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BackgroundData on serological immunity after three doses and the long-term immunogenicity (persistence) of COVID-19 vaccine in patients with inflammatory rheumatic diseases (IRD) treated with different immunomodulating drugs are still limited.ObjectivesTo elucidate if 1) a third dose COVID-19 vaccine improves antibody responses, compared to two doses, in patients with IRD treated with biologic or targeted synthetic DMARD (b/tsDMARDs) treatment given as monotherapy or in combination with conventional synthetic DMARDs (csDMARDs) compared to controls, and 2) the persistence of antibody response after two doses of COVID-19 vaccine in IRD patients.MethodsAntibody levels to two antigens representing Spike full length protein and Spike S1 and a Nucleocapsid C-terminal fragment (used to confirm previous COVID-19 infection) were measured in serum samples collected 2-12 and 21-40 weeks after the second vaccine dose and 2-12 weeks after the third dose using a multiplex bead-based serology assay. A sufficient antibody response (seropositivity) was defined as having antibodies over the cut-off level for both spike antigens (1). WT (wild type) anti-Spike IgG and omicron BA.1 and BA.2 variants were measured. Patients with IRD receiving immunomodulating treatment, regularly followed at a rheumatology department and a group of controls were recruited from five Swedish region.ResultsIn total, 323 of 414 patients with IRD and 36 controls who received three vaccine doses participated in this part of the study. Following treatment groups were included: rituximab (n=118;68% female;mean age 67 years), abatacept (n=18;72% female;mean age 64 years), IL6r inhibitors (n=60;73% female;mean age 64 years), JAK-inhibitors (n=44;80% female, mean age 52 years), TNF-inhibitors (n=59;70% female;mean age 47 years;), IL12/23/17 inhibitors (n=24;46% female;mean age 54 years) and controls (n=36;75% female, mean age 51 years). b/ts DMARD treatment was given as monotherapy or in combination with csDMARD, methotrexate (MTX) being the most frequently used csDMARD (32.5%). Compared to results after two vaccine doses, proportion (%) of seropositivity after three vaccine doses increased significantly in groups rituximab +/- DMARD (p=0.003 and p=0.004, respectively), IL6r inhibitors +DMARD (p=0.02), and abatacept+DMARD (p=0.01). However, the proportion of seropositivity after three vaccine doses was still significantly lower in rituximab treated patients (52%) compared to other treatment groups or controls (p<0.001) (Figure 1A/B). Antibody response to WT, omicron sBA.1 and sBA.2 showed similar pattern with the lowest levels among patients treated with rituximab.When antibody response was compared between 2-12 weeks and 21-40 weeks after second dose, the proportion of seropositive rituximab treated patients decreased from 34.9 % to 32.6%. All patients with JAK inhibitors and with JAK-inhibitors and IL6r-inhibitors seropositive 21-40 weeks after the second vaccine dose. Patients treated with other bDMARDs were not included in this analysis due to limited number participants.ConclusionIn this Swedish study including IRD patients receiving different b/t DMARDs, a sufficient immunogenicity of the third dose of COVID-19 vaccine was observed in all treatments with exception for rituximab. However, the increased proportion of seropositivity after the third COVID-19 vaccine doses in rituximab and other patients with insufficient response to two doses including response to the omicron variants, supports the current recommendations on additional booster doses. The immunogenicity of two vaccine doses was preserved to 40 weeks in majority of patients treated with different immunomodulating treatment with exception for rituximab.Figure 1.AcknowledgementsThe study has been supported by the independent research grants from Roche.Disclosure of InterestsMartina Frodlund: None declared, Per Nived: None declared, Katerina Chatzidionysiou Consultant of: consultancy fees from Eli Lilly, AbbVie and Pfizer., Grant/research support from: Research grand from Galapagos, Anna ödergren: None declared, Eva Klingberg: None declared, Monika Hansson: None declared, Elisa Pin: None declared, Lars Klareskog: None declared, Meliha C Kapetanovic Grant/research support from: independent research grants från Pfizer and Roche.
