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 (RECOVAC): a randomised clinical trial

Kho, Marcia M. L.; Messchendorp, A. Lianne; Frölke, Sophie C; Imhof, Céline; Koomen, Vera JCH; Malahe, S. Reshwan K.; Vart, Priya; Geers, Daryl; Vries, Rory D de; GeurtsvanKessel, Corine H.; Baan, Carla C.; Molen, Renate G. van der; Diavatopoulos, Dimitri A.; Remmerswaal, Ester B. M.; Baarle, Debbie van; Binnendijk, Rob van; Hartog, Gerco den; Vries, Aiko P.J. de; Gansevoort, Ron T.; Bemelman, Fréderike J.; Reinders, Marlies E.J.; Sanders, Jan-Stephan F.; Hilbrands, Luuk B.; Abrahams, Alferso C; Baas, Marije C.; Bouwmans, Pim; Dam, Marc A.G.J. ten; Gommers, Lennert; Standaar, Dorien; Heiden, Marieke van der; Adema, Yvonne M.R.; Boer-Verschragen, Marieken J.; Mattheussens, Wouter B.; Philipsen, Ria; Mourik, Djenolan van; Bogers, Susanne; Dijk, Laura L.A. van; Rots, Nynke Y.; Smits, Gaby; Kuijer, Marjan; Hemmelder, Marc H

doi:10.1016/s1473-3099(22)00650-8

Cited by 49 publications

(55 citation statements)

References 32 publications

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“…Multiple nonrandomized studies have recently described the positive effect of mycophenolic acid withdrawal on seroconversion rates and antibody titers, supporting such a strategy 28–30 . In contrast, a recent randomized trial showed no statistical significant difference in seroconversion rate and IgG titers between KTRs in which mycophenolate was temporarily halted or continued, with seroconversion rates of 80% and 67% after three vaccination doses, respectively 31 . There are, however, two important limitations to mention.…”

Section: Discussionmentioning

confidence: 99%

Mycophenolic Acid Exposure Determines Antibody Formation Following SARS‐CoV‐2 Vaccination in Kidney Transplant Recipients: A Nested Cohort Study

Meziyerh

Bouwmans

Gelder

et al. 2023

Clin Pharma and Therapeutics

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Despite (repeated) boosting, kidney transplant recipients (KTRs) may remain at increased risk of severe COVID-19 since a substantial number of individuals remain seronegative or with low antibody titers. In particular, mycophenolic acid use has been shown to affect antibody formation negatively and may be an important modifiable risk factor. We investigated the exposure-response relationship between mycophenolic acid 12-hour area under the curve (AUC 0-12h ) exposure and seroconversion including antibody titers after vaccination using mRNA-1273 SARS-CoV-2 vaccine (Moderna) in 316 KTRs from our center that participated in the national Dutch renal patients COVID-19 vaccination -long term efficacy and safety of SARS-CoV-2 vaccination in kidney disease patients vaccination study. After two vaccination doses, 162 (51%) KTRs seroconverted. KTRs treated with mycophenolic acid showed less seroconversion and lower antibody titers compared with KTRs without mycophenolic acid (44% vs. 77%, and 36 binding antibody units (BAU)/mL vs. 340 BAU/mL; P < 0.001). The mean mycophenolic acid AUC 0-12h exposure was significantly lower in KTRs who seroconverted compared with KTRs who did not (39 vs. 29 mg⋅h/L; P < 0.001). High mycophenolic acid exposure (±90 mg⋅h/L) and no exposure to mycophenolic acid resulted in a seroconversion rate ranging from 10% to 80%. Every 10 mg⋅h/L increase in mycophenolic acid AUC 0-12h gave an adjusted odds ratio for seroconversion of 0.87 (95% confidence interval (CI), 0.79-0.97; P = 0.010) and 0.89 (95% CI, 0.85-0.93; P < 0.001) for KTRs on dual and triple maintenance immunosuppressive therapy, respectively. Higher mycophenolic acid AUC 0-12h correlated with lower antibody titers (R = 0.44, P < 0.001). This study demonstrates the exposure-response relationship between gold standard mycophenolic acid exposure and antibody formation to support interventional studies investigating mycophenolic acid adjustment to improve antibody formation after further boosting.

