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Clinically Significant COVID-19 Following SARS-CoV-2 Vaccination in Kidney Transplant Recipients

      To the Editor:
      Vaccination against SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) represents an important path toward ending the COVID-19 (coronavirus disease 2019) pandemic and alleviating the severity of COVID-19 in most patient populations.
      • Walsh E.E.
      • Frenck Jr., R.W.
      • Falsey A.R.
      • et al.
      Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates.
      • Baden L.R.
      • El Sahly H.M.
      • Essink B.
      • et al.
      Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
      • Polack F.P.
      • Thomas S.J.
      • Kitchin N.
      • et al.
      Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
      Solid organ transplant recipients are a vulnerable population with significant COVID-19–associated morbidity and mortality.
      • Kates O.S.
      • Haydel B.M.
      • Florman S.S.
      • et al.
      COVID-19 in solid organ transplant: a multi-center cohort study.
      ,
      Columbia University Kidney Transplant Program
      Early description of coronavirus 2019 disease in kidney transplant recipients in New York.
      Initial reports indicate an impaired anti–SARS-CoV-2 antibody response among transplant recipients following mRNA vaccination, likely because of maintenance immunosuppression.
      • Boyarsky B.J.
      • Werbel W.A.
      • Avery R.K.
      • et al.
      Immunogenicity of a single dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients.
      • Benotmane I.
      • Gautier-Vargas G.
      • Cognard N.
      • et al.
      Weak anti-SARS-CoV-2 antibody response after the first injection of an mRNA COVID-19 vaccine in kidney transplant recipients.
      • Husain S.A.
      • Tsapepas D.
      • Paget K.F.
      • Chang J.H.
      • Crew R.J.
      • Dube G.K.
      • Fernandez H.E.
      • Morris H.K.
      • Mohan S.
      • Cohen D.J.
      Post-vaccine anti-SARS-CoV-2 spike protein antibody development in kidney transplants recipients.
      • Boyarsky B.J.
      • Werbel W.A.
      • Avery R.K.
      • Tobian A.A.R.
      • Massie A.B.
      • Segev D.L.
      • Garonzik-Wang J.M.
      Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients.
      Whether kidney transplant recipients have low levels of virus-neutralizing antibody not detected by these assays or protective anti–SARS-CoV-2 T-cell immunity is currently unknown, and the critical question is whether the impaired antibody response corresponds to disease susceptibility. Here, we document 13 cases of COVD-19 in vaccinated kidney transplant recipients. The Columbia University Institutional Review Board approved this study with a complete waiver of informed consent before its conduct.
      Between January 12 and April 22, 2021, there were 904 kidney and pancreas transplant recipients at our transplant center who received a COVID-19 vaccine with emergency use authorization in the United States: Pfizer-BioNTech (n = 658), Moderna (n = 229), and Janssen/Johnson & Johnson (n = 17). As of April 22, 13 (1.4%) developed PCR-positive SARS-CoV-2 infection after vaccination, of which 7 cases (0.8% of all vaccinated recipients) met the CDC definition of a breakthrough infection with a positive PCR test from a respiratory specimen collected ≥14 days after completing the primary vaccination series.
      Centers for Disease Control and Prevention CDC
      Twelve cases were clinically significant and 1 was identified on routine surveillance in an asymptomatic patient. Eight patients had completed a 2-dose mRNA vaccine series and 1 received Janssen/J&J, while 4 had received only 1 dose of vaccine (Pfizer-BioNTech) at the time of infection (Table 1).
      Table 1Population Summary: SARS-CoV-2 Infection Following Vaccination
      CaseAge, SexTime Post KTxBlood GroupDM & HTNBMI, kg/m2Scr, mg/dLISSymptoms; Hospitalization RequirementVaccine TypeAnti-Spike Protein IgG
      Days indicate time since vaccination (counted from date of first vaccination for patients who only received 1 dose and from date of second vaccination for those who completed the 2-dose series).
      COVID-19 Dx
      Days indicate time since vaccination (counted from date of first vaccination for patients who only received 1 dose and from date of second vaccination for those who completed the 2-dose series).
      1
      Meets US Centers for Disease Control and Prevention criteria for breakthrough COVID-19.
      50 y, F6.5 yABoth29.31.33Tac/MPAFever, cough; not hospitalizedPfizer-BioNTech; series completeNegative at 32 d46 d
      2
      Meets US Centers for Disease Control and Prevention criteria for breakthrough COVID-19.
      68 y, M4 yOBoth20.72.21Tac/MPACough, fatigue/malaise; hospitalizedPfizer-BioNTech; series complete--35 d
      3
      Meets US Centers for Disease Control and Prevention criteria for breakthrough COVID-19.
      65 y, M17 yOHTN301.4SRL/MPACough, headache, fatigue/malaise; not hospitalizedPfizer-BioNTech; series completeNegative at 27 d35 d
      4
      Meets US Centers for Disease Control and Prevention criteria for breakthrough COVID-19.
      29 y, F6 yAHTN36.41.86Tac/MPACough, dyspnea, GI, myalgia/arthralgia, fatigue/malaise; not hospitalizedModerna; series complete--23 d
      5
      Meets US Centers for Disease Control and Prevention criteria for breakthrough COVID-19.
      51 y, M6.5 yBBoth35.22.44Tac/MPA/PredFever, myalgia/arthralgia, fatigue/malaise; hospitalizedModerna; series completeNegative at 23 d21 d
      6
      Meets US Centers for Disease Control and Prevention criteria for breakthrough COVID-19.
      53 y, F1.5 yAHTN35.50.72Tac/MPACough, headache, GI, myalgia/arthralgia, fatigue/malaise; not hospitalizedPfizer-BioNTech; series complete--18 d
      7
      Meets US Centers for Disease Control and Prevention criteria for breakthrough COVID-19.
      60 y, M18 yONone26.31Tac/MPA/PredNone; not hospitalizedPfizer-BioNTech; series completePositive at 38 d
      Tested after found to be SARS-CoV-2 polymerase chain reaction positive.
      17 d
      874 y, F1 yOBoth23.41.01Tac/MPA/PredNone; not hospitalizedPfizer-BioNTech; series complete--12 d
