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Abstract The COVID-19 pandemic posed a challenge for people living with HIV (PLWH), particularly immune non-responders (INR) with compromised CD4 T-cell reconstitution following antiretroviral therapy (CD4 count

Summary: Background: Understanding cellular responses to SARS-CoV-2 immunisations is important for informing vaccine recommendations in patients with inflammatory bowel disease (IBD) and other vulnerable patients on immunosuppressive therapies. This study investigated the magnitude and quality of T cell responses after multiple SARS-CoV-2 vaccine doses and COVID-19 breakthrough infection. Methods: This prospective, observational study included patients with IBD and arthritis on tumour necrosis factor inhibitors (TNFi) receiving up to four SARS-CoV-2 vaccine doses. T cell responses to SARS-CoV-2 peptides were measured by flow cytometry before and 2–4 weeks after vaccinations and breakthrough infection to assess the frequency and polyfunctionality of responding cells, along with receptor-binding domain (anti-RBD) antibodies. Findings: Between March 2, 2021, and December 20, 2022, 143 patients (118 IBD, 25 arthritis) and 73 healthy controls were included. In patients with either IBD or arthritis, humoral immunity was attenuated compared to healthy controls (median anti-RBD levels 3391 vs. 6280 BAU/ml, p = 0.008) after three SARS-CoV-2 vaccine doses. Patients with IBD had comparable quantities (median CD4 0.11% vs. 0.11%, p = 0.26, CD8 0.031% vs. 0.047%, p = 0.33) and quality (polyfunctionality score: 0.403 vs. 0.371, p = 0.39; 0.105 vs. 0.101, p = 0.87) of spike-specific T cells to healthy controls. Patients with arthritis had lower frequencies but comparable quality of responding T cells to controls. Breakthrough infection increased spike-specific CD8 T cell quality and T cell responses against non-spike peptides. Interpretation: Patients with IBD on TNFi have T cell responses comparable to healthy controls despite attenuated humoral responses following three vaccine doses. Repeated vaccination and breakthrough infection increased the quality of T cell responses. Our study adds evidence that, in the absence of other risk factors, this group may in future be able to follow the general recommendations for COVID-19 vaccines. Funding: South-Eastern Norway Regional Health Authority, Coalition for Epidemic Preparedness Innovations (CEPI), Norwegian Institute of Public Health, Akershus University Hospital, Diakonhjemmet Hospital.

BackgroundSARS-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).MethodsWe 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.FindingsThe 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.InterpretationSARS-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.

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.

Abstract The microenvironment of chronic lymphocytic leukemia (CLL) cells in lymph nodes, spleen, and bone marrow provides survival, proliferation, and drug resistance signals. Therapies need to be effective in these compartments, and pre-clinical models of CLL that are used to test drug sensitivity must mimic the tumor microenvironment to reflect clinical responses. Ex vivo models have been developed that capture individual or multiple aspects of the CLL microenvironment, but they are not necessarily compatible with high-throughput drug screens. Here, we report on a model that has reasonable associated costs, can be handled in a regularly equipped cell lab, and is compatible with ex vivo functional assays including drug sensitivity screens. The CLL cells are cultured with fibroblasts that express the ligands APRIL, BAFF and CD40L for 24 h. The transient co-culture was shown to support survival of primary CLL cells for at least 13 days, and mimic in vivo drug resistance signals. Ex vivo sensitivity and resistance to the Bcl-2 antagonist venetoclax correlated with in vivo responses. The assay was used to identify treatment vulnerabilities and guide precision medicine for a patient with relapsed CLL. Taken together, the presented CLL microenvironment model enables clinical implementation of functional precision medicine in CLL.

