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1.
Front Immunol ; 13: 1007089, 2022.
Article in English | MEDLINE | ID: covidwho-2055023

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to NF-κB activation and induction of pro-inflammatory cytokines, though the underlying mechanism for this activation is not fully understood. Our results reveal that the SARS-CoV-2 Nsp14 protein contributes to the viral activation of NF-κB signaling. Nsp14 caused the nuclear translocation of NF-κB p65. Nsp14 induced the upregulation of IL-6 and IL-8, which also occurred in SARS-CoV-2 infected cells. IL-8 upregulation was further confirmed in lung tissue samples from COVID-19 patients. A previous proteomic screen identified the putative interaction of Nsp14 with host Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2), which is known to regulate NF-κB signaling. We confirmed the Nsp14-IMPDH2 protein interaction and identified that IMPDH2 knockdown or chemical inhibition using ribavirin (RIB) and mycophenolic acid (MPA) abolishes Nsp14- mediated NF-κB activation and cytokine induction. Furthermore, IMPDH2 inhibitors (RIB, MPA) or NF-κB inhibitors (bortezomib, BAY 11-7082) restricted SARS-CoV-2 infection, indicating that IMPDH2-mediated activation of NF-κB signaling is beneficial to viral replication. Overall, our results identify a novel role of SARS-CoV-2 Nsp14 in inducing NF-κB activation through IMPDH2 to promote viral infection.


Subject(s)
COVID-19 , Exoribonucleases , IMP Dehydrogenase , NF-kappa B , Viral Nonstructural Proteins , Bortezomib , Cytokines/metabolism , Exoribonucleases/metabolism , Humans , IMP Dehydrogenase/metabolism , Inosine , Interleukin-6 , Interleukin-8 , Mycophenolic Acid , NF-kappa B/metabolism , Oxidoreductases , Proteomics , Ribavirin , SARS-CoV-2 , Viral Nonstructural Proteins/metabolism
2.
Transplantation ; 106(10): e441-e451, 2022 10 01.
Article in English | MEDLINE | ID: covidwho-2051786

ABSTRACT

BACKGROUND: The chronic use of immunosuppressive drugs is a key risk factor of death because of coronavirus disease 2019 (COVID-19) in kidney transplant recipients (KTRs), although no evident association between the class of immunosuppressive and outcomes has been observed. Thus, we aimed to compare COVID-19-associated outcomes among KTRs receiving 3 different immunosuppressive maintenance regimes. METHODS: This study included data from 1833 KTRs with COVID-19 diagnosed between March 20 and April 21 extracted from the national registry before immunization. All patients were taking calcineurin inhibitor associated with mycophenolate acid (MPA, n = 1258), azathioprine (AZA, n = 389), or mammalian targets of rapamycin inhibitors (mTORi, n = 186). Outcomes within 30 and 90 d were assessed. RESULTS: Compared with patients receiving MPA, the 30-d (79.9% versus 87.9% versus 89.2%; P < 0.0001) and 90-d (75% versus 83.5% versus 88.2%; P < 0.0001) unadjusted patient survivals were higher in those receiving AZA or mTORi, respectively. Using adjusted multivariable Cox regression, compared with patients receiving AZA, the use of MPA was associated with a higher risk of death within 30 d (adjusted hazard ratio [aHR], 1.70; 95% confidence interval [CI], 1.21-2.40; P = 0.003), which was not observed in patients using mTORi (aHR, 0.78; 95% CI, 0.45-1.35; P = 0.365). At 90 d, although higher risk of death was confirmed in patients receiving MPA (aHR, 1.46; 95% CI, 1.09-1.98; P = 0.013), a reduced risk was observed in patients receiving mTORi (aHR, 0.59; 95% CI, 0.35-0.97; P = 0.04) compared with AZA. CONCLUSIONS: This national cohort data suggest that, in KTRs receiving calcineurin inhibitor and diagnosed with COVID-19, the use of MPA was associated with higher risk of death, whereas mTORi use was associated with lower risk of death.


Subject(s)
COVID-19 , Kidney Transplantation , Azathioprine , Calcineurin Inhibitors/adverse effects , Enzyme Inhibitors , Humans , Immunosuppressive Agents/adverse effects , Kidney Transplantation/adverse effects , Mycophenolic Acid/adverse effects , Sirolimus/adverse effects , TOR Serine-Threonine Kinases
3.
Int J Mol Sci ; 23(19)2022 Sep 24.
Article in English | MEDLINE | ID: covidwho-2043774

