Convergence of immune escape strategies highlights plasticity of SARS-CoV-2 spike

The SARS-CoV-2 spike protein is the target of neutralizing antibodies and the immunogen used in all currently approved vaccines. The global spread of the virus has resulted in emergence of lineages which are of concern for the effectiveness of immunotherapies and vaccines based on the early Wuhan isolate. Here we describe two SARS-CoV-2 isolates with large deletions in the N-terminal domain (NTD) of the spike. Cryo-EM structural analysis showed that the deletions result in complete reshaping of the antigenic surface of the NTD supersite. The remodeling of the NTD affects binding of all tested NTD-specific antibodies in and outside of the NTD supersite for both spike variants. A unique escape mechanism with high antigenic impact observed in the ΔN135 variant was based on the loss of the Cys15-Cys136 disulfide due to the P9L-mediated shift of the signal peptide cleavage site and deletion of residues 136-144. Although the observed large loop and disulfide deletions are rare, similar modifications became independently established in several other lineages, highlighting the possibility of a general escape mechanism via the NTD supersite. The observed plasticity of the NTD foreshadows its broad potential for immune escape with the continued spread of SARS-CoV-2. ### Competing Interest Statement The authors declare no competing financial interests. J.J., L.R., M.J.G.B. and J.P.L. are co-inventors on related vaccine patents. X.Y., J.J., L.R., M.J.G.B, S.B., N.J.F.vdB, A.Y.W.V., P.A., J.V., J.N., S.S.and J.P.L. are employees of Janssen Vaccines & Prevention BV J.J., LR, J.V. and J.P.L hold stock of Johnson & Johnson.