Summary: Background: Kidney transplant recipients (KTR) are at high risk for severe COVID-19 and have demonstrated poor response to vaccination, making it unclear whether successive vaccinations offer immunity and protection. Methods: We conducted a serologically guided interventional study where KTR patients that failed to seroconvert were revaccinated and also monitored seroconversion of KTR following the Norwegian vaccination program. We analysed IgG anti-RBD Spike responses from dose 2 (n = 432) up to after the 6th (n = 37) mRNA vaccine dose. The frequency and phenotype of Spike-specific T and B cell responses were assessed in the interventional cohort after 3–4 vaccine doses (n = 30). Additionally, we evaluated the Specific T and B cell response to breakthrough infection (n = 32), measured inflammatory cytokines and broadly cross-neutralizing antibodies, and defined the incidence of COVID-19-related hospitalizations and deaths. The Norwegian KTR cohort has a male dominance (2323 males, 1297 females), PBMC were collected from 114 male and 78 female donors. Findings: After vaccine dose 3, most KTR developed Spike-specific T cell responses but had significantly reduced Spike-binding B cells and few memory cells. The B cell response included a cross-reactive subset that could bind Omicron VOC, which expanded after breakthrough infection (BTI) and gave rise to a memory IgG+ B cell response. After BTI, KTR had increased Spike-specific T cells, emergent non-Spike T and B cell responses, and a systemic inflammatory signature. Late seroconversion occurred after doses 5–6, but 38% (14/37) of KTR had no detectable immunity even after multiple vaccine doses. Interpretation: Boosting vaccination can induce Spike-specific immunity that may expand in breakthrough infections highlighting the benefit of vaccination to protect this vulnerable population. Funding: CEPI and internal funds.

Abstract Diagnostic assays currently used to monitor the efficacy of COVID-19 vaccines measure levels of antibodies to the receptor-binding domain of ancestral SARS-CoV-2 (RBDwt). However, the predictive value for protection against new variants of concern (VOCs) has not been firmly established. Here, we used bead-based arrays and flow cytometry to measure binding of antibodies to spike proteins and receptor-binding domains (RBDs) from VOCs in 12,000 serum samples. Effects of sera on RBD-ACE2 interactions were measured as a proxy for neutralizing antibodies. The samples were obtained from healthy individuals or patients on immunosuppressive therapy who had received two to four doses of COVID-19 vaccines and from COVID-19 convalescents. The results show that anti-RBDwt titers correlate with the levels of binding- and neutralizing antibodies against the Alpha, Beta, Gamma, Delta, Epsilon and Omicron variants. The benefit of multiplexed analysis lies in the ability to measure a wide range of anti-RBD titers using a single dilution of serum for each assay. The reactivity patterns also yield an internal reference for neutralizing activity and binding antibody units per milliliter (BAU/ml). Results obtained with sera from vaccinated healthy individuals and patients confirmed and extended results from previous studies on time-dependent waning of antibody levels and effects of immunosuppressive agents. We conclude that anti-RBDwt titers correlate with levels of neutralizing antibodies against VOCs and propose that our method may be implemented to enhance the precision and throughput of immunomonitoring.

Abstract Background The durability of vaccine-induced humoral immunity against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive therapy is not known. The aim of this study was to compare the persistence of anti-Spike antibodies following two-dose SARS-CoV-2 vaccination between IMID patients and healthy controls and to identify factors associated with antibody decline. Methods IMID patients on immunosuppressive medication enrolled in the prospective observational Nor-vaC study were included. Participants received two-dose SARS-CoV-2 vaccination. Serum collected at two time points following vaccination (first assessment within 6–48 days, second within 49–123 days) were analyzed for antibodies binding the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein. Multivariable regression models estimated percent reduction in anti-RBD over 30 days and factors associated with reduction. Results A total of 1108 patients (403 rheumatoid arthritis, 195 psoriatic arthritis, 195 spondyloarthritis, 124 ulcerative colitis, 191 Crohn’s disease) and 134 controls provided blood samples within the defined intervals (median 19 days [IQR 15–24] and 97 days [87–105] after second vaccine dose). Antibody levels were lower in patients compared to controls at both time points, with median anti-RBD 2806 BAU/ml [IQR 1018–6068] in patients and 6187 BAU/ml [4105–7496] in controls (p

Immune responses in people with multiple sclerosis (pwMS) receiving disease-modifying therapies (DMTs) have been of significant interest throughout the COVID-19 pandemic. Lymphocyte-targeting immunotherapies, including anti-CD20 treatments and sphingosine-1-phosphate receptor (S1PR) modulators, attenuate Ab responses after vaccination. Evaluation of cellular responses after vaccination, therefore, is of particular importance in these populations. In this study, we used flow cytometry to analyze CD4 and CD8 T cell functional responses to SARS-CoV-2 spike peptides in healthy control study participants and pwMS receiving 5 different DMTs. Although pwMS receiving rituximab and fingolimod therapies had low Ab responses after both 2 and 3 vaccine doses, T cell responses in pwMS taking rituximab were preserved after a third vaccination, even when an additional dose of rituximab was administered between vaccine doses 2 and 3. PwMS taking fingolimod had low detectable T cell responses in peripheral blood. CD4 and CD8 T cell responses to SARS-CoV-2 variants of concern Delta and Omicron were lower than to the ancestral Wuhan-Hu-1 variant. Our results indicate the importance of assessing both cellular and humoral responses after vaccination and suggest that, even in the absence of robust Ab responses, vaccination can generate immune responses in pwMS.