ABSTRACT

Coronaviruses as possible cross-species viruses have caused several epidemics. The ongoing emergency of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has posed severe threats to the global economy and public health, which has generated great concerns about zoonotic viruses. Swine acute diarrhea syndrome coronavirus (SADS-CoV), an alpha-coronavirus, was responsible for mass piglet deaths, resulting in unprecedented economic losses, and no approved drugs or vaccines are currently available for SADS-CoV infection. Given its potential ability to cause cross-species infection, it is essential to develop specific antiviral drugs and vaccines against SADS-CoV. Drug screening was performed on a total of 3523 compound-containing drug libraries as a strategy of existing medications repurposing. We identified five compounds (gemcitabine, mycophenolate mofetil, mycophenolic acid, methylene blue and cepharanthine) exhibiting inhibitory effects against SADS-CoV in a dose-dependent manner. Cepharanthine and methylene blue were confirmed to block viral entry, and gemcitabine, mycophenolate mofetil, mycophenolic acid and methylene blue could inhibit viral replication after SADS-CoV entry. This is the first report on SADS-CoV drug screening, and we found five compounds from drug libraries to be potential anti-SADS-CoV drugs, supporting the development of antiviral drugs for a possible outbreak of SADS-CoV in the future.


Subject(s)
Antiviral Agents , COVID-19 , Alphacoronavirus , Animals , Antiviral Agents/pharmacology , Methylene Blue , Mycophenolic Acid , SARS-CoV-2 , Swine
4.
RMD Open ; 8(2)2022 09.
Article in English | MEDLINE | ID: covidwho-2038338

ABSTRACT

BACKGROUND: Patients with inflammatory rheumatic and musculoskeletal diseases (iRMD) receiving mycophenolic acid (MPA) may have a less favourable outcome from COVID-19 infection. Our aim was to investigate whether MPA treatment is associated with severe infection and/or death. METHODS: IRMD patients with and without MPA treatment with highly suspected/confirmed COVID-19 were included in this observational multicentre study. The primary outcome was death rate from COVID-19 with secondary objectives to determine the severity of infection and length of hospital stay. Outcome comparisons were made using regression models with and without adjustment on prespecified confounding factors. ORs, sub-HR (sHR) and 95% CIs were calculated using patients not treated with MPA as a reference group. RESULTS: Of the 1977 patients, 1928 were not treated with MPA (393 were MPA eligible), and 49 patients were treated with MPA. MPA-treated patients had more severe disease, longer hospital stays and higher death rate from COVID-19 than non-MPA patients (OR 8.02 (95% CI 3.35 to 19.20), p<0.001; sHR 0.57 (95% CI 0.33 to 0.98), p=0.040; OR 11.58 (95% CI 4.10 to 32.69), p<0.001). In adjusted analyses, however, no outcome was independently associated with MPA treatment. Death rate, severity and length of hospital stay of MPA-treated patients were not significantly different from those of not treated but MPA-eligible patients. CONCLUSION: MPA therapy is not associated with a more severe COVID-19 infection. However, due to increased vulnerability of developing a severe form of COVID-19, careful consideration should be taken with iRMD patients likely to be treated with MPA. TRIAL REGISTRATION NUMBER: NCT04353609.


Subject(s)
COVID-19 , Mycophenolic Acid , COVID-19/epidemiology , Cohort Studies , Humans , Mycophenolic Acid/therapeutic use
5.
Clin Rheumatol ; 41(12): 3879-3885, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2007159

ABSTRACT

BACKGROUND: The COVID-19 outbreak has led to the rapid development and administration of the COVID-19 vaccines worldwide. Data about the immunogenicity and adverse effects of the vaccine on patients with systemic autoimmune rheumatic diseases (SARDs) is emerging. AIM: To evaluate Pfizer/BioNTech (BNT162b2) mRNA-based vaccine second-dose immunogenicity and safety, and the relation between them, in patients with SARDs. METHODS: A total of one hundred forty tow adults who received two doses of the BNT162b2 vaccine were included in the study. The SARDs group included Ninety-nine patients and the control group (forty-three participants) comprised a mixture of healthy participants and patients who were seen at the rheumatology clinic for non-SARDs. Anti-SARS-CoV-2 IgG antibodies against the Spike protein were evaluated using a SARS-CoV-2 IgG immunoassay. A level of > 150 AU/mL was considered positive. An adverse effects questionnaire was given to the participants upon their first visit to the clinic after their BNT162b2 vaccination. RESULTS: Of the 142 participants, 116 were seropositive (81.7%) and 26 (18.3%) were seronegative. Of the seronegative participants, 96.2% were SARDs patients. The proportion of seropositivity in the SARDs patients treated with any immunosuppressant was significantly lower (69.9%) compared to the control group and SARDs patients not receiving immunosuppressants (96.8%). A significant negative correlation between seronegativity and treatment with rituximab, mycophenolate mofetil (MMF), and prednisone was found in the SARDs group (p = 0.004, 0.044, 0.007 respectively). No fever was observed following the BNT162b2 vaccine in seronegative patients, and the frequency of musculoskeletal adverse effects upon the second dose of the BNT162b2 vaccine was significantly higher in seropositive compared to seronegative patients and in the control group compared to the SARDs patients (p = 0.045, p = 0.02 respectively). CONCLUSION: A decline in the immunogenicity to the second dose of BNT162b2 mRNA is seen in patients with SARDs, especially in patients treated with rituximab, MMF, and prednisone. Adverse effects of the vaccine including fever and musculoskeletal symptoms might be a signal for the acquisition of immunity in those patients. KEY POINTS: • BNT162b2 mRNA vaccine is less immunogenic in SARDs patients compared to the control group. • Rituximab, prednisone, and mycophenolate mofetil significantly reduced immunogenicity to the vaccine. • There is a correlation between immunogenicity and adverse effects of the vaccine.


