Cell-mediated and Neutralizing Antibody Responses to the SARS-CoV-2 Omicron BA.4/BA.5-adapted Bivalent Vaccine Booster in Kidney and Liver Transplant Recipients

Abstract

Background: The immunogenicity elicited by the Omicron BA.4/BA.5-adapted bivalent booster vaccine after solid organ transplantation (SOT) has not been characterized.

Methods: We assessed cell-mediated and neutralizing IgG antibody responses against the BA.4/BA.5 spike receptor-binding domain at baseline and 2 wk after the administration of an mRNA-based bivalent (ancestral strain and BA.4/BA.5 subvariants) vaccine among 30 SOT recipients who had received ≥3 monovalent vaccine doses. Previous coronavirus disease 2019 history was present in 46.7% of them. We also recruited a control group of 19 nontransplant healthy individuals. Cell-mediated immunity was measured by fluorescent ELISpot assay for interferon (IFN)-γ secretion, whereas the neutralizing IgG antibody response against the BA.4/BA.5 spike receptor-binding domain was quantified with a competitive ELISA.

Results: The median number of BA.4/BA.5 spike-specific IFN-γ-producing spot-forming units (SFUs) increased from baseline to 2 wk postbooster (83.8 versus 133.0 SFUs/10⁶ peripheral blood mononuclear cells; P = 0.0017). Seropositivity rate also increased (46.7%-83.3%; P = 0.001), as well as serum neutralizing activity (4.2%-78.3%; P < 0.0001). Patients with no prior coronavirus disease 2019 history experienced higher improvements in cell-mediated and neutralizing responses after booster vaccination. There was no correlation between BA.4/BA.5 spike-specific IFN-γ-producing SFUs and neutralizing activity. Nontransplant controls showed more robust postbooster cell-mediated immunity than SOT recipients (591.1 versus 133.0 IFN-γ-producing SFUs/10⁶ peripheral blood mononuclear cells; P < 0.0001), although no differences were observed for antibody responses in terms of postbooster seropositivity rates or neutralizing activity.

Conclusions: Booster with the BA.4/BA.5-adapted bivalent vaccine generated strong subvariant-specific responses among SOT recipients. Booster-induced cell-mediated immunity, however, remained lower than in immunocompetent individuals.

Graphical abstract

FIGURE 1.

SARS-CoV-2 Omicron BA.4/BA.5–specific immune responses at baseline and at 2 wk after the booster vaccination and individual trajectories between both time points. A, Cell-mediated immunity in terms of number of BA.4/BA.5 spike–specific IFN-γ–producing SFUs (n = 27 [immunity was not measured in 3 patients because of insufficient PBMCs in the postbooster sample]). B, Antibody-neutralizing activity semiquantitatively estimated according to the percent inhibition of the sample with reference to the negative control (n = 30). The cutoff value for assay positivity (percent inhibition ≥20%) is denoted by the blue dotted line. Red bars and whiskers represent median values and interquartile ranges, respectively. IFN-γ, interferon-gamma; PBMC, peripheral blood mononuclear cell; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SFU, spot-forming unit.

FIGURE 2.

Comparison of the magnitude of cell-mediated immune responses elicited by the BA.4/BA.5–adapted booster vaccine between SOT recipients (n = 27) and the nontransplant control group (n = 18). Red bars and whiskers represent median values and interquartile ranges, respectively. Cell-mediated immunity was not measured in 1 nontransplant healthy individual because of insufficient PBMCs in the postbooster sample. IFN-γ, interferon-gamma; ns, nonsignificant; PBMC, peripheral blood mononuclear cell; SFU, spot-forming unit; SOT, solid organ transplantation.

FIGURE 3.

Comparison of antibody-mediated response elicited by the BA.4/BA.5-adapted booster vaccination between SOT recipients (n = 30) and the nontransplant control group (n = 16). A, IgG seropositivity rates at baseline and 2 wk after vaccination. B, Antibody-neutralizing activity at both points. Red bars and whiskers represent median values and interquartile ranges, respectively. The cutoff value for positivity in the competitive ELISA (percent inhibition ≥20%) is denoted by the blue dotted line. Three nontransplant healthy individuals lacked postbooster samples. ns, nonsignificant; SOT, solid organ transplantation.