The SARS-CoV-2 Omicron variant possess many mutations within the receptor binding domain of the Spike protein, which confer increased transmissibility and higher antibody escape. Here, the authors carry out analysis of the serological and cellular immune responses of individuals with Omicron breakthrough infection.

The management of multiple myeloma (MM) is challenging: An assortment of available drug combinations adds complexity to treatment selection, and treatment resistance frequently develops. Given the heterogeneous nature of MM, personalized testing tools are required to identify drug sensitivities. To identify drug sensitivities in MM cells, we established a drug testing pipeline to examine ex vivo drug responses. MM cells from 44 patients were screened against 30 clinically relevant single agents and 44 double‐ and triple‐drug combinations. We observed variability in responses across samples. The presence of gain(1q21) was associated with low sensitivity to venetoclax, and decreased ex vivo responses to dexamethasone reflected the drug resistance observed in patients. Less heterogeneity and higher efficacy was detected with many combinations compared to the corresponding single agents. We identified new synergistic effects of melflufen plus panobinostat using low concentrations (0.1–10 nm and 8 nm, respectively). In agreement with clinical studies, clinically approved combinations, such as triple combination of selinexor plus bortezomib plus dexamethasone, acted synergistically, and synergies required low drug concentrations (0.1 nm bortezomib, 10 nm selinexor and 4 nm dexamethasone). In summary, our drug screening provided results within a clinically actionable 5‐day time frame and identified synergistic drug efficacies in patient‐derived MM cells that may aid future therapy choices.

Aim: T-helper cells could play an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), a common B-cell neoplasm. Although CLL cells can present soluble antigens targeted from the B-cell receptor to T-helper cells via major histocompatibility complex (MHC) class II, antigens recognized by some CLL cells may be encountered in a particulate form. Here the ability of CLL cells to internalize and present anti-immunoglobulin M (IgM) beads as a model for the interaction of CLL cells with particulate antigens was investigated. Methods: The effect of anti-IgM beads on antigen presentation pathways was analyzed using RNA-seq and internalization of anti-IgM beads by primary CLL cells was investigated using confocal microscopy and flow cytometry. Antigen presentation was investigated by analyzing activation of a T-cell line expressing a T-cell receptor specific for a peptide derived from mouse κ light chains after incubating CLL cells with a mouse κ light chain-containing anti-IgM monoclonal antibody. Kinase inhibitors were used to characterize the pathways mediating internalization and antigen presentation. Results: Stimulation of surface IgM of CLL cells increased expression of the antigen presentation machinery and CLL cells were able to phagocytose anti-IgM beads. Internalization of anti-IgM beads was associated with MHC class II-restricted activation of cognate T-helper cells. Antigen presentation by CLL cells was dependent on activity of spleen tyrosine kinase (SYK) and phosphatidylinositol 3-kinase delta (PI3Kδ) but was unaffected by inhibitors of Bruton’s tyrosine kinase (BTK). Conclusions: CLL cells can internalize and present antigen from anti-IgM beads. This capacity of CLL cells may be particularly important for recruitment of T-cell help in vivo in response to particulate antigens.

Summary: Humoral immunity relies on the efficient differentiation of memory B cells (MBCs) into antibody-secreting cells (ASCs). T helper (Th) signals upregulate B cell receptor (BCR) signaling by potentiating Src family kinases through increasing CD45 phosphatase activity (CD45 PA).In this study, we show that high CD45 PA in MBCs enhances BCR signaling and is essential for their effective ASC differentiation. Mechanistically, Th signals upregulate CD45 PA through intensifying the surface binding of a CD45 ligand, Galectin-1. CD45 PA works as a sensor of T cell help and defines high-affinity germinal center (GC) plasma cell (PC) precursors characterized by IRF4 expression in vivo. Increasing T cell help in vitro results in an incremental CD45 PA increase and enhances ASC differentiation by facilitating effective induction of the transcription factors IRF4 and BLIMP1. This study connects Th signals with BCR signaling through Galectin-1-dependent regulation of CD45 PA and provides a mechanism for efficient ASC differentiation of MBCs.