      942 y, F3 yABNone351.63Tac/MPA/PredCough; not hospitalizedPfizer-BioNTech; 1 dose--29 d
      1055 y, F2.5 yABoth35.91.35Tac/AZAFever, dyspnea, GI, fatigue/malaise; not hospitalizedPfizer-BioNTech; 1 dose--18 d
      1164 y, F3 yOHTN28.60.87Tac/MPAFever, GI, myalgia/arthralgia; not hospitalizedPfizer-BioNTech; 1 dose--8 d
      1265 y, F13 yADM231.34CsA/MPADyspnea, GI, myalgia/arthralgia, fatigue/malaise; hospitalizedPfizer-BioNTech; 1 dose--6 d
      1362 y, M0.5 yABoth30.72.22CsA/MPA/IVIGHeadache, GI, fatigue/malaise; not hospitalizedJanssen/J&J; series complete--1 d
      Abbreviations: AZA, azathioprine; BMI, body mass index; CsA, cyclosporine; DM, diabetes; Dx, diagnosis; HTN, hypertension; IS, immunosuppression; IVIG, intravenous Immunoglobulin; KTx, kidney transplant; MPA, mycophenolate; Pred, prednisone; Scr, serum creatinine; SRL, sirolimus; Tac, tacrolimus.
      a Meets US Centers for Disease Control and Prevention criteria for breakthrough COVID-19.
      b Tested after found to be SARS-CoV-2 polymerase chain reaction positive.
      c Days indicate time since vaccination (counted from date of first vaccination for patients who only received 1 dose and from date of second vaccination for those who completed the 2-dose series).
      As summarized in Table 1, patients infected with SARS-CoV-2 after partial vaccination did so 6 to 29 days after initial vaccination, whereas those who had completed the vaccine series developed infection 1 to 46 days after vaccination. Time after transplantation ranged from 1 to 18 years. Seven patients had diabetes and all but 1 had hypertension. Only 1 patient each was not taking a calcineurin inhibitor or mycophenolate. Presenting symptoms were typical: 8 patients (62%) reported fatigue/malaise; 6 (46%), GI symptoms; 5 (38%), cough; 4 (31%), fever; 3 (23%), dyspnea; and 3 (23%), headache. Three patients had a negative anti–SARS-CoV-2-S IgG test. One patient with detectable anti–SARS-CoV-2-S IgG was asymptomatic (testing was performed after COVID-19 diagnosis).
      While 10 cases were successfully managed as outpatients, 3 (0.3% of all vaccinated patients) needed hospitalization. One patient required a 4-day hospitalization to manage dyspnea and hypoxia (requiring 2-L nasal cannula). Another presented to the hospital 6 days after the first vaccine dose with weakness and GI symptoms and had a >30-day hospitalization to manage acute pancreatitis and hypoxic respiratory failure, both attributed to COVID-19, requiring a non-rebreather mask for 3 days and ICU care for 4 days. The final hospitalized patient presented with hypotension and a fall deemed related to concomitant urinary tract infection and COVID-19. The patient developed severe COVID-19, including septic shock, acute kidney injury, and hypoxic respiratory failure requiring mechanical ventilation, before dying 5 days after admission.
      Initial SARS-CoV-2 vaccine trials demonstrated great efficacy in preventing severe COVID-19, with a 0.04% to 0.08% incidence after completion of the primary vaccination series.
      • Walsh E.E.
      • Frenck Jr., R.W.
      • Falsey A.R.
      • et al.
      Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates.
      • Baden L.R.
      • El Sahly H.M.
      • Essink B.
      • et al.
      Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
      • Polack F.P.
      • Thomas S.J.
      • Kitchin N.
      • et al.
      Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
      Our data indicate a 0.8% incidence of breakthrough COVID-19 and 1.4% overall incidence of COVID-19 following any vaccination in a short follow-up period. Unlike the breakthrough cases observed in general population trials, our cases include patients who developed severe COVID-19 requiring hospitalization and mechanical ventilation. These cases suggest reduced SARS-CoV-2 vaccine efficacy in this vulnerable patient population, likely stemming from the use of maintenance immunosuppression. Our cases are too few to draw any conclusions about patient characteristics contributing to the likelihood of COVID-19 following vaccination. The potential for severe COVID-19 despite vaccination is a concern among transplant recipients, and these cases supplement recent reports that most transplant recipients do not develop a measurable antibody response to standard anti-SARS-CoV-2 mRNA vaccination schedules, although immunogenicity is higher once both doses are administered.
      • Boyarsky B.J.
      • Werbel W.A.
      • Avery R.K.
      • et al.
      Immunogenicity of a single dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients.
      • Benotmane I.
      • Gautier-Vargas G.
      • Cognard N.
      • et al.
      Weak anti-SARS-CoV-2 antibody response after the first injection of an mRNA COVID-19 vaccine in kidney transplant recipients.
      • Husain S.A.
      • Tsapepas D.
      • Paget K.F.
      • Chang J.H.
      • Crew R.J.
      • Dube G.K.
      • Fernandez H.E.
      • Morris H.K.
      • Mohan S.
      • Cohen D.J.
      Post-vaccine anti-SARS-CoV-2 spike protein antibody development in kidney transplants recipients.
      • Boyarsky B.J.
      • Werbel W.A.
      • Avery R.K.
      • Tobian A.A.R.
      • Massie A.B.
      • Segev D.L.
      • Garonzik-Wang J.M.
      Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients.
      It is important to recognize that the efficacy of vaccination without the presence of detectable antibodies is presently unclear, as is the degree of protection afforded by the presence of a detectable anti–spike antibody response. Results from this single-center summary must be considered in relation to changes in SARS-CoV-2 infections, in the context of community disease transmission and vaccination rates. For example, high vaccination rates in the community may benefit transplant recipients by reducing the likelihood of disease exposure and infection even if the vaccines do not confer a robust protective response to the immunosuppressed recipient. Patients should be educated on the importance of vaccination but also on the need to remain vigilant and exercise caution and diligence with public health measures of mask wearing, social distancing, and hand washing even after vaccination.

