mRNA booster immunization elicits potent neutralizing serum activity against the SARS-CoV-2 Omicron variant

Abstract

The Omicron variant of SARS-CoV-2 is causing a rapid increase in infections across the globe. This new variant of concern carries an unusually high number of mutations in key epitopes of neutralizing antibodies on the viral spike glycoprotein, suggesting potential immune evasion. Here we assessed serum neutralizing capacity in longitudinal cohorts of vaccinated and convalescent individuals, as well as monoclonal antibody activity against Omicron using pseudovirus neutralization assays. We report a near-complete lack of neutralizing activity against Omicron in polyclonal sera from individuals vaccinated with two doses of the BNT162b2 COVID-19 vaccine and from convalescent individuals, as well as resistance to different monoclonal antibodies in clinical use. However, mRNA booster immunizations in vaccinated and convalescent individuals resulted in a significant increase of serum neutralizing activity against Omicron. This study demonstrates that booster immunizations can critically improve the humoral immune response against the Omicron variant.

Fig. 1. SARS-CoV-2-neutralizing serum activity in vaccinated and convalescent individuals.

a, Neutralizing serum activity was determined in samples obtained 1 month after two doses of BNT162b2 against the ancestral Wu01 strain of SARS-CoV-2 and four VOCs. Residues with changes relative to the Wu01 strain are indicated by intersecting lines. Fifty percent inhibitory serum dilutions (ID₅₀s) were determined by pseudovirus neutralization assays. Bars indicate geometric mean ID₅₀s with 95% confidence intervals (CIs). Numbers above the graph indicate the geometric mean ID₅₀s, and the percentages of samples with detectable neutralizing activity above the lower limit of quantification (LLOQ) are given in parentheses. b, Serum ID₅₀s against the Wu01 strain and the Omicron variant of SARS-CoV-2 in a longitudinal cohort of 30 vaccinated individuals. Samples were collected at a median of 1 month (Early) and 5 months (Late) after two doses of BNT162b2, and 1 month after a subsequent single dose of BNT162b2 (Booster). Colored lines connect geometric mean ID₅₀s and error bars indicate the 95% CIs. c, Serum ID₅₀s against the Wu01 strain and the Omicron variant of SARS-CoV-2 in a longitudinal cohort of 30 COVID-19-convalescent individuals. Samples were collected at a median of 1.5 months (Early) and 12 months (Late) after diagnosis of SARS-CoV-2 infection, as well as 1.5 months after a single BNT162b2 vaccination (Hybrid). Colored lines connect geometric mean ID₅₀s and error bars indicate 95% CIs. In a, b and c, ID₅₀s below the LLOQ (ID₅₀ of 10, indicated by the black dashed lines) were imputed to half the LLOQ (ID₅₀ = 5). NTD, N-terminal domain; TP, time point.

Fig. 2. SARS-CoV-2-neutralizing activity of monoclonal antibodies.

Fifty percent inhibitory concentrations (IC₅₀s) of monoclonal antibodies against the ancestral Wu01 strain of SARS-CoV-2 and four variants of concern determined by pseudovirus neutralization assays. IC₅₀ > 10 µg ml⁻¹ indicates failure to achieve 50% neutralizing activity at the highest tested antibody concentration of 10 µg ml⁻¹.