There is increasing interest in the chronic lymphocytic leukemia (CLL) microenvironment and the mechanisms that may promote CLL cell survival and proliferation. A role for T helper (Th) cells has been suggested, but current evidence is only circumstantial. Here we show that CLL patients had memory Th cells that were specific for endogenous CLL antigens. These Th cells activated autologous CLL cell proliferation in vitro and in human → mouse xenograft experiments. Moreover, CLL cells were efficient antigen-presenting cells that could endocytose and process complex proteins through antigen uptake pathways, including the B cell receptor. Activation of CLL cells by Th cells was contact and CD40L dependent. The results suggest that CLL is driven by ongoing immune responses related to Th cell–CLL cell interaction. We propose that Th cells support malignant B cells and that they could be targeted in the treatment of CLL.

Background To counteract a decreasing number of physician-scientists, a national intercalated Medical Student Research Programme (MSRP) was launched in Norway in 2002. We aimed to assess whether the students’ favourable perceptions and satisfaction with the program had prevailed since the inception in 2002 and until 2015, and to identify factors associated with pursuing a PhD.Methods The study was an incorporation of data from two previous national evaluations of the MSRP performed in 2007 and 2015. We used electronic questionnaires to explore demographic characteristics, area and type of research, student satisfaction, and future scientific goals. In 2007, questionnaires were sent to all 208 students, and 183 (88%) replied. In 2015, the corresponding numbers were 279, and 240 (86%). Categorical data were analysed using either Kruskal-Wallis or Pearson’s chi square test. Differences between sample means were assessed with Student`s t-test while logistic regression was used to test associations between selected covariates and the students’ ambitions to pursue a PhD degree.Results Overall, the student satisfaction was 79%. However, more students in 2015 received less regular and less supervision time and expressed a need for more of it. Seventy-seven per cent expressed an ambition to pursue a PhD. Students were more likely to have a PhD ambition if they were satisfied with the program, had a supervisor with high expectations for them, or had already published some of their results. At both time points, students (86% vs. 89%) responded that the MSRP had a positive impact on their regular curriculum achievements.Conclusions The high degree of satisfaction with the national MSRP among undergraduate students has prevailed since the inception in 2002. By far, the program has also met its goal to increase the number of aspiring physician-scientists. However, to maintain that goal over time, adequate and personal supervision is a prerequisite.

Over the last decades there has been a decline in the recruitment of medical students into academia in all medical fields. Concurrently, medical research has increasingly included other disciplines in multidisciplinary convergence, introducing an unmet recruitment gap and requirement for medical researchers. To counteract the trend and recruit students to academic medicine, a national intercalated Medical Student Research Program (MSRP) was established in Norway in 2002. A preliminary evaluation in 2009 suggested that the MSRP had resulted in recruitment, but could not conclude on a lasting effect beyond graduation in a study that did not include any controls. These results led us to hypothesize that the MSRP could increase the number of PhD degrees and attract medical students towards academic medicine. Adopting a case cohort design, we here report that the intercalated MSRP had a significant impact of the throughput of physician-scientists to PhD, by increasing the rate of PhD completion 10-fold (p

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 MHCIIPOS and MHCIINEG 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 MHCIIPOS and MHCIINEG tumor cells differ. In a TCR transgenic B16 melanoma model, MHCIIPOS melanoma cells are directly killed by cytotoxic CD4+ T cells in a perforin/granzyme B-dependent manner. By contrast, MHCIINEG myeloma cells are killed by IFN-g stimulated M1-like macrophages. In summary, while the priming phase of CD4+ T cells appears similar for MHCIIPOS and MHCIINEG tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed.

