SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral Spike vaccines

Abstract

The SARS-CoV-2 Spike glycoprotein mediates virus entry and is a major target for neutralizing antibodies. All current vaccines are based on the ancestral Spike with the goal of generating a protective neutralizing antibody response. Several novel SARS-CoV-2 variants with multiple Spike mutations have emerged, and their rapid spread and potential for immune escape have raised concerns. One of these variants, first identified in the United Kingdom, B.1.1.7 (also called VUI202012/01), contains eight Spike mutations with potential to impact antibody therapy, vaccine efficacy and risk of reinfection. Here we employed a lentivirus-based pseudovirus assay to show that variant B.1.1.7 remains sensitive to neutralization, albeit at moderately reduced levels (~2-fold), by serum samples from convalescent individuals and recipients of two different vaccines based on ancestral Spike: mRNA-1273 (Moderna), and protein nanoparticle NVX-CoV2373 (Novavax). Some monoclonal antibodies to the receptor binding domain (RBD) of Spike were less effective against the variant while others were largely unaffected. These findings indicate that B.1.1.7 is not a neutralization escape variant that would be a major concern for current vaccines, or for an increased risk of reinfection.

Figure 1.

Epidemiology tracing of mutations in B.1.1.7 and co-circulating relevant mutations in the UK and Danish SARS-CoV-2 epidemics. A. Entropy scores summarizing the level of diversity found in positions in Spike. These scores are dependent on sampling, and recent sampling from the United Kingdom and Denmark has been particularly intense relative to other regions of the world (Fig. S1). B.1.1.7 mutations are highlighted in orange. The subset of B.1.1.7 sites with greater entropy scores (69/70, 681, and 501) are also often found in the context of other variants. The most variable site in Spike is at 222, and is indicative of the GV clade. G614 has dominated global sampling since June 2020, and the entropy at 614 reflects presence of the ancestral form, D614, sampled in the early months of the pandemic. These same entropy scores are first mapped by linear position in the protein and then mapped onto the Spike structure below the graph. Regions of Spike are indicated by the same colors in the linear and structural maps. B. Frequencies of variants in relevant positions. Using the Analyze Align tool at cov.lanl.gov, we extracted the columns of interest for the B.117 Spike mutations, and the additional sites of interest at 439, 453, and 222, out of a 333,850 sequence set extracted from GISAID on Jan 23, 2021. The LOGO at the top indicates the AA frequency in the full dataset; the grey boxes indicate deletions. All common forms of combinations of mutations at these sites of interest are shown, followed by their count and percentage. The forms that were common in the UK and Denmark are each assigned a color, and used to map transition in frequencies of these forms over time in part C. C. Weekly running averages for each of the major variants in the UK and Denmark, based on the variants shown in part B, are plotted; the actual counts are on the left, and relative frequencies on the right. Some windows in time are very poorly sampled, some very richly. The vertical lines indicate when a variant is first sampled in a region. Note the lavender N501Y in Wales; this is N501Y found out of the context of B.1.1.7 and transient. The shifts in relative prevalence from the G clade (beige, D614G), to the GV clade (cream, A222V), to the B.1.1.7 variants (orange).

Figure 2.

Neutralization of variants by vaccine and convalescent sera. Serum ID50 (A) and ID80 (B) titers of neutralization of each variant, as indicated on top of each panel, relative to D614G by vaccine sera (top 2 rows) and convalescent sera. Dashed thin lines represent individual samples, thick black lines represent geometric means of each sample group as indicated on the right. NT-not tested. Also see Table S1. (C) Fold decline of ID50 (left) and ID80 (right) titers for each variant over D614G (D614G/variant) for each serum sample set as identified. Numbers on top of each plot show median fold differences. Upper and lower border of each box represent IQR of the fold differences respectively, and the middle bars in boxes represent group median. Statistical significance of comparisons are indicated in all panels as: * p<0.042 (corresponding to q<0.1). ** p<0.01. *** p<0.001. **** p<0.0001. Wilcoxon signed-rank paired test for (A) and (B); Wilcoxon rank-sum test for (C). Also see Table S2.

Fig 3.. Structural analyses for antibody resistance mutations.

(A) Top left 3 panels: Full spike trimer with antibody epitopes for S309, P2B-2F6, DH1041, DH1043, DH1047 and DH1050.1. Epitopes for P2B-2F6, DH1041 and DH1043 are similar and are grouped together. Top row, second from right panel shows location of spike sites 439, 453 and 501 with respect to S309. These spike sites are not close to S309 (>11Å). Top row rightmost panel shows the DH1047 antibody colored according to vacuum electrostatic potential, and the modeled mutations at spike sites Lys-439 and Tyr-501. Bottom row, rightmost two panels DH1047 interaction with sites 439, 453 and 501 using wildtype amino acids (second from right) and modeled mutations (rightmost). Bottom row, left 3 panels show the location of spike sites 439, 453 and 501 with P2B-2F6, DH1041 and DH1043. Polar interactions between antibody and spike residues of interest are shown with dotted black lines. (B) Similar to (A) except with B38 antibody. The modeled Tyr-501 is predicted to clash with light chain Ser-30 (~1.8Å, red star).