The role of interleukin-21 in COVID-19 vaccine-induced B cell-mediated immune responses in patients with kidney disease and kidney transplant recipients.

T-cell-mediated help to B cells is required for the development of humoral responses, in which the cytokine interleukin (IL)-21 is key. Here, we studied the mRNA-1273 vaccine-induced SARS-CoV-2-specific memory T-cell IL-21 response, memory B cell response, and immunoglobulin (Ig)G antibody levels in peripheral blood at 28 days after the second vaccination by ELISpot and the fluorescent bead-based multiplex immunoassay, respectively. We included 40 patients with chronic kidney disease (CKD), 34 patients on dialysis, 63 kidney transplant recipients (KTR), and 47 controls. We found that KTR, but not patients with CKD and those receiving dialysis, showed a significantly lower number of SARS-CoV-2-specific IL-21 producing T cells than controls (P < .001). KTR and patients with CKD showed lower numbers of SARS-CoV-2-specific IgG-producing memory B cells when compared with controls (P < .001 and P = .01, respectively). The T-cell IL-21 response was positively associated with the SARS-CoV-2-specific B cell response and the SARS-CoV-2 spike S1-specific IgG antibody levels (both Pearson r = 0.5; P < .001). In addition, SARS-CoV-2-specific B cell responses were shown to be IL-21 dependent. Taken together, we show that IL-21 signaling is important in eliciting robust B cell-mediated immune responses in patients with kidney disease and KTR.

Repeated COVID-19 Vaccination Drives Memory T- and B-cell Responses in Kidney Transplant Recipients: Results From a Multicenter Randomized Controlled Trial.

BACKGROUND: Insight into cellular immune responses to COVID-19 vaccinations is crucial for optimizing booster programs in kidney transplant recipients (KTRs). METHODS: In an immunologic substudy of a multicenter randomized controlled trial (NCT05030974) investigating different repeated vaccination strategies in KTR who showed poor serological responses after 2 or 3 doses of an messenger RNA (mRNA)-based vaccine, we compared SARS-CoV-2-specific interleukin-21 memory T-cell and B-cell responses by enzyme-linked immunosorbent spot (ELISpot) assays and serum IgG antibody levels. Patients were randomized to receive: a single dose of mRNA-1273 (100 µg, n = 25), a double dose of mRNA-1273 (2 × 100 µg, n = 25), or a single dose of adenovirus type 26 encoding the SARS-CoV-2 spike glycoprotein (Ad26.COV2.S) (n = 25). In parallel, we also examined responses in 50 KTR receiving 100 µg mRNA-1273, randomized to continue (n = 25) or discontinue (n = 25) mycophenolate mofetil/mycophenolic acid. As a reference, the data were compared with KTR who received 2 primary mRNA-1273 vaccinations. RESULTS: Repeated vaccination increased the seroconversion rate from 21% to 66% in all patients, which was strongly associated with enhanced levels of SARS-CoV-2-specific interleukin-21 memory T cells (odd ratio, 3.84 [1.89-7.78]; P < 0.001) and B cells (odd ratio, 35.93 [6.94-186.04]; P < 0.001). There were no significant differences observed in these responses among various vaccination strategies. In contrast to KTR vaccinated with 2 primary vaccinations, the number of antigen-specific memory B cells demonstrated potential for classifying seroconversion after repeated vaccination (area under the curve, 0.64; 95% confidence interval, 0.37-0.90; P = 0.26 and area under the curve, 0.95; confidence interval, 0.87-0.97; P < 0.0001, respectively). CONCLUSIONS: Our study emphasizes the importance of virus-specific memory T- and B-cell responses for comprehensive understanding of COVID-19 vaccine efficacy among KTR.