A vaccine-induced public antibody protects against SARS-CoV-2 and emerging variants

Abstract

The emergence of SARS-CoV-2 antigenic variants with increased transmissibility is a public health threat. Some variants show substantial resistance to neutralization by SARS-CoV-2 infection- or vaccination-induced antibodies. Here, we analyzed receptor binding domain-binding monoclonal antibodies derived from SARS-CoV-2 mRNA vaccine-elicited germinal center B cells for neutralizing activity against the WA1/2020 D614G SARS-CoV-2 strain and variants of concern. Of five monoclonal antibodies that potently neutralized the WA1/2020 D614G strain, all retained neutralizing capacity against the B.1.617.2 variant, four also neutralized the B.1.1.7 variant, and only one, 2C08, also neutralized the B.1.351 and B.1.1.28 variants. 2C08 reduced lung viral load and morbidity in hamsters challenged with the WA1/2020 D614G, B.1.351, or B.1.617.2 strains. Clonal analysis identified 2C08-like public clonotypes among B cells responding to SARS-CoV-2 infection or vaccination in 41 out of 181 individuals. Thus, 2C08-like antibodies can be induced by SARS-CoV-2 vaccines and mitigate resistance by circulating variants of concern.

Keywords: B cell; SARS-CoV-2; germinal center; hamster; lymph node; mRNA vaccine; neutralizing antibodies; public clone; receptor binding domain; spike protein.

Graphical abstract

Figure 1

mAb 2C08 potently neutralizes diverse SARS-CoV-2 strains (A and B) ELISA binding to recombinant RBD from (A) and neutralizing activity in Vero-TMPRSS2 cells against (B) indicated SARS-CoV-2 strains by the indicated mAbs. ELISA binding to D614G RBD previously reported in (Turner et al., 2021). Baseline for area under the curve was set to the mean + three times the standard deviation of background binding to bovine serum albumin. Dotted lines indicate limit of detection. Bars indicate mean ± SEM. Results are from one experiment performed in duplicate (A, D614G and B.1.617.2) or in singlet (A, B.1.1.7, B.1.351, and B.1.1.28), or two experiments performed in duplicate (B). See also Figure S1 and Table S1.

Figure 2

mAb 2C08 protects hamsters from SARS-CoV-2 challenge (A–C) Percent weight change over time (A) and viral RNA (B) and infectious virus titer (C) in lung homogenates 4 dpi of hamsters that received 5 mg/kg isotype (black) or 2C08 (gray) one day prior to intranasal challenge with 5×10⁵ FFU of D614G, (left), Wash-B.1.351 (center), or B.1.617.2 (right) SARS-CoV-2. In (A), symbols indicate mean ± SEM. In (B and C), bars indicate geometric mean ± geometric SD, and each symbol represents one hamster. D614G data are from two experiments, n = 10 per condition; variant data are from one experiment, n = 5 per condition. p values from two-tailed Mann-Whitney U tests.

Figure 3

mAb 2C08 recognizes a public epitope in SARS-CoV-2 RBD (A) Structure of RBD (from PDB 6M0J) with hACE2 footprint highlighted in magenta and amino acids whose substitution confers resistance to 2C08 in plaque assays highlighted in yellow. (B and C) BLI-based competition of 2C08 Fab with hACE2 (B) or S2E12 Fab with 2C08 Fab (C) for RBD binding. Maximal signal (Rmax) at steady state is plotted as a function of hACE2 (B) or 2C08 Fab (C) concentration. (D and E) Sequence alignment of 2C08 with RBD-binding mAbs from SARS-CoV-2 infected patients and vaccinees that utilize the same immunoglobulin heavy- (D) and light-chain (E) variable region genes (see also Table S2). Antibody residues that contact RBD (red stars) and secondary structure elements (yellow alpha helices and blue beta strands) are calculated from the S2E12 structure (PDB ID 7K45) (Tortorici et al., 2020). See also Figures S2 and S3 and Table S2.