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Summary Background An urgent need exists to improve the suboptimal COVID-19 vaccine response in kidney transplant recipients (KTRs). We aimed to compare three alternative strategies with a control single dose mRNA-1273 vaccination: a double vaccine dose, heterologous vaccination, and temporary discontinuation of mycophenolate mofetil or mycophenolic acid. Methods This open-label randomised trial, done in four university medical centres in the Netherlands, enrolled KTRs without seroconversion after two or three doses of an mRNA vaccine. Between Oct 20, 2021, and Feb 2, 2022, 230 KTRs were randomly assigned block-wise per centre by a web-based system in a 1:1:1 manner to receive 100 [mu]g mRNA-1273, 2,x,100 [mu]g mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 [mu]g mRNA-1273, were randomly assigned 1:1 to continue (mycophenolate mofetil+) or discontinue (mycophenolate mofetil-) mycophenolate mofetil or mycophenolic acid treatment for 2 weeks. The primary outcome was the percentage of participants with a spike protein (S1)-specific IgG concentration of at least 10 binding antibody units per mL at 28 days after vaccination, assessed in all participants who had a baseline measurement and who completed day 28 after vaccination without SARS-CoV-2 infection. Safety was assessed as a secondary outcome in all vaccinated patients by incidence of solicited adverse events, acute rejection or other serious adverse events. This trial is registered with ClinicalTrials.gov, NCT05030974 and is closed. Findings Between April 23, 2021, and July 2, 2021, of 12,158 invited Dutch KTRs, 3828 with a functioning kidney transplant participated in a national survey for antibody measurement after COVID-19 vaccination. Of these patients, 1311 did not seroconvert after their second vaccination and another 761 not even after a third. From these seronegative patients, 345 agreed to participate in our repeated vaccination study. Vaccination with 2,x,mRNA-1273 or Ad26.COV2-S was not superior to single mRNA-1273, with seroresponse rates of 49 (68%) of 72 (95% CI 56--79), 46 (63%) of 73 (51--74), and 50 (68%) of 73 (57--79), respectively. The difference with single mRNA-1273 was -0*4% (-16 to 15; p=0*96) for 2,x,mRNA-1273 and -6% (-21 to 10; p=0*49) for Ad26.COV2-S. Mycophenolate mofetil- was also not superior to mycophenolate mofetil+, with seroresponse rates of 37 (80%) of 46 (66--91) and 31 (67%) of 46 (52--80), and a difference of 13% (-5 to 31; p=0*15). Local adverse events were more frequent after a single and double dose of mRNA-1273 than after Ad26.COV2-S (65 [92%] of 71, 67 [92%] of 73, and 38 [50%] of 76, respectively; p Interpretation Repeated vaccination increases SARS-CoV-2-specific antibodies in KTRs, without further enhancement by use of a higher dose, a heterologous vaccine, or 2 weeks discontinuation of mycophenolate mofetil or mycophenolic acid. To achieve a stronger response, possibly required to neutralise new virus variants, repeated booster vaccination is needed. Funding The Netherlands Organization for Health Research and Development and the Dutch Kidney Foundation. Author Affiliation: (a) Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, Erasmus Medical Center, Rotterdam, Netherlands (b) Department Viroscience, Erasmus MC Transplant Institute, Erasmus Medical Center, Rotterdam, Netherlands (c) Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands (d) Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, Netherlands (e) Renal Transplant Unit, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands (f) Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, University of Amsterdam, Amsterdam, Netherlands (g) Department of Nephrology, Radboud University Medical Center Nijmegen, Nijmegen, Netherlands (h) Radboud Institute for Molecular Life Sciences, Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center Nijmegen, Nijmegen, Netherlands (i) Radboud Center for Infectious Diseases, Radboud University Medical Center Nijmegen, Nijmegen, Netherlands (j) Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands (k) Department of Nephrology, Leiden University Medical Center, Leiden, Netherlands * Corresponding author: Prof Luuk B Hilbrands Department of Nephrology, Radboud University Medical Center, Radboud Institute for Health Sciences, Geert Grooteplein 10, 6525GA Nijmegen, Netherlands (footnote)* Contributed equally as first authors (footnote)[Dagger] Contributed equally as last authors (footnote)[double dagger] A list of RECOVAC collaborators is added at the end of the article Byline: Marcia M L Kho, MD (a), A Lianne Messchendorp, PhD (c), Sophie C Frölke, MD (e), Celine Imhof, MD (c,d), Vera JCH Koomen, MSc (g), S Reshwan K Malahe, MD (a), Priya Vart, PhD (c), Daryl Geers, MSc (b), Rory D de Vries (a), Corine H GeurtsvanKessel, PhD (b), Prof Carla C Baan, PhD (a), Renate G van der Molen, PhD (h), Dimitri A Diavatopoulos, PhD (h,i), Ester B M Remmerswaal, PhD (f), Prof Debbie van Baarle, PhD (d,j), Rob van Binnendijk, PhD (j), Gerco den Hartog, PhD (j), Aiko P J de Vries, PhD (b,k), Prof Ron T Gansevoort, PhD (c), Prof Frederike J Bemelman, PhD (e), Prof Marlies E J Reinders, PhD (a), Jan-Stephan F Sanders, PhD (c), Prof Luuk B Hilbrands, PhD [luuk.hilbrands@radboudumc.nl] (g), Alferso C. Abrahams, Marije C. Baas, Pim Bouwmans, Marc A.G.J. ten Dam, Lennert Gommers, Dorien Standaar, Marieke van der Heiden, Yvonne M.R. Adema, Marieken J. Boer-Verschragen, Wouter B. Mattheussens, Ria H.L.A. Philipsen, Djenolan van Mourik, Susanne Bogers, Laura L.A. van Dijk, Nynke Rots, Gaby Smits, Marjan Kuijer, Marc H. Hemmelder