Antigenic cartography using sera from sequence-confirmed SARS-CoV-2 variants of concern infections reveals antigenic divergence of Omicron

Abstract

Large-scale vaccination campaigns have prevented countless hospitalizations and deaths due to COVID-19. However, the emergence of SARS-CoV-2 variants that escape from immunity challenges the effectiveness of current vaccines. Given this continuing evolution, an important question is when and how to update SARS-CoV-2 vaccines to antigenically match circulating variants, similarly to seasonal influenza viruses where antigenic drift necessitates periodic vaccine updates. Here, we studied SARS-CoV-2 antigenic drift by assessing neutralizing activity against variants of concern (VOCs) in a set of sera from patients infected with viral sequence-confirmed VOCs. Infections with D614G or Alpha strains induced the broadest immunity, whereas individuals infected with other VOCs had more strain-specific responses. Omicron BA.1 and BA.2 were substantially resistant to neutralization by sera elicited by all other variants. Antigenic cartography revealed that Omicron BA.1 and BA.2 were antigenically most distinct from D614G, associated with immune escape, and possibly will require vaccine updates to ensure vaccine effectiveness.

Keywords: Omicron; SARS-CoV-2; VOCs; antibodies; antigenic cartography; convalescent; neutralization; vaccination; variants of concern.

Graphical abstract

Figure 1

SARS-CoV-2 VOCs elicit diverse serum responses against homologous and heterologous strains (A) Molecular models of SARS-CoV-2 S, highlighting the locations of mutations in the D614G strain (blue) and Alpha (green), Beta (yellow), Gamma (orange), Delta (red), Omicron BA.1 (magenta), and Omicron BA.2 (pink) variants. Midpoint neutralization titers against the VOCs in international units per mL (IU/mL). The individuals are grouped per VOC and plotted accordingly. Median neutralization titers are highlighted while the individual points are depicted with higher transparency. The light gray bar (10 IU/mL) indicates the neutralization cutoff for all strains except Omicron (cutoff 2 IU/mL, dark gray bar). Non-hospitalized patients are indicated with dots and hospitalized patients with triangles. The individuals who were infected with an Alpha strain that also included the E484K mutation are indicated in green squares. The two individuals in the Omicron BA.1 group who may have been infected with BA.2 instead of BA.1 are indicated in magenta diamonds (see also Table S1). The homologous neutralization is highlighted using a light blue bar. The Wilcoxon signed rank test with Benjamini-Hochberg correction was used to compare cross-neutralization titers with the homologous neutralization (see Table S3A for exact p values). Only statistically significant differences are indicated. ^∗p < 0.005, ^∗∗p < 0.01, ∗∗∗ p < 0.001, ^∗∗∗∗p < 0.0001. (B) Spider plot of the median neutralization titer (IU/mL) of each group against all VOCs. A cutoff of 10 IU/mL is used for all strains.

Figure 2

Alpha-infected and D614G-infected individuals show most potent and broad neutralizing response (A) Midpoint neutralization titers against the VOCs in international units per mL (IU/mL). The individuals are grouped per VOC with which they were infected and plotted accordingly. Non-hospitalized patients are indicated with dots and hospitalized patients with triangles. The individuals who were infected with an Alpha variant that also included the E484K mutation are indicated in green squares. The two individuals in the Omicron BA.1 group who may have been infected with BA.2 instead of BA.1 are indicated in magenta diamonds (see also Table S1). A Mann-Whitney test is used to test for differences between group medians (black lines). ns, non-significant; ^∗∗∗∗ p < 0.0001. See Table S3B for exact p values. (B) Cross-neutralization is expressed as the geometric mean of the neutralization titers against all VOCs except the autologous strain in IU/mL. A cutoff of 10 IU/mL is used for all neutralization titers, as indicated by the gray bar.

Figure 3

Antigenic cartography reveals antigenic diversification of SARS-CoV-2 (A) Antigenic map of SARS-CoV-2 VOCs based on convalescent SARS-CoV-2 infection sera. SARS-CoV-2 variants are shown as circles and sera are indicated as squares. Each square corresponds to sera of one individual and is colored by the infecting SARS-CoV-2 variant. Both axes of the map are antigenic distance, and each grid square (1 antigenic unit) represents a 2-fold change in neutralization titer. The distance between points in the map can be interpreted as a measure of antigenic similarity, where the points more closely together show higher cross-neutralization and are therefore antigenically more similar. Includes both Beta subvariants used in this study. Without the Beta (Δ242–244) subvariant. See Figure S1 for an antigenic map based on convalescent SARS-CoV-2 sera, including only one of the Beta subvariants (Beta L242H, R246I) (B) Antigenic map of SARS-CoV-2 VOCs based on post-vaccination sera from individuals without prior SARS-CoV-2 infections. Each serum is colored by the vaccine that individual received.