Subject(s)
COVID-19 , Rheumatic Diseases , Adult , Humans , BNT162 Vaccine , Rituximab/therapeutic use , Prednisone/therapeutic use , COVID-19 Vaccines/adverse effects , Mycophenolic Acid/therapeutic use , COVID-19/prevention & control , SARS-CoV-2 , Rheumatic Diseases/drug therapy , Rheumatic Diseases/epidemiology , Antibodies, Viral , Immunoglobulin G/therapeutic use
6.
Transplantation ; 106(10): 2063-2067, 2022 10 01.
Article in English | MEDLINE | ID: covidwho-1961295

ABSTRACT

BACKGROUND: Solid organ transplant recipients are at high risk for fatal forms of coronavirus disease 2019 (COVID-19). We conducted a cohort study among kidney transplant (KT) recipients from the French Solid Organ Transplant COVID-19 Registry to investigate the association between maintenance immunosuppressive drugs and 60-d mortality. METHODS: Data from all KT recipients with COVID-19 included in the French Solid Organ Transplant COVID-19 Registry between February 28, 2020, and December 30, 2020, were retrieved. We evaluated associations between immunosuppressive drugs and death within 60 d using logistic regression, with all baseline characteristics considered to influence outcome or immunosuppressive regimen. The Benjamini-Hochberg correction was used for controlling false positive rate; 40 multiple imputations were performed. Adjusted P value <0.05 was considered statistically significant. RESULTS: There were 1451 KT recipients included. Median age was 58 y, and 66.4% were men. Most frequent comorbidities were hypertension (81.9%), diabetes (34.5%), and cardiovascular disease (29.5%). Median time since transplant was 71 mo. Maintenance immunosuppression regimens included calcineurin inhibitors (1295, 89.2%), antimetabolites (1205, 83%), corticosteroids (1094, 75.4%), mammalian target of rapamycin inhibitors (144, 9.9%), and belatacept (58, 4.0%). Among 1451 transplant recipients, 201 (13.9%) died within 60 d. Older age and higher baseline serum creatinine were associated with mortality (odds ratios, 1.09 [1.07-1.11] and 1.01 [1.005-1.009], P < 0.001). Corticosteroid-free regimens were associated with a significantly lower risk of death (odds ratio, 0.48 [0.31-0.76]; P = 0.011). CONCLUSIONS: Corticosteroid-free regimens were associated with a lower risk of death in KT recipients with COVID-19. Long-term exposure to corticosteroids impairs immune functions and may predispose solid organ transplant recipients to severe forms of COVID-19.


Subject(s)
COVID-19 , Kidney Transplantation , Abatacept , Antimetabolites , COVID-19/mortality , Calcineurin Inhibitors , Cohort Studies , Creatinine , Female , Humans , Immunosuppressive Agents/adverse effects , Male , Middle Aged , Mycophenolic Acid , TOR Serine-Threonine Kinases , Transplant Recipients
7.
Am J Transplant ; 22(7): 1884-1892, 2022 07.
Article in English | MEDLINE | ID: covidwho-1956680

ABSTRACT

The development of donor-specific antibodies (DSA) after lung transplantation is common and results in adverse outcomes. In kidney transplantation, Belatacept has been associated with a lower incidence of DSA, but experience with Belatacept in lung transplantation is limited. We conducted a two-center pilot randomized controlled trial of de novo immunosuppression with Belatacept after lung transplantation to assess the feasibility of conducting a pivotal trial. Twenty-seven participants were randomized to Control (Tacrolimus, Mycophenolate Mofetil, and prednisone, n = 14) or Belatacept-based immunosuppression (Tacrolimus, Belatacept, and prednisone until day 89 followed by Belatacept, Mycophenolate Mofetil, and prednisone, n = 13). All participants were treated with rabbit anti-thymocyte globulin for induction immunosuppression. We permanently stopped randomization and treatment with Belatacept after three participants in the Belatacept arm died compared to none in the Control arm. Subsequently, two additional participants in the Belatacept arm died for a total of five deaths compared to none in the Control arm (log rank p = .016). We did not detect a significant difference in DSA development, acute cellular rejection, or infection between the two groups. We conclude that the investigational regimen used in this study is associated with increased mortality after lung transplantation.


