Solid organ transplant recipients (SOTRs) demonstrate variable antibody responses after two doses of SARS-CoV-2 mRNA vaccine.1 Mycophenolate mofetil (MMF) use is associated with poor immunogenicity in SOTRs, but limited data exist on heart and lung transplant recipients (HLTRs). An increased risk of breakthrough infection in SOTRs2 has prompted interest in other methods to augment immune protection in this population, such as targeted immunosuppression reduction. This study assesses the effect of cumulative daily dose of MMF on anti-spike antibody titers after 2 doses of a SARS-CoV-2 mRNA vaccine in HLTRs.
HLTRs without a previously confirmed COVID-19 infection (N=212) were recruited as previously described.1 Immunosuppression regimens were self-reported, and participants were stratified into four groups based on reported total daily dose of MMF: Zero MMF, Low dose (<1000 mg/day), Moderate dose (1000–2000 mg/day) and High dose (≥2000mg/day). Patients receiving mycophenolic acid were excluded. Anti-spike antibody testing was performed at one, three- and six months post-dose 2 (D2) using commercially available assays, as previously described.1,3 The study was approved by the Johns Hopkins Institutional Review Board.
Clinical characteristics were compared using Wilcoxon rank sum for continuous and Fisher’s exact test for categorical variables. Multivariable Poisson regression with robust standard error was used to estimate the risk of a negative antibody response associated with the MMF dose categories, adjusting for age, sex, vaccine type (mRNA-1273 vs BNT162b2), time since transplant, and steroid use. Analyses were performed using Stata 15.1/SE for Windows (College Station, Texas).
At vaccination, 94 (44.3%) HLTRs reported receiving no MMF, 33 (15.6%) reported low dose, 54 (25.7%) reported moderate dose, and 31 (14.8%) reported high dose regimens (Table 1). After adjustment, the risk of negative response in the low dose was comparable to that in the Zero MMF group (risk ratio= 0.651.152.05, p=0.63). However, the moderate and high dose groups had over two-fold higher risk of negative antibody response (risk ratio = 1.34 2.043.10 and 1.83 2.774.21, respectively; p<0.01).
Table 1.
Demographics of Heart and Lung transplant recipients based on Daily MMF dose category.
| Factor | Zero MMF | Low <1000mg/day | Moderate 1000–1999 mg | High ≥2000 mg | P |
|---|---|---|---|---|---|
| N | 94 | 33 | 54 | 31 | |
| Vaccine Series | 0.66 | ||||
| BNT162b2 | 49 (52.1%) | 18 (54.5%) | 30 (55.6%) | 20 (64.5%) | |
| mRNA-1273 | 45 (47.9%) | 15 (45.5%) | 24 (44.4%) | 11 (35.5%) | |
| Age, Median (IQR) | 58.5 (41.9, 68.9) | 66.2 (50.8, 70.2) | 65.4 (48.5, 70.3) | 59.1 (41.2, 66.4) | 0.26 |
| Sex | 0.88 | ||||
| Male | 45 (47.9%) | 16 (48.5%) | 25 (46.3%) | 17 (54.8%) | |
| Female | 48 (51.1%) | 17 (51.5%) | 29 (53.7%) | 14 (45.2%) | |
| Other | 1 (1.1%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
| Years Since Transplant At Dose 1, Median (IQR) | 6.6 (2.7, 11.2) | 5.5 (3.0, 10.7) | 5.2 (2.6, 9.8) | 4.3 (2.8, 11.0) | 0.64 |
| History of Rejection a | 5 (5.61%) | 0 (0%) | 1 (1.81%) | 1 (3.33%) | 0.51 |
| Organ Transplanted | 0.049 | ||||
| Lung | 36 (38.3%) | 23 (69.7%) | 22 (40.7%) | 13 (41.9%) | |
| Heart | 55 (58.5%) | 10 (30.3%) | 32 (59.3%) | 18 (58.1%) | |
| Heart & Lung | 3 (3.2%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
| Azathioprine | 15 (16.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | <0.001 |
| Calcineurin Inhibitor | 92 (97.9%) | 30 (90.9%) | 53 (98.1%) | 28 (90.3%) | 0.081 |
| Tacrolimus | 84 (89.4%) | 28 (84.8%) | 52 (96.3%) | 27 (87.1%) | 0.23 |
| Steroids | 58 (61.7%) | 24 (72.7%) | 25 (46.3%) | 17 (54.8%) | 0.094 |
| mTOR inhibitor | 42 (44.7%) | 4 (12.1%) | 3 (5.6%) | 4 (12.9%) | <0.001 |
| Triple Immunosuppression b | 0 (0.0%) | 21 (63.6%) | 25 (46.3%) | 16 (51.6%) | <0.001 |
History of rejection in the 6 months preceding vaccination.
