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BackgroundTreatment with Rituximab (RTX) in patients with rheumatic diseases (RD) has presented a challenge during the COVID-19 pandemic, as RTX leads to markedly reduced and often undetectable antibody responses after COVID-19 vaccination (1).ObjectivesTo investigate the effect of COVID-19 mRNA revaccination (two doses) on the antibody response in patients with RD who were initial vaccine non-responders. Further, to examine if B-cell levels or T-cell responses before revaccination predicted seroconversion.MethodsFrom a RD cohort (COPANARD) vaccinated with the standard two-dose COVID-19 vaccinations, we enrolled cases without detectable antibody responses (n=17) and controls with detectable antibody response (n=29). Blood donors (n=32) were included as additional controls. Samples were collected before and six weeks after completed revaccination. Total antibodies (abs) and specific IgG, IgA, and IgM against SARS-CoV-2 spike protein, SARS-CoV-2 neutralizing abs, and SARS-CoV-2 reacting CD4+ and CD8+ T-cells were measured before and after revaccination. B-cells (CD19+CD45+) were quantified before revaccination. This study was funded by the Danish Rheumatism Association.ResultsPatient demographics are given in Table 1. Forty-seven percent of cases had detectable total SARS-CoV-2 abs and neutralizing abs after revaccination. However, antibody levels were significantly lower than in controls and blood donors (p<0.008), Figure 1A+B. Revaccination induced an antibody class switch in cases with a decrease in detectable IgM abs (Baseline 11/17, Followup 3/17) and increase in IgG. No significant difference was observed in T-cell responses before and after revaccination between the three groups, Figure 1C. The proportion of cases with detectable CD4+ T cells increased from 69% to 88% (p=0.25), and for CD8+ T cells, the proportion decreased from 88% to 82% (p=1.00). Only 29% of cases had measurable B-cells compared to 100% of controls and blood donors, Figure 1D. Fifty percent of revaccinated cases who seroconverted had measurable B-cells before revaccination, Figure 1D.Univariate logistic regression analysis was performed to analyze if active RTX treatment, the presence of B-cells, or a positive T-cell response prior to revaccination predicted seroconversion of total SARS-CoV-2-abs in the patient cohort. We did not find a significant explanatory effect of either variable in the univariate logistic models, data not shown.Table 1.DemographicsCases Revaccination, n=17Controls Boost, n=29Female sex, no(%)1482%2172%Age, median (IQR)6549 - 706762 - 72Disease duration, years1510 - 18229 - 31Rheumatoid Arthritis/SLE13/410/19None DMARD529%828%Prednisone424%13%Methotrexate741%1241%Hydroxychloroquine212%414%None biologic treatment424%931%Rituximab1271%0TNF-inhibitors16%724%JAK-inhibitors0621%IL-6-inhibitors, Abatacept, Benlysta0724%Previous rituximab treatmentAny rituximab treatment1694%13%RTX within the last 15 months, no1488%0Cumulative total dose, mg134-242Time from RTX to revaccination, months95-1249Figure 1.ConclusionIn conclusion, forty-seven percent of initial non-responders were able to seroconvert after two-dose revaccination. However, plasma concentrations of the antibodies against SARS-COV-2 and the levels of neutralizing capacity remained significantly lower than in immunocompetent blood donors. B-cell levels or T-cell responses before revaccination did not predict seroconversion. Our study suggests that patients with RDs who did not mount a detectable serological response to a COVID-19 mRNA vaccine have a T cell response similar to immunocompetent controls. Future studies should establish the antibody levels that identify RD patients without sufficient protection against SARS-CoV-2 infection.References[1]Troldborg A, et al. Time Since Rituximab Treatment Is Essential for Developing a Humoral Response to COVID-19 mRNA Vaccines in Patients With Rheumatic Diseases. J Rheumatol. 2022.AcknowledgementsThe Danish Rheumatism Association [grant number R203-A7217]. We acknowledge all patients and blood donors contributing to the stud for their invaluable participation. The authors would like to thank Sif Kaas Nielsen and Mads Engelhardt Knudsen, the Laboratory of Molecular Medicine at Rigshospitalet, for their excellent technical assistance in analyzing the samples.Disclosure of InterestsNone Declared.
