The alpha/B.1.1.7 SARS-CoV-2 variant exhibits significantly higher affinity for ACE-2 and requires lower inoculation doses to cause disease in K18-hACE2 mice
Rafael Bayarri-Olmos,
Laust Bruun Johnsen,
Manja Idorn,
Line S Reinert,
Anne Rosbjerg,
Søren Vang,
Cecilie Bo Hansen,
Charlotte Helgstrand,
Jais Rose Bjelke,
Theresa Bak-Thomsen,
Søren R Paludan,
Peter Garred,
Mikkel-Ole Skjoedt
Affiliations
Rafael Bayarri-Olmos
Recombinant Protein and Antibody Laboratory, Copenhagen University Hospital, Copenhagen, Denmark; Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
Laust Bruun Johnsen
Novo Nordisk A/S, Måløv, Denmark
Manja Idorn
Department of Biomedicine, Aarhus University, Århus, Denmark
Line S Reinert
Department of Biomedicine, Aarhus University, Århus, Denmark
Anne Rosbjerg
Recombinant Protein and Antibody Laboratory, Copenhagen University Hospital, Copenhagen, Denmark; Institute of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
Søren Vang
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
Cecilie Bo Hansen
Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
Charlotte Helgstrand
Novo Nordisk A/S, Måløv, Denmark
Jais Rose Bjelke
Novo Nordisk A/S, Måløv, Denmark
Theresa Bak-Thomsen
Novo Nordisk A/S, Måløv, Denmark
Søren R Paludan
Department of Biomedicine, Aarhus University, Århus, Denmark
Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark; Institute of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
The alpha/B.1.1.7 SARS-CoV-2 lineage emerged in autumn 2020 in the United Kingdom and transmitted rapidly until winter 2021 when it was responsible for most new COVID-19 cases in many European countries. The incidence domination was likely due to a fitness advantage that could be driven by the receptor-binding domain (RBD) residue change (N501Y), which also emerged independently in other variants of concern such as the beta/B.1.351 and gamma/P.1 strains. Here, we present a functional characterization of the alpha/B.1.1.7 variant and show an eightfold affinity increase towards human angiotensin-converting enzyme-2 (ACE-2). In accordance with this, transgenic hACE2 mice showed a faster disease progression and severity after infection with a low dose of B.1.1.7, compared to an early 2020 SARS-CoV-2 isolate. When challenged with sera from convalescent individuals or anti-RBD monoclonal antibodies, the N501Y variant showed a minor, but significant elevated evasion potential of ACE-2/RBD antibody neutralization. The data suggest that the single asparagine to tyrosine substitution remarkable rise in affinity may be responsible for the higher transmission rate and severity of the B.1.1.7 variant.
