Abstract
The COVID-19 vaccine will be safe and effective in solid organ transplant recipients (SOTs). However, the blunted antibody responses were also of concern. Few studies have reported prolonged serologic follow-up after 2 doses of BNT162b2 vaccine in SOTs. We performed a single-center, prospective observational study of 78 SOTs who received 2 doses of BNT162b2 vaccine. We identified the trajectory of antibody titers after vaccination among SOTs with or without mycophenolate mofetil (MMF) or withdrawn from MMF. We found low seroconversion rates (29/42: 69%) and low antibody titers in SOTs treated with MMF. An inverse linear relationship between neutralizing antibody titers and MMF concentration was confirmed in restricted cubic spline plots (P for effect < .01, P for nonlinearity = .08). For the trajectory of antibody responses, seroconversion and improved antibody titers were observed after withdrawal from MMF in SOTs who showed seronegative or low antibody titers at the first visit after 2 doses of vaccine (P for effect < .01, P for nonlinearity < .05, and P for interaction < .01). We identified increased B-cell counts after withdrawal from MMF (P < .01). The recovery of antibody responses was seen in SOTs withdrawn from MMF. The trajectories of antibody responses were modified by MMF administration.
Vaccines against SARS-CoV-2 have been found to be effective and safe in both clinical trials and real-world settings [1,2]. Antibody responses after mRNA SARS-CoV-2 vaccination are well established in the general population [3], [4], [5], [6], [7]. However, the previous pioneering works revealed blunted antibody responses in solid organ transplant recipients (SOTs) who need continuous immunosuppressive medications to prevent rejection of the transplanted organs [8], [9], [10], [11], [12], [13], [14]. There is a paucity of data in SOTs who use potent immunosuppressants because they have been specifically excluded from SARS-CoV-2 vaccine trials [1,2].
Data from recent observational studies has suggested that a substantial proportion of patients with solid organ transplant, particularly those undergoing immunosuppression with mycophenolate mofetil (MMF), show attenuated antibody response even after a second or third vaccination [8,10,12,15,16]. We have demonstrated marked attenuation of antibody titers among transplant recipients with MMF in a dose-dependent manner after second doses of a SARS-CoV-2 vaccine [10]. In addition, in a report of a case series, seroconversions were confirmed after withdrawal from MMF in vaccinated transplant recipients without a third vaccination [15]. Based on such results, the identification of the trajectories of antibody responses in SOTs in association with MMF administration is essential to elucidate optimal countermeasures in this vulnerable population.
Whether the mid-term immunogenicity of SARS-CoV-2 vaccine is maintained in SOTs remains unclear [17,18]. Hence, to fill the gap in the evidence for this vulnerable population, we conducted the present study to identify the trajectory of antibody titers after SARS-CoV-2 vaccination among SOTs with or without MMF or withdrawal from MMF. The SOTs have a normal immune system but potently inhibited T- and B-cell responses to prevent transplant rejection. We thus also explored the associations between antibody titers and trough MMF concentrations and B- and T-cell counts, together with CD4- and CD8-positive T-cell counts, in SOTs after the second dose of SARS-CoV-2 vaccine.
Materials and Methods
Study Design and Population
A prospective, single-center observational cohort study including SOTs receiving immunosuppressive therapy from Matsunami General Hospital, Japan, was conducted between July 1, 2021 and April 30, 2022. We included all patients who received second doses of the BNT162b2 mRNA SARS-CoV-2 vaccine (Pfizer/BioNTech). Patients with a history of polymerase chain reaction–confirmed diagnosis of COVID-19 or positive SARS-CoV-2 anti-nucleocapsid antibodies before the second vaccination were excluded.
The SOT enrollment was stratified into 3 categories: with MMF, without MMF, and withdrawn from MMF. SOTs in the withdrawal category were tapered from MMF using a decremental schedule according to the discretion of the attending physician. The dose of other immunosuppressants could be changed as dictated by clinical necessity. Withdrawal from MMF was attempted in the period between the first and second measurements of antibody titers. With the exception of 1 patient, weaning from MMF was successful. One patient showed an elevated liver function test during the withdrawal and thus MMF was left at the maintenance dose because of concerns about rejection. No graft failure was observed in all patients.
The trajectory of antibody titer was evaluated using density plots, linear mixed-effects models of longitudinal analysis, and nonlinear regression with a robust Huber-White sandwich estimator.
Sample Collection and Follow-Up Schedule
The first 2 doses were given at least 3 weeks apart, and blood samples for antibody measurements were taken at least 2 weeks after the second vaccination. Visit-to-visit blood sampling was scheduled over 3 regularly scheduled outpatient clinic visits.
