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The APPG on Malaria & NTDs gathered on Tuesday, March 19th in Westminster at the Houses of Parliament.
An RBD-Fc mucosal vaccine provides variant-proof protection against SARS-CoV-2 in mice and hamsters.
Current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are effective against severe disease and death, but do not prevent viral infections, probably due to the limited mucosal immunity induced by intramuscular administration of the vaccine. Fusion of SARS-CoV-2 subunit immunogens with a human IgG Fc backbone can be used as a mucosal vaccine but its effectiveness in delivery in animal models, and its immunogenicity and the vaccine-induced protection against viral infections requires further studies. Here we investigate a bivalent RBD-Fc vaccine that includes the spike receptor-binding domains (RBDs) of the ancestral and BQ.1.1 variant of SARS-CoV-2. Ex vivo fluorescent imaging demonstrates that this vaccine can be effectively delivered to the lungs of mice through intranasal administration, with enhancement of retention in the nasal cavity and lung parenchyma. In mice, the vaccine elicited potent and broad-spectrum antibody responses against different variants including KP.3 which could persist for at least 3 months after booster. Importantly, it was able to induce RBD-specific mucosal IgA responses. Further, heterologous intranasal immunisation with adeno-vectored Chadv1 and RBD-Fc elicited both potent neutralising antibody and T cell responses. Immunised BALB/c and K18-hACE2-transgenic mice were also protected against viral challenge of XBB.1 and viral transmission was effectively limited in hamsters through intranasal immunisation. This work thus demonstrates the potential of RBD-Fc antigens as mucosal vaccines for prevention of breakthrough infections and onward transmission. Moreover, Fc-fusion proteins can be used as an effective mucosal vaccine strategy which can be used either alone or in combination with other vaccine technology to constitute heterologous immunisations, enabling strong protection against SARS-CoV-2 and other respiratory viruses.
Detection of Mycoplasma pneumoniae in hospitalized children with pneumonia in Laos
Mycoplasma pneumoniae has been described worldwide as an important cause of community-acquired pneumonia. From December 2013 to December 2014, 461 children admitted to Mahosot Hospital, Vientiane, Laos, with acute respiratory infection were investigated for upper respiratory microorganisms using probe-based real-time polymerase chain reaction (PCR) (FTD33). M. pneumoniae was detected by FTD33 in the upper respiratory tract of three patients, two girls and one boy, 5.7 and 3.9 years old and 13.6 years old, respectively. They presented with clinical features compatible with M. pneumoniae infection. They improved without M. pneumoniae directed therapy. The two girls were also positive for other potential pathogens. The boy had abnormal pulmonary auscultation, and one of the girls had significant anaemia. These results suggest that enhancement of diagnostic systems for M. pneumoniae detection is needed to improve understanding of the epidemiology of M. pneumoniae infection in Laos.
Effect of a Laparoscopic Donor Nephrectomy in Healthy Living Kidney Donors on the Acute Phase Response Using Either Propofol or Sevoflurane Anesthesia
Surgical trauma elicits a complex inflammatory stress response, contributing to postoperative morbidity and recovery variability. This response is influenced by patient-specific factors and surgical and anesthetic techniques. To isolate the impact of anesthesia on the acute phase response, we investigated plasma proteomic changes in a uniquely homogeneous cohort of healthy, living kidney donors (n = 36; propofol = 19; sevoflurane = 17) undergoing laparoscopic donor nephrectomy. Proteomic profiling of plasma samples collected preoperatively and at 2 and 24 h postoperatively revealed 633 quantifiable proteins, of which 22 showed significant perioperative expression changes. Eight proteins exhibited over two-fold increases, primarily related to the acute phase response (CRP, SAA1, SAA2, LBP), tissue repair (FGL1, A2GL), and anti-inflammatory regulation (AACT). These changes were largely independent of anesthetic type, though SAA2 and MAN1A1 showed anesthetic-specific expression. The upregulation of these proteins implicates the activation of immune pathways involved in host defense, tissue remodeling, and inflammation resolution. Our findings provide a molecular reference for the surgical stress response in healthy individuals and highlight candidate biomarkers for predicting and managing postoperative outcomes. Understanding these pathways may support the development of strategies to mitigate surgical stress and enhance recovery, particularly in vulnerable patient populations.
Efficacy of artemisinin-based combination therapy (ACT) in people living with HIV (PLHIV) diagnosed with uncomplicated Plasmodium falciparum malaria in Africa: a WWARN systematic review.
