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bioRxiv · 10.1101/2021.07.23.453327

Mutations in two SARS-CoV-2 variants of concern reflect two distinct strategies of antibody escape

Fiedler, S.·Denninger, V.·Morgunov, A. S.·Ilsley, A.·Worth, R.·Meisl, G.·Xu, C. K.·Piziorska, M. A.·Ricci, F.·Malik, A. Y.·Devenish, S. R. A.·Schneider, M. M.·Kosmoliaptsis, V.·Aguzzi, A.·Iwasaki, A.·Fiegler, H.·Knowles, T. P. J.
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Abstract

Understanding the factors that contribute to antibody escape of SARS-CoV-2 and its variants is key for the development of drugs and vaccines that provide broad protection against a variety of virus variants. Using microfluidic diffusional sizing, we determined the dissociation constant (KD) for the interaction between receptor binding domains (RBDs) of SARS-CoV-2 in its original version (WT) as well as alpha and beta variants with the host-cell receptor angiotensin converting enzyme 2 (ACE2). For RBD-alpha, the ACE2-binding affinity was increased by a factor of ten when compared with RBD-WT, while ACE2-binding of RBD-beta was largely unaffected. However, when challenged with a neutralizing antibody that binds to both RBD-WT and RBD-alpha with low nanomolar KD values, RBD-beta displayed no binding, suggesting a substantial epitope change. In SARS-CoV-2 convalescent sera, RBD-binding antibodies showed low nanomolar affinities to both wild-type and variant RBD proteins--strikingly, the concentration of antibodies binding to RBD-beta was half that of RBD-WT and RBD-alpha, again indicating considerable epitope changes in the beta variant. Our data therefore suggests that one factor contributing to the higher transmissibility and antibody evasion of SARS-CoV-2 alpha and beta is a larger fraction of viruses that can form a complex with ACE2. However, the two variants employ different mechanisms to achieve this goal. While SARS-CoV-2 alpha RBD binds with greater affinity to ACE2 and is thus more difficult to displace from the receptor by neutralizing antibodies, RBD-beta is less accessible to antibodies due to epitope changes which increases the chances of ACE2-binding and infection.

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Fiedler, S., Denninger, V., Morgunov, A. S., Ilsley, A., Worth, R., Meisl, G., Xu, C. K., Piziorska, M. A., Ricci, F., Malik, A. Y., Devenish, S. R. A., Schneider, M. M., Kosmoliaptsis, V., Aguzzi, A., Iwasaki, A., Fiegler, H., Knowles, T. P. J.. 2021-07-26. Mutations in two SARS-CoV-2 variants of concern reflect two distinct strategies of antibody escape. https://doi.org/10.1101/2021.07.23.453327

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