Antibody Quantification
The serum was obtained by centrifugation at 1500 × g for 10 minutes. The S receptor-binding domain (RBD) immunoglobulin (Ig) G antibody titers were quantified using the SARS-CoV-2 S-IgG (IC) Assay Reagent assay kit (Fujirebio, Tokyo, Japan) to measure the RBD-IgG antibody titers as described previously [10,15]. All procedures were performed according to the manufacturer's instructions. Briefly, 10 μL of serum sample, 250 μL of antigen-bound particles, and 80 μL of diluted SARS-CoV-2 S-IgG were mixed and incubated at 37°C for 10 minutes. After separating bound and free fractions, 150 μL of enzyme-labeled antibody was added and incubated at 37°C for 10 minutes. After separating bound and free fractions, 200 μL of substrate solution was added and incubated at 37°C for 5 minutes. Luminescence was then measured using a LUMIPULSE G1200 fully automated chemiluminescent enzyme immunoassay system (Fujirebio) and the results were calculated. Titers greater than 1.0 arbitrary units (AU)/mL were considered to represent seropositivity.
To confirm whether previous infection had occurred, antibodies to the N antigen were also measured. A Cobas 8000 analyzer (Roche Japan, Tokyo) and Elecsys anti-SARS-CoV-2 reagent (Roche Japan) were used. All procedures were performed in accordance with the instructions from the manufacturer (measurements were contracted to SRL Corporation, Tokyo, Japan). The serum samples were incubated with biotinylated SARS-CoV-2 antigen and ruthenium-labeled SARS-CoV-2 antigen at 37°C for 9 minutes. After washing, streptavidin magnetic particles were added and incubated at 37°C for 9 minutes. The reaction mixture was aspirated into the measuring cell, and the magnetic particles were attracted to the electrode by magnetic force for separation of bound and free fractions. The target substance was then quantified by electrochemiluminescence. A result >1.00 units (cutoff index) was deemed positive.
Therapeutic Drug Monitoring of MMF
Drug monitoring of MMF was planned at the discretion of the attending physician at a regular outpatient clinic. The measurement of MMF was performed using serum samples, a BioMajesty 6070 G biochemistry analyzer (JEOL, Tokyo, Japan), and the reagent Emit 2000 MPA assay (Siemens Healthcare Diagnostics Co, Tokyo, Japan). The assays were contracted to SRL Corporation. We examined the association between MMF concentration immediately before the second vaccination and RBD-IgG antibody titer at the first routine outpatient visit after completion of the second vaccination.
Lymphocyte Subset Counts Before and After Withdrawal From MMF
To investigate factors contributing to improved immunogenicity, we comprehensively analyzed counts of lymphocyte subsets including CD4+ and CD8+ T cells and B cells in patients who were successfully tapered and withdrawn from MMF and compared the results before and after withdrawal from MMF. The CD4- and CD8-positive T- and B-cell counts were measured using heparinized blood, a FACSCant II analyzer (BD Biosciences, East Rutherford, NJ), and monoclonal antibodies (Coulter T11-RD1/B4-FITC, T4-FITC and T8-RD1; Beckman Coulter Co, Brea, CA). All measurements were contracted to SRL Corporation. The cell counts were calculated by multiplying the measured percentages of CD4- and CD8-positive T and B cells by the number of lymphocytes measured with a multiparameter automated hematology analyzer (XN-3100; Sysmex, Kobe, Japan).
Ethical Considerations
This study conformed to the principles outlined in the Declaration of Helsinki and its later amendments. We obtained written informed consent from all study participants. The study protocol was approved by the Ethics Committee of Matsunami General Hospital (Approval No. 498, 2021).
Statistical Analysis
The continuous values are expressed as median and IQR. The Mann-Whitney U test or Kruskal-Wallis test was used to analyze differences between groups of continuous variables, as appropriate. Categorical data were compared using the χ2 test. We compared lymphocyte subset counts before and after withdrawal of the same individual from MMF using the Wilcoxon signed-rank test. The presence of a nonlinear association between RBD-IgG antibody titer and MMF concentration was assessed using a restricted cubic spline regression model with 3 knots using the R rms package (R Foundation for Statistical Computing, Vienna, Austria). To examine whether RBD-IgG antibody titers changed over time, a nonlinear regression with the Huber-White robust sandwich estimator of variance-covariance matrix was used. To examine the relationship between antibody titers and the number of days elapsed since the second vaccination among SOTs with or without MMF or who were successfully withdrawn from MMF, we used a nonlinear regression with a robust Huber-White sandwich estimator. Statistical significance was set at P < .05 (2-tailed), and P for interaction < .15 was considered significant. Statistical analyses were performed using R version 4.1.3 (R Foundation for Statistical Computing).
