Immunological imprint on peripheral blood in kidney transplant recipients after two doses of SARS-CoV-2 mRNA vaccination in Japan

Abstract

The immunological imprint after two doses of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) mRNA vaccination for patients after kidney transplantation (KTx) remain unclear. This study included KTx recipients and volunteer healthy controls (HCs) who received two doses of SARS-CoV-2 mRNA vaccine (Pfizer BioNTech) from January 2021 to December 2021. We analyzed safety within 21 days after each vaccination dose and compared the immune response in peripheral blood mononuclear cells (PBMCs) between the two groups. No graft rejection was observed throughout this study. Adverse events were generally observed within 5 days. The KTx group exhibited a significantly lower degree of symptoms between doses 1 and 2 (P < 0.001). Increases in activated subsets of T and B cells expressing human leukocyte antigen (HLA)-DR and/or CD38 were observed in the HC group after dose 2 (both P < 0.001), with the greatest increases in HLA-DR⁺CD8⁺ T cells and CD38⁺CD19⁺ B cells (P = 0.042 and P = 0.031, respectively). In addition, PD1⁺CD8⁺ T cells-but not PD1⁺CD4⁺ T cells-increased significantly in the HC group (P = 0.027). In the KTx group, however, activated HLA-DR⁺, CD38⁺, and PD1⁺ cells remained at baseline levels. Immunoglobulin (Ig)G against SARS-CoV-2 was detected in only four KTx recipients (13.3%) after dose 2 (P < 0.001). Multivariate logistic regression analyses revealed that ΔHLA-DR⁺CD8⁺ T cells and ΔCD38⁺CD19⁺ B cells were significantly associated with IgG formation (both P = 0.02). SARS-CoV-2 mRNA vaccine generates impaired cellular and humoral immunity for KTx recipients. Results indicate the need for modified vaccination strategies in immunocompromised KTx recipients.

Keywords: SARS-CoV-2 mRNA vaccination; cellular and humoral immune responses; immunological imprint; kidney transplantation; safety.

FIGURE 1

Local and systemic adverse reactions after each vaccination, as recorded by KTx recipients and HCs. (A) Comparison how many days KTx recipients and HCs suffered from any local or systemic adverse events after D1 and D2 vaccination. Day 0 is the day of vaccination. (B,C) Incidence of local (B) and systemic (C) adverse events. (D) Comparison of ‘Yes’ or ‘No’ scores and change in groups. (E) Percentage of scores D1 < D2 or D1 ≥ D2 in each group. (F,G) Comparison of scores and change with regard to MMF dose (F) and number of immunosuppressive drugs (G) in KTx recipients. Blue lines represent means. Data were analyzed using the Mann-Whitney U test (***P < 0.001).

FIGURE 2

Quantification of major immune lymphocyte subsets among PBMCs. Comparison of the proportions of CD3⁺ T cells (A), CD19⁺ B cells (B), CD4⁺ T cells (C), CD8⁺ T cells (D), and CD4^–CD8^– T cells (E) in KTx recipients (n = 30) and HCs (n = 12) pre- and post-vaccination. Bar plots depict mean ± SD. Data were analyzed using the Mann-Whitney U test.

FIGURE 3

Activated CD3⁺ T cells increased after SARS-CoV-2 mRNA vaccination in HCs not but KTx recipients. Representative gating strategies and scatter plots of activated HLA-DR⁺ and/or CD38⁺ cells among CD3⁺ T cells in the two groups pre- and post-vaccination (A,D). Comparison of the proportions and change in proportions of HLA-DR⁺ (B) and HLA-DR⁺CD38⁺ (E) CD3⁺ T cells in KTx recipients (left) and HCs (right) as measured by flow cytometry. Normalized increase in HLA-DR⁺ (C) and HLA-DR⁺CD38⁺ (F) CD3⁺ cells between pre- and post-vaccination. Bar plots depict mean ± SD. Blue lines and bars represent means. Data were analyzed using the Mann-Whitney U test (***P < 0.001).

FIGURE 4

Activated CD8⁺ T cells were induced by SARS-CoV-2 mRNA vaccination in HCs. Representative gating strategies and scatter plots of activated HLA-DR⁺, PD1⁺, and Treg cells among T cell subsets in the two groups pre- and post-vaccination (A,D). Comparison of the proportions and change in proportions of HLA-DR⁺ cells among CD4⁺ (B) and CD8⁺ (E) T cells in KTx recipients (left) and HCs (right) as measured by flow cytometry. Normalized increases in HLA-DR⁺ cells among CD4⁺ (C) and CD8⁺ (F) T cells between pre- and post-vaccination. Bar plots depict mean ± SD. Blue lines and bars represent means. Data were analyzed using the Mann-Whitney U test (*P < 0.05).

FIGURE 5

PD1⁺ CD8⁺ T cells were induced by SARS-CoV-2 mRNA vaccination in HCs. Representative gating strategies and scatter plots of activated PD1⁺ cells among T cell subsets in the two groups pre- and post-vaccination (A,D). Comparison of the proportions and change in proportions of PD1⁺ cells among CD4⁺ (B) and CD8⁺ (E) T cells in KTx recipients (left) and HCs (right) as measured by flow cytometry. Normalized increases in PD1⁺ cells among CD4⁺ (C) and CD8⁺ (F) T cells between pre- and post-vaccination. Bar plots depict mean ± SD. Blue lines and bars represent means. Data were analyzed using the Mann-Whitney U test (*P < 0.05).

FIGURE 6

Activated CD19⁺ B cells increased after SARS-CoV-2 mRNA vaccination in HCs. (A) Representative gating strategies and scatter plots of activated CD38⁺ cells among CD19⁺ B cells in the two groups pre- and post-vaccination. (B) Comparison of the proportion and change in proportion of CD38⁺CD19⁺ B cells in KTx recipients (left) and HCs (right) as measured by flow cytometry. (C) Normalized increase in CD38⁺CD19⁺ B cells between pre- and post-vaccination. (D) Serologic S-RBD IgG antibody response against SARS-CoV-2 at 30 days after D2 vaccination. (E) Scatter plot of anti-S-RBD IgG values and normalized increase in CD38⁺CD19⁺ B cells by flow cytometric analysis. Data were obtained from 42 samples (30 in KTx group and 12 on HC group), and a moderate correlation was found in HC group. Bar plots depict mean ± SD. Blue lines and bars represent means. Data were analyzed using the Mann-Whitney U test (*P < 0.05, ***P < 0.001).