2X58, S2H70, S2X613, S2D19, S2N22, S2D32, S2H58, S2M11, S2D106, S2X30.
(Collier et al. (2021))
- Monoclonal antibodies 13G9 and 58G6 maintain fairly high neutralization potency, compared to others interfacing with E484K.
(Li et al. (2021))
- Ablates binding by class 2 mAbs such as C144 that directly interfere with ACE2 binding, but clonal somatic mutations of memory B cells at 6.2 months (evolving humoral immune response) show pronounced increase in binding to the variant.
(Gaebler et al. (2021))
- Mutant screen in neutralization assay with a broad range of monoclonal antibodies shows high resistence to 4 antibodies, and broad low level resistence against much of the rest of the panel.
(Liu et al. (2020))
- Resistent to all seven class 2 (Spike 'up' or 'down' conformation, RBD targeting) antibodies tested, with 10-fold or greater reduction in neutralization (plus notable reudction in two unclassfied mAbs).
(Wang et al. (2021))
- Ablates Class 1 receptor-binding-motif targeting antibodies COV2-2050, 1B07, COVOX-384 and S2H58.
(Chen et al. (2021))
- Pseudotyped virus model ablates neutralization by RBD-directed mAbs 4-20, 2-4, 2-43, 2-30, 2-15, LY-Cov555, C121.
Pseudotyped virus model impairs neutralization by RBD-directed mAb COV2-2196 (somewhat more than fully pseudotyped B.1.351 or live virus) (Wang et al. (2021))
- Massive reduction in binding efficiency vs wild type for mAb LY-CoV555.
(Rappazzo et al. (2021))
Convalescent plasma escape
- Escape mutant found after in passage in plasma pool of 26 convalescents mean 1.5 post symptom onset.
(Schmidt et al. (2021))
- As measured by surface plasmon resonance, RBD with the E484K mutation alone showed a mean 19.1x decrease in binding affinity for six batches of hyperimmune immunoglobulin (hCoV-2IG) preparations generated from SARS-CoV-2 convalescent plasma.
(Tang et al. (2021))
- The only mutation in the B.1.351 lineage that appears to contribute to neutralization reduction (~1.7x across 10 convalescent sera from April 2020 infectees) (Tada et al. (2021))
- Average ~5-fold reduction in neutralization efficacy in convalescent sera of 16 health workers infected in Spring 2020.
(Alenquer et al. (2021))
- Subtype of the B.1.526 "New York" lineage, lentivirus pseudotyped with this mutation combination in showed 3.3x reduction in IC50 serum dilution concentration for 6 convalescent sera.
(Zhou et al. (2021))
- Remarkably, several of the E484 escape mutants were resistant to neutralization at the highest concentration (1:80 initial dilution) of all 4 convalescent sera tested (triplicate experiments).
Against a wider panel of 16 convalescent plasma (no replicates), all but one show major resistance. (Liu et al. (2021))
- The neutralizing activity of 15/20 convalescent sera was significantly lower against this pseudotyped virus model (Wang et al. (2021))
- This mutation occurred in 100% of sequenced virions after 12 passages and led to a 4-fold decrease in convalescent plasma neutralization activity (Andreano et al. (2020))
Monoclonal antibody serial passage escape
- Escape variant 100% appearance in 2 passages against Regeneron monoclonal antibody REGN10989 @ 50ug/mL (99% after one passage) (Baum et al. (2020))
- Strong positive selection (up to 50% of supernatant sequences) after C121 monoclonal antibody assay, decreasing in subsequent passages.
Strong positive selection (up to 44% of supernatant sequences) after after one round of C144 monoclonal antibody passage, then waning on subsequent passages (Weisblum et al. (2020))
- The engineered mutation cause 10-fold or more increase in the disassociation constant with many monoclonal antibodies (C144/C002/C121/C104/C110).
(Barnes et al. (2020))
- Mildly effective mutant against this position in the RBD for highly neutralizing COV2-2479 monoclonal antibody.
Effective mutant against this position in the RBD for highly neutralizing COV2-2050 monoclonal antibody (Greaney et al. (2020))
- Escape mutation against monoclonal antibody LY-CoV555 (antibody that forms the basis for Eli Lilly's bamlanivimab) (Starr et al. (2021))
- Class 2 antibodies C627, C602, C671, C643, and class 2/3 antibody C603 selected for the emergence of the E484K mutation in vitro.
(Wang et al. (2021))
- Bamlanivimab (LY-CoV555) lost ~16x binding against this isolated mutation.
Casirivimab lost ~16x binding against this isolated mutation. (Engelhart et al. (2021))
- This variant alone shows a ~5x decrease in cell entry efficiency (RLU measurement in 293T cells) compared to D614G.
(Ferriera et al (2021))
- Lentiviral pseudotyped with this individual mutation from B.1.351 was tested on ACE2.293T cells. Luciferase activity was measured two days postinfection, showing no change in infection rate amongst the cells.
(Tada et al. (2021))
- In this Canadian test-negative study of 324033 individuals, two doses of either mRNA vaccine (BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna)) was not associated with appreciable vaccine escape due to E484K [given Dec 2020-Apr 2021 time frame of the study, this is assumed to entail both .
Beta and Gamma lineages]. (Chung et al. (2021))
Vaccine neutralization efficacy
- Neutralizing antibody titers of non-human primate sera after one or two doses of Ad26.COV2.S (Jannsen vaccine) against the variants containing the E484K substitution in the RBD were present but reduced (fold reduction between 3.35–7.78, 95% confidence interval all above twofold difference, one-sample t test).
(Solfrosi et al. (2021))
- E484K pseudotyped VSV was tested for neutralization in a clonal HEK-293T ACE2 TMPRSS2 cell line optimized for highly efficient S-mediated infection. A cohort of 12 Argentinian recipients of the Gamaleya Sputnik V Ad26 / Ad5 vaccine showed a mean 2.8x decrease in neutralization effiacacy.
(Ikegame et al. (2021))
- Human sera from 5 two-dose Pfizer vaccinated individuals (47-68 days post 1st-dose) neutralized this variant 3.4x less relative to reference USA-WA1/2020 strain.
8 convalescent plasma with weak IgG ELISA titre neutralized this variant 2.4x less relative to reference USA-WA1/2020 strain. One plasma failed to neutralize at all.
11 convalescent plasma with moderate IgG ELISA titre neutralized this variant 4.2x less relative to reference USA-WA1/2020 strain.
11 convalescent plasma with high IgG ELISA titre neutralized this variant 2.6x less relative to reference USA-WA1/2020 strain.
(Jangra et al. (2021))
- Nine stored sera from Pfizer BNT162b2 vaccinees were tested against a range of spike mutation bearing PV. E484K conferred a ten-fold reduction in neutralisation by vaccine sera.
(Ferreira et al. (2021))
- In a cohort of 20 patients 8+ weeks after second vaccine dose of Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines, ELISA tests show 10x reduced efficacy of a majority of isolated antibodies, but only a modest decrease for vaccine plasma overall.
(Wang et al. (2021))
- Estimated free energy change (ddG) for this variant is -0.6 kcal/mol (i.e. destabilizing relative to wild type) (Spratt et al. (2021))
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