A third injection of the BNT162b2 mRNA COVID-19 vaccine in kidney transplant recipients improves the humoral immune response
Authors: Christophe Masset, Clarisse Kerleau, Claire Garandeau, Simon Ville, Diego Cantarovich, Maryvonne Hourmant, Delphine Kervella, Aurélie Houzet, Cécile Guillot-Gueguen, Irène Guihard, Magali Giral, Jacques Dantal, Gilles Blancho
Journal: Kidney International (2021)

Several reports have highlighted the poor humoral immune response of kidney transplant recipients following coronavirus disease 2019 (COVID-19) mRNA vaccination compared with immunocompetent patients.1Benotmane 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: 1498-1500Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 2Marion O. Del Bello A. Abravanel F. et al.Safety and immunogenicity of anti–SARS-CoV-2 messenger RNA vaccines in recipients of solid organ transplants.Ann Intern Med. 2021; 174: 1336-1338Crossref PubMed Scopus (107) Google Scholar, 3Müller L. Andrée M. Moskorz W. et al.Age-dependent immune response to the Biontech/Pfizer BNT162b2 COVID-19 vaccination [e-pub ahead of print]. Clin Infect Dis.https://doi.org/10.1093/cid/ciab381Google Scholar Therefore, the French National Authority for Health has recommended the use of a third vaccine dose for immunosuppressed patients, such as solid organ transplant recipients. We retrospectively assessed the humoral response of all kidney and pancreas transplant recipients vaccinated with the BNT162b2 mRNA (Pfizer BioNTech) COVID-19 vaccine between January and May 2021 in our center. Patients with previous COVID-19 infection or positive prevaccination serology were excluded. The methods for detection of the anti-spike protein responses were dependent on laboratories' practices and included chemiluminescent microparticle immunoassay (Abbott Architect), chemiluminescence immunoassay (Siemens Atellica), and electrochemiluminescence immunoassay (Roche Elecsys). Anti-spike (IgG) responses were assessed 1 month after the second and third injection, and patients were considered positive if their anti-spike level was above the laboratory threshold. A total of 456 patients had a serologic assessment 1 month after the second injection, of whom 227 were positive, representing 49.7% of our cohort (Table 1). A total of 10.7% of these patients had a positive anti-spike protein 1 month after the first injection. Multivariate regression analysis (Table 2) revealed that there was an increased likelihood of being a nonresponder after the second mRNA injection for patients treated with antimetabolite drugs (odds ratio [OR], 5.74; 95% confidence interval [CI], 2.99–11.48; P < 0.0001) or steroids (OR, 3.68; 95% CI, 2.10–6.66; P < 0.0001), older recipients (OR, 1.03; 95% CI, 1.01–1.06; P = 0.0010), those with impaired allograft function (OR, 0.98; 95% CI, 0.96–0.99; P = 0.0011), and those with a transplant ≤4 years (OR, 2.91; 95% CI, 1.70–5.08; P = 0.0001). A total of 136 patients had a serologic assessment 1 month after the third injection (median, 30 days; quartile 1, 28 days; quartile 3, 32 days). The average time between the second and the third injection was 50 days. A total of 94 patients were positive, representing a 69.2% serologic conversion following the third mRNA injection (Figure 1a and Table 3). Among patients receiving a third dose, 85 had a serologic assessment after both second and third injections, and 34 of them (40%) became seropositive between the second and the third dose. The magnitude of immune response was investigated in 71 patients who had serologic assessment using electrochemiluminescence immunoassay (Roche Elecsys) after the second and third injections (Figure 1b and c). Nearly all patients with a positive serology after the second mRNA vaccine had a high titer of anti-spike antibody (>250 UI/L). Multivariate regression analysis (Table 4) determined that lymphocyte count <1500/mm3 increased the likelihood of being a nonresponder after the third mRNA injection (OR, 3.84; 95% CI, 1.58–19.96; P = 0.0039), as impairment of allograft function (OR, 0.97; 95% CI, 0.94–0.99; P = 0.0232). Of note, the use of antiproliferative drugs and steroids no longer seemed to significantly impact the serologic conversion after the third mRNA vaccine injection. Male recipients were more likely to respond to the third mRNA vaccine injection in our cohort, without any clear explanation so far. Kidney transplant recipients respond poorly to COVID-19 mRNA vaccination, and although cellular responses to the vaccine seem better than humoral responses,4Cucchiari D. Egri N. Bodro M. et al.Cellular and humoral response after mRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients.Am J Transplant. 