Results
Baseline Characteristics
We enrolled 78 patients (median age = 66.5 years; IQR, 56-73.8 years; 59 men [75.6%]; 19 women [24.4%]) receiving immunosuppressive regimen for SOT with no history of COVID-19 and a negative SARS-CoV-2 anti-nucleocapsid antibody test during the study period, indicating no previous exposure to COVID-19. Among these patients, 36 received an immunosuppressive regimen without MMF (46%), 19 received an immunosuppressive regimen with MMF continuously throughout the study period (24%), and 23 were successfully withdrawn from MMF after the second vaccination (29%; Table 1 ). Median days of visits 1, 2, and 3 after the second vaccination were 46 days (IQR, 22-66 days), 107 days (IQR, 94-136.2 days), and 188 days (IQR, 143-202 days), respectively.
Table 1.
Clinical Characteristics of Participants, Stratified by MMF Administration
| All Subjects (N = 78) | Without MMF (n = 36) | With MMF (n = 19) | Withdrawal From MMF (n = 23) | P Value | |
|---|---|---|---|---|---|
| Age, y | 66.5 (56.0, 73.8) | 65.0 (50.8, 71.3) | 64.0 (55.5, 73.5) | 70.0 (58.5, 77.0) | .20 |
| Sex (male), n (%) | 59 (75.6) | 25 (69.4) | 17 (89.5) | 17 (73.9) | .25 |
| BMI, kg/m2 | 23.1 (21.1, 25.0) | 22.8 (21.6, 25.0) | 23.2 (20.8, 24.5) | 23.9 (21.3, 25.3) | .70 |
| Organ | |||||
| Kidney/liver, n | 9/70 | 0/36 | 4/15 | 5/19 | < .01 |
| Donor type | |||||
| Living donor, n (%) | 17/78 (21.8) | 10 (27.8) | 6 (31.6) | 1 (4.3) | .051 |
| Deceased donor, n (%) | 61/78 (78.2) | 26 (72.2) | 13 (68.4) | 22 (95.7) | |
| Time from transplant, years | 16.0 (15.0, 19.0) | 18.0 (15.0, 21.0) | 15.0 (15.0, 18.0) | 15.0 (14.0, 16.5) | .01 |
| Immunosuppression maintenance therapy | |||||
| Calcineurin inhibitor, n (%) | 73 (93.6) | 34 (94.4) | 18 (94.7) | 22 (95.7) | .98 |
| Azathioprine, n (%) | 4 (5.1) | 4 (11.1) | 0 (0.0) | 0 (0.0) | .09 |
| Mycophenolate mofetil, n (%) | 42 (53.8) | 0 (0.0) | 19 (100.0) | 23 (100.0) | < .01 |
| Steroids, n (%) | 1 (1.3) | 1 (2.8) | 0 (0.0) | 0 (0.0) | .55 |
| mTOR inhibitor, n (%) | 1 (1.3) | 0 (0.0) | 0 (0.0) | 1 (4.3) | .30 |
Values are median (IQR) or as shown.
BMI, body mass index; MMF, mycophenolate mofetil; mTOR, mammalian target of rapamycin.
Alluvial Plot for Temporal Changes in Seropositivity in SOTs With or Without MMF or Withdrawn From MMF
Fig 1 illustrates the alluvial plot of how results of serologic tests changed over time in 3 groups (SOTs without MMF, SOTs with MMF, and SOTs withdrawn from MMF). Sixty-four of the 78 SOTs were seropositive at visit 1 (82%), comprising 35 non-MMF users (35/36, 97.2%), 15 MMF continuous users (15/19, 78.9%), and 14 users withdrawn from MMF (14/23, 60.8%; Fig 1). Seropositivity in non-MMF users persisted and was maintained from visit 1 to 3 (35/36, 97.2%; 23/24, 95.8%; and 20/21, 95.2%, respectively, at visits 1, 2, and 3). Interestingly, 5 patients in the MMF withdrawal group were seronegative at visit 1 but seroconversion was obtained by visit 2 after withdrawal from MMF without additional vaccination. In MMF continuous users who were seronegative at visit 1 (n = 5), we could not verify seroconversion at either visit 2 or visit 3 (Fig 1).
Fig 1.
Alluvial plot for seroconversion in solid organ transplant recipients with or without mycophenolate mofetil (MMF). MMF none: solid organ transplant recipients without MMF regimen. MMF on: solid organ transplant recipients who continued MMF regimen. MMF off: solid organ transplant recipients withdrawn from MMF regimen. MMF, mycophenolate mofetil.
