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Tetanus-diphtheria vaccine can prime SARS-CoV-2 cross-reactive T cells
Vaccines containing tetanus-diphtheria antigens have been postulated to induce cross-reactive immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which could protect against coronavirus disease (COVID-19). In this work, we investigated the capacity of Tetanus-diphtheria (Td) vaccine to prime existing T cell immunity to SARS-CoV-2. To that end, we first collected known SARS-CoV-2 specific CD8+ T cell epitopes targeted during the course of SARS-CoV-2 infection in humans and identified as potentially cross-reactive with Td vaccine those sharing similarity with tetanus-diphtheria vaccine antigens, as judged by Levenshtein edit distances (≤ 20% edits per epitope sequence). As a result, we selected 25 potentially cross-reactive SARS-CoV-2 specific CD8+ T cell epitopes with high population coverage that were assembled into a synthetic peptide pool (TDX pool). Using peripheral blood mononuclear cells, we first determined by intracellular IFNγ staining assays existing CD8+ T cell recall responses to the TDX pool and to other peptide pools, including overlapping peptide pools covering SARS-CoV-2 Spike protein and Nucleocapsid phosphoprotein (NP). In the studied subjects, CD8+ T cell recall responses to Spike and TDX peptide pools were dominant and comparable, while recall responses to NP peptide pool were less frequent and weaker. Subsequently, we studied responses to the same peptides using antigen-inexperienced naive T cells primed/stimulated in vitro with Td vaccine. Priming stimulations were carried out by co-culturing naive T cells with autologous irradiated peripheral mononuclear cells in the presence of Td vaccine, IL-2, IL-7 and IL-15. Interestingly, naive CD8+ T cells stimulated/primed with Td vaccine responded strongly and specifically to the TDX pool, not to other SARS-CoV-2 peptide pools. Finally, we show that Td-immunization of C57BL/6J mice elicited T cells cross-reactive with the TDX pool. Collectively, our findings support that tetanus-diphtheria vaccines can prime SARS-CoV-2 cross-reactive T cells and likely contribute to shape the T cell responses to the virus.
Comparative transcriptomic analysis of long noncoding RNAs in Leishmania-infected human macrophages
It is well established that infection with Leishmania alters the host cell’s transcriptome. Since mammalian cells have multiple mechanisms to control gene expression, different molecules, such as noncoding RNAs, can be involved in this process. MicroRNAs have been extensively studied upon Leishmania infection, but whether long noncoding RNAs (lncRNAs) are also altered in macrophages is still unexplored. We performed RNA-seq from THP-1-derived macrophages infected with Leishmania amazonensis (La), L. braziliensis (Lb), and L. infantum (Li), investigating a previously unappreciated fraction of macrophage transcriptome. We found that more than 24% of the total annotated transcripts and 30% of differentially expressed (DE) RNAs in Leishmania-infected macrophage correspond to lncRNAs. LncRNAs and protein coding RNAs with altered expression are similar among macrophages infected with the Leishmania species. Still, some species-specific alterations could occur due to distinct pathophysiology in which Li infection led to a more significant number of exclusively DE RNAs. The most represented classes among DE lncRNAs were intergenic and antisense lncRNAs. We also found enrichment for immune response-related pathways in the DE protein coding RNAs, as well as putative targets of the lncRNAs. We performed a coexpression analysis to explore potential cis regulation of coding and antisense noncoding transcripts. We identified that antisense lncRNAs are similarly regulated as its neighbor protein coding genes, such as the BAALC/BAALC-AS1, BAALC/BAALC-AS2, HIF1A/HIF1A-AS1, HIF1A/HIF1A-AS3 and IRF1/IRF1-AS1 pairs, which can occur as a species-specific modulation. These findings are a novelty in the field because, to date, no study has focused on analyzing lncRNAs in Leishmania-infected macrophage. Our results suggest that lncRNAs may account for a novel mechanism by which Leishmania can control macrophage function. Further research must validate putative lncRNA targets and provide additional prospects in lncRNA function during Leishmania infection.
Neutralizing Autoantibodies against Interleukin-10 in Inflammatory Bowel Disease.
We discovered high-titer neutralizing autoantibodies against interleukin-10 in a child with infantile-onset inflammatory bowel disease (IBD), a phenocopy of inborn errors of interleukin-10 signaling. After B-cell-depletion therapy and an associated decrease in the anti-interleukin-10 titer, conventional IBD therapy could be withdrawn. A second child with neutralizing anti-interleukin-10 autoantibodies had a milder course of IBD and has been treated without B-cell depletion. We conclude that neutralizing anti-interleukin-10 autoantibodies may be a causative or modifying factor in IBD, with potential implications for therapy. (Funded by the National Institute for Health and Care Research and others.).