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Background: In line with other reports, our group showed that patients treated with rituximab had signifcant impaired antibody response compared to patients treated with other biologic and targeted and synthetic disease modifying anti-rheumatic drugs (csDMARD). Objectives: To investigate predictors of response to COVID-19 vaccination (2 doses of mRNA vaccines, 2 doses of virus vector vaccines or combinations of these) in patients with infammatory rheumatic diseases (IRD) treated with ritux-imab and controls. Methods: Antibody levels to three antigens: Spike protein full length, Spike S1 and Nucleocapsid C-terminal fragment (to confrm previous COVID-19 infection) were measured in sera collected before vaccination and 2-12 weeks after the second vaccine using a multiplex bead-based serology assay. The antigen-specifc cut-off was defned as the median fuorescence intensity signal plus 6x standard deviations across 12 pre-pandemic controls. A good vaccine response was defned as having antibodies over the cut-off level for both spike antigens. Proportion (%) responders was compared between patients and controls (Chi2 test). Patients with IRD receiving last rituximab treatment within a mean (range) 193 (23-501) days before frst vaccination participated. Individuals without IRD served as a control group. Predictors of a good vaccine response were explored using multivariate logistic regression analysis adjusted for age, sex, disease duration, diagnosis (systemic vasculitis/RA/JIA/other), concomitant csDMARD, rituximab dose and prednisolone dose. Hazard ratio (chanse) of a good antibody response in relation to time between the last rituximab treatment and vaccination was studied by Kaplan-Meier survival analysis. Results: In total, 145 patients receiving rituximab and 61 controls were inclyded. Of these, 82 received rituximab as monotherapy (67% women;mean age 66 years, mean disease duration 13 years;33% had RA/JIA and 60% vasculi-tis) and 63 received rituximab+csDMARD (62% women;mean age 66 years;mean disease duration 17 years;76% had RA/JIA and 10 % vasculitis). Controls (n=61) were 74% women and mean age 49 years. Compared to controls, rituximab patients had lower antibody levels for both spike proteins (p<0.001). Proportion (%) responders among patients receiving rituximab as monotherapy (40.2%) and rituximab+DMARDs (25.4%) was signifcantly lower than in controls (98.4%) (p<0.001, Chi2). Higher age, concomitant csDMARD at vaccination and shorter time from last rituximab treatment predicted impaired antibody response (multivariate logistic regression model) (Table 1). Longer time between the last rituximab course and vaccination was associated with better antibody response (Figure 1). Conclusion: Patients with IRD getting vaccinated with two doses of COVID19 vaccine during the treatment with rituximab have the ability to develop antibody response although the response is impaired. For each month passed after the last rituximab course, the chance of good antibody response increases with 30%. Younger patients receiving rituximab as monotherapy and vaccinated preferably several months after the last rituximab treatment have the highest chance of achieving a good antibody response.
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We studied the clinical and immunological outcomes of covid-19 infection in strictly consecutive patients with CLL from a well-defined area during the first 13 months of the pandemic. Sixty patients with a median age of 71 years (range 43-97) were identified. Median CIRS was 8 (4-20), median BMI 25 (19-42) and 65% were men. Patients had indolent CLL (n=38), were previously treated (n=12) or had ongoing therapy (n=10, among which seven received BTKi). Forty-six patients (77%) were hospitalized due to severe covid-19 and among them, 11 (24%) were admitted to the intensive care unit (ICU). Severe covid-19 was equally distributed across subgroups irrespective of age, gender, BMI, CLL status except for comorbidities (CIRS >6, p<0.05). Fourteen patients (23%) died;age ≥75 years was the only significant risk factor (p<0.05, uni- and multivariate analyses). Comparing months 1-6 vs. 7-13 of the pandemic, death rates were reduced from 32 to 18%, ICU admission from 37 to 15% and hospitalizations remained frequent (86 vs. 71%). Seroconversion occurred in 34/41 tested patients (83%) and anti-SARS-CoV-2 antibodies remained detectable at 6 and 12 months of follow-up in 17/22 and 8/11 patients, respectively. In-depth immunological analysis revealed that 13/17 tested patients had neutralizing antibodies (including all 12 patients that were also seropositive in conventional serology in this cohort), and 19/28 (68%) had antibodies in saliva. SARS-CoV- 2-specific T-cells (IFN-gamma ELISpot) were detected in 14/17 patients (82%). We conclude that covid-19 in non-selected CLL patients continued to result in a high admission rate even among young early-stage patients. A robust and durable B and/or T cell immunity was observed in most convalescents.
