SARS-CoV-2 Omicron triggers cross-reactive neutralization and Fc effector functions in previously vaccinated, but not unvaccinated, individuals

Abstract

The SARS-CoV-2 Omicron variant escapes neutralizing antibodies elicited by vaccines or infection. However, whether Omicron triggers cross-reactive humoral responses to other variants of concern (VOCs) remains unknown. We used plasma from 20 unvaccinated and 7 vaccinated individuals infected by Omicron BA.1 to test binding, Fc effector function, and neutralization against VOCs. In unvaccinated individuals, Fc effector function and binding antibodies targeted Omicron and other VOCs at comparable levels. However, Omicron BA.1-triggered neutralization was not extensively cross-reactive for VOCs (14- to 31-fold titer reduction), and we observed 4-fold decreased titers against Omicron BA.2. In contrast, vaccination followed by breakthrough Omicron infection associated with improved cross-neutralization of VOCs with titers exceeding 1:2,100. This has important implications for the vulnerability of unvaccinated Omicron-infected individuals to reinfection by circulating and emerging VOCs. Although Omicron-based immunogens might be adequate boosters, they are unlikely to be superior to existing vaccines for priming in SARS-CoV-2-naive individuals.

Keywords: ADCC; ADCP; BA.1; BA.2; Omicron; SARS-CoV-2; breakthrough infection; neutralization; vaccines; variants of concern.

Graphical abstract

Figure 1

Binding and Fc effector function elicited by Omicron infection is cross-reactive against several variants of concern (VOCs) (A and B) Antibody binding measured by ELISA in (A) unvaccinated individuals (n = 20) or (B) individuals vaccinated with either one dose of Ad26.CoV2.S or two doses of BNT162b2 (n = 7) and infected by Omicron against D614G, Beta, Delta, and Omicron BA.1 spike proteins. (C) Bars show geometric mean (GM) binding titers for vaccinated (black) and unvaccinated (white) individuals against VOCs. (D and E) Antibody-dependent cellular phagocytosis (ADCP) of (D) unvaccinated and (E) vaccinated individuals is represented as the percentage of monocytic cells that take up spike-coated beads (D614G, Beta, Delta, and Omicron BA.1) multiplied by their GM fluorescence intensity (MFI). (F) Bars show GM ADCP scores for vaccinated (black) and unvaccinated (white) individuals against VOCs. (G and H) Antibody-dependent cellular cytotoxicity (ADCC) in (G) unvaccinated and (H) vaccinated individuals is shown as the relative light units (RLU) signaling through FcγRIIIa-expressing cells. (I) Bars show GM activity for vaccinated (black) and unvaccinated (white) individuals against VOCs. All data are representative of two independent experiments. For dot plots, lines indicate GM titer (GMT), which is also represented below the plot with fold decrease and knockout (K/O) of activity for other variants as a percentage relative to Omicron BA.1. Dotted lines indicate the limit of detection of the particular assay. For bar charts, bars indicate the median of function, error bars show standard deviations, and fold decreases relative to vaccinated individuals are indicated below the plot. Statistical significance across variants is shown by the Friedman test with Dunn’s correction, and statistical significance between vaccinated and unvaccinated samples is shown by the Mann Whitney test. ^∗p < 0.05, ^∗∗p < 0.01, ^∗∗∗p < 0.001, ^∗∗∗∗p < 0.0001, and ns = non-significant.

Figure 2

Omicron triggers cross-variant neutralizing antibodies, which are broadened by vaccination (A and B) The neutralization titer (ID₅₀) of Omicron-infected plasma against D614G, Beta, C.1.2, Delta, Omicron BA.2, and Omicron BA.1 pseudoviruses is shown for (A) unvaccinated individuals (n = 20) or (B) individuals vaccinated with either one dose of Ad26.CoV.2S or two doses of BNT162b2 (n = 7). Lines indicate GMT, which is also represented below the plot with fold decrease and knockout (K/O) of activity for other variants as a percentage relative to Omicron BA.1. Dotted lines indicate the limit of detection of the assay. Statistical significance across variants is shown by the Friedman test with Dunn’s correction. (C) Bars show GM neutralization titers for vaccinated (black) and unvaccinated (white) individuals against VOCs, error bars show standard deviations, and fold decreases relative to vaccinated individuals are indicated below the plot. Statistical significance between vaccinated and unvaccinated samples is shown by the Mann Whitney test. ^∗p < 0.05, ^∗∗p < 0.01, ^∗∗∗p < 0.001, ^∗∗∗∗p < 0.0001, and ns = non-significant. All data are representative of two independent experiments.