Dose-Dependent Impairment of the Immune Response to the Moderna-1273 mRNA Vaccine by Mycophenolate Mofetil in Patients with Rheumatic and Autoimmune Liver Diseases
Abstract
:1. Introduction
2. Materials and Methods
2.1. Participants and Setting
2.2. Study Design
2.3. Anti-SARS-CoV-2 Antibodies
2.4. Serum Microneutralization Assay
2.5. Cytotoxic T Cell Response and Chemokine/Cytokine Levels
2.6. Statistical Analysis
3. Results
3.1. Study Subjects
3.2. Anti-SARS-CoV-2 Antibody Response in the Overall Cohort
3.3. Seroconversion Rate Based on Active Treatments
3.4. Anti-SARS-CoV-2 Antibody Titer Based on Ongoing Therapies
3.5. Anti-SARS-CoV-2 Antibody-Neutralizing Activity in a Subgroup of Patients and Controls
3.6. Cytotoxic T Cell Response Markers in a Subgroup of Patients and Controls
3.7. Chemokine and Cytokine Levels after SARS-CoV-2 Peptide-Stimulation In Vitro
3.8. Adverse Events and SARS-CoV-2 Breakthrough Infections
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Patients with Immune-Mediated and Chronic Inflammatory Diseases (n = 287) | Controls (Caretakers and Family Members; n = 67) | |
---|---|---|
Females | 175 (61%) † | 23 (34%) |
Caucasians | 277 (96.5%) | 66 (98.5%) |
Age (years) | 55 (19–78) ‡ | 48 (19–70) |
Hypertension | 39 (14%) * | 2 (3%) |
Diabetes | 12 (5%) | 0 |
Cardiovascular disease | 9 (3%) | 0 |
Ex-COVID | 45 (16%) | 15 (22%) |
Ongoing treatments | ||
Mycophenolate mofetil | 28 (10%) monotherapy 7% | |
Glucocorticoids | 43 (15%) monotherapy 1% | - |
Methotrexate | 60 (21%) monotherapy 6% | - |
Azathioprine | 27 (9%) monotherapy 6% | |
AntiTNF-alpha | 108 (38%) monotherapy 30% | - |
Anti-IL17 | 20 (7%) monotherapy 5% | - |
Anti-IL6R | 12 (4%) monotherapy 2% | - |
JAK inhibitors | 27 (9%) monotherapy 6% | - |
Other therapies | 21 (7%) | - |
No immunosuppressants | 18 (6%) | 67 (100%) |
Disease | ||
Rheumatoid arthritis | 72 (25%) | - |
Spondyloarthritis | 125 (44%) | - |
Systemic sclerosis | 13 (5%) 12 (92%) on mycophenolate | - |
Systemic lupus erythematosus | 12 (4%) 3 (25%) on mycophenolate | - |
Dermato/Polymyositis | 3 (1%) 3 (100%) on mycophenolate | |
Autoimmune hepatitis | 31 (11%) 7 (23%) on mycophenolate | - |
Primary biliary cholangitis | 13 (5%) | - |
Other rheumatic diseases | 22 (8%) 3 (14%) on mycophenolate | - |
Disease duration (months) | 60 (2–500) | - |
Active disease | 81 (28%) | - |
T0 | T1 | T2 | |
---|---|---|---|
Controls | |||
Overall titer | 4 (4–22.9) | 835 (384.5–1455) | 4960 (3465–11350) |
seroconverted | 14/67 (20.9%) | 64/65 (98.4%) | 45/45 (100%) |
ex-COVID titer | 116 (44.8–238) | 2081 (1060–2081) | 11850 (5563–19625) |
seroconverted | 14/15 (93.3%) | 15/15 (100%) | 8/8 (100%) |