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Background and study design: Patients with immunodeficiencies including CLL have an increased risk of severe infections and may not respond well to conventional vaccines. Two early international surveys reported that hospital-admitted Covid-19 patients with CLL had a high fatality rate (Mato et al., 2020;Scarfo et al., 2020). We recently showed that a robust and durable B and/or T cell immunity occurred in most convalescent CLL patients (Blixt et al., 2021). In contrast, the first publication on vaccination against SARS-CoV-2 in CLL reported seroconversion in only 39.5% of patients (Herishanu et al., 2021). We conducted a prospective clinical trial (COVAXID, clinicaltrials.gov: NCT04780659) in patients with various types of immunodeficiency and matched controls (n=539). Five equally sized cohorts were included: primary immunodeficiency, HIV, allogeneic transplantation or CAR-T, solid organ transplantation as well as CLL. The primary endpoint was seroconversion measured 2 weeks after the 2nd dose of the Pfizer-BioNTech vaccine (Comirnaty). Antispike antibodies in saliva (which may better correlate with protection, Khoury et al., 2020) and T cells (IFN-gamma ELISpot) were also measured. We report here the results of the CLL cohort. Results: Ninety CLL patients were included in four predefined subgroups: indolent untreated disease (n=30);prior chemoimmunotherapy including a CD20 mAb 9-30 months ago (n=20);ongoing BTKi therapy (n=30);and stopped/paused ibrutinib (all >3 months ago) (n=10). The median age was 70 years (range 23-87) and 67% were men. Median IgG was 6.7 g/L (range 1.0-20.8) and 50% had a value below the lower normal range. Reactogenicity occurred in 82.9 and 77.1% of the CLL patients and 81.6 and 85.0% of the controls after doses 1 and 2, respectively. The severity of reactogenicity was similar in patients and controls. AEs≥grade 2 was seen in five patients within 2 weeks after dose 2 but none was considered related to the vaccine. No hematological toxicity was observed. Data analysis on seroconversion is ongoing. Preliminary analysis of saliva showed that on D35 (i.e. 14 days after 2nd dose) 62% of CLL patients (95% of healthy controls) had developed IgG to S1S2 spike antigen compared to only 23% on D21 (i.e. 21 days after dose 1). Subgroup analysis (D35) indicates that ibrutinib-treated patients showed the lowest response in saliva whilst indolent and prior chemoimmunotherapy-treated groups were the best responders. A different pattern was observed for IFNgamma positive T cells with the highest responses in the (few) patients who had paused/stopped ibrutinib with other subgroups having lower T cell responses. Conclusions: This prospective clinical trial verified that the BNT162b2 mRNA vaccine was well-tolerated in patients with CLL. Our preliminary results indicate that anti-spike antibodies in saliva and T cell responses were frequently observed after full vaccination but with different response patterns in CLL subgroups. Details of the study including seroconversion and the overall response rate will be presented at the meeting.
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Introduction: B-cell depleting therapies used in multiple sclerosis (MS) have been associated with higher risk of severe COVID- 19. However, more precise knowledge of how B-cell depletion affects development of humoral and cellular immunity to viruses, in particular to SARS-CoV-2, is still limited. Objectives: To determine humoral and cellular SARS-CoV-2 responses after COVID-19 infection or vaccination in MS patients treated with different disease modulatory therapies (DMTs), with a focus on B-cell depleting therapies. Aims: Understand the impact of B-cell depleting therapy on the ability to develop a specific SARS-CoV-2 immunological memory after a COVID-19 infection or vaccination. Methods: We analyzed sera from subjects (n=2800) in an ongoing observational drug trial comprising multiple MS DMTs (COMBAT-MS;NCT03193866). In a single center subcohort (n=137, including healthy controls) enriched for COVID-19-like symptoms, samples for more detailed cellular analyses were obtained. Lastly, a small cohort of patients on B-cell depleting therapies were analyzed either before (n=4) or after (n=6) being vaccinated against SARS-CoV-2. Specific antibodies were determined with electro-chemiluminescence immunoassay and multiplex bead array. T-cell memory responses were determined by FluoroSpot and flow cytometry. Results: Data on humoral responses in the entire cohort will be included in the final presentation. The subcohort patients on B-cell depleting therapies were stratified into three different groups depending on B-cell status at onset of COVID-19-like symptoms;a) completely depleted (<0.01;B-cell count x 10-9/L, n=14), b) partially repleted (0.01-0.08;B-cell count x 10-9/L, n=7) or c) completely repleted (>0.08;B-cell count x 10-9/L, n=3). Within the three groups, 50%/71%, 86%/100% and 100%/100% developed a SARS-CoV-2 specific antibody/T-cell response, respectively. Furthermore, antibody titers were not significantly different from those on other DMTs or healthy controls, and SARS-CoV-2 specific T-cells also displayed functional similarity. Lastly, in the vaccination cohort, all patients displayed a specific T-cell response after vaccination although only 50% of them also developed a humoral response. Conclusions: These findings indicate that B-cell depletion does not prevent a specific immunological memory after a COVID-19 infection or vaccination against SARS-CoV-2, and patients that do not develop humoral immunity might still have a specific T-cell response. Further studies are needed to determine the correlation between immunological parameters and clinical immunity.
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BACKGROUND: In Sweden, home care services is a major external contact for older persons. METHODS: Five home care service companies in Stockholm, Sweden, enrolled 405 employees to a study including serum IgG to SARS-CoV-2 and SARS-CoV-2 virus in throat swabs. RESULTS: 20.1% (81/403) of employees were seropositive, about twice as many as in a simultaneously enrolled reference population (healthcare workers entirely without patient contact, n = 3671; 9.7% seropositivity). 13/379 employees (3.4%) had a current infection (PCR positivity). Amongst these, 5 were also seropositive and 3 were positive with low amounts of virus. High amounts of virus and no antibodies (a characteristic for presymptomatic COVID-19) were present in 5 employees (1.3%). CONCLUSIONS: Personnel providing home services for older persons appear to be a risk group for SARS-CoV-2. Likely presymptomatic employees can be readily identified by screening. Increased protection of employees and of the older persons they serve is warranted.