BackgroundAfrica bears the highest double burden of HIV and malaria worldwide. In 2023, an estimated 25.9 million people were living with HIV (PLHIV), and 246 million malaria cases were diagnosed in Africa. Malaria patients co-infected with HIV are considered at a higher risk of failing malaria treatment, according to the World Health Organization (WHO) guidelines. This systematic literature review aims to assess the treatment outcomes following artemisinin-based combination therapy (ACT) in PLHIV.MethodsThe literature search was conducted up to April 2022 in the following databases: MEDLINE, EMBASE, Web of Science, Cochrane Central, WHO Global Index Medicus, Clinicaltrials.gov, and the WorldWide Antimalarial Resistance Network (WWARN) Clinical Trial Library. Studies describing any malaria treatment outcomes or anti-malarial drug exposure in PLHIV treated for uncomplicated Plasmodium falciparum malaria infection were eligible for inclusion.ResultsA total of 26 articles describing 19 studies conducted between 2003 and 2017 in six countries were included in this review; it represented 2850 malaria episodes in PLHIV across various transmission settings. The most studied artemisinin-based combination was artemether-lumefantrine (in 16 studies). PLHIV were treated with various antiretroviral therapy (ART) regimens, namely efavirenz (EFV), nevirapine (NVP), atazanavir-ritonavir (ATVr), lopinavir-ritonavir (LPV/r), and/or on prophylaxis with trimethoprim-sulfamethoxazole (TS), or were untreated (in 3 studies). There was no evidence of an increased risk of recrudescence in PLHIV compared to those without HIV. When treated with artemether-lumefantrine, PLHIV receiving LPV/r had a lower risk of malaria recurrence compared to PLHIV on NVP-based or EFV-based ART, or those without HIV. LPV/r increased lumefantrine exposure and EFV-treated patients had a reduced exposure to both artemether and lumefantrine; NVP reduced artemether exposure only.ConclusionsLimited data on ACT outcomes or drug exposure in PLHIV in Africa remains a reality to date, and the effect of antivirals appears inconsistent in the literature. Considering the heterogeneity in study designs, these review's findings support conducting an individual patient data meta-analysis to explore the impact of antiretroviral therapy on anti-malarial treatment.Trial registrationThe protocol for the original search was published on PROSPERO with registration number CRD42018089860.
CD4+ tissue-resident memory Th17 cells are a major source of IL-17A in Spondyloarthritis synovial tissue.
OBJECTIVES: Interleukin (IL)-17A is a key driver of spondyloarthritis (SpA) joint pathology. We aimed to identify its cellular source in synovial tissue from patients with 2 forms of SpA, namely axial SpA (AxSpA) and psoriatic arthritis (PsA). METHODS: Synovial tissue from patients with SpA was profiled using single-cell RNA sequencing (scRNA-seq; AxSpA, n = 5; PsA, n = 6) or spatial RNA profiling (PsA, n = 4). CellPhoneDB was used to infer cell-cell communication. Tissue-resident memory Th17 (TRM17)-like cells were generated in vitro using blood memory CD4+ T cells from SpA patients. An epigenetic inhibitor library, siRNA, and clustered regularly interspaced short palindromic repeats (CRISPR) were used to identify epigenetic regulator(s) for TRM17. RESULTS: scRNA-seq showed that CD4+CXCR6+ TRM17 cells are the predominant spontaneous IL17A producers in SpA synovium. Cell-cell communication and single-cell spatial analysis support the interaction between TRM17 and CLEC10A+ dendritic cells, which were activated in SpA. Both sublining and lining fibroblasts in SpA synovium showed evidence of interleukin (IL)-17A activation. In vitro-generated CD4+ TRM17-like cells phenocopied joint tissue TRM17, producing IL-17A/F upon T cell-receptor (TCR) stimulation, which was further enhanced by cytokines. Perturbation of BRD1 inhibited the generation of TRM17-like cells. CONCLUSIONS: CD4+ TRM17 cells are the predominant source of IL-17A in SpA synovial tissue. TCR stimulation is essential for the secretion of IL-17A by CD4+TRM17-like cells. The epigenetic regulator bromodomain-containing protein 1 (BRD1) contributes to the generation of CD4+TRM17. Depleting CD4+TRM17 cells in SpA is thus a therapeutic strategy with potential to induce long-term remission.
Treatment outcomes in patients with VEXAS syndrome: a retrospective cohort study.
