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Alternative Strategies to Increase the Immunogenicity of Covid-19 Vaccines in Kidney Transplant Recipients Not Responding to Two or Three Doses of an mRNA Vaccine. A Randomized Clinical Trial

31 Pages Posted: 29 Jul 2022

See all articles by Marcia ML Kho

Marcia ML Kho

Erasmus University Rotterdam (EUR) - Department of Internal Medicine, Nephrology and Transplantation

A. Lianne Messchendorp

University of Groningen - Division of Nephrology

Sophie Frölke

University of Amsterdam - Renal Transplant Unit

Celine Imhof

University of Groningen - Division of Nephrology

Vera JCH Koomen

Radboud University Nijmegen - Department of Nephrology

S. Reshwan K. Malahe

Erasmus University Rotterdam (EUR) - Department of Internal Medicine, Nephrology and Transplantation

Daryl Geers

Erasmus University Rotterdam (EUR) - Department of Viroscience

Carla C. Baan

Erasmus University Rotterdam (EUR) - Department of Internal Medicine, Nephrology and Transplantation

Renate Van der molen

Donders Institute for Brain Cognition and Behaviour - Radboudumc

Dimitri A. Diavatopoulos

Donders Institute for Brain Cognition and Behaviour - Radboudumc

Ester Remmerswaal

University of Amsterdam - Department of Experimental Immunology

Debbie van Baarle

University of Groningen - Department of Medical Microbiology and Infection Prevention

Robert Samuel van Binnendijk

National Institute for Public Health and the Environment (RIVM) - Department for Immunology of Infectious Diseases and Vaccination (IIV)

Gerco den Hartog

National Institute for Public Health and the Environment (RIVM) - Department of Immune Surveillance

Ron T. Gansevoort

University of Groningen - Division of Nephrology

Frederike J. Bemelman

University of Amsterdam - Renal Transplant Unit

Marlies EJ Reinders

Erasmus University Rotterdam (EUR) - Department of Internal Medicine, Nephrology and Transplantation

Jan-Stephan Sanders

University of Groningen - Division of Nephrology

Luuk B. Hilbrands

Donders Institute for Brain Cognition and Behaviour - Radboudumc

RECOVAC Collaborators

Independent

More...

Abstract

Background: An urgent need exists to improve the suboptimal COVID-19 vaccine response in kidney transplant recipients (KTR). We compared 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 (MMF/MPA).

Methods: This prospective, multicentre, open-label randomized trial, enrolled KTR without seroconversion after two or three doses of an mRNA vaccine. Between October 20, 2021 and February 2, 2022, 230 KTR were randomized to receive 100 µg mRNA-1273, 2x 100 µg mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTR receiving 100 µg mRNA-1273, were randomized to continue (MMF+) or discontinue (MMF-) MMF/MPA treatment for two weeks. Primary outcome was the percentage of participants with an S1-specific IgG concentration ≥ 10 BAU/mL at 28 days after vaccination. Trial registration number: NCT05030974, ClinicalTrials.gov, closed.

Findings: Seroresponse rates did not differ between single mRNA-1273 (69%), double mRNA-1273 (68%), and Ad26.COV2-S (63%), nor between the MMF+ (67%) and MMF- (80%) groups. Neutralizing antibody levels against the SARS-CoV-2 ancestral, Delta and Omicron (BA.1) variants correlated with S1-specific IgG levels (P<0.001) and did not differ between groups. T-cell response rates also did not differ between single mRNA-1273 (52·4%), double mRNA-1273 (52·4%), and Ad26.COV2-S (28·6%), nor between MMF+ (66·7%) and MMF- (54·2%) groups. Local adverse events were more frequent after a single and double dose of mRNA-1273 than after Ad26.COV2-S (91%, 93% and 49%, respectively; P<0·001).

Interpretation: Repeated vaccination increases SARS-CoV-2-specific antibodies and T-cell responses in KTR, without further enhancement by using a higher dose, a heterologous vaccine, or two weeks discontinuation of MMF/MPA. To achieve a stronger response, possibly required to neutralize new virus variants, repeated booster vaccination is needed, and perhaps longer discontinuation of MMF/MPA.

