SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma

Abstract

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.

Fig. 1|. SARS-CoV-2 501Y.V2 is resistant to monoclonal antibodies.

a, Structure of SARS-CoV-2 RBD (yellow) modeled in complex with class 1 (translucent green) or class 2 (translucent purple) neutralizing antibodies. Side chains of residues K417, E484 and N501 are indicated. mAb, monoclonal antibody. b, A plot showing percentage of K417 accessible surface area (x axis) buried (buried surface area) in class 1 antibody paratopes (listed on the y axis). VH3–53/66 antibodies are separated below the horizontal line. c, ELISA binding for CA1, LyCoV016 and CC12.1 to the original (black) or the 501Y.V2 RBD (red). d, Neutralization curves for the same antibodies shown in c, against the original pseudovirus (black), 501Y.V2 (red) or a chimeric construct that includes only the RBD substitutions K417N, E484K and N501Y (orange). e, Percentage of E484 accessible surface area buried in class 2 antibody paratopes (listed on y axis). VH1–2 antibodies (middle) or sy-/nanobodies (bottom) are separated with horizontal lines. f, ELISA binding for BD23, C119 and P2B-2F6 to the original (black) or 501Y.V2 RBD (red). g, Neutralization curves for the same antibodies shown in f, against original (black), 501Y.V2 (red) or RBD chimeric pseudoviruses (orange). h, Structure of SARS-CoV-2 NTD (cyan) modeled in complex with VH1–24 neutralizing antibody (translucent maroon). The N5-loop supersite and residue R246 are indicated. i, Contribution of N5 loop and R246 to NTD-directed neutralizing antibodies is indicated. j, Modeling of the Δ242–244 deletion (lime green). NTD loops N1, N3 and N5 are shown and the position of R246 in the original NTD and 501Y.V2 NTD is labeled with black and pink, respectively. The minimum displacement for 501Y.V2 loop N5 and the accompanying clash with R102 are indicated with pink arrows. k, ELISA binding for 4A8 to original (black) or 501Y.V2 NTD (red). l, Neutralization curves for 4A8 against the original (black) or 501Y.V2 (red) pseudovirus. All experiments were performed in duplicate.

Fig. 2|. SARS-CoV-2 501Y.V2 increased resistance to neutralization by convalescent plasma/serum.

Plasma/serum collected from individuals infected with SARS-CoV-2 was assessed for neutralization to the original lineage (Wuhan-1 D614G, left), an RBD chimeric mutant containing K417N, E484K and N501Y substitutions only (middle) or the 501Y.V2 lineage pseudovirus. Twelve of the samples were collected from donors hospitalized for >10 d with COVID-19 (black). The graph is colored according to the magnitude of neutralization titer, with ID₅₀ greater or lesser than 1:400 colored dark or light blue, respectively and titer <100 colored orange. The limit of detection (knockout) was an ID₅₀ < 20 (red). Pie charts above each set of data points summarize the proportion of samples in each titer group.