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Letter to the Editor

Low Immunization Rate in Kidney Transplant Recipients Also After Dose 2 of the BNT162b2 Vaccine: Continue to Keep Your Guard up!

Midtvedt, Karsten MD, PhD1; Tran, Trung PhD2; Parker, Krystina MD, PhD3; Marti, Hans-Peter MD4; Stenehjem, Aud-E. MD, PhD5; Gøransson, Lasse Gunnar MD, PhD6,7; Mørkve Soldal, Kari MD8; Madsen, Camilla MD9; Smedbråten, Julia MD, PhD10; Vaage, Eline Benno2; Lund-Johansen, Fridtjof MD, PhD2; Åsberg, Anders PhD1,11,12

Author Information
doi: 10.1097/TP.0000000000003856
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We read with interest the report from Georgery et al1 addressing the very low immunization rate of 3.8% in kidney transplant recipients (KTRs) 28 d after 1 dose of the BNT162b2 (Pfizer/BioNTech) vaccine. As addressed by the authors, this is markedly lower than what has been reported in other recent publications on mRNA vaccines (BNT162b2, Pfizer/BioNTech; mRNA-1273, Moderna) in this population.2,3 Our findings after 2 doses of BNT162b2 are in line with their observations. We assessed the serological response 25–89 d after the second dose of the BNT162b2 vaccine in 141 KTRs without a known history of COVID-19 infection and negative SARS-CoV-2 anti-nucleocapsid IgG before vaccination. Antibodies to SARS-CoV-2 spike, the receptor-binding domain of spike and nucleocapsid were measured with a multiplexed bead-based flow cytometric assay as previously described.4 The assay was calibrated to the World Health Organization international standard (National Institute for Biological Standards and Control code 20/136) to assess binding antibody units (BAU).

Table 1 summarizes the baseline characteristics and findings following the second dose of BNP162b2 vaccine in the 141 KTRs. The median age was 75 (range, 21–91) y, 56% were male individuals. The median time since transplantation was 9.6 y (range, 0.4–47.1), 72% were transplanted >5 y ago. The majority of the recipients were on a combination of calcineurin inhibitor (CNI), mycophenolate (MPA), and prednisolone (n = 105, 74%). On the day of measurement, only 25 patients (18%) had seroconverted with a mean SARS-CoV-2 spike IgG antibody titer of 21 ± 32 BAU/mL (threshold for positive response: 1.0 BAU/mL). Out of these 25 responders, 16 (64%) did not use MPA and only 6 (24%) were treated with triple maintenance immunosuppression with CNI, MPA, and prednisolone. Patients who seroconverted tended to be younger and had been living with a functioning kidney transplant for a longer time (Table 1). The impact of immunosuppression is obvious, but from the present data, it is not possible to differentiate the exact cause of the negative impact on seroconversion. However, treatment with MPA, especially in triple therapy, appears to lower seroconversion rates.

TABLE 1. - Baseline characteristics and findings following the second dose of BNP162b2 (Pfizer/BioNTech) vaccine in kidney transplant recipients
All (N = 141) POSitive IgG (N = 25) NEGative IgG (N = 116) Missing P (POS vs NEG)
Demographics
 Age (y) 67.4 ± 17.2 59.1 ± 19.7 69.1 ± 16.2 0 0.02
 Male sex 79 (56%) 12 (48%) 67 (58%) 0 0.50
 Weight (kg) 74.9 ± 15.2 73.3 ± 12.9 75.3 ± 15.7 2 0.50
 BMI (kg/m2) 25.2 ± 4.3 25.6 ± 3.8 25.1 ± 4.4 2 0.52
 Time since Tx (y) 11.7 ± 9.8 17.1 ± 13.5 10.4 ± 8.4 0 0.01
 First Tx 122 (87%) 20 (80%) 102 (88%) 0 0.41
 Living donor 55 (39%) 14 (56%) 41 (35%) 0 0.09
 Years in RRT 14.1 ± 9.9 21.8 ± 12.5 12.4 ± 8.4 0 0.001
 P-creatinine (µmol/L) 136 ± 78 141 ± 120 135 ± 66 1 0.80
Maintenance immunosuppression
 CNI + MPA + prednisolonea 105 (74%) 6 (24%) 99 (85%) <0.0001
 CNI + prednisolone 19 (13%) 12 (48%) 7 (6%) <0.0001
 Other combinationsb 17 (12%) 7 (28%) 10 (9%) 0.02
 MPA use 115 (82%) 9 (36%) 106 (91%) <0.0001
Data presented as mean ± SD and number (%). Statistical comparison between groups with positive and negative SARS-CoV-2 IgG samples performed with Student’s T test and chi-square tests. Bold values indicate statistical significance.
aCNI type; 35 cyclosporine and 70 tacrolimus.
bEverolimus + MPA + prednisolone (n = 7), azathioprine + prednisolone (n = 4), cyclosporine + azathioprine + prednisolone (n = 2), belatacept + MPA + prednisolone (n = 2), belatacept + everolimus + prednisolone (n = 1), tacrolimus + MPA (n = 1).
BMI, body mass index; CNI, calcineurin inhibitor; IgG, immunoglobulin G; MPA, mycophenolate; RRT, renal replacement therapy; Tx, transplantation.

It is well known that KTRs are at increased risk of a severe outcome if infected with SARS-CoV-2, and there is a hope that vaccination will be protective. Short-term safety data on mRNA vaccines in KTRs seems similar to the general population, but the immunogenicity seems to be markedly reduced.5 To date, it has not been proven that low levels of antibodies to spike predict a lack of protection against severe COVID-19. Although KTRs receiving MPA seem to have a reduced vaccine response rate, with the current knowledge, we do not promote reducing or withholding MPA during revaccination. Early results showing an increase in seroconversion after the second vaccine dose have prompted initiatives to administer a third jab. Whether or not this will enhance the immune response remains to be determined. In the meantime, KTRs should be informed to keep their guard up and behave as if they were not vaccinated!

REFERENCES

1. Georgery H, Devresse A, Yombi JC, et al. Very low immunization rate in kidney transplant recipients after one dose of the BNT162b2 vaccine: beware not to lower the guard! Transplantation. [Epub ahead of print. May 12, 2021]. doi:10.1097/TP.0000000000003818
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. Benotmane I, Gautier-Vargas G, Cognard N, et al. Low immunization rates among kidney transplant recipients who received 2 doses of the mRNA-1273 SARS-CoV-2 vaccine. Kidney Int. 2021;99:1498–1500.
4. Holter JC, Pischke SE, de Boer E, et al. Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients. Proc Natl Acad Sci U S A. 2020;117:25018–25025.
5. Ou MT, Boyarsky BJ, Motter JD, et al. Safety and reactogenicity of 2 doses of SARS-CoV-2 vaccination in solid organ transplant recipients. Transplantation. [Epub ahead of print. April 9, 2021]. doi: 10.1097/TP.0000000000003780
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.