Subject(s)
Lung Transplantation , Tacrolimus , Abatacept/therapeutic use , Antilymphocyte Serum/therapeutic use , Graft Rejection/drug therapy , Graft Rejection/etiology , Graft Rejection/prevention & control , Graft Survival , Humans , Immunosuppression Therapy , Immunosuppressive Agents/therapeutic use , Lung Transplantation/adverse effects , Mycophenolic Acid/therapeutic use , Pilot Projects , Prednisone
8.
Transplantation ; 106(10): e452-e460, 2022 10 01.
Article in English | MEDLINE | ID: covidwho-1948635

ABSTRACT

BACKGROUND: Solid organ transplant recipients (SOTRs) are less likely to mount an antibody response to SARS-CoV-2 mRNA vaccines. Understanding risk factors for impaired vaccine response can guide strategies for antibody testing and additional vaccine dose recommendations. METHODS: Using a nationwide observational cohort of 1031 SOTRs, we created a machine learning model to explore, identify, rank, and quantify the association of 19 clinical factors with antibody responses to 2 doses of SARS-CoV-2 mRNA vaccines. External validation of the model was performed using a cohort of 512 SOTRs at Houston Methodist Hospital. RESULTS: Mycophenolate mofetil use, a shorter time since transplant, and older age were the strongest predictors of a negative antibody response, collectively contributing to 76% of the model's prediction performance. Other clinical factors, including transplanted organ, vaccine type (mRNA-1273 versus BNT162b2), sex, race, and other immunosuppressants, showed comparatively weaker associations with an antibody response. This model showed moderate prediction performance, with an area under the receiver operating characteristic curve of 0.79 in our cohort and 0.67 in the external validation cohort. An online calculator based on our prediction model is available at http://transplantmodels.com/covidvaccine/ . CONCLUSIONS: Our machine learning model helps understand which transplant patients need closer follow-up and additional doses of vaccine to achieve protective immunity. The online calculator based on this model can be incorporated into transplant providers' practice to facilitate patient-centric, precision risk stratification and inform vaccination strategies among SOTRs.


Subject(s)
COVID-19 Vaccines , COVID-19 , Transplant Recipients , Antibodies, Viral , Antibody Formation , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , Immunosuppressive Agents/adverse effects , Machine Learning , Mycophenolic Acid , SARS-CoV-2 , Vaccines , Vaccines, Synthetic , mRNA Vaccines
9.
BMC Nephrol ; 23(1): 199, 2022 05 31.
Article in English | MEDLINE | ID: covidwho-1933094

ABSTRACT

BACKGROUND: Dialysis patients and immunosuppressed renal patients are at increased risk of COVID-19 and were excluded from vaccine trials. We conducted a prospective multicentre study to assess SARS-CoV-2 vaccine antibody responses in dialysis patients and renal transplant recipients, and patients receiving immunosuppression for autoimmune disease. METHODS: Patients were recruited from three UK centres (ethics:20/EM/0180) and compared to healthy controls (ethics:17/EE/0025). SARS-CoV-2 IgG antibodies to spike protein were measured using a multiplex Luminex assay, after first and second doses of Pfizer BioNTech BNT162b2(Pfizer) or Oxford-AstraZeneca ChAdOx1nCoV-19(AZ) vaccine. RESULTS: Six hundred ninety-two patients were included (260 dialysis, 209 transplant, 223 autoimmune disease (prior rituximab 128(57%)) and 144 healthy controls. 299(43%) patients received Pfizer vaccine and 379(55%) received AZ. Following two vaccine doses, positive responses occurred in 96% dialysis, 52% transplant, 70% autoimmune patients and 100% of healthy controls. In dialysis patients, higher antibody responses were observed with the Pfizer vaccination. Predictors of poor antibody response were triple immunosuppression (adjusted odds ratio [aOR]0.016;95%CI0.002-0.13;p < 0.001) and mycophenolate mofetil (MMF) (aOR0.2;95%CI 0.1-0.42;p < 0.001) in transplant patients; rituximab within 12 months in autoimmune patients (aOR0.29;95%CI 0.008-0.096;p < 0.001) and patients receiving immunosuppression with eGFR 15-29 ml/min (aOR0.031;95%CI 0.11-0.84;p = 0.021). Lower antibody responses were associated with a higher chance of a breakthrough infection. CONCLUSIONS: Amongst dialysis, kidney transplant and autoimmune populations SARS-CoV-2 vaccine antibody responses are reduced compared to healthy controls. A reduced response to vaccination was associated with rituximab, MMF, triple immunosuppression CKD stage 4. Vaccine responses increased after the second dose, suggesting low-responder groups should be prioritised for repeated vaccination. Greater antibody responses were observed with the mRNA Pfizer vaccine compared to adenovirus AZ vaccine in dialysis patients suggesting that Pfizer SARS-CoV-2 vaccine should be the preferred vaccine choice in this sub-group.