Abstract Background During the initial wave of the COVID-19 pandemic, there was a surprisingly low incidence of SARS-CoV-2 among People Who Use Drugs (PWUD) in Oslo, Norway, despite their heightened vulnerability regarding risk of infection and severe courses of the disease.This study aims to investigate the seroprevalence of SARS-CoV-2 antibodies among PWUD, their antibody responses to relevant virus infections and COVID-19 mRNA vaccines, and their vaccination coverage compared to the general population. Methods Conducted as a prospective cohort study, data was collected from residents in six institutions for homeless PWUD and users of a low-threshold clinic for opioid agonist treatment. Ninety-seven participants were recruited for SARS-CoV-2 seroprevalence analysis. Additional two participants with known positive SARS-CoV-2 test results were recruited for further analyses. Twenty-five participants completed follow-up. Data included questionnaires, nasal swabs and blood samples. Data on vaccination coverage was obtained from the National Vaccine Register. Serologic methods included detection of antibodies to relevant virus proteins, neutralizing antibodies to SARS-CoV-2, antibodies to the full-length spike protein, and receptor-binding domain from SARS-CoV-2. Results Among PWUD, antibodies to SARS-CoV-2 were detected in 2 out of 97 samples before vaccines against SARS-CoV-2 were available, comparable to a 2.8% frequency in population-based screening. Levels of serum antibodies to seasonal coronaviruses and Epstein-Barr-Virus (EBV) in PWUD were similar to population-based levels. After the second vaccine dose, binding and neutralizing antibody levels to SARS-CoV-2 in PWUD were comparable to controls. Eighty-four of PWUD received at least one dose of COVID-19 mRNA vaccine, compared to 89% in the general population. Conclusion Results indicate that PWUD did not exhibit increased SARS-CoV-2 seroprevalence or elevated serum antibodies to seasonal coronaviruses and EBV. Moreover, vaccine responses in PWUD were comparable to controls, suggesting that vaccination is effective in conferring protection against SARS-CoV-2 also in this population.

Objectives To assess incidence, severity and predictors of COVID-19, including protective post-vaccination levels of antibodies to the receptor-binding domain of SARS-CoV-2 spike protein (anti-RBD), informing further vaccine strategies for patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive medication.Methods IMIDs on immunosuppressives and healthy controls (HC) receiving SARS-CoV-2 vaccines were included in this prospective observational study. COVID-19 and outcome were registered and anti-RBD antibodies measured 2–5 weeks post-immunisation.Results Between 15 February 2021 and 15 February 2023, 1729 IMIDs and 350 HC provided blood samples and self-reported COVID-19. The incidence of COVID-19 was 66% in patients and 67% in HC, with re-infection occurring in 12% of patients. Severe COVID-19 was recorded in 22 (2%) patients and no HC. No COVID-19-related deaths occurred. Vaccine-induced immunity gave higher risk of COVID-19 (HR 5.89 (95% CI 4.45 to 7.80)) than hybrid immunity. Post-immunisation anti-RBD levels

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.

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.

Objectives Humoral vaccine responses to SARS-CoV-2 vaccines are impaired and short lasting in patients with immune-mediated inflammatory diseases (IMID) following two vaccine doses. To protect these vulnerable patients against severe COVID-19 disease, a three-dose primary vaccination strategy has been implemented in many countries. The aim of this study was to evaluate humoral response and safety of primary vaccination with three doses in patients with IMID.Methods Patients with IMID on immunosuppressive therapy and healthy controls receiving three-dose and two-dose primary SARS-CoV-2 vaccination, respectively, were included in this prospective observational cohort study. Anti-Spike antibodies were assessed 2–4 weeks, and 12 weeks following each dose. The main outcome was anti-Spike antibody levels 2–4 weeks following three doses in patients with IMID and two doses in controls. Additional outcomes were the antibody decline rate and adverse events.Results 1100 patients and 303 controls were included. Following three-dose vaccination, patients achieved median (IQR) antibody levels of 5720 BAU/mL (2138–8732) compared with 4495 (1591–6639) in controls receiving two doses, p=0.27. Anti-Spike antibody levels increased with median 1932 BAU/mL (IQR 150–4978) after the third dose. The interval between the vaccine doses and vaccination with mRNA-1273 or a combination of vaccines were associated with antibody levels following the third dose. Antibody levels had a slower decline-rate following the third than the second vaccine dose, p

Systemic lupus erythematosus (SLE) is marked by a T helper (Th) cell dependent B cell hyperresponsiveness, with frequent germinal center reactions, and gammaglobulinemia. A hallmark 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 other self peptides, matched sequences were increased 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 towards histone peptides similar to anti-dsDNA CDR3 sequences. The results suggest that Th cell in lupus may have multiple cross-reactive specificities linked to the IgVH CDR3 Id-peptide sequences as well as similar DNA-associated protein motifs.

We analyzed for association between the Family with sequence similarity 46, member A (FAM46A) gene (located on chromosome 6q14.1), BCL2-Associated Athanogene 6 (BAG6) gene (located on chromosome 6p21.3) and tuberculosis in Croatian Caucasian. We genotyped the FAM46A rs11040 SNP, FAM46A VNTR and BAG6 rs3117582 polymorphisms in a case-control study with 257 tuberculosis patients and 493 healthy individuals in a Croatian Caucasian population. We found that genotype FAM46A 3/3 (three VNTR repeats homozygote) was associated with susceptibility to tuberculosis (p