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Background: The ongoing COVID-19 pandemic has resulted in more than 419 million cases and more than 5.9 million deaths. Preious studies hae indicated inferior responses to SARS-CoV-2 accination across different hematological diseases. Through this prospectie cohort study, we examined the deelopment and durability of anti-receptor binding domain (RBD) IgG after two doses of BNT162b2 in 179 patients with either multiple myeloma (MM) or Chronic Lymphatic B-cell Leukemia (B-CLL) six months after accination and compared to immunocompetent controls. Aims: We aimed to inestigate the durability of immune responses to COVID-19 accination in patients with MM or B-CLL compared to healthy controls, and to identify risk factors for humoral non-response, including type of diagnosis. Methods: We measured anti-receptor binding domain (RBD) IgG after two doses of BNT162b2 in 179 patients (MM: n=78, B-CLL: n=101) and 179 age and sex matched healthy controls up to six months after first accination. Anti- RBD IgG leels and neutralizing capacity of antibodies were measured at first and second dose of BNT162b2 and two and six months after first dose. Humoral response was defined as anti-RBD IgG > 225 AU/mL with a neutralizing index ≥ 25%. Humoral non-response was defined as the absence of a humoral response. T-cell responses were assessed six months after the first dose using an ELISA-based interferon-gamma release assay. A positie T-cell response was defined as IFN-γ release > 200 mIU/mL. Data on diagnoses were obtained through medical records, and data on accination status were obtained from the Danish Vaccination Register. Results: In patients with MM or B-CLL, the geometric mean concentration (GMC) of anti-RBD IgG increased from baseline 1.49 AU/mL (95% CI: 1.21-1.84) to three weeks after the first accine dose 15.10 AU/mL (95% CI: 9.39- 24.29) and after receiing the second dose 1179.60 AU/mL (95% CI: 727.78-1919.85). From two to six months after first accine there was a significant decline in the GMC of anti-RBD IgG to 252.75 AU/mL (95% CI: 159.17-403.43). The mean neutralizing capacity in patients with MM or B-CLL was lower than in controls at all time points after the first accine dose. Six months after first accine dose, 79 of 179 (44.1%) patients with MM or B-CLL had a positie humoral response, while this was the case for 170 of 179 controls (95.0%), p<0.001. Haing MM or B-CLL was significantly associated with risk of humoral non-response. This was most pronounced in B-CLL patients who had an age and sex adjusted risk ratio (RR) of 12.25 (95% CI: 6.42-23.38, p< 0.001) of humoral non-response compared to healthy controls. For MM patients the RR was 4.65 (95% CI: 2.21-9.80, p< 0.001). T-cell response was assessed in a subset of 48 patients with MM (n=28) or B-CLL (n=20) and 26 controls, six months after first accine dose. A total of 21 (43.8%) patients with MM (12/28) or B-CLL (9/20) and 14 (53.8%) controls had a positie T-cell response (p =0.56). Seen of 20 (35.0%) patients with MM or B-CLL who did not deelop a humoral response, deeloped a T-cell response (MM: 3/8, B-CLL: 4/12), while 14 of 28 (50.0%) patients with MM or B-CLL who deeloped a humoral response deeloped a T-cell response (p =0.46, MM: 9/11, B-CLL: 5/8). In healthy controls 14 of 25 (56.0%) people who deeloped a humoral response also deeloped a T-cell response. Summary/Conclusion: Humoral response to BNT162b2 was impaired in patients with MM or B-CLL compared to healthy controls. Both patients with MM and B-CLL were at higher risk of humoral non-response compared to healthy controls.
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Introduction. Knowledge of the seroprevalence and duration of antibodies against SARS-CoV-2 was needed in the early phases of the COVID-19 pandemic and is still necessary for policy makers and healthcare professionals. This information allows us to better understand the risk of reinfection in previously infected individuals. Methods. We investigated the prevalence and duration of detectable antibodies against SARS-CoV-2 in sequentially collected samples from 379 healthcare professionals. Results. SARS-CoV-2 seroprevalence at inclusion was 5.3% (95% confidence interval (CI): 3.3-8.0%) and 25% of seropositive participants reverted during follow-up. At the end of follow-up, the calculated probability of having detectable antibodies among former seropositive participants was 72.2% (95% CI: 54.2-96.2%). Conclusion. Antibodies against SARS-CoV-2 were detectable in a subset of infected individuals for a minimum of 39 weeks.
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Background: Previous studies have shown an inferior response to mRNA SARS-CoV-2 vaccination in solid organ transplant (SOT) recipients up to four months after vaccination. We examined the development in anti-receptor binding domain (RBD) IgG after two doses of BNT162b2 in SOT recipients six months after vaccination compared to immunocompetent controls. Methods: in 200 SOT recipients and 200 age-and sex-matched controls, we measured immunogenicity of two doses of BNT162b2 vaccine up to 6 months after vaccination. An in-house enzyme-linked immunosorbent assay (ELISA) based system was used to measure concentrations of anti-receptor binding domain (RBD) IgG. Neutralizing capacity of antibodies was estimated using an in-house ELISA based pseudo-neutralization assay. Presence of anti-SARS-CoV-2 nucleocapsid (N) antibodies was assessed using an electrochemiluminescence based kit from Roche diagnostics. Presence of N-antibodies was used as evidence of previous natural infection. In a subset of participants an interferon-gamma releasing assay was used to assess T-cell responses. Results: SOT recipients and controls demonstrated an increase in anti-RBD IgG after both first and second dose of BNT162b2. Six months after the first dose, GMC of anti-RBD IgG declined in both groups but remained higher in controls (55.85 AU/mL, 95% CI 36.95-83.33 vs. 1448.94 AU/mL, 95% CI 1139.43-1799.48). Furthermore, more controls had a cellular response six months after vaccination (13.1% of SOT recipients vs. 59.4% of controls, p<0.001). We found increasing age (RR 1.23 pr year, 95% CI 1.11-1.35, p<0.001), being within one year of transplantation (RR 1.55, 95% CI 1.30-1.85, p<0.001), use of mycophenolate (RR 1.53, 95% CI 1.18-1.99 p=0.001), kidney transplanation (RR 1.70, 95% CI 1.25-2.30, p=0.001), lung-transplantation (RR 1.63, 95% CI 1.16-2.29, p=0.005) and cancer comorbidity (RR 1.52, 95% CI 1.26-1.82, p <0.001) to be significantly associated with humoral non-response. Conclusion: Humoral and cellular responses to two doses of BNT162b2 are inferior in SOT recipients compared to controls. Furthermore, anti-RBD concentration decline 6 months after first vaccine dose. Further investigations of clinical significance of anti-RBD IgG concentration and vaccine non-response is warranted to optimize the timing and use of booster vaccines. Multiple risk factors for non-response were identified and may help identify SOT recipients at high risk of vaccine non-response.