Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2

Abstract

Background: Individuals with chronic inflammatory diseases (CID) are frequently treated with immunosuppressive medications that can increase their risk of severe COVID-19. While novel mRNA-based SARS-CoV-2 vaccination platforms provide robust protection in immunocompetent individuals, the immunogenicity in CID patients on immunosuppression is not well established. Therefore, determining the effectiveness of SARS-CoV-2 vaccines in the setting of immunosuppression is essential to risk-stratify CID patients with impaired protection and provide clinical guidance regarding medication management.

Methods: We conducted a prospective assessment of mRNA-based vaccine immunogenicity in 133 adults with CIDs and 53 immunocompetent controls. Blood from participants over 18 years of age was collected before initial immunization and 1-2 weeks after the second immunization. Serum anti-SARS-CoV-2 spike (S) IgG ⁺ binding, neutralizing antibody titers, and circulating S-specific plasmablasts were quantified to assess the magnitude and quality of the humoral response following vaccination.

Results: Compared to immunocompetent controls, a three-fold reduction in anti-S IgG titers (P=0.009) and SARS-CoV-2 neutralization (p<0.0001) were observed in CID patients. B cell depletion and glucocorticoids exerted the strongest effect with a 36- and 10-fold reduction in humoral responses, respectively (p<0.0001). Janus kinase inhibitors and antimetabolites, including methotrexate, also blunted antibody titers in multivariate regression analysis (P<0.0001, P=0.0023, respectively). Other targeted therapies, such as TNF inhibitors, IL-12/23 inhibitors, and integrin inhibitors, had only modest impacts on antibody formation and neutralization.

Conclusions: CID patients treated with immunosuppressive therapies exhibit impaired SARS-CoV-2 vaccine-induced immunity, with glucocorticoids and B cell depletion therapy more severely impeding optimal responses.

Figure 1.. Glucocorticoids Reduce Immunogenicity of mRNA-based SARS-CoV-2 Vaccination.

Immunocompetent (control) and chronic inflammatory disease (CID) participants underwent blood draws pre- and post-vaccination (~1-2 weeks after boost) and concurrent medication use was collected. Quantification of circulating anti-S IgG for immunocompetent (left) and CID (right) participants pre- and post-immunization is shown in Panel A. Each symbol represents an individual for each timepoint. Dotted lines indicate limits of detection (LoD). Horizontal red lines indicate median value. A lower titer of anti-SARS-CoV-2 antibodies post-vaccination in CID vs immunocompetent participants is shown in Panel B. Neutralization of SARS-CoV-2 S protein by serum of immunocompetent and CID participants post-vaccination is shown in Panel C. Pseudotyped vesicular stomatitis virus with SARS-CoV-2 S protein was introduced to Vero cells with decreasing concentrations of serum to identify the dilution required for 50% neutralization. Values are normalized to the median of immunocompetent participants. A lower titer of anti-SARS-CoV-2 antibodies is found in CID participants taking glucocorticoids is shown in Panel D. CID participants are split by prednisone use (shaded black). A decrease in neutralization of SARS-CoV-2 S for CID participants on or off glucocorticoids is shown in Panel E. P values are indicated for each comparison (Dunn’s multiple comparison test).

Figure 2.. Antimetabolites Modestly Reduce Immunogenicity of mRNA-based SARS-CoV-2 Vaccination.

Decreases in circulating anti-S IgG post-immunization for CID participants either not taking antimetabolites, taking any antimetabolite, or specifically taking methotrexate are shown in Panel A. Methotrexate use is denoted by square symbols. Glucocorticoid use was excluded. Dotted lines indicate limits of detection (LoD). A decrease in neutralization of SARS-CoV-2 S for CID participants on or off antimetabolites is shown in Panel B. Values are normalized to the median of immunocompetent participants. Each symbol represents an individual for each timepoint. Horizontal red lines indicate median value. P values are indicated for each comparison (Dunn’s multiple comparison test).

Figure 3.. B Cell Depletion Therapy Reduces Immunogenicity of mRNA-based SARS-CoV-2 Vaccination.

Quantification of circulating anti-S IgG for immunocompetent (control) and CID participants on TNF inhibitors (TNFi), JAK inhibitors (JAKi), B cell depletion therapy (BCDT), anti-integrin agents, and anti-IL-12/23 agents are shown in Panel A. Combined use with prednisone (PDN) is denoted by solid fill and with methotrexate (MTX) is denoted by square symbols. Dotted lines indicate limits of detection (LoD). Neutralization for the same sub-groups is shown in Panel B. Values are normalized to the median of immunocompetent participants. Quantification of circulating anti-S IgG for CID participants on TNFi, separated by methotrexate use is shown in Panel C. A reduction in neutralization for participants on an TNFi alone is shown in Panel D. Each symbol represents an individual for each timepoint. Horizontal red lines indicate median value. P values are indicated for each comparison (Dunn’s multiple comparison test).