Molecular definition of severe acute respiratory syndrome coronavirus 2 receptor‐binding domain mutations: Receptor affinity versus neutralization of receptor interaction

Vogel, Monique; Augusto, Gilles; Chang, Xinyue; Liu, Xuelan; Speiser, Daniel E.; Mohsen, Mona O.; Bachmann, Martin F.

doi:10.1111/all.15002

Cited by 28 publications

(39 citation statements)

References 33 publications

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“…BLI sensorgrams illustrating the interaction between ACE2 and (A) wild-type RBD (RBD WT ); (B) E484K single-mutant RBD (RBD E484K ); (C) L452R/E484Q double-mutant RBD (RBD L452R/E484Q ; and (D)) N440 singlemutant RBD (RBD N440K ) Note: *RBD WT =Receptor-Binding Domain wild type, *RBD L452R/E484Q = Receptor-Binding Domain L452R, E484Q mutations, *RBD E484K = Receptor-Binding Domain E484K mutation, *RBD N440K = Receptor-Binding Domain N440Kmutation.TA B L E 1 Kinetic parameters for the RBD-ACE2 interaction calculated by BLIThis result is not surprising, as mutation E484K has already been shown to evade immunity in the context of variants B.1.351 and P.1 12,13,16. Likewise point mutations conferred by L452R or E484Q alone have been shown to reduce sensitivity to antibodies elicited by BNT162b2 vaccine 17.…”

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confidence: 89%

In vitro data suggest that Indian delta variant B.1.617 of SARS‐CoV‐2 escapes neutralization by both receptor affinity and immune evasion

Augusto

Mohsen

Zinkhan

et al. 2021

Allergy

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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 (K D = 4.6 nM) than wild‐type (K D = 21.3 nM) or single mutants N440K (K D = 9.9 nM) and E484K (K D = 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.

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confidence: 89%

In vitro data suggest that Indian delta variant B.1.617 of SARS‐CoV‐2 escapes neutralization by both receptor affinity and immune evasion

Augusto

Mohsen

Zinkhan

et al. 2021

Allergy

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“…Subsequent reports have demonstrated that increased transmissibility and immune escape are linked to these lineages, which are defined by spike receptor binding domain (RBD) mutations, including N501Y, K417N/T, L452R, and E484K. Notably, the E484K and L452R mutations in RBD had previously been demonstrated to confer immune escape in cell culture selection experiments 5 , which is consistent with their increasing prevalence 6,7 , possibly due to increased viral fitness 8,9 . Therefore, vigilant monitoring of circulating strains for these mutations is of critical importance for potentially preventing their spread.…”

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confidence: 68%

“…In addition to strains carrying L452R individually, variant strains carrying a combination of L452R + N501Y (3/117, 2.6%) were also identified. The N501Y mutation confers higher affinity for the ACE2 receptor and is present in several variants of concern (alpha, beta, gamma) while L452R is a signature escape mutation found in the delta and epsilon lineages that also increases infectivity 4,8,9,15,16 . The combination of both of these mutations in one strain is of concern for potential rapid spread of an immune escape variant.…”

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confidence: 99%

Emergence of novel combinations of SARS-CoV-2 spike receptor binding domain variants in Senegal

Ahouidi

Rodgers

Padane

et al. 2021

Sci Rep

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The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages that carry mutations in the spike gene are of concern for potential impact to treatment and prevention efforts. To monitor for new SARS-CoV-2 mutations, a panel of specimens were sequenced from both wave one (N = 96), and wave two (N = 117) of the pandemic in Senegal by whole genome next generation sequencing. Amongst these genomes, new combinations of SARS-CoV-2 spike mutations were identified, with E484K + N501T, L452R + N501Y, and L452M + S477N exclusively found in second wave specimens. These sequences are evidence of local diversification over the course of the pandemic and parallel evolution of escape mutations in different lineages.

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“…Contrary were the results with the E484K mutation, where no enhanced binding to ACE2 was shown but much lower recognition by convalescent sera. Triple mutant RBD (K417N/E484K/N501Y) exhibited both features: stronger affinity to ACE2 and much lower detection by convalescent sera 33 . Since vaccines optimally mediate protection for many years, vaccine induced Abs should therefore be able to recognize new virus variants as well.…”

Section: Discussionmentioning

confidence: 99%

Intranasal administration of a VLP-based vaccine against COVID-19 induces neutralizing antibodies against SARS-CoV-2 and Variants of Concerns

Rothen

Krenger

Nonic

et al. 2021

Preprint

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Background: The highly contagious SARS-CoV-2 is mainly transmitted by respiratory droplets and aerosols. Consequently, people are required to wear masks and maintain a social distance to avoid spreading of the virus. Despite the success of the commercially available vaccines, the virus is still uncontained globally. Given the tropism of SARS-CoV-2, a mucosal immune reaction would help to reduce viral shedding and transmission locally. Only seven out of hundreds of ongoing clinical trials are testing the intranasal delivery of COVID-19 vaccines. Methods: In the current study, we tested in murine model the immunogenicity of a conventional vaccine platform based on virus-like particles (VLPs) displaying RBD of SARS-CoV-2 for intranasal vaccination. The candidate vaccine, CuMVTT-RBD, has been immunologically optimized to incorporate tetanus-toxin and is self-adjuvanted with TLR7/8 ligands. Results: CuMVTT-RBD elicited strong RBD- and spike- specific systemic IgG and IgA antibody responses of high avidity. Local immune responses were assessed and results demonstrate strong mucosal antibody and plasma cell production in lung tissue. The induced systemic antibodies could efficiently recognize and neutralize different Variants of Concerns of mutated SARS-CoV-2 RBDs. Conclusion: In summary, intranasal vaccination with CuMVTT-RBD shows high immunogenicity and induces protective systemic and local specific antibody response against SARS-CoV-2 and its variants.

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Molecular definition of severe acute respiratory syndrome coronavirus 2 receptor‐binding domain mutations: Receptor affinity versus neutralization of receptor interaction

Cited by 28 publications

References 33 publications

In vitro data suggest that Indian delta variant B.1.617 of SARS‐CoV‐2 escapes neutralization by both receptor affinity and immune evasion

In vitro data suggest that Indian delta variant B.1.617 of SARS‐CoV‐2 escapes neutralization by both receptor affinity and immune evasion

Emergence of novel combinations of SARS-CoV-2 spike receptor binding domain variants in Senegal

Intranasal administration of a VLP-based vaccine against COVID-19 induces neutralizing antibodies against SARS-CoV-2 and Variants of Concerns

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