Subject(s)
Autoimmune Diseases , COVID-19 , Viral Vaccines , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Mycophenolic Acid , Renal Dialysis , Rituximab , SARS-CoV-2
10.
Front Immunol ; 13: 888385, 2022.
Article in English | MEDLINE | ID: covidwho-1924104

ABSTRACT

Objective: This is the first systematic review and meta-analysis to determine the factors that contribute to poor antibody response in organ transplant recipients after receiving the 2-dose severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Method: Data was obtained from Embase, PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBM). Studies reporting factors associated with antibody responses to the 2-dose SARS-CoV-2 vaccine in solid organ transplant recipients were included in our study based on the inclusion and exclusion criteria. Two researchers completed the literature search, screening, and data extraction. Randomized models were used to obtain results. Egger's test was performed to determine publication bias. Sensitivity analysis was performed to determine the stability of the result. The heterogeneity was determined using the Galbraith plot and subgroup analysis. Results: A total of 29 studies were included in the present study. The factors included living donor, BNT162b2, tacrolimus, cyclosporine, antimetabolite, mycophenolic acid (MPA) or mycophenolate mofetil (MMF), azathioprine, corticosteroids, high-dose corticosteroids, belatacept, mammalian target of rapamycin (mTOR) inhibitor, tritherapy, age, estimated glomerular filtration rate (eGFR), hemoglobin, and tacrolimus level were significantly different. Multivariate analysis showed significant differences in age, diabetes mellitus, MPA or MMF, high-dose corticosteroids, tritherapy, and eGFR. Conclusion: The possible independent risk factors for negative antibody response in patients with organ transplants who received the 2-dose SARS-CoV-2 vaccine include age, diabetes mellitus, low eGFR, MPA or MMF, high-dose corticosteroids, and triple immunosuppression therapy. mTOR inhibitor can be a protective factor against weak antibody response. Systematic Review Registration: PROSPERO, identifier CRD42021257965.


Subject(s)
COVID-19 , Diabetes Mellitus , Kidney Transplantation , Adult , Antibody Formation , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines , Diabetes Mellitus/drug therapy , Graft Rejection/prevention & control , Humans , Kidney Transplantation/methods , Mycophenolic Acid , Risk Factors , SARS-CoV-2 , TOR Serine-Threonine Kinases , Tacrolimus
11.
Transplantation ; 106(10): 2068-2075, 2022 10 01.
Article in English | MEDLINE | ID: covidwho-1909080

ABSTRACT

BACKGROUND: The rapid development and universal access to vaccines represent a milestone in combating the coronavirus disease 2019 (COVID-19) pandemic. However, there are major concerns about vaccine response in immunocompromised populations in particular transplant recipients. In the present study, we aim to comprehensively assess the humoral response to COVID-19 vaccination in both orthotopic organ transplant and allogeneic hematopoietic stem cell transplant recipients. METHODS: We performed a systematic review and meta-analysis of 96 studies that met inclusion criteria. RESULTS: The pooled rates of seroconversion were 49% (95% confidence interval [CI], 43%-55%) in transplant recipients and 99% (95% CI, 99%-99%) in healthy controls after the second dose of vaccine. The pooled rate was 56% (95% CI, 49%-63%) in transplant recipients after the third dose. Immunosuppressive medication is the most prominent risk factor associated with seroconversion failure, but different immunosuppressive regimens are associated with differential outcomes in this respect. Calcineurin inhibitors, steroids, or mycophenolate mofetil/mycophenolic acid are associated with an increased risk of seroconversion failure, whereas azathioprine or mammalian target of rapamycin inhibitors do not. Advanced age, short interval from receiving the vaccine to the time of transplantation, or comorbidities confers a higher risk for seroconversion failure. CONCLUSIONS: Transplant recipients compared with the general population have much lower rates of seroconversion upon receiving COVID-19 vaccines. Immunosuppressants are the most prominent factors associated with seroconversion, although different types may have differential effects.


Subject(s)
COVID-19 Vaccines , COVID-19 , Transplant Recipients , Antibodies, Viral , Azathioprine , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Calcineurin Inhibitors/therapeutic use , Humans , Immunosuppressive Agents/adverse effects , Mycophenolic Acid/adverse effects , TOR Serine-Threonine Kinases
12.
Clin Rheumatol ; 41(11): 3537-3542, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-1906097

ABSTRACT

There is paucity of data on extended dosing interval between two doses of AZD1222 (AstraZeneca) in patients with Autoimmune Rheumatic Diseases (AIRD). We aimed to study the humoral response and rate of breakthrough infections between the two groups who had received the second dose of vaccine at 4 weeks (Group 1) and 10-14 weeks (Group 2). From established cohort [COVID-19 vaccination cohort from CARE(CVCC)] of vaccinated patients with AIRD, those who had received AZD1222 were included and divided into two groups. Anti-Receptor Binding Domain (RBD) antibodies (IU/ml) were measured 1 month after the second dose. Its predictors and rate of breakthrough infections were studied. Four hundred ninety-five patients with AIRD were included in this study. Group 2 had higher anti-RBD antibody titres [1310.6 (±977.8) and [736 (±864.7), p = 0.0001. On univariate analysis, presence of Diabetes Mellitus; use of Methotrexate, Sulfasalazine, and Mycophenolate Mofetil; and vaccine interval were significantly associated with anti-RBD antibodies. Diabetes Mellitus and vaccine interval were independent predictors on multivariate analysis. Breakthrough infections were higher in Group 1 numerically on survival analysis but the difference was not significant (7.5% and 4.5%; log rank test: p = 0.25). In conclusion, increasing the gap between doses of the AZD1222 vaccine from 4 week to 10-14 weeks was found to be more beneficial in terms of antibody response in patients with AIRD. There was a trend towards higher breakthrough infections in the short interval group, supporting the antibody data. Key Points • There is paucity of data on effectiveness of increased dosing interval from 4-6 to 10-14 weeks for AZD1222 in patients with AIRDs • We observed a better humoral response with increased dosing interval with the interval and Diabetes Mellitus being independent predictors of the anti-RBD antibody levels • Breakthrough infections were numerically higher in the short interval group but the difference wasn't significant.


