Protecting kidney transplant recipients against SARS-CoV-2 infection: A third dose of vaccine is necessary now

Abstract

To the Editor: We have read the article written by Ison et al.1Ison MG, Blumberg E, Halasa N, et al. Antibodies, boosters, and optimizing SARS-CoV-2 vaccines for transplantation: a call for more research [published online ahead of print 2021]. Am J Transplant. doi:10.1111/ajt.16758.Google Scholar that has raised some issues we would like to discuss. COVID-19 breakthrough infection rates in vaccinated kidney transplant (KT) recipients much higher than in the general vaccinated population have been reported.2Quin CX, Morre LW, Anjan S, et al. Risk of breakthrough SARS-CoV-2 infections in adult transplant recipients [published online ahead of print 2021]. Transplant. doi:10.1097/TP.0000000000003907.Google Scholar Furthermore, the severity remains markedly high. Although Ison et al. referred cases are rarely severe, other series, and among them, the largest cohort published so far, have reported 27% of very serious cases.3Caillard S Chavarot N Bertrand D et al.Occurrence of severe COVID-19 in vaccinated transplant patients.Kidney Int. 2021; 100 (doi:10.1016/j.kint.2021.05.011.): 477-479Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar By August 2021, 843 KT recipients at our center have been fully vaccinated against COVID-19. During this period, 15 patients developed COVID-19 after two doses of mRNA-based vaccines: 1.8% versus 0.01% in the general population.2Quin CX, Morre LW, Anjan S, et al. Risk of breakthrough SARS-CoV-2 infections in adult transplant recipients [published online ahead of print 2021]. Transplant. doi:10.1097/TP.0000000000003907.Google Scholar Of them, five needed hospitalization (33.3%): three remain in critical care units and one died. Contrary to what Ison et al. stated, also in our experience, severe COVID-19 has not been uncommon in infected vaccinated KT patients. Although serological protective thresholds are not established yet, higher antibodies titers are associated with a less severe COVID-19 in the general population.4Bergwerk M, Gonen T, Lustig Y, et al. Covid-19 breakthrough infections in vaccinated health care workers [published online ahead of print 2021]. N Engl J Med. doi: 10.1056/NEJMoa2109072.Google Scholar We analyzed the response after two doses of mRNA-based vaccine in 97 randomly selected stable KT recipients (Abbott SARS-CoV-2 IgG chemiluminescent microparticle immunoassay). Six patients had COVID-19 previously; they all had detectable antibodies prior to vaccination, with a 20-fold increase 1 month after the second dose (201.8 vs. 3601.2 U/ml; p = .005). The rest of the patients were seronegative before the vaccine; in this group, the seroconversion rate was 62.6% 1 month after two vaccine doses. A shorter post-KT time, renal function, treatment with mycophenolic acid (MPA) and age were related to a lower response (Table 1). These last two factors have already been identified for a weak immune response.5Del Bello A, Abravenil F, Marion O, et al. Efficiency of a boost with a third dose of anti-SARS-CoV-2 messenger RNA-based vaccines in solid organ transplant recipients [published online ahead of print 2021]. Am J Transplant. doi:10.1111/ajt.16775.Google Scholar Thus, temporary withdrawal of MPA during the vaccination could be a strategy to increase the serological response in selected patients, although this needs to be carefully analyzed.TABLE 1Factors associated with response to mRNA-based vaccinesTotal(n = 91)Seroconversion(n = 57)No seroconversion(n = 34)pVaccine type, n (mRNA-1273/BNT162b2)84/756/128/6Antibody titer U/ml, median [IQR]20.5 [1.5–95]63.9 [27.1–268.7]0.72 [0.2–2.8]<.001Male gender, n (%)61 (67)42 (73.7)19 (55.9).091Age, median [IQR]59 [51–66]59 [50–64.5]62.5 [58–70.5].022Age ≥65 years, n (%)aPercentage within age < or ≥65 years.30 (33)14 (46.7)16 (53.3).027Time from KT to COVID-19 vaccine (months), median [IQR]64 [22–158]96 [41–187]27.5 [17.5–110.7].004Thymoglobulin, n (%)bIn the last year prior to COVID-19 vaccine.5 (5.5)2 (3.5)3 (8.8).282RituximabbIn the last year prior to COVID-19 vaccine.1 (1.1)01 (2.9).193Prednisone, n (%)87 (95.6)53 (93)34 (100).114Tacrolimus, n (%)84 (92.3)51 (89.5)33 (97.1).189MPA, n (%)76 (83.5)44 (77.2)32 (94.1).035mTOR inhibitors, n (%)10 (11)8 (14)2 (5.9).229Azathioprine, n (%)2 (2.2)1 (1.8)1 (2.9).709AR episode, n (%)bIn the last year prior to COVID-19 vaccine.3 (3.5)2 (3.6)1 (3.2).921Serum creatinine, median [IQR]1.3 [1.1–1.6]1.2 [0.9–1.5]1.4 [1.3–1.8].002Multiple logistic regression analysis for seroconversionOR (95% CI)pRecipient age0.94 (0.89–0.99).024Time from KT to COVID-19 vaccine1.00 (1.00–1.01).011Serum creatinine0.28 (0.12–0.68).005MPA0.08 (0.01–0.53).008Abbreviations: CI, confidence interval; IQR, interquartile range; MPA, mycophenolic acid; OR, odds ratio.a Percentage within age < or ≥65 years.b In the last year prior to COVID-19 vaccine. Open table in a new tab Abbreviations: CI, confidence interval; IQR, interquartile range; MPA, mycophenolic acid; OR, odds ratio. As in other series, these results have aroused interest in the administration of a booster dose in KT. The early data showed that, after this third dose, the seroconversion rate increased about 20% and there were no breakthrough infections during the follow-up.1Ison MG, Blumberg E, Halasa N, et al. Antibodies, boosters, and optimizing SARS-CoV-2 vaccines for transplantation: a call for more research [published online ahead of print 2021]. Am J Transplant. doi:10.1111/ajt.16758.Google Scholar,5Del Bello A, Abravenil F, Marion O, et al. Efficiency of a boost with a third dose of anti-SARS-CoV-2 messenger RNA-based vaccines in solid organ transplant recipients [published online ahead of print 2021]. Am J Transplant. doi:10.1111/ajt.16775.Google Scholar Recently the Food and Drug Administration approved a third dose in immunocompromised population but most European countries, including Spain, have not yet made a decision. Ison et al. presented their concern about the potential risk of acute rejection (AR) after the third dose of the vaccine. Notwithstanding, only one case has been reported,1Ison MG, Blumberg E, Halasa N, et al. Antibodies, boosters, and optimizing SARS-CoV-2 vaccines for transplantation: a call for more research [published online ahead of print 2021]. Am J Transplant. doi:10.1111/ajt.16758.Google Scholar so it is difficult to establish a causal association. The French study, with 396 solid organ transplant patients who received the third dose, did not observe any AR episode.5Del Bello A, Abravenil F, Marion O, et al. Efficiency of a boost with a third dose of anti-SARS-CoV-2 messenger RNA-based vaccines in solid organ transplant recipients [published online ahead of print 2021]. Am J Transplant. doi:10.1111/ajt.16775.Google Scholar In conclusion, we think that vaccination programs with a third dose should be fostered in KT recipients as long as we do not have more effective treatments or vaccines. A booster dose increases the response and it is unlikely to be associated with AR. Changes in immunosuppressive therapy could perhaps be proposed in some patients to improve the response to vaccine. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

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