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Section: Discussionmentioning

confidence: 99%

Mycophenolic Acid Exposure Determines Antibody Formation Following SARS‐CoV‐2 Vaccination in Kidney Transplant Recipients: A Nested Cohort Study

Meziyerh

Bouwmans

Gelder

et al. 2023

Clin Pharma and Therapeutics

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“…The lower immune response in KTR using MMF raises the question of whether the response to SARS-CoV-2 vaccination in KTR can be optimized by temporary discontinuation of MMF [ 5 , 30 , 31 ]. One randomized controlled trial recently investigated withdrawal of MMF 1 week before and after a third or fourth vaccination in 103 previous non-responding KTR [ 32 ]. No difference in antibody response was found between the intervention and the placebo group.…”

Section: Discussionmentioning

confidence: 99%

Impact of immunosuppressive treatment and type of SARS-CoV-2 vaccine on antibody levels after three vaccinations in patients with chronic kidney disease or kidney replacement therapy

Bouwmans

Messchendorp

Imhof

et al. 2022

Clinical Kidney Journal

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Background Patients with chronic kidney disease or kidney replacement therapy demonstrate lower antibody levels after SARS-CoV-2 vaccination compared to healthy controls. In a prospective cohort, we analysed the impact of immunosuppressive treatment and type of vaccine on antibody levels after three SARS-CoV-2 vaccinations. Methods Control subjects (n = 186), patients with CKD G4/5 (n = 400), dialysis patients (n = 480) and kidney transplant recipients (KTR) (n = 2468) were vaccinated with either mRNA-1273 (Moderna), BNT162b2 (Pfizer-BioNTech) or AZD1222 (Oxford/AstraZeneca) in the Dutch SARS-CoV-2 vaccination programme. Third vaccination data were available in a subgroup of patients (n = 1829). Blood samples and questionnaires were obtained one month after the second and third vaccination. Primary endpoint was the antibody level in relation to immunosuppressive treatment and type of vaccine. Secondary endpoint was occurrence of adverse events after vaccination. Results Antibody levels after two and three vaccinations were lower in patients with CKD G4/5 and dialysis patients with immunosuppressive treatment compared to patients without immunosuppressive treatment. After two vaccinations, we observed lower antibody levels in KTR using mycophenolate mofetil (MMF) compared to KTR not using MMF (20 BAU/ml [3–113] versus 340 BAU/ml [50–1492], P < 0.001). Seroconversion was observed in 35% of KTR using MMF, compared to 75% of KTR not using MMF. Of the KTR who used MMF and did not seroconvert, eventually 45% seroconverted after a third vaccination. mRNA-1273 induces higher antibody levels as well as a higher frequency of adverse events compared to BNT162b2 in all patient groups. Conclusions Immunosuppressive treatment adversely affects the antibody levels after SARS-CoV-2 vaccination in patients with CKD G4/5, dialysis patients and KTR. mRNA-1273 vaccine induces a higher antibody level and higher frequency of adverse events.

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“…However, these approaches induced seroconversion rates comparable to that of a standard RNA vaccine dose. 30 Overall, these findings highlight the benefits of repeated COVID-19 vaccination in RRT recipients, while emphasising the need for alternative strategies (e.g. pre-exposure prophylaxis with monoclonal antibodies) that might reduce the burden of disease in this vulnerable population.…”

Section: Discussionmentioning

confidence: 80%

Comparative effectiveness of two- and three-dose COVID-19 vaccination schedules involving AZD1222 and BNT162b2 in people with kidney disease: a linked OpenSAFELY and UK Renal Registry cohort study

Parker

Horne

Hulme

et al. 2023

The Lancet Regional Health - Europe

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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 (RECOVAC): a randomised clinical trial

Cited by 49 publications

References 32 publications

Mycophenolic Acid Exposure Determines Antibody Formation Following SARS‐CoV‐2 Vaccination in Kidney Transplant Recipients: A Nested Cohort Study

Mycophenolic Acid Exposure Determines Antibody Formation Following SARS‐CoV‐2 Vaccination in Kidney Transplant Recipients: A Nested Cohort Study

Impact of immunosuppressive treatment and type of SARS-CoV-2 vaccine on antibody levels after three vaccinations in patients with chronic kidney disease or kidney replacement therapy

Comparative effectiveness of two- and three-dose COVID-19 vaccination schedules involving AZD1222 and BNT162b2 in people with kidney disease: a linked OpenSAFELY and UK Renal Registry cohort study

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