Clinical profile of paediatric acute rheumatic fever and rheumatic heart disease in Western Australia: 1987 to 2020.
AIM: To describe the clinical profile of acute rheumatic fever (ARF) presentations to paediatric cardiology tertiary services in Western Australia (WA). METHODS: A retrospective clinical audit of individuals with confirmed ARF referred to the only paediatric tertiary cardiac service in WA (1 January 1987 to 31 December 2020). Comparisons between inpatient, outpatient, remote and non-remote groups were assessed. RESULTS: Four hundred seventy-one episodes of ARF in 457 individuals (235 male; median age = 8 years) met clinical criteria. The majority were Aboriginal and Torres Strait Islander children (91.2%), with 62.1% living in remote areas. The number of ARF and rheumatic heart disease (RHD) diagnoses per year increased from 1987 to 2017 with notable peaks in 2013 and 2017. The average annual incidence of tertiary-referred ARF in WA of 4-15-year-olds from 1987 to 2020 was 4.96 per 100 000. ARF features included carditis (59.9%), chorea (31%), polyarthritis (30%) and polyarthralgia (24.2%). RHD was evident in 61.8% of cases and predominantly manifested as mitral regurgitation (55.7%). Thirty-four children (7.4%) with severe RHD underwent valvular surgery. 12% had at least one recurrent ARF episode. Remote individuals had more than double the rate of recurrence compared to non-remote individuals (P = 0.0058). Compared to non-remote episodes, remote presentations had less polyarthritis (P = 0.0022) but greater proportions of raised ESR (P = 0.01), ASOT titres (P = 0.0073), erythema marginatum (P = 0.0218) and severe RHD (P = 0.0133). CONCLUSION: The high proportion of Aboriginal and Torres Strait Islander Australians affected by ARF/RHD in WA reflects the significant burden of disease within this population. Children from remote communities were more likely to present with concurrent severe RHD. Our study reinforces the persisting need to improve primary and secondary ARF initiatives in rural and remote communities.
Relationship Between Hand Strength and Function in Duchenne Muscular Dystrophy and Spinal Muscular Atrophy: Implications for Clinical Trials.
BACKGROUND: Measurement of muscle strength and motor function is recommended in clinical trials of neuromuscular diseases, but the loss of hand strength at which motor function is impacted is not documented. OBJECTIVES: To establish the relationship between hand strength and function, and to determine the strength threshold that differentiates normal and abnormal hand function in individuals with Duchenne Muscular Dystrophy (DMD) or Spinal Muscular Atrophy (SMA). METHODS: Maximal handgrip and key pinch strength were measured with the MyoGrip and MyoPinch dynamometers, respectively. Hand function was assessed using the MoviPlate, the Motor Function Measure items for distal upper limb (MFM-D3-UL) and the Cochin Hand Function Scale (CHFS). RESULTS: Data from 168 participants (91 DMD and 77 SMA, age 6-31 years) were analyzed. Relationships between strength and function were significant (P
Investigating brain alterations in the Dp1Tyb mouse model of Down syndrome.
Down syndrome (DS) is one of the most common birth defects and the most prevalent genetic form of intellectual disability. DS arises from trisomy of chromosome 21, but its molecular and pathological consequences are not fully understood. In this study, we compared Dp1Tyb mice, a DS model, against their wild-type (WT) littermates of both sexes to investigate the impact of DS-related genetic abnormalities on the brain phenotype. We performed in vivo whole brain magnetic resonance imaging (MRI) and hippocampal 1H magnetic resonance spectroscopy (MRS) on the animals at 3 months of age. Subsequently, ex vivo MRI scans and histological analyses were conducted post-mortem. Our findings unveiled the following neuroanatomical and biochemical alterations in the Dp1Tyb brains: a smaller surface area and a rounder shape compared to WT brains, with DS males also presenting smaller global brain volume compared with the counterpart WT. Regional volumetric analysis revealed significant changes in 26 out of 72 examined brain regions, including the medial prefrontal cortex and dorsal hippocampus. These alterations were consistently observed in both in vivo and ex vivo imaging data. Additionally, high-resolution ex vivo imaging enabled us to investigate cerebellar layers and hippocampal sub-regions, revealing selective areas of decrease and remodelling in these structures. An analysis of hippocampal metabolites revealed an elevation in glutamine and the glutamine/glutamate ratio in the Dp1Tyb mice compared to controls, suggesting a possible imbalance in the excitation/inhibition ratio. This was accompanied by the decreased levels of taurine. Histological analysis revealed fewer neurons in the hippocampal CA3 and DG layers, along with an increase in astrocytes and microglia. These findings recapitulate multiple neuroanatomical and biochemical features associated with DS, enriching our understanding of the potential connection between chromosome 21 trisomy and the resultant phenotype.
