Different Neutralization Profiles After Primary SARS-CoV-2 Omicron BA.1 and BA.2 Infections

Abstract

Background and methods: The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Omicron (B.1.1.529) variant is the antigenically most distinct variant to date. As the heavily mutated spike protein enables neutralization escape, we studied serum-neutralizing activities of naïve and vaccinated individuals after Omicron BA.1 or BA.2 sub-lineage infections in live virus neutralization tests with Omicron BA.1, Omicron BA.2, wildtype (WT, B1.1), and Delta (B.1.617.2) strains. Serum samples obtained after WT infections and three-dose mRNA vaccinations with and without prior infection were included as controls.

Results: Primary BA.1 infections yielded reduced neutralizing antibody levels against WT, Delta, and Omicron BA.2, while samples from BA.2-infected individuals showed almost no cross-neutralization against the other variants. Serum neutralization of Omicron BA.1 and BA.2 variants was detectable after three-dose mRNA vaccinations, but with reduced titers. Vaccination-breakthrough infections with either Omicron BA.1 or BA.2, however, generated equal cross-neutralizing antibody levels against all SARS-CoV-2 variants tested.

Conclusions: Our study demonstrates that although Omicron variants are able to enhance cross-neutralizing antibody levels in pre-immune individuals, primary infections with BA.1 or BA.2 induced mostly variant-specific neutralizing antibodies, emphasizing the differently shaped humoral immunity induced by the two Omicron variants. These data thus contribute substantially to the understanding of antibody responses induced by primary Omicron infections or multiple exposures to different SARS-CoV-2 variants and are of particular importance for developing vaccination strategies in the light of future emerging variants.

Keywords: Omicron sub-lineages; SARS-CoV-2; SARS-CoV-2 neutralization; SARS-CoV-2 variant of concern; immune escape.

Figure 1

Neutralizing antibody titers against an ancestral wildtype (WT) strain and three variants of concern (Delta, Omicron BA.1, and Omicron BA.2) in post-vaccination and post-infection serum samples. (A) Serum samples from individuals who had received three doses of an mRNA vaccine collected one month and three months after the last vaccination (n=15). (B) Serum samples from individuals who were infected with a WT strain, followed by three doses of an mRNA vaccine collected three weeks after the last vaccination (n=9). (C) Serum samples from individuals who were infected with a WT strain collected three weeks and seven months after infection (n=11). (D) Serum samples obtained from individuals who had a primary infection with Omicron BA.1 collected one month after infection (n=22). (E) Serum samples obtained from individuals who had a primary infection with Omicron BA.2 collected one month after infection (n=21). (F) Serum samples from individuals who were infected with an Omicron variant and had previously been vaccinated collected one month after infection (Omicron breakthrough infections, n=43). Horizontal dotted lines show the cut-off, dots individual sera, and red lines median titers. Black asterisks indicate significant differences to WT (D614G). The Kruskal-Wallis test with Dunn’s post-hoc test was used for significance testing (*, p < 0.05; **, p < 0.01; ***, p <0.001; ****, p < 0.0001). Significant differences between Omicron BA.1 and BA.2 neutralization titers are indicated by red asterisks (Mann-Whitney test; ***, p < 0.001). WT, wildtype strain (B.1.1) with the D614G substitution; Delta, Delta VOC (B.1.617.2-like, sub-lineage AY.122); O_BA.1, Omicron (B.1.1.529) sub-lineage BA.1 VOC; O_BA.2, Omicron sub-lineage BA.2 VOC; NT, neutralization test.

Figure 2

Structural representation of mutations present in Omicron BA.1 and BA.2 sub-lineages. (A, B) Cartoon representation of one monomer of the spike protein (side view) combined with a semi-transparent surface representation of the trimeric spike in its RBD-up-conformation [PDB 7KRR, (25)]. The three protomers are colored in red, grey, and bright orange. The S1 subunit is colored blue in the single protomer, with the RBD highlighted in red and the NTD highlighted in purple. S2 is colored in orange. The black spheres indicate the mutations present in sub-lineages BA.1 (A) and BA.2 (B). The structures were generated with PyMol (https://pymol.org). (C) Venn diagram illustrating the BA.1 and BA.2 sub-lineage-specific and shared mutations, colored according to the regions highlighted in panels A and B. The grey underlines indicate mutations present in the Delta variant. RBD, Receptor-binding domain; NTD, N-terminal domain; S1, Subunit 1; S2, Subunit 2.