Omicron spike function and neutralizing activity elicited by a comprehensive panel of vaccines

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern comprises several sublineages, with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1 and with BA.4 and BA.5 increasing in prevalence worldwide. We show that the large number of Omicron sublineage spike mutations leads to enhanced angiotensin-converting enzyme 2 (ACE2) binding, reduced fusogenicity, and severe dampening of plasma neutralizing activity elicited by infection or seven clinical vaccines relative to the ancestral virus. Administration of a homologous or heterologous booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 across all vaccines evaluated. Our data suggest that although Omicron sublineages evade polyclonal neutralizing antibody responses elicited by primary vaccine series, vaccine boosters may provide sufficient protection against Omicron-induced severe disease.

Fig. 1.. Omicron sublineage RBDs bind ACE2 with enhanced affinity but exhibit impaired S-mediated fusogenicity relative to the ancestral virus.

(A to C) Prevalence of the different variants of concern measured globally (A), in the United States (B), or in South Africa (C). Alpha comprises B.1.1.7 and all Q sublineages; Delta comprises B.1.617.2 and all AY sublineages; and BA.1, BA.2, BA.4, and BA.5 comprise their respective sublineages (including BA.2.12.1 for BA.2). Prevalence calculations rely on shared GISAID (Global Initiative on Sharing Avian Influenza Data) sequences and may be biased by sampling. (D and E) Equilibrium dissociation constants (K_D) of binding of the monomeric ACE2 ectodomain to immobilized biotinylated Wuhan-Hu-1, Delta, BA.1, BA.2, BA2.12.1, and BA.4/5 RBDs assessed by BLI (D) or SPR (E). Data presented are the results of at least two independent biological replicates for BLI and for SPR (except for the BA.1 RBD SPR data, which come from four technical replicates). (F) Quantification of cell-cell fusion after 24 hours mediated by Wuhan-Hu-1/G614, Delta, BA.1, BA.2, BA.2.12.1, and BA.4/5 S glycoproteins expressed as the fraction of the total area with GFP fluorescence assessed using a split GFP system. Data are from 16 fields of view from a single experiment and are representative of results obtained from two independent biological replicates. Comparisons between fusion mediated by the Wuhan-Hu-1/G614 S and other S variants were completed using the Wilcoxon rank sum test. **P < 0.01; ***P < 0.001; ****P < 0.0001. (G) Kinetics of cell-cell fusion mediated by Wuhan-Hu-1/G614, Delta, BA.1, BA.2, BA.2.12.1, and BA.4/5 S glycoproteins expressed as the fraction of the total area with GFP fluorescence assessed using a split GFP system.

Fig. 2.. SARS-CoV-2 Omicron sublineages evade human plasma neutralizing antibodies elicited by infection or primary vaccine series.

Plasma neutralizing antibody titers elicited by primary COVID-19 vaccination series determined using SARS-CoV-2 S VSV pseudotypes using VeroE6/TMPRSS2 as target cells. One-time (1×) infected samples (n = 24) were obtained 26 to 78 days (mean, 41) after symptom onset, two-dose (2×) mRNA-1273 samples (n = 14) were obtained 6 to 50 days (mean, 13) after second dose, 2× BNT162b2 samples (n = 14) were obtained 6 to 33 days (mean, 14) after second dose, 2× NVX-CoV2373 samples (n = 10) were obtained 17 to 168 days (mean, 82) after second dose, one-dose (1×) Ad26.COV2.S samples (n = 10) were obtained 9 to 142 days (mean, 79) after first dose, 2× AZD1222 samples (n = 16) were obtained ~30 days after second dose, 2× Sputnik V samples (n = 12) were obtained 60 to 90 days after second dose, and BBIBP-CorV samples (n = 12) were obtained 9 to 104 days (mean, 69) after second dose. Individual points are representative geometric mean titers from two independent experiments consisting of two replicates each. Bars represent geometric means, and error bars represent geometric standard deviations for each group. Statistical significance between groups of paired data was determined by Wilcoxon rank sum test. ***P < 0.001; ****P < 0.0001. Patient demographics are shown in table S4. Normalized curves and fits are shown in fig. S5. G614 indicates Wuhan-Hu-1/G614. ID₅₀, median inhibitory dose.

Fig. 3.. Administration of a booster dose rescues neutralization potency against Omicron sublineages for all vaccines.

Plasma neutralizing antibody titers elicited by COVID-19 vaccine boosters determined using SARS-CoV-2 S VSV pseudotypes and VeroE6/TMPRSS2 as target cells. Three-dose (3×) mRNA-1273 or BNT162b2 samples (n = 13) were donated 13 to 97 days (mean, 30) after third dose; 2× NVX-CoV2373 plus 1× BNT162b2 or NVX-CoV2373 samples (n = 5) were donated 14 to 20 days (mean, 15) after third dose; 1× Ad26.COV2.S plus 1× Ad26.COV2.S or BNT162b2 samples (n = 14) were donated 12 to 16 days (mean, 14) after second dose; 2× AZD1222 plus 1× BNT162b2 or mRNA-1273 samples (n = 18) were donated 30 to 123 days (mean, 87) after third dose; 2× Sputnik V plus 1× AZD1222 or BNT162b2 samples (n = 14) were donated 45 to 60 days after third dose; and 2× BBIBP-CorV plus 1× BNT162b2 or mRNA-1273 samples (n = 18) were donated 29 to 89 days (mean, 50) after third dose. Individual points are representative geometric mean titers from two to four independent experiments consisting of two replicates each. Bars represent geometric means, and error bars represent geometric standard deviations for each group. Statistical significance between groups of paired data was determined by Wilcoxon rank sum test. **P < 0.01; ***P < 0.001; ****P < 0.0001. Patient demographics are shown in table S4. Normalized curves and fits are shown in fig. S8.