Long-term humoral and cellular immunity against vaccine strains and Omicron subvariants (BQ.1.1, BN.1, XBB.1, and EG.5) after bivalent COVID-19 vaccination

Abstract

Background: The assessment of long-term humoral and cellular immunity post-vaccination is crucial for establishing an optimal vaccination strategy.

Methods: This prospective cohort study evaluated adults (≥18 years) who received a BA.4/5 bivalent vaccine. We measured the anti-receptor binding domain immunoglobulin G antibody and neutralizing antibodies (NAb) against wild-type and Omicron subvariants (BA.5, BQ.1.1, BN.1, XBB.1 and EG.5) up to 9 months post-vaccination. T-cell immune responses were measured before and 4 weeks after vaccination.

Results: A total of 108 (28 SARS-CoV-2-naïve and 80 previously infected) participants were enrolled. Anti-receptor binding domain immunoglobulin G (U/mL) levels were higher at 9 months post-vaccination than baseline in SAR-CoV-2-naïve individuals (8,339 vs. 1,834, p<0.001). NAb titers against BQ.1.1, BN.1, and XBB.1 were significantly higher at 9 months post-vaccination than baseline in both groups, whereas NAb against EG.5 was negligible at all time points. The T-cell immune response (median spot forming unit/10⁶ cells) was highly cross-reactive at both baseline (wild-type/BA.5/XBB.1.5, 38.3/52.5/45.0 in SARS-CoV-2-naïve individuals; 51.6/54.9/54.9 in SARS-CoV-2-infected individuals) and 4 weeks post-vaccination, with insignificant boosting post-vaccination.

Conclusion: Remarkable cross-reactive neutralization was observed against BQ.1.1, BN.1, and XBB.1 up to 9 months after BA.4/5 bivalent vaccination, but not against EG.5. The T-cell immune response was highly cross-reactive.

Keywords: EG.5; SARS-CoV-2; cellular immunity; cross-reactivity; durability; humoral immunity; vaccines.

Figure 1

Anti-receptor binding domain immunoglobulin G antibodies after BA.4/5 bivalent mRNA COVID-19 vaccination. The columns represent the geometric mean titers and black bars represent 95% confidence intervals. Statistically significant p-values are marked with asterisks (*p < 0.05, ****p < 0.0001). GMT, geometric mean titer; IgG, immunoglobulin G; ns, not significant; RBD, receptor binding domain.

Figure 2

Comparison of neutralizing activity against wild-type and Omicron subvariants at different time points after BA.4/5 bivalent mRNA COVID-19 vaccination. The columns represent the geometric mean titers and black bars represent 95% confidence intervals. Time points are presented as T0 (baseline), T1 (4 weeks after vaccination), T2 (3 months after vaccination), and T4 (9 months after vaccination). Statistically significant p-values are marked with asterisks (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). ND₅₀, 50% neutralization dilution; ns, not significant; WT, wild-type.

Figure 3

Comparison of neutralizing activity against wild-type and Omicron subvariants by prior SARS-CoV-2 infection after BA.4/5 bivalent mRNA COVID-19 vaccination. The columns represent the geometric mean titers and black bars represent 95% confidence intervals. Statistically significant p-values are marked with asterisks (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). ND₅₀, 50% neutralization dilution; ns, not significant; WT, wild-type.

Figure 4

T-cell immune responses against wild-type, BA.5, and XBB.1.5 subvariants of SARS-CoV-2 at baseline (pre-vaccination) and 4 weeks (post-vaccination) after BA.4/5 bivalent mRNA COVID-19 vaccination. The black bar represents the median with interquartile range. ELISpot, enzyme-linked ImmunoSpot; IFN-γ, interferon-γ; ns, not significant; SFU, spot forming unit; WT, wild-type.