SARS-CoV-2 B.1.1.7 and B.1.351 Spike variants bind human ACE2 with increased affinity

Ramanathan, Muthukumar; Ferguson, Ian; Miao, Weili; Khavari, Paul A.

doi:10.1101/2021.02.22.432359

Cited by 84 publications

(75 citation statements)

References 5 publications

(2 reference statements)

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“…1B). The 3- to 4-fold higher ACE2 binding affinity of the B.1.351 S-Trimer compared to Prototype S-Trimer is similar to previously-reported results ( 18,19,20 ), which appears to be due mainly to a slower off-rate (K off ) and is speculated to further exacerbate the lower potency observed in B.1.351 cross-neutralization assays, since antibodies of lower affinity may struggle to compete with B.1.351 spike protein for ACE2 binding.…”

Section: Resultssupporting

confidence: 92%

Broad neutralization against SARS-CoV-2 variants induced by a modified B.1.351 protein-based COVID-19 vaccine candidate

et al. 2021

Preprint

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Beginning in late 2020, the emergence and spread of multiple variant SARS-CoV-2 strains harboring mutations which may enable immune escape necessitates the rapid evaluation of second generation COVID-19 vaccines, with the goal of inducing optimized immune responses that are broadly protective. Here we demonstrate in a mouse immunogenicity study that two doses of a modified B.1.351 spike (S)-Trimer vaccine (B.1.351 S-Trimer) candidate can induce strong humoral immune responses that can broadly neutralize both the original SARS-CoV-2 strain (Wuhan-Hu-1) and Variants of Concern (VOCs), including the UK variant (B.1.1.7), South African variant (B.1.351) and Brazil variant (P.1). Furthermore, while immunization with two doses (prime-boost) of Prototype S-Trimer vaccine (based on the original SARS-CoV-2 strain) induced lower levels of cross-reactive neutralization against the B.1.351 variant, a third dose (booster) administered with either Prototype S-Trimer or B.1.351 S-Trimer was able to increase neutralizing antibody titers against B.1.351 to levels comparable to neutralizing antibody titers against the original strain elicited by two doses of Prototype S-Trimer.

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Section: Resultssupporting

confidence: 92%

Broad neutralization against SARS-CoV-2 variants induced by a modified B.1.351 protein-based COVID-19 vaccine candidate

et al. 2021

Preprint

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“…Measuring the interactions with ACE2 revealed many SARS-CoV-2 RBD variants with tighter receptor binding. In particular, all 5 of the CDC's variants of concern showed increased binding affinity to ACE2, which is supported by previously reported affinities for B.1.1.7 and B.1.351 (29) and molecular dynamics simulations for B.1.1.7, B.1.351, and P.1 (30).…”

Section: Resultssupporting

confidence: 85%

Massively Multiplexed Affinity Characterization of Therapeutic Antibodies Against SARS-CoV-2 Variants

Engelhart¹,

Lopez²,

Emerson³

et al. 2021

Preprint

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Antibody therapies represent a valuable tool to reduce COVID-19 deaths and hospitalizations. Multiple antibody candidates have been granted emergency use authorization by the FDA and many more are in clinical trials. Most antibody therapies for COVID-19 are engineered to bind to the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein and disrupt its interaction with ACE2. Notably, several SARS-CoV-2 strains have accrued mutations throughout the RBD that improve ACE2 binding affinity, enhance viral transmission, and escape some existing antibody therapies. Here, we measure the binding affinity of 33 therapeutic antibodies against a large panel of SARS-CoV-2 variants and related strains of clinical significance to determine epitopic residues, determine which mutations result in loss of binding, and predict how future RBD variants may impact antibody efficacy.

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“…To our knowledge, comparison of ACE2 affinity and biophysical properties for the SARS-CoV-2 variants S1 domains has not yet been reported. An enhanced affinity has been shown for the RBD domain of the B.1.1.7 and B.1.351 variants, however, this may not reflect the effect of the full S1 domain 41 . To this end, we generated recombinant S1 domains for the SARS-CoV-2 WT (Wuhan Hu-1), D614G, B.1.1.7 and B.1.351 variants to assess ACE2 binding affinities.…”

Section: Discussionmentioning

confidence: 84%

Characterisation of a novel ACE2-based therapeutic with enhanced rather than reduced activity against SARS-CoV2 variants

Ferrari

Mekkaoui

Ilca

et al. 2021

Preprint

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The human angiotensin-converting enzyme 2 acts as the host cell receptor for SARS-CoV-2 and the other members of the Coronaviridae family SARS-CoV-1 and HCoV-NL63. Here we report the biophysical properties of the SARS-CoV-2 spike variants D614G, B.1.1.7 and B.1.351 with affinities to the ACE2 receptor and infectivity capacity, revealing weaknesses in the developed neutralising antibody approaches. Furthermore, we report a pre-clinical characterisation package for a soluble receptor decoy engineered to be catalytically inactive and immunologically inert, with broad neutralisation capacity, that represents an attractive therapeutic alternative in light of the mutational landscape of COVID-19. This construct efficiently neutralised four SARS-CoV-2 variants of concern. The decoy also displays antibody-like biophysical properties and manufacturability, strengthening its suitability as a first-line treatment option in prophylaxis or therapeutic regimens for COVID-19 and related viral infections.

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SARS-CoV-2 B.1.1.7 and B.1.351 Spike variants bind human ACE2 with increased affinity

Cited by 84 publications

References 5 publications

Broad neutralization against SARS-CoV-2 variants induced by a modified B.1.351 protein-based COVID-19 vaccine candidate

Broad neutralization against SARS-CoV-2 variants induced by a modified B.1.351 protein-based COVID-19 vaccine candidate

Massively Multiplexed Affinity Characterization of Therapeutic Antibodies Against SARS-CoV-2 Variants

Characterisation of a novel ACE2-based therapeutic with enhanced rather than reduced activity against SARS-CoV2 variants

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