Relationship Between RBD-IgG Antibody Titers and MMF Concentration in SOTs
A restricted cubic spline plot (Fig 2 ) shows the relationship between antibody titers and MMF concentration in SOTs. An inverse linear relationship between antibody titers and MMF concentration was identified (P for effect < .01, P for nonlinearity = .08).
Fig 2.
Association between antibody titers and mycophenolate mofetil concentrations in solid organ transplant recipients by restricted cubic spline model with three knots. The shaded area represents the 95% CI. MMF, mycophenolate mofetil.
Density Plot for Trajectories of RBD-IgG Antibody Titers From Second Vaccination
Fig 3 depicts the kernel density plot showing distributions of antibody titers for samples from SOTs without MMF, SOTs with MMF, and SOTs withdrawn from MMF at visits 1 to 3. Comparison of RBD-IgG antibody titers against SARS-CoV-2 revealed higher antibody titers in SOTs without MMF compared to other recipient groups at visit 1. However, as expected, the distribution of antibody titers shifted toward 0 at visits 2 and 3 (Fig 3).
Fig 3.
Density plot for trajectories of antibody titers from second vaccination. Kernel density plot (A) showing distribution of antibody titers stratified by solid organ transplant recipients without mycophenolate mofetil (MMF) and those with MMF at baseline immunosuppressive regimen or (B) stratified by solid organ transplant recipients without MMF, solid organ transplant recipients with MMF, and solid organ transplant recipients with MMF withdrawing at visits 1-3. MMF, mycophenolate mofetil.
Linear Mixed-Effects Model for Evaluating Visit-to-Visit RBD-IgG Antibody Titer Variations
Mixed-effects models were used to compare serial changes to RBD-IgG antibody titers in 2 (with or without MMF) or 3 (with or without MMF or withdrawn from MMF) groups at visits 1, 2, and 3. The linear mixed-effects model showed differences in antibody titers between groups at visits 1, 2, and 3 (P = .048 and P = .11, respectively; Fig 4 ).
Fig 4.
Linear mixed-effects model for evaluating visit-to-visit antibody titer variations. Linear mixed-effects models comparing serial changes of antibody titers in 2 (with or without mycophenolate mofetil [MMF]) (left panel) or 3 (with or without MMF or withdrawn from MMF) (right panel) groups at visits 1, 2, and 3. Open circles represent mean antibody titers, and bars represent 95% confidence intervals. MMF, mycophenolate mofetil.
Nonlinear Restricted Cubic Spline Model Between RBD-IgG Antibody Titers and Days From Second Vaccination
We created a nonlinear regression model analysis between time after the second vaccination and RBD-IgG antibody titers together with interaction analysis according to MMF administration. The Huber-White robust sandwich variance-covariance estimator was used to account for repeated observations. The RBD-IgG antibody titers decreased over time (both P for effect < .01 and P for nonlinearity < .05; Fig 5 ). Regression models including an interaction term showed reverse U-shaped serial changes in SOTs withdrawn from MMF. Antibody titers were modified significantly depending on MMF administration (Fig 5; P for interaction = .01 and P for interaction < .01, respectively).
Fig 5.
Association between days from second vaccination and log-transformed antibody titers (restricted cubic spline). (A) Stratified by mycophenolate mofetil (MMF) administration at baseline regimen. (B) Stratified by with or without MMF, or withdrawn from MMF. MMF, mycophenolate mofetil.
Comparison of CD4- and CD8-Positive T- and B-Cell Counts Before and After Withdrawal From MMF
For lymphocyte subset counts measured in 20 SOTs withdrawn from MMF, we compared CD4+ and CD8+ T- and B-cell counts before and after withdrawal from MMF. Fig 6 exhibits the result for B-cell counts before and after withdrawal from MMF within the same individual using the Wilcoxon signed-rank test. A significant difference in B-cell counts was seen between before and after withdrawal from MMF (P < .01). Conversely, no significant differences were detected in CD4+ or CD8+ T-cell counts between before and after withdrawal from MMF.
Fig 6.
Violin charts wrapping a box plot for B-cell count in solid organ transplant recipients after mycophenolate mofetil discontinuation.
Discussion
We reported in this study the trajectory of RBD-IgG antibody titers after 2 doses of BNT162b2 mRNA COVID-19 vaccine in SOTs. First, we found low antibody response rates and low antibody titers in SOTs treated with MMF. Second, an inverse linear relationship between RBD-IgG antibody titers and MMF concentration was detected. Third, seroconversion and improved antibody titers were observed after withdrawal from MMF in SOTs who showed seronegative or low antibody titers at visit 1 after 2 doses of the vaccine. Last, we identified increased B-cell counts after withdrawal from MMF.
