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  • Kho MML
  • Messchendorp AL
  • Frölke SC
  • Imhof C
  • Koomen VJ
  • et al.
Lancet Infect Dis. 2023 Mar;23(3):307-319 doi: 10.1016/S1473-3099(22)00650-8.
CET Conclusion
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This is another very interesting study on vaccine responses in kidney transplant recipients. In this complex study kidney transplant recipients were randomised to receive either an mRNA vaccine of 100 or 200 micrograms (mRNA-1273) versus a viral vector vaccine (Ad26.COV2-s) . A small group was also randomised to continue or discontinue mycophenolate for 1 week before and 1 week after. The study showed again, as has been seen elsewhere, that a significant proportion of transplant recipients do not seroconvert after two or even three doses of SARS-CoV-2 vaccine (34% and 20%). Vaccination with 200 micrograms mRNA vaccine was not significantly better than 100 micrograms or the viral vector vaccine. Stopping mycophenolate for 1 week and before and 1 week after did not have any significant impact on vaccine response either. The study was adequately randomised and powered, however it was not blinded. Given the objective nature of the results this is not of significant concern for systematic bias in the reporting of the results. The study was funded by The Netherlands Organization for Health Research and Development and the Dutch Kidney Foundation.
Expert Review
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Review: The study by Kho et al is from four centres in the Netherlands, and includes 345 patients, although the study was complex with multiple subdivisions and randomisations. Kidney transplant recipients who remained seronegative after two, or three, doses of mRNA vaccine were included. Patients were randomised to receive an mRNA vaccine of 100 or 200 microg (mRNA-1273) versus a viral vector vaccine (Ad26.COV2-s). In addition, a small group receiving 100 microg mRNA vaccine was also randomised to continue or discontinue mycophenolate for 1 week before until 1 week after the third vaccine dose (n=108). A significant proportion of these recipients still did not seroconvert after two or even three doses of SARS-CoV-2 vaccine (34% and 20%). There was no significant difference in seroconversion rate comparing 200 microg mRNA vaccine to 100 microg, or the viral vector vaccine. Stopping mycophenolate for 1 week before and 1 week after did not have any significant impact on vaccine response either. This study highlights the need for the third and even fourth COVID-19 booster vaccines to improve seroconversion in transplant recipients. Whilst this second study did not show an improved vaccine response when stopping mycophenolate, it was for a relatively short period only. Stopping mycophenolate for a longer period may be necessary to improve the immune response, however it may require the addition of another immune suppressant (such as sirolimus) to therapy during the switch period. Published studies assessing this concept have so far been small and therefore not reliable in assessing safety.
Aims: This study aimed to compare the immunogenicity of a double dose vaccine, heterologous vaccination, and temporary discontinuation of mycophenolate mofetil or mycophenolic acid to that of a control single dose mRNA-1273 vaccination, in kidney transplant recipients who do not respond to two or three doses of an mRNA vaccine.
Interventions: In the first cohort, participants were randomised to receive a single dose of mRNA-1273, two doses of mRNA-1273, or the Ad26.COV2-S vaccine. In the second cohort, patients receiving triple immunosuppressive therapy were randomised to either continue mycophenolate mofetil or mycophenolic acid, or discontinue mycophenolate mofetil or mycophenolic acid, from 1 week before until 1 week after being vaccinated with a single 100 μg dose of mRNA-1273.
Participants: 230 kidney transplant recipients were randomised in the first cohort and 103 kidney transplant recipieints were randomised in the second cohort.
Outcomes: The primary endpoint was the percentage of participants with a spike protein (S1)-specific IgG concentration ≥10 BAU/mL 28 days following vaccination. Secondary endpoints included the presence of virus neutralising antibodies, serum concentration of S1-specific IgG, and SARS-CoV-2 specific T-cell response and safety.
Follow Up: 28 days
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 μg mRNA-1273, 2 × 100 μg mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 μg 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 × 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 × 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<0·0001). No acute rejection occurred. There were no serious adverse events related to vaccination.

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.

  • Mulder MB
  • van der Eijk AA
  • GeurtsvanKessel CH
  • Erler NS
  • de Winter BCM
  • et al.
Gut. 2022 Dec;71(12):2605-2608 doi: 10.1136/gutjnl-2021-326755.
  • Sanders JF
  • Bemelman FJ
  • Messchendorp AL
  • Baan CC
  • van Baarle D
  • et al.
Transplantation. 2022 Apr 1;106(4):821-834 doi: 10.1097/TP.0000000000003983.
BACKGROUND:

In kidney patients COVID-19 is associated with severely increased morbidity and mortality. A comprehensive comparison of the immunogenicity, tolerability, and safety of COVID-19 vaccination in different cohorts of kidney patients and a control cohort is lacking.

METHODS:

This investigator driven, prospective, controlled multicenter study included 162 participants with chronic kidney disease (CKD) stages G4/5 (eGFR < 30 mL/min/1.73m2), 159 participants on dialysis, 288 kidney transplant recipients, and 191 controls. Participants received 2 doses of the mRNA-1273 COVID-19 vaccine (Moderna). The primary endpoint was seroconversion.

RESULTS:

Transplant recipients had a significantly lower seroconversion rate when compared with controls (56.9% versus 100%, P < 0.001), with especially mycophenolic acid, but also, higher age, lower lymphocyte concentration, lower eGFR, and shorter time after transplantation being associated with nonresponder state. Transplant recipients also showed significantly lower titers of neutralizing antibodies and T-cell responses when compared with controls. Although a high seroconversion rate was observed for participants with CKD G4/5 (100%) and on dialysis (99.4%), mean antibody concentrations in the CKD G4/5 cohort and dialysis cohort were lower than in controls (2405 [interquartile interval 1287-4524] and 1650 [698-3024] versus 3186 [1896-4911] BAU/mL, P = 0.06 and P < 0.001, respectively). Dialysis patients and especially kidney transplant recipients experienced less systemic vaccination related adverse events. No specific safety issues were noted.

CONCLUSIONS:

The immune response following vaccination in patients with CKD G4/5 and on dialysis is almost comparable to controls. In contrast, kidney transplant recipients have a poor response. In this latter, patient group development of alternative vaccination strategies are warranted.