Functional antibody responses targeting the Spike protein of SARS-CoV-2 Omicron XBB.1.5 in elderly nursing home residents following Wuhan-Hu-1-based mRNA booster vaccination

Abstract

The immune effector mechanisms involved in protecting against severe COVID-19 infection in elderly nursing home residents following vaccination or natural infection are not well understood. Here, we measured SARS-CoV-2 Spike (S)-directed functional antibody responses, including neutralizing antibodies (NtAb) and antibody Fc-mediated NK cell activity (degranulation and IFNγ production), against the Wuhan-Hu-1, BA.4/5 (for NtAb), and Omicron XBB.1.5 variants in elderly nursing home residents (n = 39; median age, 91 years) before and following a third (pre- and post-3D) and a fourth (pre- and post-4D) mRNA COVID-19 vaccine dose. Both 3D and 4D boosted NtAb levels against both (sub)variants. Likewise, 3D and 4D increased the ability of sera to trigger both LAMP1- and IFNγ-producing NK cells, in particular against XBB.1.5. In contrast to NtAb titres, the frequencies of LAMP1- and IFNγ-producing NK cells activated by antibodies binding to Wuhan-Hu-1 and Omicron XBB.1.5 S were comparable at all testing times. Stronger functional antibody responses were observed in vaccine-experienced participants compared to vaccine-naïve at some testing times. These findings can contribute to identifying a reliable correlate of protection in elderly nursing home residents against severe COVID-19 and inform future vaccine strategies in this population group.

Figure 1

Anti-Receptor binding domain (RBD) total antibodies (in log₁₀ in BAU/mL) in plasma from elderly nursing home residents. A antibody levels prior to and after one (pre-3D and post-3D, respectively) or two (pre-4D and post-4D, respectively) COVID-19 vaccine booster doses. B Antibody levels in vaccinated/SARS-CoV-2-experienced (Vac-ex) and vaccinated/SARS-CoV-2-naïve subjects (Vac-n) at the different sampling times. The number of plasma samples available for analyses at the different sampling times is shown. Bars indicate medians and IQRs. P values for differences are shown.

Figure 2

Anti-Receptor binding domain (RBD) IgG avidity in plasma from elderly nursing home residents. Total antibodies. A Anti-RBD IgG avidity indexes (%) before and after one (pre-3D and post-3D, respectively) or two (pre-4D and post-4D, respectively) COVID-19 vaccine booster doses. B Anti-RBD IgG avidity indexes (%) in vaccinated/SARS-CoV-2-experienced (Vac-ex) and vaccinated/SARS-CoV-2 naïve (Vac-n) at the different sampling times. The number of plasma samples available for analyses at the different sampling times is shown. Bars indicate medians and IQRs. P values for differences are shown.

Figure 3

Neutralizing antibody titres (reciprocal IC₅₀) against the spike protein of Wuhan-Hu-1 (A), Omicron BA.4/5 (B), and Omicron XBB.1.5 (C) in elderly nursing home residents before and after one (pre-3D and post-3D, respectively) or two (pre-4D and post-4D, respectively) COVID-19 vaccine booster doses. The number of plasma samples analysed at the different sampling times is shown. Bars indicate medians and IQRs. P values for differences are shown.

Figure 4

Neutralizing antibody titres (reciprocal IC₅₀) against the spike protein of Wuhan-Hu-1, Omicron BA.4/5 , and Omicron XBB.1.5 in elderly nursing home residents before and after one (pre-3D and post-3D, respectively) or two (pre-4D and post-4D, respectively) COVID-19 vaccine booster doses, according to their SARS-CoV-2 infection status (experienced/Vac-ex or naïve/Vac-n). The number of plasma samples analysed at the different sampling times is shown. Bars indicate medians and IQRs. P values for differences are shown.

Figure 5

Comparison of antibody-dependent NK cell-mediated responses against SARS-CoV-2 Wuhan-Hu-1 and Omicron XBB.1.5 spike variants in elderly nursing home residents before and after one (pre-3D and post-3D, respectively) or two (pre-4D and post-4D, respectively) COVID-19 vaccine booster doses. Frequencies of LAMP1- (lysosomal-associated membrane protein 1) and IFN (interferon) γ-producing NK cells are shown in panels A and B, respectively. The number of participants analysed at the different sampling times is shown. Bars indicate medians and IQRs. P values for differences are shown.

Figure 6

Impact of COVID-19 booster vaccination on antibody-dependent NK cell-mediated responses against SARS-CoV-2 Wuhan-Hu-1 and Omicron XBB.1.5 spike variants in elderly nursing home residents. The frequencies of LAMP1 (lysosomal-associated membrane protein 1)-producing NK cells against Wuhan-Hu-1 and Omicron XBB.1.5 are shown in (A) and (B), respectively. The frequencies of IFN (interferon) γ-producing NK cells against Wuhan-Hu-1 and Omicron XBB.1.5 are shown in (C) and (D), respectively. The number of participants analysed at the different sampling times is shown. Bars indicate medians and IQRs. P values for differences are shown.

Figure 7

Antibody-dependent NK cell-mediated responses against SARS-CoV-2 Wuhan-Hu-1 and Omicron XBB.1.5 spike variants in elderly nursing home residents according to their SARS-CoV-2 infection status (experienced/Vac-ex or naïve/Vac-n). The frequencies of LAMP1- (lysosomal-associated membrane protein 1)-producing NK cells against Wuhan-Hu-1 and Omicron XBB.1.5 at the different testing times are shown in (A) and (B), respectively. The frequencies of IFN (interferon)γ-producing NK cells against Wuhan-Hu-1 and Omicron XBB.1.5 are shown in (C) and (D), respectively. The number of participants analysed at the different sampling times is shown. Bars indicate medians and IQRs. P values for differences are shown.

Figure 8

Correlation between Neutralizing antibody (NtAb) levels and frequencies of LAMP1- (lysosomal-associated membrane protein 1)-producing or (interferon)γ-producing NK cells against Wuhan-Hu-1 (A and B, respectively) and Omicron XBB.1.5 (C and D, respectively). Rho and P values by the Spearman Rank test are shown.