COVID-naïve titer | 4 (4–4) | 632.5 (319.8–1195) | 4790 (3290–10325) p < 0.0001 vs. MFM |
seroconverted | - | 49/50 (98%) | 37/37 (100%) |
Patients | |||
Overall titer | 4 (4–4) | 284 (91.8–746) p < 0.0001 | 3505 (1398–6520) p = 0.0002 |
seroconverted | 38/287 (13.2%) | 239/281 (85.1%) p = 0−006 | 211/219 (96.3%) |
ex-COVID titer | 99.1 (58.7–271) | 2081 (634.5–2081) | 6520 (3518–19475) |
seroconverted | 38/45 (84.4%) | 45/45 (100%) | 36/36 (100%) |
COVID-naïve titer | 4 (4–4) | 222 (68.3–489) p < 0.0001 | 3160 (1328–6170) p = 0.0002 |
seroconverted | - | 194/236 (82.2%) p = 0.009 | 175/183 (95.6%) |
Active immunosuppressive therapy | |||
Overall titer | 4 (4–4) | 293.5 (94.4–779.5) p < 0.0001 | 3280 (1390–6505) p = 0.002 |
seroconverted | 35/268 (13%) | 223/262 (85.1%) p = 0.006 | 197/206 (95.6%) |
ex-COVID titer | 98.2 (51.4–282.3) | 2081 (635.3–2081) | 6700 (3423–21400) |
seroconverted | 35/42 (83.3%) | 42/42 (100%) | 34/34 (100%) |
COVID-naïve titer | 4 (4–4) | 225.5 (67–518) p < 0.0001 | 3035 (1305–6128) p = 0.006 |
seroconverted | - | 181/221 (81.9%) p = 0.008 | 165/172 (95.9%) |
No immunosuppressive therapy | |||
Overall titer | 4 (4–6.4) | 215 (80.6–541) p = 0.0002 | 4540 (2875–5865) |
seroconverted | 3/18 (16.6%) | 15/18 (83.3%) p = 0.04 | 13/13 (100%) |
ex-COVID titer | 143 (88.5–221) | 2081 (622–2081) | 4565 (4210–4920) |
seroconverted | 3/3 (100%) | 3/3 (100%) | 2/2 (100%) |
COVID-naïve titer | 4 (4–4) | 169 (71–409) p = 0.004 | 4540 (2200–6630)p = 0.003 vs. MFM |
seroconverted | - | 12/15 (80%) | 11/11 (100%) |
Active disease | |||
Overall titer | 4 (4–4) | 222.5 (80.5–498.8) p < 0.0001 | 3220 (1760–7085) p = 0.002 |
seroconverted | 9/81 (11.1) | 64/76 (84.2) p = 0.009 | 55/58 (94.8) |
ex-COVID titer | 99.1 (65.5–225) | 2081 (502–2081) | 5070 (3220–7350) |
seroconverted | 9/9 (100) | 9/9 (100) | 7/7 (100) |
COVID-naïve titer | 4 (4–4) | 186 (65–332) p < 0.0001 | 3040 (1655–7118) p = 0.002 |
seroconverted | - | 55/67 (82.1) p = 0.01 | 48/51 (94.1) |
Inactive disease | |||
Overall titer | 4 (4–5.16) | 343 (95.2–827) p < 0.0001 | 3600 (1370–6435) p = 0.0004 |
seroconverted | 29/206 (14) | 175/205 (85.3) p = 0.008 | 156/161 (96.8) |
ex-COVID titer | 98.7 (46–272.5) | 2081 (638–2081) | 6820 (3545–21900) |
seroconverted | 32/36 (88.8) | 36/36 (100) | 36/36 (100) |
COVID-naïve titer | 4 (4–4) | 239 (69.4–608.5) p < 0.0001 | 3210 (1303–5660) p = 0.002 |
seroconverted | - | 139/169 (82.2) p = 0.01 | 127/132 (96.2) |
T1 | T2 | |
---|---|---|
Rheumatoid arthritis titer | 155 (50–484) p < 0.0001 | 2310 (1230–6375) p = 0.007 |
seroconverted | 49/61 (80.3%) p = 0.01 | 49/49 (100%) |
