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In vitro data suggest that Indian delta variant B.1.617 of SARS-CoV-2 escapes neutralization by both receptor affinity and immune evasion.
Allergy. 2022 01; 77(1):111-117.A

Abstract

BACKGROUND

Emerged mutations can be attributed to increased transmissibility of the B.1.617 and B.1.36 Indian delta variants of SARS-CoV-2, most notably substitutions L452R/E484Q and N440K, respectively, which occur in the receptor-binding domain (RBD) of the Spike (S) fusion glycoprotein.

OBJECTIVE

We aimed to assess the effects of mutations L452R/E484Q and N440K (as well as the previously studied mutation E484K present in variants B.1.351 and P.1) on the affinity of RBD for ACE2, SARS-CoV-2 main receptor. We also aimed to assess the ability of antibodies induced by natural infection or by immunization with BNT162b2 mRNA vaccine to recognize the mutated versions of the RBD, as well as blocking the interaction RBD-ACE2, an important surrogate readout for virus neutralization.

METHODS

To this end, we produced recombinant wild-type RBD, as well as RBD containing each of the mutations L452R/E484Q, N440K, or E484K (the latest present in variants of concern B.1.351 and P.1), as well as the ectodomain of ACE2. Using Biolayer Interferometry (BLI), we measured the binding affinity of RBD for ACE2 and the ability of sera from COVID-19 convalescent donors or subjects immunized with BNT162b2 mRNA vaccine to block this interaction. Finally, we correlated these results with total anti-RBD IgG titers measured from the same sera by direct ELISA.

RESULTS

The binding assays showed L452R/E484Q double-mutant RBD to interact with ACE2 with higher affinity (KD = 4.6 nM) than wild-type (KD = 21.3 nM) or single mutants N440K (KD = 9.9 nM) and E484K (KD = 19.7 nM) RBDs. Meanwhile, the anti-RBD IgG titration resulted in lower recognition of mutants E484K and L452R/E484Q by infection-induced antibodies, whereas only mutant E484K was recognized less by antibodies induced by vaccination. More interestingly, sera from convalescent as well as immunized subjects showed reduced ability to block the interaction between ACE2 and RBD mutants E484K and L452R/E484Q, as shown by the inhibition assays.

CONCLUSION

Our data suggest that the newly emerged SARS-CoV-2 variant B.1.617, as well as the better-studied variants B.1.351 and P.1 (all containing a mutation at position E484) display increased transmissibility both due to their higher affinity for the cell receptor ACE2 and their ability to partially bypass immunity generated against the wild-type virus. For variant B.1.36 (with a point mutation at position N440), only increased affinity seems to play a role.

Authors+Show Affiliations

Department of Immunology, University clinic of Rheumatology and Immunology, Inselspital, Bern, Switzerland. Department of BioMedical Research, University of Bern, Bern, Switzerland. The Jenner Institute, University of Oxford, Oxford, UK.Department of Immunology, University clinic of Rheumatology and Immunology, Inselspital, Bern, Switzerland. Department of BioMedical Research, University of Bern, Bern, Switzerland.Department of Immunology, University clinic of Rheumatology and Immunology, Inselspital, Bern, Switzerland. Department of BioMedical Research, University of Bern, Bern, Switzerland.Department of Immunology, University clinic of Rheumatology and Immunology, Inselspital, Bern, Switzerland. International Immunology Centre, Anhui Agricultural University, Hefei, China.Department of Immunology, University clinic of Rheumatology and Immunology, Inselspital, Bern, Switzerland. Department of BioMedical Research, University of Bern, Bern, Switzerland.Department of Immunology, University clinic of Rheumatology and Immunology, Inselspital, Bern, Switzerland. Department of BioMedical Research, University of Bern, Bern, Switzerland. The Jenner Institute, University of Oxford, Oxford, UK. International Immunology Centre, Anhui Agricultural University, Hefei, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34453338

Citation

Augusto, Gilles, et al. "In Vitro Data Suggest That Indian Delta Variant B.1.617 of SARS-CoV-2 Escapes Neutralization By Both Receptor Affinity and Immune Evasion." Allergy, vol. 77, no. 1, 2022, pp. 111-117.
Augusto G, Mohsen MO, Zinkhan S, et al. In vitro data suggest that Indian delta variant B.1.617 of SARS-CoV-2 escapes neutralization by both receptor affinity and immune evasion. Allergy. 2022;77(1):111-117.
Augusto, G., Mohsen, M. O., Zinkhan, S., Liu, X., Vogel, M., & Bachmann, M. F. (2022). In vitro data suggest that Indian delta variant B.1.617 of SARS-CoV-2 escapes neutralization by both receptor affinity and immune evasion. Allergy, 77(1), 111-117. https://doi.org/10.1111/all.15065
Augusto G, et al. In Vitro Data Suggest That Indian Delta Variant B.1.617 of SARS-CoV-2 Escapes Neutralization By Both Receptor Affinity and Immune Evasion. Allergy. 2022;77(1):111-117. PubMed PMID: 34453338.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro data suggest that Indian delta variant B.1.617 of SARS-CoV-2 escapes neutralization by both receptor affinity and immune evasion. AU - Augusto,Gilles, AU - Mohsen,Mona O, AU - Zinkhan,Simon, AU - Liu,Xuelan, AU - Vogel,Monique, AU - Bachmann,Martin F, Y1 - 2021/09/14/ PY - 2021/08/05/revised PY - 2021/07/06/received PY - 2021/08/10/accepted PY - 2021/8/29/pubmed PY - 2022/1/5/medline PY - 2021/8/28/entrez KW - RBD KW - SARS-CoV-2 KW - affinity KW - neutralization KW - vaccine SP - 111 EP - 117 JF - Allergy JO - Allergy VL - 77 IS - 1 N2 - BACKGROUND: Emerged mutations can be attributed to increased transmissibility of the B.1.617 and B.1.36 Indian delta variants of SARS-CoV-2, most notably substitutions L452R/E484Q and N440K, respectively, which occur in the receptor-binding domain (RBD) of the Spike (S) fusion glycoprotein. OBJECTIVE: We aimed to assess the effects of mutations L452R/E484Q and N440K (as well as the previously studied mutation E484K present in variants B.1.351 and P.1) on the affinity of RBD for ACE2, SARS-CoV-2 main receptor. We also aimed to assess the ability of antibodies induced by natural infection or by immunization with BNT162b2 mRNA vaccine to recognize the mutated versions of the RBD, as well as blocking the interaction RBD-ACE2, an important surrogate readout for virus neutralization. METHODS: To this end, we produced recombinant wild-type RBD, as well as RBD containing each of the mutations L452R/E484Q, N440K, or E484K (the latest present in variants of concern B.1.351 and P.1), as well as the ectodomain of ACE2. Using Biolayer Interferometry (BLI), we measured the binding affinity of RBD for ACE2 and the ability of sera from COVID-19 convalescent donors or subjects immunized with BNT162b2 mRNA vaccine to block this interaction. Finally, we correlated these results with total anti-RBD IgG titers measured from the same sera by direct ELISA. RESULTS: The binding assays showed L452R/E484Q double-mutant RBD to interact with ACE2 with higher affinity (KD = 4.6 nM) than wild-type (KD = 21.3 nM) or single mutants N440K (KD = 9.9 nM) and E484K (KD = 19.7 nM) RBDs. Meanwhile, the anti-RBD IgG titration resulted in lower recognition of mutants E484K and L452R/E484Q by infection-induced antibodies, whereas only mutant E484K was recognized less by antibodies induced by vaccination. More interestingly, sera from convalescent as well as immunized subjects showed reduced ability to block the interaction between ACE2 and RBD mutants E484K and L452R/E484Q, as shown by the inhibition assays. CONCLUSION: Our data suggest that the newly emerged SARS-CoV-2 variant B.1.617, as well as the better-studied variants B.1.351 and P.1 (all containing a mutation at position E484) display increased transmissibility both due to their higher affinity for the cell receptor ACE2 and their ability to partially bypass immunity generated against the wild-type virus. For variant B.1.36 (with a point mutation at position N440), only increased affinity seems to play a role. SN - 1398-9995 UR - https://www.unboundmedicine.com/medline/citation/34453338/In_vitro_data_suggest_that_Indian_delta_variant_B_1_617_of_SARS_CoV_2_escapes_neutralization_by_both_receptor_affinity_and_immune_evasion_ L2 - https://doi.org/10.1111/all.15065 DB - PRIME DP - Unbound Medicine ER -