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

Abstract

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.

FIGURE 1.

SARS-CoV-2-specific T-cell responses. A, IL-21 memory T-cell response. B, IFN-γ response. The MMF+ group continued and the MMF− group discontinued mycophenolate mofetil/mycophenolic acid treatment 1 wk before and 1 wk after receiving repeated vaccination with 1 dose (100 μg) of mRNA-1273. Data are presented as paired data. Mann-Whitney U test (pairwise deletion) or Wilcoxon singed-rank test (listwise deletion) was used to compare medians. The LLoD response was 3.3 spots for IL-21 memory T-cell response and 1.7 spots for IFN-γ response. Each symbol represents an individual. Number of missing cases (of total 125) is 23 for IL-21 and 18 for IFN-γ. Ad26.COV2.S, adenovirus type 26 encoding the SARS-CoV-2 spike glycoprotein; IFN-γ, interferon gamma; IL-21, interleukin-21; LLoD, lower limit of detection; MMF, mycophenolate mofetil; mRNA-1273, messenger RNA-1273; PBMCs, peripheral blood mononuclear cells; S1, spike protein.

FIGURE 2.

Vaccine-induced SARS-CoV-2-specific B-cell–mediated immune responses. A, Memory B-cell response. B, Antibody response. The MMF+ group continued and the MMF− group discontinued mycophenolate mofetil/mycophenolic acid treatment 1 wk before and 1 wk after receiving repeated vaccination with 1 dose (100 μg) of mRNA-1273. Data are presented as paired data. Mann-Whitney U test (pairwise deletion) or Wilcoxon singed-rank test (listwise deletion) was used to compare medians. The LLoD response was 10 spots for memory B-cell response. Dotted line in B represents the cutoff value for being a serological responder (≥10 BAU/mL). Each symbol represents an individual. Number of missing cases (of total 125) = 35 for memory B-cell response. Ad26.COV2.S, adenovirus type 26 encoding the SARS-CoV-2 spike glycoprotein; BAU, binding antibody units; LLoD, lower limit of detection; MMF, mycophenolate mofetil; mRNA-1273, messenger RNA-1273; PBMCs, peripheral blood mononuclear cells; S1, spike protein.

FIGURE 3.

Correlations between IL-21 memory T-cell and B-cell–mediated immune responses at 28 d after repeated vaccination. A, Correlation IL-21 and memory B-cell response. B, Correlation IL-21 and antibody response. The MMF+ group continued and the MMF− group discontinued mycophenolate mofetil/mycophenolic acid treatment 1 wk before and 1 wk after receiving repeated vaccination with 1 dose (100 μg) of mRNA-1273. The horizontal dotted line represents the LLoD of memory B-cell response (=10 spots) or the cutoff value for being a serological responder (≥10 BAU/mL) and the vertical dotted line represents the LLoD of IL-21 memory T-cell response (=3.3 spots). Ad26.COV2.S, adenovirus type 26 encoding the SARS-CoV-2 spike glycoprotein; BAU, binding antibody units; IL-21, interleukin-21; LLoD, lower limit of detection; MMF, mycophenolate mofetil; mRNA-1273, messenger RNA-1273; PBMCs, peripheral blood mononuclear cells; S1, spike protein.

FIGURE 4.

Correlation between SARS-CoV-2-specific memory B-cell response and SARS-CoV-2 spike S1-specific IgG antibody level at 28 d after repeated vaccination. The MMF+ group continued and the MMF− group discontinued mycophenolate mofetil/mycophenolic acid treatment 1 wk before and 1 wk after receiving repeated vaccination with 1 dose (100 μg) of mRNA-1273. The horizontal dotted line represents the cutoff value for being a serological responder (≥10 BAU/mL) and the vertical dotted line represents the LLoD of memory B-cell response (=10 spots). Ad26.COV2.S, adenovirus type 26 encoding the SARS-CoV-2 spike glycoprotein; BAU, binding antibody units; LLoD, lower limit of detection; MMF, mycophenolate mofetil; mRNA-1273, messenger RNA-1273; PBMCs, peripheral blood mononuclear cells; S1, spike protein.

FIGURE 5.

Association between cellular memory activity and seroconversion. Correlation between SARS-CoV-2-specific IL-21 memory T-cell and antibody level at 28 d after the second vaccination in healthy individuals (A) and in KTRs (B), and at 28 d after repeated vaccination in KTR (C). Correlation between SARS-CoV-2-specific memory B-cell and antibody level at 28 d after the second vaccination in healthy individuals (D) and in KTRs (E), and at 28 d after repeated vaccination in KTR (F). The horizontal line represents the cutoff value for being a serological responder (≥10 BAU/mL), and the vertical line represents the LLoD of the IL-21 memory T-cell (=3.3 spots) or memory B-cell response (≤10 spots). B, C, E, and F, Receiver operating characteristic (ROC) curves are presented using IL-21 or memory B-cell response as continuous variable and seroconversion (yes or no) as a binary outcome. The number of IL-21–producing memory T cells showed potential for classifying seroconversion in KTR after both 2 primary vaccinations (B; AUC, 0.75; 95% CI, 0.62-0.88; P < 0.01) and repeated vaccination (C; AUC, 0.73; 95% CI, 0.63-0.83; P < 0.01). The number of antigen-specific memory B cells did not show potential for classifying seroconversion in KTR after 2 primary vaccinations (E; AUC, 0.64; 95% CI, 0.37-0.90; P = 0.26), but did after repeated vaccination (F; AUC, 0.92; 95% CI, 0.87-0.97; P < 0.0001). AUC, area under the curve; BAU, binding antibody units; CI, confidence interval; IL-21, interleukin-21; KTR, kidney transplant recipient; LLoD, lower limit of detection; mRNA, messenger RNA; PBMCs, peripheral blood mononuclear cells; S1, spike protein.