Triple immunosuppression consisted of any combination of MMF, Calcineurin inhibitor, Steroid, Azathioprine or mTOR inhibitor.
In this study of the effect of MMF dosing on antibody response to mRNA vaccination against SARS-CoV-2 in HLTRs, an MMF dose of greater than 1000mg/day was associated with increased risk of negative antibody response after a 2-dose SARS-CoV-2 mRNA vaccine series. Though the association of MMF use with poor antibody responses to SARS-CoV-2 vaccination in HLTRs has been previously reported,4 this is the first study to delineate the effect of MMF dosing on the antibody response in this population. There was a possibility for recall bias, as MMF doses were self-reported. Data regarding changes to MMF dose leading up to vaccination was unavailable. Additionally, though antibodies to the S1/RBD domain are correlated with plasma neutralizing activity,5 neutralizing titers were not formally assessed.
In conclusion, higher MMF doses increase the risk of a negative antibody response to the two-dose mRNA vaccine series in HLTRs. These findings may help guide approaches to 3rd and booster doses, variant-specific next generation vaccines as well as the potential role for transient immunosuppression reduction strategies in ongoing trials where appropriate.
Acknowledgements:
The authors thank the participants of the Johns Hopkins transplant vaccine study, without whom this work would be impossible. They also thank the Johns Hopkins transplant vaccine study team, including Brian Boyarsky, MD PhD; Mayan Teles, BS, Carolyn Sidoti, BS, Michael T. Ou, BS; Ross S. Greenberg, BA; Jake A. Ruddy, BS; Muhammad Asad Munir, MBBS; Michelle R. Krach, MS; Iulia Barbur, BSE. They also thank Andrew H. Karaba, MD, PhD; and Ms. Yolanda Eby for project support and guidance.
FUNDING/GRANT/AWARD INFORMATION
This research was made possible with the generous support of the Ben-Dov family and the Trokhan Patterson family. This work was supported by the ASTS Jon Fryer Resident Scientist Award (Dr. Mitchell), grants T32DK007713 (Dr. Alejo), T32DK007732 (Dr. Chang), K01DK114388-03 (Dr. Levan), K01DK101677 (Dr. Massie), and K23DK115908 (Dr. Garonzik-Wang) from the National Institute of Diabetes and Digestive and Kidney Diseases; K23AI157893 and U01AI138897 (Dr. Werbel) and K24AI144954 (Dr. Segev) from the National Institute of Allergy and Infectious Disease. The analyses described here are the sole responsibility of the authors and do not necessarily reflect the views or policies of the Department of Health and Human Services or the National Institutes of Health, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.
DISCLOSURE
Dr. Segev has the following financial disclosures: consulting and speaking honoraria from Sanofi, Novartis, CLS Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt, and Thermo Fisher Scientific. Dr. Avery has study/grant support from Aicuris, Astellas, Chimerix, Merck, Oxford Immunotec, Qiagen, Regeneron, Takeda/Shire, and Vir/GSK, and is an associate editor for Transplantation. Dr. Levan is the Social Media Editor for Transplantation. The remaining authors of this manuscript have no financial disclosures or conflicts of interest to disclose as described by Transplantation.
ABBREVIATIONS:
- D2
Dose 2
- HLTRs
Heart and Lung Transplant Recipients
- mRNA
Messenger Ribonucleic Acid
- mTOR
mechanistic target of rapamycin inhibitor
- SOTRs
Solid Organ Transplant Recipients
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