Antibody Affinity Governs the Inhibition of SARS-CoV-2 Spike/ACE2 Binding in Patient Serum

Sebastian Fiedler, Monika A. Piziorska, Viola Denninger, Alexey S. Morgunov, Alison Ilsley, Anisa Y. Malik, Matthias M. Schneider, Sean R. A. Devenish, Georg Meisl, Adriano Aguzzi, Heike Fiegler, Tuomas P. J. Knowles

ACS Infect. Dis. 2021


The humoral immune response plays a key role in suppressing the pathogenesis of SARS-CoV-2. The molecular determinants underlying the neutralization of the virus remain, however, incompletely understood. Here, we show that the ability of antibodies to disrupt the binding of the viral spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor on the cell, the key molecular event initiating SARS-CoV-2 entry into host cells, is controlled by the affinity of these antibodies to the viral antigen.

By using microfluidic antibody-affinity profiling, we were able to quantify the serum-antibody mediated inhibition of ACE2–spike binding in two SARS-CoV-2 seropositive individuals. Measurements to determine the affinity, concentration, and neutralization potential of antibodies were performed directly in human serum. Using this approach, we demonstrate that the level of inhibition in both samples can be quantitatively described using the binding energies of the binary interactions between the ACE2 receptor and the spike protein, and the spike protein and the neutralizing antibody. These experiments represent a new type of in-solution receptor binding competition assay, which has further potential areas of application ranging from decisions on donor selection for convalescent plasma therapy, to identification of lead candidates in therapeutic antibody development, and vaccine development.

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