COVID-19 Evidence Alerts
from McMaster PLUSTM

Current best evidence for clinical care (more info)

Treatment Kho MML, Messchendorp AL, Frolke SC, et al. 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. Lancet Infect Dis. 2023 Mar;23(3):307-319. doi: 10.1016/S1473-3099(22)00650-8. Epub 2022 Oct 27.
PICO Terms
adult (P) adverse reactions; safety (O) booster; fourth dose (I/C) booster; third dose (I/C) heterologous, prime-boost (I/C) immunogenicity (O) Johnson & Johnson vaccine; Janssen Pharmaceutical Companies; Ad26.COV2.S; non-replicating viral vector (I/C) kidney transplant patients (P) neutralizing antibodies (O) non-responders (P) reactogenicity (O) SARS-CoV-2 spike protein-binding antibodies (O) seroconversion (O) spike-specific T cell response (O) Spikevax; Moderna vaccine; mRNA-1273 SARS-CoV-2; ModernaTX; mRNA (I/C) T-cell response (O) vaccine efficacy (O)
Demographic Information
Geriatric Population
60 years to <70 years 70 years to <80 years
Female Male
Asian Black White

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, 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.

Discipline / Specialty Area Score
Infectious Disease
Internal Medicine
Comments from MORE raters

Infectious Disease rater

Unfortunately, the study population is less than 20% of the original seronegative patients and the outcome is just antibodies. Thus, we need a bigger trial with a clinical primary outcome.

Infectious Disease rater

Although restricted to a very selective cohort, the study's design data quality are reliable. This approach could also be useful in other conditions that demand significant immunosuppressive therapy.

Internal Medicine rater

Very interesting but very few patients included.

Nephrology rater

As a transplant physician, these results are not what I would have expected. This study provides evidence to decide on the best way to manage patients who have had a kidney transplant with suboptimal COVID-19 vaccine response.