Spondyloarthritis titer | 317 (133–622) p = 0.02 | 4040 (2230–6385) |
seroconverted | 103/108 (95.3%) | 79/79 (100%) |
Systemic sclerosis titer | 4 (4–4) p < 0.0001 | 25.6 (8.1–380) p < 0.0001 |
seroconverted | 2/11 (18.1%) p < 0.0001 | 3/11 (27.2%) p < 0.0001 |
Systemic lupus erythematosus titer | 77.5 (5.6–464) p = 0.005 | 1320 (498–3100) p = 0.007 |
seroconverted | 7/11 (58.3%) p = 0.002 | 10/10 (100%) |
Dermatomyositis titer | 4 (4–4.87) p = 0.001 | 134 (121–178) p = 0.004 |
seroconverted | 0/3 (0%) p < 0.0001 | 3/3 (100%) |
Autoimmune hepatitis titer | 323 (75–556) p = 0.04 | 3280 (1300–5340) |
seroconverted | 23/26 (88.4%) | 19/19 (100%) |
Mycophenolate mofetil | ||
overall titer | 4 (4–43.8) p < 0.0001 | 156 (27–353) p < 0.0001 |
seroconverted | 6/23 (26%) p < 0.0001 | 14/22 (63.6%) p = 0.0004 |
monotherapy titer | 4 (4–7.12) p < 0.0001 | 121 (13.8–517) p < 0.0001 |
seroconverted | 3/17 (17.6%) p < 0.0001 | 9/16 (56.2%) p = 0.0001 |
with glucocorticoids titer | 24.3 (4–81.8) p = 0.001 | 399 (141–1948) |
seroconverted | 3/6 (50%) | 5/6 (83.3%) |
Glucocorticoids | ||
monotherapy titer | 229 (222–235) | 5270 (-) |
seroconverted | 3/3 (100%) | 1/1 (100%) |
with other therapies titer | 85 (7.6–222) p < 0.0001 | 1620 (797–6650) p = 0.005 |
seroconverted | 22/35 (62.8%) p < 0.0001 | 26/27 (96.3%) |
Methotrexate | ||
monotherapy titer | 285 (104–663) p = 0.03 vs. MFM | 3160 (2470–6690)p = 0.003 vs. MFM |
seroconverted | 13/14 (92.8%) | 11/11 (100%) |
with glucocorticoids titer | 87 (40–638) | 9220 (8500–9640) |
seroconverted | 3/4 (75%) | 4/4 (100%) |
Azathioprine | ||
monotherapy titer | 492 (240–825) p < 0.0001 vs. MFM | 3280 (1735–5960) p = 0.02 vs. MFM |
seroconverted | 16/16 (100%) | 13/13 (100%) |
with glucocorticoids titer | 37.8 (20.9–461) p = 0.003, p = 0.03 vs. AZA mono | 1620 (804–6605) |
seroconverted | 4/7 (57.1%) | 5/5 (100%) |
Anti-TNFalpha | ||
monotherapy titer | 382 (177–790) p < 0.0001 vs. MFM | 3405 (1715–5340) p = 0.0002 vs. MFM |
seroconverted | 66/69 (95.6%) | 54/54 (100%) |
with glucocorticoid titer | 67.8 (4–326) | 1370 (1320–6659) |
seroconverted | 2/3 (66.6%) | 3/3 (100%) |
with methotrexate titer | 231 (89.3–899) | 4130 (1830–6340) |
seroconverted | 11/13 (84.6%) | 11/11 (100%) |
Anti-IL17 | ||
monotherapy titer | 228 (96.9–332) p = 0.02 | 3105 (2485–4850) |
seroconverted | 15/15 (100%) | 10/10 (100%) |
Anti-IL6R | ||
monotherapy titer | 262 (109–1043) | 3700 (2020–5290) |
seroconverted | 6/6 (100%) | 5/5 (100%) |
JAK inhibitors | ||
monotherapy titer | 140 (51–493) p = 0.04 | 3750 (1039–6775) |
seroconverted | 13/15 (86.6%) | 10/10 (100%) |
with methotrexate titer | 33.9 (8.2–262.2) p = 0.02 | 512 (-) |