Altered oxidative neurometabolic response to methylene blue in bipolar disorder revealed by quantitative neuroimaging.
BACKGROUND: Cerebral mitochondrial and hemodynamic abnormalities have been implicated in Bipolar Disorder pathophysiology, likely contributing to neurometabolic vulnerability-leading to worsen clinical outcomes and mood instability. To investigate neurometabolic vulnerability in patients with BD, we combined multi-modal quantitative MRI assessment of cerebral oxygenation with acute administration of Methylene Blue, a neurometabolic/hemodynamic modulator acting on cerebral mitochondria. METHODS: Fifteen euthymic patients with chronic BD-type 1, and fifteen age/gender-matched healthy controls underwent two separate MRI sessions in a single-blinded randomized cross-over design, each after intravenous infusion of either MB (0.5 mg/kg) or placebo. MRI-based measures of Cerebral Blood Flow and Oxygen Extraction Fraction were integrated to compute Cerebral Metabolic Rate of Oxygen in Frontal Lobe, Anterior Cingulate, and Hippocampus-implicated in BD neurometabolic pathophysiology. Inter-daily variation in mood rating was used to assess mood instability. RESULTS: A decrease in global CBF and CMRO2 was observed after acutely administrating MB to all participants. Greater regional CMRO2 reductions were observed after MB, in patients compared to controls in FL (mean = -14.2 ± 19.5 % versus 2.3 ± 14.8 %), ACC (mean = -14.8 ± 23.7 % versus 2.4 ± 15.7 %). The effects on CMRO2 in those regions were primarily driven by patients with longer disease duration and higher mood instability. LIMITATIONS: Sample size; medications potentially impacting on response to MB. CONCLUSIONS: An altered neurometabolic response to MB, a mitochondrial/hemodynamic modulator, was observed in patients, supporting the hypothesis of vulnerability to neurometabolic stress in BD. Integrating quantitative imaging of cerebral oxygen metabolism with a mitochondrial-targeting pharmacological challenge could provide a novel biomarker of neurometabolic and cerebrovascular pathophysiology in BD.
A systematic review of immunosuppressive protocols used in AAV gene therapy for monogenic disorders.
The emergence of adeno-associated virus (AAV)-based gene therapy has brought hope to patients with severe monogenic disorders. However, immune responses to AAV vectors and transgene products present challenges that require effective immunosuppressive strategies. This systematic review focuses on the immunosuppressive protocols employed in 38 clinical trials and 35 real-world studies, considering a range of monogenic diseases, AAV serotypes, and administration routes. The review underscores the need for a deeper understanding of immunosuppressive regimens to enhance the safety and effectiveness of AAV-based gene therapy. Characterizing the immunological responses associated with various gene therapy treatments is crucial for optimizing treatment protocols and ensuring the safety and efficacy of forthcoming gene therapy interventions. Further research and understanding of the impact of immunosuppression on disease, therapy, and route of administration will contribute to the development of more effective and safer gene therapy approaches in the future.
A machine learning artefact detection method for single-channel infant event-related potential studies.
Objective Automated detection of artefact in stimulus-evoked electroencephalographic (EEG) data recorded in neonates will improve the reproducibility and speed of analysis in clinical research compared with manual identification of artefact. Some studies use very short, single-channel epochs of EEG data with little recorded EEG per infant - for example because the clinical vulnerability of the infants limits access for recording. Current artefact-detection methods that perform well on adult data and resting-state and multi-channel data in infants are not suitable for this application. The aim of this study was to create and test an automated method of detecting artefact in single-channel 1500 ms epochs of infant EEG. Approach A total of 410 epochs of EEG were used, collected from 160 infants of 28-43 weeks postmenstrual age. This dataset - which was balanced to include epochs of background activity and responses to visual, auditory, tactile and noxious stimuli - was presented to seven independent raters, who independently labelled the epochs according to whether or not they were able to visually identify artefacts. The data was split into a training set (340 epochs) and an independent test set (70 epochs). A random forest model was trained to identify epochs as either artefact or not artefact. Main results This model performs well, achieving a balanced accuracy of 0.81, which is as good as manual review of data. Accuracy was not significantly related to the infant age or type of stimulus. Significance This method provides an objective tool for automated artefact rejection for short epoch, single-channel EEG in neonates and could increase the utility of EEG in neonates in both the clinical and research setting. .
