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Objectives: Methotrexate (MTX) is one of the most commonly used medications to treat rheumatoid arthritis (RA). However, the effect of MTX treatment on cellular immune responses remains incompletely understood. This raises concerns about the vulnerability of these patients to emerging infections and following vaccination., Methods: In the current study, we investigated the impact of MTX treatment in patients with immune-mediated inflammatory disease on B and CD4 T cell SARS-CoV-2 vaccination responses. Eighteen patients with RA and two patients with psoriatic arthritis on MTX monotherapy were included, as well as 10 patients with RA without immunosuppressive treatment, and 29 healthy controls. CD4 T and B cell responses were analysed 7 days and 3-6 months after two SARS-CoV-2 messenger RNA vaccinations. High-dimensional flow cytometry analysis was used to analyse fresh whole blood, an activation-induced marker assay to measure antigen-specific CD4 T cells, and spike probes to study antigen-specific B cells., Results: Seven days following two SARS-CoV-2 vaccinations, total B and T cell counts were similar between MTX-treated patients and controls. In addition, spike-specific B cell frequencies were unaffected. Remarkably, the frequency of antigen-specific CD4 T cells was reduced in patients using MTX and correlated strongly with anti-RBD IgG antibodies. These results suggest that decreased CD4 T cell activity may result in slower vaccination antibody responses in MTX-treated patients., Conclusion: Taken together, MTX treatment reduces vaccine-induced CD4 T cell activation, which correlates with lower antibody responses., Trial Registration Number: NL8900., Competing Interests: Competing interests: FE, GW, SMvH and TWK report (governmental) grants from ZonMw to study immune response after SARS-Cov-2 vaccination in auto-immune diseases. FE also reports grants from Prinses Beatrix Spierfonds, CSL Behring, Kedrion, Terumo BCT, Grifols, Takeda Pharmaceutical and GBS-CIDP Foundation; consulting fees from UCB Pharma and CSl Behring; honoraria from Grifols. All other authors report no disclosures relevant to the manuscript., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To compare the cumulative incidence and disease severity of reported SARS-CoV-2 omicron breakthrough infections between patients with immune-mediated inflammatory diseases (IMID) on immunosuppressants and controls, and to investigate determinants for breakthrough infections., Methods: Data were used from an ongoing national prospective multicentre cohort study on SARS-CoV-2 vaccination responses in patients with IMID in the Netherlands (Target-to-B! (T2B!) study). Patients wih IMID on immunosuppressants and controls (patients with IMID not on immunosuppressants and healthy controls) who completed primary immunisation were included. The observation period was between 1 January 2022 and 1 April 2022, during which the SARS-CoV-2 omicron (BA.1 and BA.2 subvariant) was dominant. A SARS-CoV-2 breakthrough infection was defined as a reported positive PCR and/or antigen test at least 14 days after primary immunisation. A multivariate logistic regression model was used to investigate determinants., Results: 1593 patients with IMID on immunosuppressants and 579 controls were included. The cumulative incidence of breakthrough infections was 472/1593 (29.6%; 95% CI 27% to 32%) in patients with IMID on immunosuppressants and 181/579 (31.3%; 95% CI 28% to 35%) in controls (p=0.42). Three (0.5%) participants had severe disease. Seroconversion after primary immunisation (relative risk, RR 0.71; 95% CI 0.52 to 0.96), additional vaccinations (RR 0.61; 95% CI 0.49 to 0.76) and a prior SARS-CoV-2 infection (RR 0.60; 95% CI 0.48 to 0.75) were associated with decreased risk of breakthrough infection., Conclusions: The cumulative incidence of reported SARS-CoV-2 omicron breakthrough infections was high, but similar between patients with IMID on immunosuppressants and controls, and disease severity was mostly mild. Additional vaccinations and prior SARS-CoV-2 infections may reduce the incidence of breakthrough infections., Competing Interests: Competing interests: FE and TWK report (governmental) grants from ZonMw to studyimmune response after SARS-Cov-2 vaccination in autoimmune diseases.FE also reports grants from Prinses Beatrix Spierfonds, CSL Behring,Kedrion, Terumo BCT, Grifols, Takeda Pharmaceutical Company, andGBS-CIDP Foundation; consulting fees from UCB Pharma and CSlBehring; and honoraria from Grifols. AJvdK reports grants from CSLBehring and participation on an advisory board for Argen-X. ML reports agrant from Galapagos not related to this study, and honoraria from BristolMyers Squibb, Pfizer, Takeda, and Tillotts. PIS is involved in clinical trialswith many pharmaceutical industries that manufacture drugs used for thetreatment of, for example, psoriasis and atopic dermatitis, for whichfinancial compensation is paid to the department or hospital, and is achief investigator of the TREAT NL registry taskforce and SECURE-ADregistry. MWB is a secretary for the Dutch Experimental DermatologyBoard; head of the pigmentary disorders group within the DutchDermatology Board; and reports honoraria from Pfizer, Sanofi, Novartis,and Fondation René Touraine. JK has speaking relationships with MerckSerono, Biogen Idec, TEVA, Sanofi, Genzyme, Roche, and Novartis;received financial support to his institution for researchactivities from Merck Serono, Bayer Shcering Pharma, Biogen Idec,GlaxoSmithKline (GSK), Roche, Teva, Sanofi, Genzyme, and Novartis. BHreports unpaid positions as a medical adviser for several patient groups, aboard position for ERN-SKIN, and associate editor for The British Journalof Dermatology; reports grants from AbbVIe, Akari Therapeutics, Celgene, and Novartis; consulting fees from UCB Pharma, Novartis, and Janssen; and honoraria from AbbVie. JJGMV reports consulting fees from Argenx,Alexion, and NMD Pharma, and is a co-inventor on patent applicationsbased on MuSK-related research. DJH reportsgrants from AbbVie, AstraZeneca, Janssen, LEO Pharma, and UCB;honoraria from AbbVie, Galderma, Janssen, Lilly, Pfizer, Sanofi, and UCB;and a paid position on an advisory board for BIOMAP IMI. PAvDparticipated on an advisory board for Octapharma. PvP reports grantsfrom Alexion Pharma and GSK, and participation on advisory boards forGSK and Vifor Pharma. GRAMD’H reports consulting fees from AbbVie,Agomab, AstraZeneca, AM Pharma, AMT, Arena Pharmaceuticals, BristolMyers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, ExeliomBiosciences, Exo Biologics, Galapagos, Index Pharmaceuticals, Kaleido,Roche, Gilead, GSK, Gossamerbio, Pfizer, Immunic, Johnson andJohnson, Origo, Polpharma, Procise Diagnostics, PrometheusLaboratories, Prometheus Biosciences, Progenity, and Protagonist;honoraria from AbbVie, Arena, Galapagos, Gilead, Pfizer, Bristol MyersSquibb, and Takeda; and participation on advisory boards for AbbVie,Seres Health, Galapagos, and AstraZeneca. RBT reports honoraria fromSobi and Norgine, and participation on an advisory board for Norgine.SHG is a board member of the Dutch Society of Clinical Neurophysiology(unpaid), reports grants from Prinses Beatrix Spierfonds, and receivedspeaker fees from Shire/Takeda. KAHZ reports paid data safetymonitoring board positions for Torrent and Foresee. All other authorsdeclare no competing interests., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. Understanding the immune response that provides specific immunity but may also lead to immunopathology is crucial for the design of potential preventive and therapeutic strategies. Here, we characterized and quantified SARS-CoV-2-specific immune responses in patients with different clinical courses. Compared to individuals with a mild clinical presentation, CD4 + T-cell responses were qualitatively impaired in critically ill patients. Strikingly, however, in these patients the specific IgG antibody response was remarkably strong. Furthermore, in these critically ill patients, a massive influx of circulating T cells into the lungs was observed, overwhelming the local T-cell compartment, and indicative of vascular leakage. The observed disparate T- and B-cell responses could be indicative of a deregulated immune response in critically ill COVID-19 patients., (© 2020 Wiley-VCH GmbH.)