2021; 21: 2727-2739Crossref PubMed Scopus (184) Google Scholar severe COVID-19 pneumonia can occur following 2 mRNA vaccine injections.5Caillard S. Chavarot N. Bertrand D. et al.Occurrence of severe COVID-19 in vaccinated transplant patients.Kidney Int. 2021; 100: 477-479Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Our data support the use of a third mRNA injection to improve the humoral response to vaccination from about 50% to 70%, reducing the negative impact of antimetabolite drugs and steroids on seroconversion. Moreover, for previously seropositive patients, the third mRNA vaccine largely improved the intensity of humoral response, reaching titers suggestive of neutralizing antibody activity. Indeed, seropositive assessment (especially weak titers in immunocompromised patients) is not constantly associated with protective antibodies titers.5Caillard S. Chavarot N. Bertrand D. et al.Occurrence of severe COVID-19 in vaccinated transplant patients.Kidney Int. 2021; 100: 477-479Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar However, severe lymphopenia and impaired graft function remained as risk factors for a nonserologic response. In this particular situation, a fourth dose, with or without immunomodulation, could be discussed to improve the humoral response of this highly immunosuppressed population. These data will need confirmation from other series.Table 1Characteristics associated with risk of nonhumoral response to a second dose of mRNA COVID-19 vaccine after univariate analysis (n = 456)CharacteristicsGlobal (n = 456)Negative (n = 229)Positive (n = 227)P valueNAn%NAn%NAn%Transplantation ≤4 yr033673.7014663.8019083.7<0.0001Male recipient027560.3013056.8014563.90.1455Transplant rank ≥208117.804017.504118.10.9653Transplant type (kidney vs. SPK/pancreas)042192.3021493.4020791.20.3845Primitive kidney disease0000.5491 Unknown398.6156.62410.6 Glomerulonephritis14331.471317231.7 Other2054510947.69642.3 Vascular disease286.1135.7156.6 Diabetes419219.2208.8Deceased donor037682.5019685.6018079.30.1002ABDR incompatibilities >4010222.405925.804318.90.0920Blood type0000.4043 O19242.110244.59039.6 A20645.21034510345.4 B4610.1187.92812.3 AB122.662.662.6Depleting induction123952.5112956.6011048.50.1009Lymphocytes <1500/mm33622052.42012660.3169444.50.0017Calcineurin inhibitor treatment2036984.61119187.6917881.70.1110Belatacept treatment18112.61094.4820.90.0343mTOR inhibitor treatment206815.611209.294822<0.0001Antimetabolite treatment2032574.51118082.6914566.50.0002Steroid treatment2015034.4119443.195625.70.0002Diabetes history07917.304620.103314.50.1493Cardiovascular history017939.30944108537.40.4890Neoplasia history08919.505423.603515.40.0375DSA before transplant136216.647168.88953.60.1050DSA de novo65612.452611.613013.30.6944Episode of rejection05111.203013.10219.30.2479NAMeanSDNAMeanSDNAMeanSDRecipient age, yr061.412.1062.711.1060.213.00.0289Recipient BMI, kg/m23125.44.91625.54.81525.45.00.7514Time from transplantation, yr010.58.508.57.6012.48.9<0.0001Allograft function by MDRD, ml/min2448.719.41443.416.81053.920.3<0.0001Total leukocyte count, G/L3032.1376.21857.9534.0126.72.00.1653C0 cyclosporine, ng/ml419100.635.921899.550.3201101.129.00.9217C0 tacrolimus, ng/ml1935.91.9836.12.01105.61.70.0239BMI, body mass index; C0, trough level; COVID-19, coronavirus disease 2019; DSA, donor-specific antibody; MDRD, Modification of Diet in Renal Disease; mTOR, mechanistic target of rapamycin; NA, not available; SPK, simultaneous pancreas–kidney.Values in bold are significant (P < 0.05). Open table in a new tab Table 2Characteristics associated with risk of nonhumoral response to a second dose of mRNA COVID-19 vaccine after multivariate analysis (n = 394)CharacteristicsOR95% CIP valueRecipient age at vaccination, yr1.031.01–1.060.0010Transplantation ≤4 yr2.911.70–5.080.0001Allograft function by MDRD, ml/min0.980.96–0.990.0011Calcineurin inhibitor treatment1.550.73–3.300.2555mTOR inhibitor treatment0.730.33–1.620.4402Antimetabolite treatment5.742.99–11.48<0.0001Steroid treatment3.682.10–6.66<0.0001Lymphocytes <1500/mm31.480.93–2.350.0961CI, confidence interval; COVID-19, coronavirus disease 2019; MDRD, Modification of Diet in Renal Disease; mTOR, mechanistic target of rapamycin; OR, odds ratio.Values in bold are significant (P < 0.05). Open table in a new tab Table 3Characteristics associated with risk of nonhumoral response to a third dose of mRNA COVID-19 vaccine after univariate analysis (n = 136)CharacteristicsGlobal (n = 136)Negative (n = 42)Positive (n = 94)P valueNAn%NAn%NAn%Transplantation ≤4 yr04633.802047.602627.70.0378Male recipient08663.201740.506973.4<0.0001Transplant rank ≥202014.70819.001212.80.4879Transplant type (kidney vs. SPK/pancreas)012491.203890.508691.51.0000Primitive kidney disease0000.6077 Unknown107.4511.955.3 Glomerulonephritis4432.41228.63234 Other5439.71535.73941.5 Vascular disease128.849.588.5 Diabetes1611.8614.31010.6Deceased donor011483.803788.107781.90.5142ABDR incompatibilities >403324.301228.602122.30.5167Blood type0000.4838 O5238.22047.63234 A6648.51842.94851.1 B1410.337.11111.7 AB42.912.433.2Depleting induction08058.80296905154.30.1525Lymphocytes <1500/mm36655022972.5436400.0012Calcineurin inhibitor treatment211585.813687.817984.90.8662mTOR inhibitor treatment22014.9124.911819.40.0569Antimetabolite treatment210175.41327816974.20.7950Steroid treatment24332.111843.912526.90.0811Diabetes history02820.601126.201718.10.3950Cardiovascular history05641.201740.503941.51.0000Neoplasia history02921.301228.601718.10.2490DSA before transplant3587.98411.827460.4370DSA de novo51713261531112.10.8615Episode of rejection0139.60614.3077.40.2207NAMeanSDNAMeanSDNAMeanSDRecipient age, yr063.711.7065.310.9063.011.90.2679Recipient BMI, kg/m2325.54.7124.53.7225.95.00.0642Time from transplantation, yr09.48.107.06.7010.48.50.0143Allograft function by MDRD, ml/min349.119.3141.115.1252.620.00.0004Total leukocyte count, G/L56.62.216.72.446.52.20.7306C0 cyclosporine, ng/ml125103.025.040129.029.78597.221.50.3526C0 tacrolimus, ng/ml556.01.8136.21.9425.91.80.5758BMI, body mass index; C0, trough level; COVID-19, coronavirus disease 2019; DSA, donor-specific antibody; MDRD, Modification of Diet in Renal Disease; mTOR, mechanistic target of rapamycin; NA, not available; SPK, simultaneous pancreas–kidney.Values in bold are significant (P < 0.05). Open table in a new tab Table 4Characteristics associated with risk of nonhumoral response to a third dose of mRNA COVID-19 vaccine after multivariate analysis (n = 129)CharacteristicsOR95% CIP valueMale recipient0.250.10–0.610.0027Allograft function by MDRD, ml/min0.970.94–0.990.0232Antimetabolite treatment1.760.59–5.640.3237Steroid treatment2.450.91–6.810.0795Lymphocytes <1500/mm33.841.58–9.960.0039CI, confidence interval; COVID-19, coronavirus disease 2019; MDRD, Modification of Diet in Renal Disease; OR, odds ratio.Values in bold are significant (P < 0.05). Open table in a new tab BMI, body mass index; C0, trough level; COVID-19, coronavirus disease 2019; DSA, donor-specific antibody; MDRD, Modification of Diet in Renal Disease; mTOR, mechanistic target of rapamycin; NA, not available; SPK, simultaneous pancreas–kidney. Values in bold are significant (P < 0.05). CI, confidence interval; COVID-19, coronavirus disease 2019; MDRD, Modification of Diet in Renal Disease; mTOR, mechanistic target of rapamycin; OR, odds ratio. Values in bold are significant (P < 0.05). BMI, body mass index; C0, trough level; COVID-19, coronavirus disease 2019; DSA, donor-specific antibody; MDRD, Modification of Diet in Renal Disease; mTOR, mechanistic target of rapamycin; NA, not available; SPK, simultaneous pancreas–kidney. Values in bold are significant (P < 0.05). CI, confidence interval; COVID-19, coronavirus disease 2019; MDRD, Modification of Diet in Renal Disease; OR, odds ratio. Values in bold are significant (P < 0.05). Occurrence of severe COVID-19 in vaccinated transplant patientsKidney InternationalVol. 100Issue 2PreviewVaccination plays a paramount role in the current coronavirus disease 2019 (COVID-19) pandemic response. Although mRNA-based vaccines elicit a strong immune response in the general population, the immunization rates of immunocompromised patients—including solid organ transplant recipients—have not been specifically investigated in mRNA-1273 and BNT162b2 pivotal trials.1,2 This knowledge gap should be addressed urgently, as these patients are highly prone to developing severe COVID-19. Full-Text PDF Low immunization rates among kidney transplant recipients who received 2 doses of the mRNA-1273 SARS-CoV-2 vaccineKidney InternationalVol. 99Issue 6PreviewThe efficacy rates of vaccines to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have not been specifically investigated in kidney transplant recipient (KTRs). Preliminary results suggest that among KTRs who received the first injection of an mRNA-based vaccine, the antibody response is weak.1,2 This study reports on the immunization rates of KTRs who received 2 doses of the mRNA-1273 SARS-CoV-2 vaccine (Moderna).3 Full-Text PDF Observations on improving COVID-19 vaccination responses in kidney transplant recipients: heterologous vaccination and immunosuppression modulationKidney InternationalVol. 101Issue 3PreviewSolid organ transplant recipients have a weaker humoral response to coronavirus disease 2019 (COVID-19) vaccination because of several factors, including lymphopenia associated with immunosuppressive therapies (particularly belatacept, antiproliferative drugs, and steroids).1 Because of the high probability of severe COVID-19 symptoms in this at-risk population,2 a third vaccine dose has been proposed for immunocompromised patients by the French National Authority for Health to improve humoral responses and vaccine efficiency. 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