Kidney transplant recipients (KTRs) have an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mortality1 and a markedly decreased immune response after 2 doses of mRNA vaccination.2 The optimal vaccination strategy for KTRs without sufficient immune response after standard vaccination protocols remains unknown. Here, we report combined cellular and humoral response rates after a third dose of the BNT162b2 mRNA vaccine (Tozinameran; Pfizer–BioNTech COVID-19 vaccine).
In this single-center study (subanalysis of the DIA-Vacc cohort3), we reported KTRs’ response rates after the first (T1), second (T2), and third (T3) dose of BNT162b2 vaccination. Seventy-one KTRs (mean age ± SD, 57 ± 14.4 y, 63% men) received first and second vaccinations with BNT162b2 at a 3-wk interval. Forty-eight KTRs with insufficient humoral response after 2 vaccinations received the third dose of BNT162b2 vaccine 68 ± 1 d after the second vaccination. Immune responses to the third vaccination were assessed 4 wk after application (T3; Figure 1A). Humoral response was determined using immunoglobulin (Ig) A and IgG antibody ELISAs against spike S1 protein and IgG ELISA against the receptor-binding domain (RBD). To exclude SARS-CoV-2 contact before or after vaccination, IgG antibodies against the nucleocapsid protein subunit were analyzed in parallel.
Causes of end-stage renal disease were glomerulonephritis in 27%; hypertensive, diabetic, or vascular disease in 18%; cystic kidney disease in 13%; vasculitis in 3%; and unknown cause in ~39% of cases. Immunosuppressive therapy included a calcineurin inhibitor in 87%, mycophenolic acid in 73%, or a mechanistic target of rapamycin inhibitor in 24%, while only 38% of KTRs had glucocorticosteroids as maintenance immunosuppression. The median time after transplantation was 7.5 ± 6 y.
Cumulative humoral response rates in all 71 KTRs were 6% (T1), 32% (T2), and 55% (T3; Figure 1B). Cellular response was 11% at T1 (n = 7/63 patients, no T1 results were reported for 8 patients) and 34% at T2 (n = 23/68 patients, no T2 results were reported for 3 patients; Figure 1B). At T3, cellular response was present in 26% (n = 9/35 patients, no T3 results were reported for 13 patients) and 40% showed a total humoral response (Figure 1C). Among the patients with a humoral response, frequencies of RBD antibodies increased to 94% after the third vaccination (T3; n = 15/16 patients) compared with 56% at T2 (n = 10/18 patients; Figure 1C; additional accurate ELISA/interferon-γ release assay readings; Figure 1D–F).
The humoral response rates after a third mRNA vaccination to SARS-CoV-2 reported here are consistent with a recent publication by Kamar et al.4 We demonstrate that not only the humoral but also the cellular vaccination response rates to a third dose in primary nonresponders are at least comparable with de novo responses after 2 vaccinations. The frequency of neutralizing RBD antibody responses even seemed to be improved. These data do not support the concept of T-cell exhaustion after 2 vaccinations due to high antigen presentation as previously described for viral infections including SARS-CoV-2.4,5
In our view, adapted vaccination protocols with additional vaccinations or higher vaccine doses in KTRs taking immunosuppressants should be encouraged and further investigated.
The authors acknowledge DIA-Vacc Investigators. EUROIMMUN Medizinische Labordiagnostika AG, Lubeck, Germany provided antibody ELISAs and interferon-gamma release assays for this study.
1. Hilbrands LB, Duivenvoorden R, Vart P, et al.; ERACODA Collaborators. COVID-19-related mortality in kidney transplant and dialysis patients: results of the ERACODA collaboration. Nephrol Dial Transplant. 2020;35:1973–1983.
2. Boyarsky BJ, Werbel WA, Avery RK, et al. Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients. JAMA. 2021;325:2204–2206.
3. Stumpf J, Siepmann T, Lindner T, et al. Humoral and cellular immunity to SARS-CoV-2 vaccination in renal transplant versus dialysis patients: a prospective, multicenter observational study using mRNA-1273 or BNT162b2 mRNA vaccine. Lancet Reg Health Eur. 2021;9:100178.
4. Kamar N, Abravanel F, Marion O, et al. Three doses of an mRNA Covid-19 vaccine in solid-organ transplant recipients. N Engl J Med. 2021;385:661–662.
5. Gutiérrez-Bautista JF, Rodriguez-Nicolas A, Rosales-Castillo A, et al. Negative clinical evolution in COVID-19 patients is frequently accompanied with an increased proportion of undifferentiated Th cells and a strong underrepresentation of the Th1 subset. Front Immunol. 2020;11:596553.