The SOTs are at higher risk of COVID-19 because of the immunosuppressants needed to prevent graft rejection [9,[18], [19], [20]]. This is because the immunosuppressive agents used may impair responses to COVID-19 vaccines. Patients treated with MMF before vaccination did not mount sufficient antibody response to BNT162b2 vaccination and might have been rendered unprotected from COVID-19, as suggested by breakthrough infections. We and others have reported poor antibody response after 2 doses of BNT162b2 mRNA vaccine in SOTs treated with MMF [8,10,12,16]. We also confirmed previous findings that both MMF administration dose and concentration were inversely related to antibody titers in a linear, dose-response–dependent manner [8,10]. Those receiving MMF as maintenance immunosuppression therapy were less likely to develop an antibody response and seroconversion. We found increased antibody titers and serologic recovery after withdrawal from MMF. These findings were consistent with our report of seroconversion in SOTs who achieved withdrawal from MMF [15] and with the statement that temporarily withholding MMF could be considered when the disease condition is stable [21].
In SOTs requiring continuous immunosuppression, no specific strategy to reinforce vaccine immunogenicity has been proposed for these blunted antibody responses [19,20,22]. One potential strategy for enhancing antibody titers in SOTs could be to minimize or potentially withhold MMF administration at the time of vaccination in patients who show failed seroconversion after completion of scheduled vaccinations [8,15,21]. The benefit-risk balance of this strategy, however, should be assessed individually and close monitoring is advised to avoid organ rejection and allograft complications. For example, long-standing SOTs with stable conditions, such as our study population, could be candidates for modulating immunosuppressive regimens at the time of booster vaccination. Also, the withdrawal of MMF to achieve a greater antibody titer is still a controversial issue because SOTs are exposed to a risk of organ rejection while obtaining effective antibody titers. Continued research evaluating immunogenicity, clinical efficacy, and safety and development of strategies to improve antibody response in this vulnerable population are thus warranted.
In SOTs, increased B-cell counts were observed after the withdrawal from MMF. Depletion of B-cell responses is a possible mechanism for the diminished antibody titers in SOTs receiving MMF [23], [24], [25]. Similar results have been reported in patients with hematological cancer who need anti-B-cell therapy [23], [24], [25], [26] and in patients with chronic inflammatory diseases receiving B-cell-depleting therapies [26, 27]. However, a complex interplay between cellular and humoral immunity is required to achieve adequate antibody response after vaccination. Data on such immune responses after vaccinations in SOTs on immunosuppressants are conflicting [28], [29], [30]. Whether impaired vaccination-induced humoral responses are associated with the level of circulating B cells and/or with CD4+ or CD8+ T-cell responses in SOTs remains unclear.
Limitations
This study had several limitations. First, the investigation was limited by the single-center design and the study participants had a relatively long period since transplantation. Therefore, further studies, registries, and/or clinical trials including participants with diverse backgrounds are warranted. Second, our study population comprised SOTs who had received 2 doses of BNT162b2 mRNA vaccine and none who had received a third (booster) vaccination. Long-term follow-up is thus needed to assess the durability of antibody responses and side effects, including organ rejection and allograft complications. Third, we assessed both CD4+ and CD8+ T- and B-cell counts in our study but not viral-specific helper CD4+ T-cell responses or viral-specific CD8+ cellular assays [31], and their cytokines were not commercially available. Comprehensive analysis of immunogenicity in SOTs may thus reveal the mechanisms underlying diminished antibody titers in SOTs receiving immunosuppressants.
Conclusion
Antibody titers were diminished at the final visit in all 3 groups of SOTs: with or without MMF and withdrawn from MMF. A third vaccination of SOTs has been considered one alternative to achieve adequate antibody responses. Also, with careful consideration, withdrawal from MMF could provide a potential strategy for enhancing antibody titers in SOTs. In some SOTs who achieve only low antibody titers, clinicians and patients should continue nonpharmaceutical interventions, including mask wearing and social distancing.
Acknowledgments
We are greatly indebted to the staff of Matsunami General Hospital and Matsunami Health Promotion Clinic for their generous cooperation in establishing the study. We also gratefully acknowledge the special efforts of Matsunami Research Park. We thank Dr Moriwaki for his help in interpreting the significance of the study results.
Footnotes
This study was supported by the Sosaikouseikai Clinical Foundation.
Data Availability
The authors do not have permission to share data.
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