Trial Registration Details: This study was registered in www.ClinicalTrials.gov (NCT05030974).

Funding Information: The study is funded by The Netherlands Organization for Health Research and Development (ZonMW, project number: 10430072010002) and Dutch kidney foundation (project number: 21OP+036).

Declaration of Interests: We declare no competing interests.

Ethics Approval Statement: Ethical approval was obtained from the Dutch Central Committee on Research Involving Human Subjects (CCMO, NL78963.042.21), the central ethics committee at the UMC Groningen (METC 2021/507), and the local ethics committees of the participating centers.

Keywords: COVID-19, mRNA-1273, Ad26.COV2-S, Vaccine, kidney transplantation, immunogenicity

Suggested Citation

Kho, Marcia ML and Messchendorp, A. Lianne and Frölke, Sophie and Imhof, Celine and Koomen, Vera JCH and Malahe, S. Reshwan K. and Geers, Daryl and Baan, Carla C. and Van der molen, Renate and Diavatopoulos, Dimitri A. and Remmerswaal, Ester and van Baarle, Debbie and van Binnendijk, Robert Samuel and den Hartog, Gerco and Gansevoort, Ron T. and Bemelman, Frederike J. and Reinders, Marlies EJ and Sanders, Jan-Stephan and Hilbrands, Luuk B. and Collaborators, RECOVAC, Alternative Strategies to Increase the Immunogenicity of Covid-19 Vaccines in Kidney Transplant Recipients Not Responding to Two or Three Doses of an mRNA Vaccine. A Randomized Clinical Trial. Available at SSRN: https://ssrn.com/abstract=4176376 or http://dx.doi.org/10.2139/ssrn.4176376

Marcia ML Kho

Erasmus University Rotterdam (EUR) - Department of Internal Medicine, Nephrology and Transplantation ( email )

Rotterdam
Netherlands

A. Lianne Messchendorp

University of Groningen - Division of Nephrology ( email )

Groningen
Netherlands

Sophie Frölke

University of Amsterdam - Renal Transplant Unit ( email )

Celine Imhof

University of Groningen - Division of Nephrology ( email )

Vera JCH Koomen

Radboud University Nijmegen - Department of Nephrology ( email )

S. Reshwan K. Malahe

Erasmus University Rotterdam (EUR) - Department of Internal Medicine, Nephrology and Transplantation ( email )

Daryl Geers

Erasmus University Rotterdam (EUR) - Department of Viroscience ( email )

Netherlands

Carla C. Baan

Erasmus University Rotterdam (EUR) - Department of Internal Medicine, Nephrology and Transplantation ( email )

Rotterdam
Netherlands

Renate Van der molen

Donders Institute for Brain Cognition and Behaviour - Radboudumc ( email )

Dimitri A. Diavatopoulos

Donders Institute for Brain Cognition and Behaviour - Radboudumc ( email )

Nijmegen
Netherlands

Ester Remmerswaal

University of Amsterdam - Department of Experimental Immunology ( email )

Netherlands

Debbie Van Baarle

University of Groningen - Department of Medical Microbiology and Infection Prevention ( email )

Groningen
Netherlands

Robert Samuel Van Binnendijk

National Institute for Public Health and the Environment (RIVM) - Department for Immunology of Infectious Diseases and Vaccination (IIV) ( email )

Bilthoven
Netherlands

Gerco Den Hartog

National Institute for Public Health and the Environment (RIVM) - Department of Immune Surveillance ( email )

Bilthoven
Netherlands

Ron T. Gansevoort

University of Groningen - Division of Nephrology ( email )

Groningen
Netherlands

Frederike J. Bemelman

University of Amsterdam - Renal Transplant Unit ( email )

Amsterdam
Netherlands

Marlies EJ Reinders

Erasmus University Rotterdam (EUR) - Department of Internal Medicine, Nephrology and Transplantation ( email )

Rotterdam
Netherlands

Jan-Stephan Sanders

University of Groningen - Division of Nephrology ( email )

Groningen
Netherlands

Luuk B. Hilbrands (Contact Author)

Donders Institute for Brain Cognition and Behaviour - Radboudumc ( email )

Nijmegen
Netherlands

RECOVAC Collaborators

Independent

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