Subject(s)
Autoimmune Diseases , COVID-19 , Rheumatic Diseases , Vaccines , COVID-19 Vaccines , ChAdOx1 nCoV-19 , Humans , Methotrexate , Mycophenolic Acid , Rheumatic Diseases/drug therapy , Sulfasalazine
13.
Transplant Proc ; 54(6): 1483-1488, 2022.
Article in English | MEDLINE | ID: covidwho-1867841

ABSTRACT

BACKGROUND: The immune response to COVID-19 vaccination in kidney transplant (KTx) recipients is significantly lower than that in healthy controls. We evaluated immune responses after the COVID-19 vaccine and their possible relationship with other cofactors in KTx recipients. METHODS: This retrospective single-center cohort study included 29 KTx recipients 2-8 weeks after receiving 2 doses of the Pfizer-BioNTech SARS-CoV-2 messenger RNA vaccine. Anti-SARS-CoV-2 spike (S) immunoglobulin (Ig)-G levels were evaluated to define cofactors influencing the immune response between the responder (anti-SARS-CoV-2 IgG level ≥0.8 U/mL) (n = 16) and nonresponder groups (anti-SARS-CoV-2 IgG level <0.8 U/mL) (n = 13). The kinetics of antibodies between 2 and 6 months after the second vaccination was also compared between the groups. RESULTS: KTx recipients with IgG levels ≥0.8 U/mL were younger (54 [interquartile range {IQR}, 46.5-61] years vs 65 [IQR, 55-71.5] years; P = .01), had been transplanted for a longer median time (1588 [IQR, 1382-4751] days vs 1034 [IQR, 548.5-1833] days; P = .02), and were more often treated with a lower mycophenolate mofetil dosage (765.6 ± 119.6 vs 1077 ± 76.9 mg; P = .04) than KTx recipients with IgG levels <0.8 U/mL. There was no significant difference in antibody titers between time periods after the second dose in the responder group. At the 6-month follow-up, a serologic response against the SARS-CoV-2 S was observed in 44.4% of KTx recipients in the nonresponder group. CONCLUSIONS: More than 50% of KTx recipients developed a higher antibody response after the second dose of COVID-19 vaccination.


Subject(s)
COVID-19 Vaccines , COVID-19 , Kidney Transplantation , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Cohort Studies , Humans , Immunoglobulin G , Kidney Transplantation/adverse effects , Mycophenolic Acid , Retrospective Studies , SARS-CoV-2 , Transplant Recipients , Vaccination , Vaccines, Synthetic , mRNA Vaccines
14.
Transplant Proc ; 54(6): 1572-1574, 2022.
Article in English | MEDLINE | ID: covidwho-1799689

ABSTRACT

Management of COVID-19 in lung transplant recipients is challenging. We report a case of a 71-year-old male who underwent bilateral lung transplantation with an unexpected case of COVID-19. The patient had been fully vaccinated. The patient and donor tested negative for pretransplant COVID-19. On routine bronchoscopy on day 1 after transplant, the COVID-19 test was positive. Mycophenolic mofetil and the second dose of basiliximab were skipped, but tacrolimus and prednisone were continued. He was treated with casirivimab/imdevimab and remdesivir. He was discharged on day 14 and has had no episodes of acute rejection during the 3 months.


Subject(s)
COVID-19 , Kidney Transplantation , Lung Transplantation , Aged , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Basiliximab , Graft Rejection/prevention & control , Humans , Immunosuppressive Agents/adverse effects , Lung Transplantation/adverse effects , Male , Mycophenolic Acid/therapeutic use , Prednisone/therapeutic use , Tacrolimus/therapeutic use
15.
Sci Rep ; 12(1): 5876, 2022 04 07.
Article in English | MEDLINE | ID: covidwho-1784026