Computational mining of B cell receptor repertoires reveals antigen-specific and convergent responses to Ebola vaccination
Outbreaks of Ebolaviruses, such as Sudanvirus (SUDV) in Uganda in 2022, demonstrate that species other than the Zaire ebolavirus (EBOV), which is currently the sole virus represented in current licensed vaccines, remain a major threat to global health. There is a pressing need to develop effective pan-species vaccines and novel monoclonal antibody-based therapeutics for Ebolavirus disease. In response to recent outbreaks, the two dose, heterologous Ad26.ZEBOV/MVA-BN-Filo vaccine regimen was developed and was tested in a large phase II clinical trial (EBL2001) as part of the EBOVAC2 consortium. Here, we perform bulk sequencing of the variable heavy chain (VH) of B cell receptors (BCR) in forty participants from the EBL2001 trial in order to characterize the BCR repertoire in response to vaccination with Ad26.ZEBOV/MVA-BN-Filo. We develop a comprehensive database, EBOV-AbDab, of publicly available Ebolavirus-specific antibody sequences. We then use our database to predict the antigen-specific component of the vaccinee repertoires. Our results show striking convergence in VH germline gene usage across participants following the MVA-BN-Filo dose, and provide further evidence of the role of IGHV3–15 and IGHV3–13 antibodies in the B cell response to Ebolavirus glycoprotein. Furthermore, we found that previously described Ebola-specific mAb sequences present in EBOV-AbDab were sufficient to describe at least one of the ten most expanded BCR clonotypes in more than two thirds of our cohort of vaccinees following the boost, providing proof of principle for the utility of computational mining of immune repertoires.
An Interrupted Time Series Analysis of the Impact of the COVID-19 Pandemic on Routine Vaccination Uptake in Kenya
A strategic priority of the World Health Organization’s Immunization Agenda 2030 is to increase vaccination coverage and equity through reaching “zero-dose” children. Through an ecological study, we sought to quantify the impact of the COVID-19 pandemic on the coverage of the pentavalent and the measles/rubella vaccines in Kenya, without implying causality. The monthly number of doses from January 2017 to August 2022 were obtained from the Kenya Health Information System for the pentavalent and the measles/rubella vaccines. Immediate (step) and long-term (ramp) changes following interruptions occurring during the period from March 2020 to December 2020 were assessed through an interrupted time series analysis using an autoregressive integrated moving average (ARIMA) model, accounting for seasonality. In December 2020, there was an immediate decrease of 8337, 12,212, and 20,848 in the number of doses for the first, second, and third dose of the pentavalent vaccine, respectively (statistically significant for the third dose only). This corresponded to a percentage relative difference of −21.6, −20.1, and −24.5, respectively, for three doses of pentavalent vaccines, while for measles/rubella vaccine it was −27.3 and −33.6, respectively, for the first and second dose. COVID-19 resulted in interruptions affecting routine immunization, but recovery occurred within four months.
Review of the current TB human infection studies for use in accelerating TB vaccine development: A meeting report.
Tools to evaluate and accelerate tuberculosis (TB) vaccine development are needed to advance global TB control strategies. Validated human infection studies for TB have the potential to facilitate breakthroughs in understanding disease pathogenesis, identify correlates of protection, develop diagnostic tools, and accelerate and de-risk vaccine and drug development. However, key challenges remain for realizing the clinical utility of these models, which require further discussion and alignment amongst key stakeholders. In March 2023, the Wellcome Trust and the International AIDS Vaccine Initiative (IAVI) convened international experts involved in developing both TB and Bacillus Calmette-Guerin (BCG) human infection studies (including mucosal and intradermal challenge routes) to discuss the status of each of the models and the key enablers to move the field forward. This report provides a summary of the presentations and discussion from the meeting. Discussions identified key issues, including demonstrating model validity, to provide confidence for vaccine developers, which may be addressed through demonstration of known vaccine effects, e.g. BCG vaccination in specific populations, and by comparing results from field efficacy and human infection studies. The workshop underscored the importance of establishing safe and acceptable studies in high-burden settings, and the need to validate more than one model to allow for different scientific questions to be addressed as well as to provide confidence to vaccine developers and regulators around use of human infection study data in vaccine development and licensure pathways.
Emergency medical services utilisation among febrile children attending emergency departments across Europe: an observational multicentre study.