      American Society of Transplantation. Statement on COVID-19 vaccination in solid organ transplant recipients. Updated May 7, 2021. Accessed May 11, 2021. https://www.myast.org/statement-covid-19-vaccination-solid-organ-transplant-recipients#

      Additionally, clinicians should include COVID-19 in the list of differential diagnoses for symptomatic transplant recipients even after COVID-19 vaccination. These findings underscore the urgent need to implement trials for the development of alternate effective vaccine dosing schedules for these patients.

      Article Information

      Authors’ Contributions

      Research area and study design: DT, KP, SM, DJC, SAH; data acquisition: DT, KP; data analysis and interpretation: DT, SM, SAH; supervision or mentorship: SM, DJC. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual’s own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate.

      Support

      SAH is supported by the National Center for Advancing Translational Sciences (KL2 TR001874). The funder did not have a role in study design, data collection, analysis, reporting, or the decision to submit for publication.

      Financial Disclosure

      The authors declare that they have no relevant financial interests.

      Peer Review

      Received April 23, 2021. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form May 12, 2021.

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      1. American Society of Transplantation. Statement on COVID-19 vaccination in solid organ transplant recipients. Updated May 7, 2021. Accessed May 11, 2021. https://www.myast.org/statement-covid-19-vaccination-solid-organ-transplant-recipients#