Neutralization of SARS-CoV-2 Omicron sub-lineages BA.1, BA.1.1, and BA.2

Abstract

Recent reports of SARS-CoV-2 Omicron variant sub-lineages, BA.1, BA.1.1, and BA.2, have reignited concern over potential escape from vaccine- and infection-induced immunity. We examine the sensitivity of these sub-lineages and other major variants to neutralizing antibodies from mRNA-vaccinated and boosted individuals, as well as recovered COVID-19 patients, including those infected with Omicron. We find that all Omicron sub-lineages, especially BA.1 and BA.1.1, exhibit substantial immune escape that is largely overcome by mRNA vaccine booster doses. While Omicron BA.1.1 escapes almost completely from neutralization by early-pandemic COVID-19 patient sera and to a lesser extent from sera of Delta-infected patients, BA.1.1 is sensitive to Omicron-infected patient sera. Critically, all Omicron sub-lineages, including BA.2, are comparably neutralized by Omicron patient sera. These results highlight the importance of booster vaccine doses for protection against all Omicron variants and provide insight into the immunity from natural infection against Omicron sub-lineages.

Keywords: BA.1; BA.1.1; BA.2; COVID-19; Omicron; SARS-CoV-2; mRNA vaccine; neutralizing antibody.

Graphical abstract

Figure 1

The Omicron SARS-CoV-2 variant BA.1.1 exhibits strong vaccine-induced immune escape that is overcome by booster vaccination (A) Diagrams of SARS-CoV-2 S variants used for pseudotyping, which indicate the location of specific mutations as well as the S1 and S2 subunits of S, the N-terminal domain (NTD), receptor binding domain (RBD), fusion peptide (FP), and transmembrane domain (TM). (B) Sera from 48 HCWs collected 3–4 weeks after second mRNA vaccine dose were used to neutralize pseudotyped variants, and the resulting 50% neutralization titers (NT₅₀) are displayed. (C) Heatmaps showing patient/vaccinee NT₅₀ values against each variant with patient numbers identified as “M” for Moderna mRNA-1273-vaccinated/boosted HCW and “P” for Pfizer/BioNTech BNT162b2-vaccinated/boosted HCW. (D) Sera from 19 HCWs following homologous mRNA booster vaccination were assessed for nAb titers. Geometric mean NT₅₀ values in (B) and (D) are displayed at the top of plots along with the percent of subjects with NT₅₀ values above the limit of detection; bars represent geometric mean ±95% confidence interval, and significance relative to D614G is determined by one-way repeated measures ANOVA with Bonferroni’s multiple testing correction. P values are represented as ^∗p < 0.05, ^∗∗∗p < 0.001, ^∗∗∗∗p < 0.0001; ns, not significant. See also Figure S1.

Figure 2

The Omicron variant BA.1.1 exhibits strong immune escape from D614G- and Delta-infected, but not Omicron-infected, patients (A) Sera from nine ICU COVID-19 patient samples and nine hospitalized non-ICU COVID-19 patient samples collected in 2020 prior to the approval of any SARS-CoV-2 vaccines were assessed for nAb titers. (B) Heatmaps showing patient NT₅₀ values against each variant. Patients are identified as “I” for ICU patient samples collected during the 2020 D614G wave and “H” for hospitalized non-ICU patient samples collected during the 2020 D614G wave; Delta wave ICU patients are identified as “U” for unvaccinated or “V” for vaccinated; and Omicron wave hospitalized non-ICU patients are identified as “U” for unvaccinated, “V” for two-dose vaccinated, and “B” for booster dose vaccinated. (C) Sera from 18 ICU COVID-19 patient samples collected during the Delta wave of the pandemic were assessed for nAb titers. (D) NT₅₀ values for unvaccinated (n = 12) and vaccinated (n = 6) Delta wave COVID-19 ICU patients are plotted according to vaccination status. (E) Sera from 31 hospitalized COVID-19 patient samples collected during the Omicron wave of the pandemic were assessed for nAb titers. (F) NT₅₀ values for unvaccinated (n = 15), two-dose-vaccinated (n = 8), and booster-vaccinated (n = 8) Omicron wave COVID-19-hospitalized patients are plotted according to vaccination status. Geometric mean NT₅₀ values in (A) and (C)–(E) are displayed at the top of plots along with the percentage of patients with NT₅₀ values above the limit of detection; bars represent geometric mean ±95% confidence interval, and significance relative to D614G is determined by one-way repeated measures ANOVA with Bonferroni’s multiple testing correction (A, C, and E); significance between vaccination statuses is determined by two-way repeated measures ANOVA with Bonferroni’s multiple testing correction (D) or by one-way ANOVA with Bonferroni’s multiple testing correction (F). P values are represented as ^∗p < 0.05, ^∗∗p < 0.01; ns, not significant. See also Figure S2.

Figure 3

Omicron sub-lineages exhibit comparable relative immune escape from two-dose-vaccinated and booster-vaccinated HCW sera and show similar nAb titers in Omicron-infected patient sera (A and B) Sera from 10 random HCWs collected post-two-dose vaccination (A) or post-booster vaccination (B) were assessed for nAb titers against D614G and the Omicron variant sub-lineages. (C) Sera from 31 hospitalized COVID-19 patient samples collected during the Omicron wave of the pandemic were assessed for nAb titers against Omicron variant sub-lineages. (D–G) Representative neutralization curves against D614G and the Omicron sub-lineages are shown for four representative patients hospitalized during the Omicron wave of the pandemic. (H) NT₅₀ values against each Omicron sub-lineage for unvaccinated (n = 15), two-dose vaccinated (n = 8), and boosted (n = 8) Omicron wave COVID-19 ICU-patients are plotted according to vaccination status. Geometric mean NT₅₀ values in (A)–(C) and (H) are displayed at the top of plots along with the percentage of patients with NT₅₀ values above the limit of detection; bars represent geometric mean ±95% confidence interval, and significance relative to D614G (A and B) or to BA.1.1 (C) is determined by one-way repeated measures ANOVA with Bonferroni’s multiple testing correction. Significance between vaccination statuses was determined by one-way ANOVA with Bonferroni’s multiple testing correction (H). P values are represented as ^∗p < 0.05; ns, not significant. See also Figure S3.