Children constitute 6-10% of all patients attending the emergency department (ED) by emergency medical services (EMS). However, discordant EMS use in children occurs in 37-61% with fever as an important risk factor. We aimed to describe EMS utilisation among febrile children attending European EDs. This study is part of an observational multicentre study assessing management and outcome in febrile children up to 18 years (MOFICHE) attending twelve EDs in eight European countries. Discordant EMS use was defined as the absence of markers of urgency including intermediate/high triage urgency, advanced diagnostics, treatment, and admission in children transferred by EMS. Multivariable logistic regression analyses were performed for the association between (1) EMS use and markers of urgency, and (2) patient characteristics and discordant EMS use after adjusting all analyses for the covariates age, gender, visiting hours, presenting symptoms, and ED setting. A total of 5464 (15%, range 0.1-42%) children attended the ED by EMS. Markers of urgency were more frequently present in the EMS group compared with the non-EMS group. Discordant EMS use occurred in 1601 children (29%, range 1-59%). Age and gender were not associated with discordant EMS use, whereas neurological symptoms were associated with less discordant EMS use (aOR 0.2, 95%CI 0.1-0.2), and attendance out of office hours was associated with more discordant EMS use (aOR 1.6, 95%CI 1.4-1.9). Settings with higher percentage of self-referrals to the ED had more discordant EMS use (p
Changes in bone marrow fibrosis during momelotinib or ruxolitinib therapy do not correlate with efficacy outcomes in patients with myelofibrosis.
Bone marrow fibrosis (BMF) is a pathological feature of myelofibrosis, with higher grades associated with poor prognosis. Limited data exist on the association between outcomes and BMF changes. We present BMF data from Janus kinase (JAK) inhibitor-naive patients from SIMPLIFY-1 (NCT01969838), a double-blind, randomized, phase 3 study of momelotinib vs ruxolitinib. Baseline and week 24 bone marrow biopsies were graded from 0 to 3 as per World Health Organization criteria. Other assessments included Total Symptom Score, spleen volume, transfusion independence status, and hemoglobin levels. Paired samples were available from 144 and 160 patients randomized to momelotinib and ruxolitinib. With momelotinib and ruxolitinib, transfusion independence was achieved by 87% and 44% of patients with BMF improvement of ≥1 grade and 76% and 56% of those with stable/worsening BMF; there was no association between BMF changes and transfusion independence for either arm (momelotinib, p = .350; ruxolitinib, p = .096). Regardless of BMF changes, hemoglobin levels also generally increased on momelotinib but decreased on ruxolitinib. In addition, no associations between BMF changes and spleen (momelotinib, p = .126; ruxolitinib, p = .407)/symptom (momelotinib, p = .617; ruxolitinib, p = .833) outcomes were noted, and no improvement in overall survival was observed with ≥1-grade BMF improvement (momelotinib, p = .395; ruxolitinib, p = .407). These data suggest that the anemia benefit of momelotinib is not linked to BMF changes, and question the use of BMF assessment as a surrogate marker for clinical benefit with JAK inhibitors.
Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis.
The ACE-536-MF-001 trial enrolled patients with myelofibrosis (n = 95) into 4 cohorts: patients in cohorts 1 and 3A were non-transfusion dependent (NTD) and had anemia; patients in cohorts 2 and 3B were transfusion dependent (TD); patients in cohort 3A/3B had stable ruxolitinib treatment prior to and during the study. All patients received luspatercept (1.0-1.75 mg/kg, 21-day cycles). Treatment was extended if clinical benefit was observed at day 169. The primary endpoint was anemia response rate (NTD, ≥1.5 g/dL hemoglobin increase from baseline; TD, transfusion-independence) over any 12-week period during the primary treatment period (weeks 1-24). Overall, 14% of patients in cohorts 1 and 3A, 10% in cohort 2, and 26% in cohort 3B met the primary endpoint. In cohorts 1 and 3A (NTD), 27% and 50% of patients respectively had mean hemoglobin increase ≥1.5 g/dL from baseline. Among TD patients, ~50% had ≥50% reduction in transfusion burden. Reduction in total symptom score was observed in all cohorts, with the greatest response rate seen in cohort 3A. Overall, 94% of patients had ≥1 adverse event (AE); 47% had ≥1 treatment-related AE (TRAE; 11% grade ≥3), most frequently hypertension (18%), managed with medical intervention. One patient had a serious TRAE leading to luspatercept discontinuation. Nine patients died on treatment (unrelated to study drug). In most patients, ruxolitinib dose and spleen size remained stable. In patients with myelofibrosis, luspatercept improved anemia and transfusion burden across cohorts; the safety profile was consistent with previous studies. NCT03194542 clinicaltrials.gov.