Background: Rheumatoid factors (RFs) are autoantibodies that target the Fc region of IgG, and are found in patients with rheumatic diseases as well as in the healthy population. Many studies suggest that an immune trigger may (transiently) elicit RF responses. However, discrepancies between different studies make it difficult to determine if and to which degree RF reactivity can be triggered by vaccination or infection. Objective: We quantitatively explored longitudinal RF responses after SARSCoV- 2 vaccination and infection in a well-defined, large cohort using a dual ELISA method that differentiates between true RF reactivity and background IgM reactivity. In addition, we reviewed existing literature on RF responses after vaccination and infection. Methods: 151 healthy participants and 30 RA patients were included to measure IgM-RF reactivity before and after SARS-CoV-2 vaccinations by ELISA. Additionally, IgM-RF responses after a SARS-CoV-2 breakthrough infection were studied in 51 healthy participants. Results: Published prevalence studies in subjects after infection report up to 85% IgM-RF seropositivity. However, seroconversion studies (both infection and vaccination) report much lower incidences of 2-33%, with a trend of lower percentages observed in larger studies. In the current study, SARS-CoV-2 vaccination triggered low-level IgM-RF responses in 5.5% (8/151) of cases, of which 1.5% (2/151) with a level above 10 AU/mL. Breakthrough infection was accompanied by development of an IgM-RF response in 2% (1/51) of cases. Conclusion: Our study indicates that de novo RF induction following vaccination or infection is an uncommon event, which does not lead to RF epitope spreading. [ABSTRACT FROM AUTHOR]

