SARS-CoV-2 501Y.V2 (B.1.351), a novel lineage of coronavirus causing COVID-19, contains substitutions in two immunodominant domains of the spike protein. Here, we show that pseudovirus expressing 501Y.V2 spike protein completely escapes three classes of therapeutically relevant antibodies. This pseudovirus also exhibits substantial to complete escape from neutralization, but not binding, by convalescent plasma. These data highlight the prospect of reinfection with antigenically distinct variants and foreshadows reduced efficacy of spike-based vaccines. Individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), develop neutralizing antibodies that can persist for months 1,2. Neutralizing antibodies are considered the primary correlate of protection from infection and are being pursued as therapeutics 3,4. Interim analyses with monoclonal neutralizing antibodies have shown success, facilitating their authorization for emergency use 5,6. The SARS-CoV-2 receptor binding domain (RBD) exists in either an 'up' (receptor-accessible) or 'down' (receptor-shielded) conformation. RBD is the dominant neutralization target for this and other human coronaviruses 7,8. These antibodies can be broadly divided into four main classes, of which two overlap with the angiotensin converting enzyme 2 (ACE2) receptor binding site (Fig. 1a and Supplementary Fig. 1a) 9. Class 1 antibodies are most frequently elicited in SARS-CoV-2 infection and include a public antibody response to an epitope only accessible in the RBD 'up' conformation 10. Class 2 antibodies use more diverse VH-genes and bind to RBD 'up' and RBD 'down' conformations of spike. After RBD, the N-terminal domain (NTD) of spike is the next most frequently targeted by neutralizing antibodies, most of which target a single immunodominant site 11. We, and others, recently described a new SARS-CoV-2 lineage in South Africa, defined as Nextstrain clade 20H/501Y.V2 (PANGOLin lineage B.1.351) 12. This lineage is defined by nine

SARS-CoV-2 501Y.V2, a novel lineage of the coronavirus causing COVID-19, contains multiple mutations within two immunodominant domains of the spike protein. Here we show that this lineage exhibits complete escape from three classes of therapeutically relevant monoclonal antibodies. Furthermore 501Y.V2 shows substantial or complete escape from neutralizing antibodies in COVID-19 convalescent plasma. These data highlight the prospect of reinfection with antigenically distinct variants and may foreshadow reduced efficacy of current spike-based vaccines.

The emergence of highly transmissible SARS-CoV-2 variants of concern (VOC) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identify four receptor-binding domain targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 23 variants including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526 and B.1.617 VOCs. Two antibodies are ultrapotent, with sub-nanomolar neutralization titers (IC50 0.3 to 11.1 ng/mL; IC80 1.5 to 34.5 ng/mL). We define the structural and functional determinants of binding for all four VOC-targeting antibodies and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting their potential in mitigating resistance development.