ABSTRACT

We aimed to evaluate the seroprevalence and investigated factors associated with seropositivity after the second SARS-CoV-2 mRNA vaccination in kidney transplant (KT) recipients. This retrospective study conducted between June and November 2021 included 106 KT recipients and 127 healthy controls who received the second dose of the BNT162b2 mRNA vaccine at least 7 days before the measurement of antibody titers. The antibody titer against the receptor-binding domain of SARS-CoV-2 spike (S) protein was determined. We compared seroprevalence rates (immunoglobulin G [IgG] level of ≥ 0.8 or ≥ 15 U/mL) between the healthy controls and KT recipients and identified factors associated with impaired humoral response. The seroprevalence rate of the healthy controls and KT recipients was 98% and 22%, respectively. Univariate logistic regression analysis revealed that age > 53 years, rituximab use, mycophenolate mofetil use, and KT vintage < 7 years were negatively associated with the rate of anti-SARS-CoV-2 S IgG ≥ 15 U/mL in KT recipients. ABO blood type incompatible KT was not significantly associated with seroprevalence. Humoral response after the second BNT162b2 mRNA vaccine was greatly hindered by immunosuppression therapy in KT recipients. Older age, rituximab use, mycophenolate mofetil use, and KT vintage may play key roles in seroconversion.


Subject(s)
COVID-19 , Kidney Transplantation , Antibodies, Viral , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immunoglobulin G , Japan , Middle Aged , Mycophenolic Acid , Retrospective Studies , Rituximab , SARS-CoV-2 , Seroepidemiologic Studies , Transplant Recipients , Vaccines, Synthetic
16.
Transpl Int ; 35: 10239, 2022.
Article in English | MEDLINE | ID: covidwho-1779974

ABSTRACT

Background: An impaired humoral response to full dose of BNT162b2 vaccine was observed in renal transplant recipients (RTR). Methods: To reveal predictors for humoral response to third vaccine, patients were stratified to positive (N = 85) and negative (N = 14) response groups based on receptor-binding domain (RBD) IgG ≥1.1 and neutralizing antibodies (NA) ≥ 16 dilution versus RBD IgG <1.1 or NA < 16, respectively. NA were detected using a SARS-CoV-2 pseudo-virus. Results: Response rate increased from 32.3% (32/99) before the third dose to 85.9% (85/99) post-third vaccine with a significant rise in geometric mean titers (GMTs) for RBD IgG and NA [0.79 (95% CI 0.65-0.96) vs. 3.08 (95% CI 2.76-3.45), p < 0.001 and 17.46 (95% CI 12.38-24.62) vs. 362.2 (95% CI 220.7-594.6), p < 0.001 respective. 80.6% (54/67) seroconverted and 96.9% (31/32) remained positive following the vaccine with a significant increase in GMTs for RBD IgG and NA. Age, ESRD secondary to diabetic nephropathy (DN) and renal allograft function were independent predictors for antibody response in RTR. Mycophenolic acid (MPA) use and dose had no impact on humoral response following the third booster. AEs were recorded for 70.1% of RTR population. Systemic AEs were more common in recipients with a positive humoral response as opposed to non-responders (45.2% versus 15.4% respectively, p = 0.04). Conclusion: 85.9% of RTR develop NA to BNT162b2 third vaccine, found effective in both negative and positive responders prior to the vaccine. Antigenic re-exposure overcame the suppressive effect of MPA on antibody response in RTR.


Subject(s)
COVID-19 , Kidney Transplantation , Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , Humans , Immunoglobulin G , Mycophenolic Acid , SARS-CoV-2 , Transplant Recipients
17.
Liver Int ; 42(8): 1872-1878, 2022 08.
Article in English | MEDLINE | ID: covidwho-1765003

ABSTRACT

BACKGROUND AND AIMS: After 2 doses, the efficacy of anti-SARS-CoV-2 vaccination seems to be lower in solid organ transplant recipients than in the immunocompetent population. The objective of this study was to determine the humoral response rate after vaccination, including with a booster dose, and to identify risk factors for non-responsiveness in liver transplant recipients. METHODS: We included all patients seen in consultation in two French liver transplant centres between January 1, 2021, and March 15, 2021. RESULTS: 598 liver transplant recipients were enrolled and 327 were included for analysis. Sixteen patients received one dose, 63 patients two doses and 248 patients three doses. Anti-SARS-Cov-2 antibodies were detected in 242 out of 327 (74.0%) liver transplant patients after vaccination. Considering an optimal serologic response defined as an antibody titre >260 BAU/ml, 172 patients (52.6%) were responders. Mycophenolate mofetil (MMF) treatment was an independent risk factor for a failure to develop anti-SARS-CoV-2 antibodies after vaccination (OR 0.458; 95%CI 0.258-0.813; p = .008). Conversely, male gender (OR 2.247, 95%CI 1.194-4.227; p = .012) and receiving an mRNA vaccine (vs a non-mRNA vaccine) (OR 4.107, 95%CI 1.145-14.731; p = .030) were independent predictive factors for developing an optimal humoral response after vaccination. None of the patients who received the vaccine experienced any serious adverse events. CONCLUSIONS: Even after a third booster dose, response rate to vaccination is decreased in liver transplant recipients. MMF appears to be a major determinant of seroconversion and optimal response to vaccination in these patients.