Background: Humoral responses after SARS-CoV-2 vaccination are greatly impaired in multiple sclerosis (MS) patients on fingolimod. Effects of repeated vaccination and infections on long-term responses are unclear. Methods: Prospective study in 60 MS patients on fingolimod measuring humoral responses after up to four vaccinations and 8 months after fourth vaccination. Results: Anti-WH1 antibody titers increased with each additional vaccination. At long-term follow-up titers increased further and most patients developed new humoral responses against the BA.1 omicron variant. Conclusion: Repeated SARS-CoV-2 vaccinations boost humoral immunity and, probably together with SARS-CoV-2 infections, induce humoral responses on the long-term in almost all patients. [ABSTRACT FROM AUTHOR]

Ocrelizumab, an anti‐CD20 monoclonal antibody, counteracts induction of humoral immune responses after severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) vaccinations in patients with multiple sclerosis (MS). We aimed to assess if serum ocrelizumab concentration measured at the time of vaccination could predict the humoral response after SARS‐CoV‐2 vaccination. In 52 patients with MS, we found ocrelizumab concentration at the time of vaccination to be a good predictor for SARS‐CoV‐2 IgG anti‐RBD titers after vaccination (comparable to B‐cell count). As the course of ocrelizumab concentration may be predicted using pharmacokinetic models, this may be a superior biomarker to guide optimal timing for vaccinations in B‐cell depleted patients with MS. ANN NEUROL 2023;93:103–108 [ABSTRACT FROM AUTHOR]

Introduction: During the COVID-19 pandemic, certain disease modifying therapies (DMTs) used in multiple sclerosis (MS), such as anti-CD20 therapies, have been associated with decreased humoral responses after SARS-CoV-2 vaccination. Hybrid immunity, referring to immunity after both vaccination and SARS-CoV-2 infection might increase humoral responses. Methods: This was a substudy of two prospective cohort studies on SARS-CoV-2 antibodies after SARS-CoV-2 infection and vaccination. RBD-specific IgG titers of patients with MS and healthy controls who had experienced SARS-CoV-2 infection prior to the first vaccination were compared with those patients and healthy controls without prior infection. Humoral responses were measured at various time points after SARS-CoV-2 infection in convalescent patients and all patients prior to the first vaccination, 28 days after the first vaccination, and 28 days after the second vaccination. Results: One hundred and two individuals [of which 34 patients with MS and DMTs (natalizumab or ocrelizumab), 30 patients without DMTs, and 38 healthy controls] were included. Fifty one of these individuals were convalescent. Median SARS-CoV-2 antibody titers were higher after the first vaccination in convalescent individuals compared with individuals without infection prior to vaccination. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody titers were comparable after the second vaccination in patients with MS with and without prior infection. However, in the convalescent ocrelizumab-treated patients, SARS-CoV-2 antibody titers did not increase after vaccinations. Conclusion: In patients with MS without anti-CD20 therapies, SARS-CoV-2 infection before vaccination increases humoral responses after the first vaccination, similar to the healthy controls. In patients with MS treated with ocrelizumab (convalescent and non-convalescent), humoral responses remained low. [ABSTRACT FROM AUTHOR]

Objectives: High‐magnitude CD8+ T cell responses are associated with mild COVID‐19 disease; however, the underlying characteristics that define CD8+ T cell‐mediated protection are not well understood. The antigenic breadth and the immunodominance hierarchies of epitope‐specific CD8+ T cells remain largely unexplored and are essential for the development of next‐generation broad‐protective vaccines. This study identified a broad spectrum of conserved SARS‐CoV‐2 CD8+ T cell epitopes and defined their respective immunodominance and phenotypic profiles following SARS‐CoV‐2 infection. Methods: CD8+ T cells from 51 convalescent COVID‐19 donors were analysed for their ability to recognise 133 predicted and previously described SARS‐CoV‐2‐derived peptides restricted by 11 common HLA class I allotypes using heterotetramer combinatorial coding, which combined with phenotypic markers allowed in‐depth ex vivo profiling of CD8+ T cell responses at quantitative and phenotypic levels. Results: A comprehensive panel of 49 mostly conserved SARS‐CoV‐2‐specific CD8+ T cell epitopes, including five newly identified low‐magnitude epitopes, was established. We confirmed the immunodominance of HLA‐A*01:01/ORF1ab1637–1646 and B*07:02/N105–113 and identified B*35:01/N325–333 as a third epitope with immunodominant features. The magnitude of subdominant epitope responses, including A*03:01/N361–369 and A*02:01/S269–277, depended on the donors' HLA‐I context. All epitopes expressed prevalent memory phenotypes, with the highest memory frequencies in severe COVID‐19 donors. Conclusion: SARS‐CoV‐2 infection induces a predominant CD8+ T memory response directed against a broad spectrum of conserved SARS‐CoV‐2 epitopes, which likely contributes to long‐term protection against severe disease. The observed immunodominance hierarchy emphasises the importance of T cell epitopes derived from nonspike proteins to the overall protective and cross‐reactive immune response, which could aid future vaccine strategies. [ABSTRACT FROM AUTHOR]