In a recent study posted to the medRxiv* preprint server, researchers analyzed whether repeated vaccinations against coronavirus disease 2019 (COVID-19) increase serological response in non-responding kidney transplant recipients (KTR).
About the study
In the present study, researchers recruited 1,478 KTR who received SARS-CoV-2 vaccinations from December 27, 2020, until December 31, 2021. First, they immunized all the study participants with a two-dose regimen of four COVID-19 vaccines - BNT162b2, messenger ribonucleic acid (mRNA)-1273, ChAdOx1-S, or Ad26.COV2.S. Only non-responding KTRs, who provided their written and informed consent received up to five doses of SARS-CoV-2 vaccines. The team retrospectively evaluated the effects of immunosuppressive reduction regimens on the serological response.
As the primary outcome, the team analyzed the maximum serological response 14 days after each immunization, i.e., two, three, four, and five doses COVID-19 vaccine regimen.
The team performed enzyme-linked immunosorbent assays (ELISA) on the sera obtained from the study participants to quantify the immunoglobulin G (IgG) antibodies against the SARS-CoV-2 spike (S) protein; a cut-off index ≥ 1.1 indicated the presence of IgGs.
Alternatively, they performed the electrochemiluminescence immunoassay (ECLIA) to detect IgG, IgA, and IgM levels in the sera against the S receptor-binding (RBD) domain. Here, a cut-off index ≥ 264 U/ml indicated a positive result.
They computed the serological response rate as the rate of responders after two, three, four, and five dose-immunization. Responders elicited sufficient serological response as indicated by a positive SARS-CoV-2 antibody titer (cut-off value of ≥ 1.1 or ≥ 264 U/ml for ELISA and ECLIA, respectively).
The researchers calculated cumulative serological responses using the Kaplan-Meier method. The vaccination dosage varied over time, and the event of interest was the first positive serological response. They censored all the KTRs who failed to elicit a positive serological result after a five-dose vaccine regimen.
Using multivariable analyses based on logistic regression models, the team monitored 19 other study variables. These included transplantation data, vaccination characteristics, recent immunosuppressive medication, and routine laboratory test results, to name a few; accordingly, test subjects whose information was missing had to be excluded from the study.
Mycophenolic acid (MPA) dose could influence the serological response to immunization. Hence, the researchers adjusted the MPA doses before the fourth SARS-CoV-2 immunization according to each patient’s risk factors, including anti-human leukocyte antigen (HLA) antibodies, previous rejection episodes, and response to COVID-19 vaccines.
In calcineurin inhibitors (CNI)-treated patients, they either reduced or stopped MPA treatment from one week before until four weeks after immunization and assigned them to three groups based on the MPA doses as steady, reduced, and paused MPA doses. They used Mann–Whitney U tests and t-tests to compare the serological response rates and continuous variables between these groups, respectively.
They computed the serological response rate in patients on CNI and belatacept-based immunosuppression separately. Further, they analyzed responders receiving the belatacept-based treatment.
One of the key study findings was that repeated COVID-19 vaccination (five doses) was safe for the non-responding KTR and induced sufficient serological response in most patients, except for belatacept-treated patients. Accordingly, the authors observed a serological response rate of 19.5% after a 1,203 two-dose vaccine regimen. These response rates surged to 29.4%, 55.6%, and 57.5% after 603 three-dose, 250 four-dose, and 40 five-dose vaccine regimens ensuing in an aggregate serological response rate of 88.7%.
In CNI-treated non-responders after a three-dose vaccine regimen, pausing MPA and giving 5 mg prednisolone improved the serological response at the time of the fourth vaccination to 75%. In comparison, the serological response increased to 46% after dose reduction, thus indicating that MPA dose reduction did not improve the response rate.
On the contrary, additional immunizations had a limited effect on the serological response of the belatacept-receiving KTR, specifically when receiving full-dose MPA. They showed a 12.5% serological response rate after four vaccinations; thus, the authors recommended new treatment approaches for these patients.
The two modifiable risk factors of impaired serological response were MPA dose and belatacept treatment. Contrastingly, higher BMI, younger age, and time after transplantation were non-modifiable risk factors. This further validates that immunosenescence in the elderly results in a reduced response to COVID-19 vaccines in general, especially in KTR.
Similarly, the findings showed that more time-lapse after transplantation led to a lower reduction of immunosuppression due to waning steroids and reduced CNI levels.
Most transplant centers have provided monoclonal antibody treatment to KTR who are unresponsive to COVID-19 vaccines. This study demonstrated that repeated vaccination is a safe and effective alternative immunization strategy to induce a humoral serological response in non-responding KTR. To further enhance the immunity of non-responding KTR, the authors recommended pausing the MPA treatment with 5 mg of prednisolone (in case of steroid-free treatment), albeit under close monitoring only.
More importantly, an optimal strategy needs to be defined for patients receiving belatacept as they failed to respond to COVID-19 vaccination even after a five-dose vaccine regimen. The authors recommended switching from belatacept to a CNI-based regimen or pre-exposure prophylaxis with monoclonal anti-S-protein antibodies for protecting this high-risk population.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.