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Background: SARS-CoV-2 vaccination in rheumatoid arthritis (RA) patients treated with B cell-depleting drugs induced limited seroconversion but robust cellular response. We aimed to document specific T and B cell immunity in response to vaccine booster doses and breakthrough infection (BTI)., Methods: We included 76 RA patients treated with rituximab who received up to four SARS-CoV-2 vaccine doses or three doses plus BTI, in addition to vaccinated healthy donors (HD) and control patients treated with tumor necrosis factor inhibitor (TNFi). We quantified anti-SARS-CoV-2 receptor-binding domain (RBD) Spike IgG, anti-nucleocapsid (NC) IgG, 92 circulating inflammatory proteins, Spike-binding B cells, and Spike-specific T cells along with comprehensive high-dimensional phenotyping and functional assays., Findings: The time since the last rituximab infusion, persistent inflammation, and age were associated with the anti-SARS-CoV-2 RBD IgG seroconversion. The vaccine-elicited serological response was accompanied by an incomplete induction of peripheral Spike-specific memory B cells but occurred independently of T cell responses. Vaccine- and BTI-elicited cellular immunity was similar between RA and HD ex vivo in terms of frequency or phenotype of Spike-specific cytotoxic T cells and in vitro in terms of the functionality and differentiation profile of Spike-specific T cells., Interpretation: SARS-CoV-2 vaccination in RA can induce persistent effector T-cell responses that are reactivated by BTI. Paused rituximab medication allowed serological responses after a booster dose (D4), especially in RA with lower inflammation, enabling efficient humoral and cellular immunity after BTI, and contributed overall to the development of potential durable immunity., Competing Interests: JV reports grants from the Coalition of Epidemic Preparedness Innovations. GG reports funding from the South-Eastern Norway Regional Health Authority, Dr. Trygve Gythfeldt og frues forskningsfond, Karin Fossum Foundation, the Research Foundation at Diakonhjemmet Hospital, speakers’ bureaus from AbbVie, Galapagos, Pfizer, and Union Chimique Belge; and participation on advisory board of AbbVie, Galapagos, Pfizer, and Union Chimique Belge. LM reports funding from the KG Jebsen Foundation, support for infrastructure and biobanking from the University of Oslo and Oslo University Hospital, grants from the Coalition of Epidemic Preparedness Innovations, RCN Covid 312693, a KG Jebsen Foundation grant 19, and speakers bureaus from Novartis, and Cellgene. EH reports grants from The Research Council of Norway during the conduct of the study; and for the last 36 months outside of the submitted work: speaker/consultant fees from Pfizer, AbbVie, Gilead, UCB Pharma, Galapagos, Eli Lilly, Novartis, Boehringer Ingelheim. KJ reports speaker fees from BMS and Janssen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kared, Jyssum, Alirezaylavasani, Egner, The Tran, Tietze, Lund, Tveter, Provan, Ørbo, Haavardsholm, Vaage, Jørgensen, Syversen, Lund-Johansen, Goll and Munthe.)

People who use drugs (PWUD) are at a high risk of contracting and developing severe coronavirus disease 2019 (COVID-19) and other infectious diseases due to their lifestyle, comorbidities, and the detrimental effects of opioids on cellular immunity. However, there is limited research on vaccine responses in PWUD, particularly regarding the role that T cells play in the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we show that before vaccination, PWUD did not exhibit an increased frequency of preexisting cross-reactive T cells to SARS-CoV-2 and that, despite the inhibitory effects that opioids have on T-cell immunity, standard vaccination can elicit robust polyfunctional CD4 + and CD8 + T-cell responses that were similar to those found in controls. Our findings indicate that vaccination stimulates an effective immune response in PWUD and highlight targeted vaccination as an essential public health instrument for the control of COVID-19 and other infectious diseases in this group of high-risk patients., Competing Interests: Authors MG, RS, ST, BM and TC were employed by company NEC OncoImmunity AS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gainullin, Federico, Røkke Osen, Chaban, Kared, Alirezaylavasani, Lund-Johansen, Wildendahl, Jacobsen, Sarwar Anjum, Stratford, Tennøe, Malone, Clancy, Vaage, Henriksen, Wüsthoff and Munthe.)

During the COVID-19 pandemic we utilized an AI-driven T cell epitope prediction tool, the NEC Immune Profiler (NIP) to scrutinize and predict regions of T cell immunogenicity (hotspots) from the entire SARS-CoV-2 viral proteome. These immunogenic regions offer potential for the development of universally protective T cell vaccine candidates. Here, we validated and characterized T cell responses to a set of minimal epitopes from these AI-identified universal hotspots. Utilizing a flow cytometry-based T cell activation-induced marker (AIM) assay, we identified 59 validated screening hits, of which 56% (33 peptides) have not been previously reported. Notably, we found that most of these novel epitopes were derived from the non-spike regions of SARS-CoV-2 (Orf1ab, Orf3a, and E). In addition, ex vivo stimulation with NIP-predicted peptides from the spike protein elicited CD8 + T cell response in PBMC isolated from most vaccinated donors. Our data confirm the predictive accuracy of AI platforms modelling bona fide immunogenicity and provide a novel framework for the evaluation of vaccine-induced T cell responses., Competing Interests: BM, ST, RS, and TC are employees of the commercial company NEC OncoImmunity. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Federico, Malone, Tennøe, Chaban, Osen, Gainullin, Smorodina, Kared, Akbar, Greiff, Stratford, Clancy and Munthe.)

