Immunosuppressive Therapy Modifies Anti-Spike IgG Subclasses Distribution After Four Doses of mRNA Vaccination in a Cohort of Kidney Transplant Recipients

Abstract

Background: IgG4 is the least immunogenic subclass of IgG. Immunization with mRNA vaccines against SARS-CoV-2, unlike other vaccines, induces an increase in IgG4 against the spike protein in healthy populations. This study investigated whether immunosuppressive therapy affects the immune response, focusing on IgG subclass changes, to four doses of mRNA vaccine in kidney transplant recipients (KTRs). Methods: This study includes 146 KTRs and 23 dialysis patients (DPs) who received three mRNA-1273 vaccine doses and a BNT162b2 booster. We evaluated anti-spike IgG titers and subclasses, T-CD4+ and T-CD8+ cellular responses, and serum neutralizing activity (SNA). Results: At the fourth dose, 75.8% of COVID-19 naïve KTRs developed humoral and cellular responses (vs. 95.7% in DPs). There was a correlation between anti-spike IgG titers/subclasses and SNA (p < 0.001). IgG subclass kinetics after the third/fourth dose differed between COVID-19 naïve KTRs and DPs. Immunosuppressive therapy influenced IgG subclasses: mTOR inhibitors (mTORi) positively influenced IgG1 and IgG3 (p < 0.05), while mycophenolic acid negatively affected IgG1, IgG3, and IgG4 (p < 0.05). SNA is correlated with breakthrough infections after four doses of vaccine in KTRs. mTORi was the only factor associated with SNA > 65% in naïve KTRs [4.29 (1.21-15.17), p = 0.024]. Conclusions: KTRs show weaker cellular and humoral immune responses to mRNA vaccines and a class shift towards non-inflammatory anti-S IgG4 upon booster doses. IgG subclasses show a positive correlation with SNA and are influenced by immunosuppression. Increased SNA after four doses of vaccine is protective against infection. mTORi may benefit non-responding KTRs.

Keywords: COVID-19; IgG subclasses; SARS-CoV-2 vaccine; kidney transplant recipients; serum neutralizing activity.

Figure 1

Flow chart of kidney transplant recipients (KTRs) included in the study and exclusion criteria. Each extraction (P0, P1, P2, P3, and P4) involved the following laboratory determinations: SARS-CoV-2 Serology Analysis, Assessment of Cell-Mediated Immunity, Assessment of Serum Neutralizing Activity of ACE2-RBD, and Measurement of IgG subclasses. Patients were tested for SARS-CoV-2 infection by anti-N antibodies, determined by ELISA.

Figure 2

Immunosuppressive treatments modulate IgG subtypes in response to SARS-CoV-2 mRNA vaccination after booster dose. (A) Mycophenolate mofetil treatment (MPA) decreases IgG1 and IgG4 levels, whereas (B) mTOR inhibitors (mTORi) increase IgG1, IgG3, and IgG4 levels in these patients. Untreated condition refers to patients not treated with the analyzed immunosuppressant (e.g., not treated with mTORi, but with other immunosuppression). These findings highlight the distinct immunomodulatory effects of mTORi and MMF on specific IgG subclasses, suggesting possible impacts on treatment efficacy. Only significant p-values (<0.05) are shown, * p-value < 0.05, ** p-value < 0.01. The cut-offs were established as follows: IgG1: 0.0085; IgG2: 0.0075; IgG3: 0.0559; IgG4: 0.018.

Figure 3

Correlation of IgG subclasses and total IgG levels with serum neutralizing activity (SNA) in kidney transplant recipients. Total IgG (r = 0.823, p-value < 0.001) and IgG subclasses showed a positive correlation with SNA, with IgG1 subclass having the higher r-value (0.706, p-value < 0.001).