Subject(s)
COVID-19 , Liver Transplantation , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Male , Mycophenolic Acid/therapeutic use , SARS-CoV-2 , Transplant Recipients
18.
J Hepatol ; 77(1): 152-162, 2022 07.
Article in English | MEDLINE | ID: covidwho-1734733

ABSTRACT

BACKGROUND & AIMS: The long-term immunogenicity of anti-SARS-CoV-2 vaccines in liver transplant (LT) recipients is unknown. We aimed to assess the long-term antibody response of the Pfizer-BioNTech® BNT162b2 vaccine in LT recipients compared to controls. METHODS: LT recipients underwent anti-SARS-CoV-2 anti-receptor-binding domain protein IgG (anti-RBD) and anti-nucleocapsid protein IgG antibody (anti-N) measurements at the first and 1, 4 and 6 months after the second vaccination dose. RESULTS: One hundred forty-three LT recipients and 58 controls were enrolled. At baseline, 131/143 (91.6%) LT recipients tested anti-N negative (COVID-19 naïve), and 12/143 (8.4%) tested positive (COVID-19 recovered) compared to negative controls. Among COVID-19 naïve, 22.1% were anti-RBD positives 1 month after the first vaccine dose, while 66.4%, 77%, and 78.8% were 1, 4 and 6 months following the second vaccine dose. In contrast, 100% of controls were positive at 4 months (p <0.001). The median anti-RBD titer 4 months after the second vaccine dose was significantly lower (32 U/ml) in COVID-19 naïve than in controls (852 U/ml, p <0.0001). A higher daily dose of mycophenolate mofetil (MMF) (p <0.001), higher frequency of ascites (p = 0.012), and lower serum leukocyte count (p = 0.016) were independent predictors of anti-RBD negativity at 6 months. All COVID-19 recovered patients tested positive for anti-RBD at each time point. The median antibody titer was similar in those taking MMF (9,400 U/ml, 11,925 U/ml, 13,305 U/ml, and 10,095 U/ml) or not taking MMF (13,950 U/ml, 9,575 U/ml, 3,500 U/ml, 2,835 U/ml, p = NS) 3 weeks after the first and 1, 4 and 6 months after the second vaccine dose, respectively. CONCLUSIONS: In COVID-19-naïve LT recipients, the immunogenicity of anti-SARS-CoV-2 vaccination was significantly lower than that in controls. MMF was the main determinant of vaccination failure in SARS-CoV-2-naïve patients. LAY SUMMARY: The immunogenicity of anti-SARS-CoV-2 vaccination in liver transplant recipients is currently unknown. Herein, we show that liver transplant recipients who have not previously had COVID-19 are less likely to mount effective antibody responses to vaccination than a control population. The main determinant of vaccination failure was the use of the immunosuppressive drug mycophenolate mofetil.


Subject(s)
COVID-19 , Liver Transplantation , Antibodies, Viral , BNT162 Vaccine , COVID-19/prevention & control , Humans , Immunoglobulin G , Immunosuppressive Agents/therapeutic use , Mycophenolic Acid/therapeutic use , SARS-CoV-2 , Transplant Recipients , Vaccination
20.
Nephrol Dial Transplant ; 37(8): 1400-1410, 2022 07 26.
Article in English | MEDLINE | ID: covidwho-1730704

ABSTRACT

Patients with immune-mediated kidney diseases are at increased risk of severe coronavirus disease 2019 (COVID-19). The international rollout of COVID-19 vaccines has provided varying degrees of protection and enabled the understanding of vaccine efficacy and safety. The immune response to COVID-19 vaccines is lower in most patients with immune-mediated kidney diseases; either related to immunosuppression or comorbidities and complications caused by the underlying disease. Humoral vaccine response, measured by the presence of antibodies, is impaired or absent in patients receiving rituximab, mycophenolate mofetil (MMF), higher doses of glucocorticoids and likely other immunosuppressants, such as cyclophosphamide. The timing between the use of these agents and administration of vaccines is associated with the level of immune response: with rituximab, vaccine response can only be expected once B cells start to recover and patients with transient discontinuation of MMF mount a humoral response more frequently. The emergence of new COVID-19 variants and waning of vaccine-induced immunity highlight the value of a booster dose and the need to develop mutant-proof vaccines. COVID-19 vaccines are safe, exhibiting a very low risk of de novo or relapsing immune-mediated kidney disease. Population-based studies will determine whether this is causal or coincidental. Such cases respond to standard management, including the use of immunosuppression. The Immunonephrology Working Group and European Vasculitis Society recommend that patients with immune-mediated kidney diseases follow national guidance on vaccination. Booster doses based on antibody measurements could be considered.


Subject(s)
COVID-19 Vaccines , Kidney Diseases , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Humans , Kidney Diseases/drug therapy , Kidney Diseases/immunology , Mycophenolic Acid/therapeutic use , Rituximab/therapeutic use
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