Poor overall survival of hematopoietic stem cell transplantation (HSCT) recipients who developed COVID-19 underlies the importance of SARS-CoV-2 vaccination. Previous studies of vaccine efficacy have reported weak humoral responses but conflicting results on T cell immunity. Here, we have examined the relationship between humoral and T cell response in 48 HSCT recipients who received two doses of Moderna's mRNA-1273 or Pfizer/BioNTech's BNT162b2 vaccines. Nearly all HSCT patients had robust T cell immunity regardless of protective humoral responses, with 18/48 (37%, IQR 8.679-5601 BAU/mL) displaying protective IgG anti-receptor binding domain (RBD) levels (>2000 BAU/mL). Flow cytometry analysis of activation induced markers (AIMs) revealed that 90% and 74% of HSCT patients showed reactivity towards immunodominant spike peptides in CD8 + and CD4 + T cells, respectively. The response rate increased to 90% for CD4 + T cells as well when we challenged the cells with a complete set of overlapping peptides spanning the entire spike protein. T cell response was detectable as early as 3 months after transplant, but only CD4 + T cell reactivity correlated with IgG anti-RBD level and time after transplantation. Boosting increased seroconversion rate, while only one patient developed COVID-19 requiring hospitalization. Our data suggest that HSCT recipients with poor serological responses were protected from severe COVID-19 by vaccine-induced T cell responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Federico, Tvedt, Gainullin, Osen, Chaban, Lund, Tietze, Tran, Lund-Johansen, Kared, Lind, Vaage, Stratford, Tennøe, Malone, Clancy, Myhre, Gedde-Dahl and Munthe.)

Systemic lupus erythematosus (SLE) is marked by a T helper (Th) cell-dependent B cell hyperresponsiveness, with frequent germinal center reactions, and gammaglobulinemia. A feature of SLE is the finding of IgG autoantibodies specific for dsDNA. The specificity of the Th cells that drive the expansion of anti-dsDNA B cells is unresolved. However, anti-microbial, anti-histone, and anti-idiotype Th cell responses have been hypothesized to play a role. It has been entirely unclear if these seemingly disparate Th cell responses and hypotheses could be related or unified. Here, we describe that H chain CDR3 idiotypes from IgG(+) B cells of lupus mice have sequence similarities with both microbial and self peptides. Matched sequences were more frequent within the mutated CDR3 repertoire and when sequences were derived from lupus mice with expanded anti-dsDNA B cells. Analyses of histone sequences showed that particular histone peptides were similar to VDJ junctions. Moreover, lupus mice had Th cell responses toward histone peptides similar to anti-dsDNA CDR3 sequences. The results suggest that Th cells in lupus may have multiple cross-reactive specificities linked to the IgVH CDR3 Id-peptide sequences as well as similar DNA-associated protein motifs.

CD4(+) T cells contribute to tumor eradication, even in the absence of CD8(+) T cells. Cytotoxic CD4(+) T cells can directly kill MHC class II positive tumor cells. More surprisingly, CD4(+) T cells can indirectly eliminate tumor cells that lack MHC class II expression. Here, we review the mechanisms of direct and indirect CD4(+) T cell-mediated elimination of tumor cells. An emphasis is put on T cell receptor (TCR) transgenic models, where anti-tumor responses of naïve CD4(+) T cells of defined specificity can be tracked. Some generalizations can tentatively be made. For both MHCII(POS) and MHCII(NEG) tumors, presentation of tumor-specific antigen by host antigen-presenting cells (APCs) appears to be required for CD4(+) T cell priming. This has been extensively studied in a myeloma model (MOPC315), where host APCs in tumor-draining lymph nodes are primed with secreted tumor antigen. Upon antigen recognition, naïve CD4(+) T cells differentiate into Th1 cells and migrate to the tumor. At the tumor site, the mechanisms for elimination of MHCII(POS) and MHCII(NEG) tumor cells differ. In a TCR-transgenic B16 melanoma model, MHCII(POS) melanoma cells are directly killed by cytotoxic CD4(+) T cells in a perforin/granzyme B-dependent manner. By contrast, MHCII(NEG) myeloma cells are killed by IFN-γ stimulated M1-like macrophages. In summary, while the priming phase of CD4(+) T cells appears similar for MHCII(POS) and MHCII(NEG) tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed.