Boosting of serum neutralizing activity against the Omicron variant among recovered COVID-19 patients by BNT162b2 and CoronaVac vaccines

Abstract

Background: SARS-CoV-2 Omicron variant evades immunity from past infection or vaccination and is associated with a greater risk of reinfection among recovered COVID-19 patients. We assessed the serum neutralizing antibody (NAb) activity against Omicron variant (Omicron NAb) among recovered COVID-19 patients with or without vaccination.

Methods: In this prospective cohort study with 135 recovered COVID-19 patients, we determined the serum NAb titers against ancestral virus or variants using a live virus NAb assay. We used the receiver operating characteristic analysis to determine the optimal cutoff for a commercially-available surrogate NAb assay.

Findings: Among recovered COVID-19 patients, the serum live virus geometric mean Omicron NAb titer was statistically significantly higher among BNT162b2 recipients compared to non-vaccinated individuals (85.4 vs 5.6,P < 0.0001). The Omicron seropositive rates in live virus NAb test (NAb titer ≥10) were statistically significantly higher among BNT162b2 (90.6% [29/32];P < 0.0001) or CoronaVac (36.7% [11/30]; P = 0.0115) recipients when compared with non-vaccinated individuals (12.3% [9/73]). Subgroup analysis of CoronaVac recipients showed that the Omicron seropositive rates were higher among individuals with two doses than those with one dose (85.7% vs 21.7%; P = 0.0045). For the surrogate NAb assay, a cutoff of 109.1 AU/ml, which is 7.3-fold higher than the manufacturer's recommended cutoff, could achieve a sensitivity and specificity of 89.5% and 89.8%, respectively, in detecting Omicron NAb.

Interpretation: Among individuals with prior COVID-19, one dose of BNT162b2 or two doses of CoronaVac could induce detectable serum Omicron NAb. Our result would be particularly important for guiding vaccine policies in countries with COVID-19 vaccine shortage.

Funding: Health and Medical Research Fund, Richard and Carol Yu, Michael Tong (see acknowledgments for full list).

Keywords: Beta variant; COVID-19; Delta variant; Inactivated vaccine; Neutralizing antibody; Omicron variant; SARS-CoV-2; Spike protein receptor binding domain; Surrogate neutralizing antibody test; mRNA vaccine.

Figure 1

Long term antibody kinetics in 73 non-vaccinated recovered COVID-19 patients. (a) Each black dot represents a serum sample from a recovered patient. The thick blue line represents the best fit curve whereas the surrounding blue area represents the 95% confidence interval. Horizontal green dotted line represents either the limit of detection or the cutoff recommended by the manufacturer. For the purpose of calculating the trend, we have excluded one outlier for spike IgM, and 4 outliers for RBD IgG. The p-values for selecting the best fit curves for each dataset are given in Supplementary Table S2. Abbreviations: N, nucleoprotein; NAb. Neutralizing antibody; PSO, post-symptom onset; RBD, receptor binding domain; S/C: signal-to-cutoff ratio. (b) Antibody titers at different periods. For x-axis, the median interval between symptom onset and sample collection of the 2 months, 6 months and 12 months time points are 61 days, 184 days and 376 days. The thick black horizontal line indicates the geometric mean. Statistical analysis was performed using Kruskal-Wallis test. ns, not significant; *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. (c) Comparison of seropositive rate between live virus neutralizing antibody, surrogate neutralizing antibody, and binding antibody assays. For live virus neutralizing antibody assay, a serum specimen is considered to be seropositive if the neutralizing antibody titer was ≥10.

Figure 2

Comparison of live virus neutralizing antibody titer against ancestral virus and variants between recovered COVID-19 patients who are non-vaccinated (n = 73) and those who have received BNT162b2 (n = 32) or CoronaVac (n = 30). (a) Ancestral virus; (b) Beta variant; (c) Delta variant; (d) Omicron variant. The serum specimens were for all groups were collected at a median of 12 months post-symptom onset. Thick black horizontal bars indicate the geometric mean neutralizing antibody titer. Horizontal dotted line represents the limit of detection for the live virus neutralizing antibody assay. Statistical analysis was performed using Kruskal-Wallis test. ns, not significant; *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Figure 3

Comparison of live virus neutralizing antibody activity against ancestral virus and different variants. (a) Non-vaccinated (n = 73); (b) BNT162b2 recipients (n = 32); (c) CoronaVac recipients (n = 30). The serum specimens for all groups were collected at a median of 12 months post-symptom onset. For each variant, the fold reduction compared with ancestral virus is shown. Thick black horizontal bars indicate the geometric mean neutralizing antibody titer. Horizontal dotted line represents the limit of detection for the live virus neutralizing antibody assay. Statistical analysis was performed using Friedman's test.

Figure 4

Comparison of live virus neutralizing antibody activity against the Omicron variant between one (n = 23) and two doses (n = 7) of CoronaVac. (a) Comparison of live virus neutralizing antibody titer against the Omicron variant. Horizontal bars indicate the geometric mean neutralizing antibody titer. Horizontal dotted line represents the limit of detection for the live virus neutralizing antibody assay. Mann Whitney U test was used for the statistical analysis. (b) Comparison of seropositive rate for Omicron variant. A neutralizing antibody titer of ≥10 was considered as seropositive. Fisher's exact test was used for the statistical analysis.

Figure 5

Correlation between surrogate neutralizing antibody level and live virus neutralizing antibody titer. (a, b) Correlation between surrogate neutralizing antibody titer and live virus neutralizing antibody titer against ancestral virus (a) and the Omicron variant (b). (c, d) Receiver operating characteristic curve analysis for ancestral virus (c) and the Omicron variant (d). The data points included the serum specimens collected at approximately 12 months post-symptom onset from the 135 recovered COVID-19 patients.