seroconverted | 2/4 (50%) p = 0.004 | 1/1 (100%) |
Patients on MFM >1 g/daily (n = 20) | |
---|---|
Females Caucasians | 18 (90%) 18 (90%) |
Age (years) | 59.5 (48.5–64.5) |
Hypertension | 1 (5%) |
Diabetes | 0 |
Cardiovascular disease | 0 |
Lymphocyte count at baseline (*103/mm3)§ Disease | 1700 (960–2100) |
Systemic sclerosis | 11 (55%) |
Systemic lupus erythematosus | 3 (15%) |
Dermato/Polymyositis | 2 (10%) |
Autoimmune hepatitis | 2 (10%) |
Primary biliary cholangitis | 1 (5%) |
Other rheumatic diseases | 1 (5%) |
Disease duration (months) | 62 (27–132) |
Active disease Seroconversion at T2 in COVID-naïve patients | 3 (15%) 8 (40%) |
Antibody titer at T2 (BAU/mL) in COVID-naïve patients | 34.2 (9.8–443.5) |
Patients (n = 219) | |
---|---|
Adverse events Mild Moderate Severe | 152/219 (69.4%) 105/219 (48%) 46/219 (21%) 1/219 (0.4%) |
Adverse events in ex-COVID | 22/30 (73.3%) |
Adverse events in COVID-naïve | 127/184 (69%) |
Anti-SARS-CoV-2 titer | |
COVID-naïve with adverse events COVID-naïve without adverse events | 3265 (1375–6423) 2570 (1170–4973) |
Controls (n = 45) | |
Adverse events | 35/45 (77.7%) |
Mild Moderate Severe | 26/45 (57.7%) 9/45 (20%) 0/45 (0%) |
Adverse events in ex-COVID | 7/8 (87.5%) |
Adverse events in COVID-naïve | 28/38 (73.6) |
Anti-SARS-CoV-2titer | |
COVID-naïve with adverse events COVID-naïve without adverse events | 6525 (3950–11,375) * 3300 (2770–3855) |
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De Santis, M.; Motta, F.; Isailovic, N.; Clementi, M.; Criscuolo, E.; Clementi, N.; Tonutti, A.; Rodolfi, S.; Barone, E.; Colapietro, F.; et al. Dose-Dependent Impairment of the Immune Response to the Moderna-1273 mRNA Vaccine by Mycophenolate Mofetil in Patients with Rheumatic and Autoimmune Liver Diseases. Vaccines 2022, 10, 801. https://doi.org/10.3390/vaccines10050801
De Santis M, Motta F, Isailovic N, Clementi M, Criscuolo E, Clementi N, Tonutti A, Rodolfi S, Barone E, Colapietro F, et al. Dose-Dependent Impairment of the Immune Response to the Moderna-1273 mRNA Vaccine by Mycophenolate Mofetil in Patients with Rheumatic and Autoimmune Liver Diseases. Vaccines. 2022; 10(5):801. https://doi.org/10.3390/vaccines10050801
Chicago/Turabian StyleDe Santis, Maria, Francesca Motta, Natasa Isailovic, Massimo Clementi, Elena Criscuolo, Nicola Clementi, Antonio Tonutti, Stefano Rodolfi, Elisa Barone, Francesca Colapietro, and et al. 2022. "Dose-Dependent Impairment of the Immune Response to the Moderna-1273 mRNA Vaccine by Mycophenolate Mofetil in Patients with Rheumatic and Autoimmune Liver Diseases" Vaccines 10, no. 5: 801. https://doi.org/10.3390/vaccines10050801