BACKGROUND: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently described autoinflammatory disorder with little therapeutic evidence. We compared treatment outcomes of targeted therapies versus prednisolone alone in the largest UK cohort of patients with VEXAS syndrome to date. METHODS: In this retrospective cohort study, we analysed the outcomes of targeted therapies in patients with VEXAS syndrome in six tertiary referral centres across the UK between July 22, 2014, and Oct 19, 2024. The inclusion criteria were genetically confirmed VEXAS syndrome and receipt of at least one targeted therapy or prednisolone alone. Patients without clinical information at all timepoints after baseline were excluded. Data collection forms were used to record clinical and biochemical data at the following timepoints: time of diagnosis, initiation of treatment, and follow-up at 3 months, 6 months, and 12 months from the initiation of treatment (±28 days). Laboratory parameters, including C-reactive protein (CRP) and haemoglobin, and glucocorticoid doses were collected at each timepoint and compared between timepoints. Primary outcomes were complete response (ie, clinical remission, CRP ≤10 mg/L, and prednisolone ≤10 mg per day) and partial response (ie, clinical remission with ≥50% reductions in both CRP and glucocorticoid dose from baseline) to treatment. Treatment discontinuation and adverse events were documented for each treatment. Due to the high prevalence of cytopenias in VEXAS syndrome, these were only recorded as adverse events when necessitating treatment change. People with lived experience were not involved in the study. FINDINGS: We analysed 71 targeted therapies in 59 patients with genetically confirmed VEXAS syndrome. Of the 59 patients, 58 (98%) were male and one (2%) was female, with a mean age of 71 years (SD 8), and 27 (46%) had myelodysplastic syndrome. The treatments included tocilizumab (n=19), anakinra (n=13), azacitidine (n=13), baricitinib (n=11), and prednisolone only (n=10). At 6 months, in those who continued therapy, ten (91%) of 11 patients receiving azacitidine showed a response (three [27%] complete responses), as well as did seven (64%) of 11 receiving tocilizumab (four [36%] complete responses), three (100%) of three receiving anakinra (one [33%] complete response), and two (40%) of five receiving baricitinib (no complete responses). Although all patients who tolerated anakinra had a response, the discontinuation rate was high (eight [62%] of 13), mostly due to severe injection-site reactions (n=5). Patients were more likely to respond to azacitidine than to other therapies at 6 months (risk ratio 2·47, 95% CI 1·18-5·20; p=0·018). Absence of fever or thromboembolism at diagnosis was associated with better outcomes. By 6 months, median CRP concentrations had decreased in patients receiving tocilizumab (from 30 mg/L [IQR 13-45] to 4 mg/L [3-37]) or anakinra (from 18 mg/L [11-52] to 2 mg/L [1-28]), whereas azacitidine showed the greatest increase in haemoglobin (from mean concentration 104 g/L [SD 17·5] to 120 g/L [14·4]). 28 (39%) of 71 treatments were discontinued, most commonly due to serious adverse events (12 [17%]) and death (nine [13%]). Infections were most frequent with azacitidine (eight [62%] of 13) and tocilizumab (nine [47%] of 19). INTERPRETATION: In this UK cohort of patients with VEXAS syndrome, azacitidine and tocilizumab showed superior effectiveness compared with anakinra, baricitinib, and prednisolone only. Treatment selection should consider individual risk factors and tolerability. Prospective studies are needed to confirm optimal treatment strategies and develop standardised protocols. FUNDING: None.
Early mucosal responses following a randomised controlled human inhaled infection with attenuated Mycobacterium bovis BCG
Abstract The development of an effective vaccine against Mycobacterium tuberculosis is hampered by an incomplete understanding of immunoprotective mechanisms. We utilise an aerosol human challenge model using attenuated Mycobacterium bovis BCG, in BCG-naïve UK adults. The primary endpoint of this study (NCT03912207) was to characterise the early immune responses induced by aerosol BCG infection, the secondary endpoint was to identify immune markers associated with in-vitro protection. Blinded volunteers were randomised to inhale 1 × 107 CFU aerosolised BCG or 0.9% saline (20:6); and sequentially allocated to bronchoscopy at day 2 or 7 post-inhalation (10 BCG, 3 saline each timepoint). In the bronchoalveolar lavage post-aerosol BCG infection, there was an increase in frequency of eosinophils, neutrophils, NK cells and Donor-Unrestricted T cells at day 7, and the frequency of antigen presenting cells decreased at day 7 compared with day 2. The frequency of interferon-gamma+ BCG-specific CD4+ T cells increased in the BAL and peaked in the blood at day 7 post-BCG infection compared to day 2. BAL cells at day 2 and day 7 upregulated gene pathways related to phagocytosis, MHC-II antigen loading, T cell activation and proliferation. BCG’s lack of key virulence factors and its failure to induce granulomas, may mean the observed immune responses do not fully recapitulate Mycobacterium tuberculosis infection. However, human infection models can provide unique insights into early immune mechanisms, informing vaccine design for complex pathogens.
A pragmatic randomized controlled trial of standard care versus corticosteroids plus standard care for treatment of pneumonia in adults admitted to Kenyan hospitals (SONIA)
Background Mortality among adults admitted to hospital with community acquired pneumonia in resource-limited settings is high. Recent studies conducted in high-income settings have demonstrated beneficial effects of low-dose corticosteroids in reducing mortality in patients with severe community acquired pneumonia. It is unknown whether these findings apply to low-income settings such as sub-Saharan Africa. This pragmatic randomized-controlled open-label trial will determine the effect of adjunctive low-dose corticosteroids in the management of adults admitted to hospital with community acquired pneumonia on mortality 30-days post-randomization. Methods We will enroll and randomize 2180 patients admitted with a diagnosis of community acquired pneumonia into two arms: the control and intervention arm. Those in the control arm will receive standard care for the treatment of community acquired pneumonia i.e., combination therapy with a beta-lactam and macrolide antibiotic. Those in the intervention arm will receive up to 10-days treatment with low-dose oral corticosteroids in addition to standard care. All participants will be followed up to 30- days post randomization and their final status recorded (alive or dead). Discussion If adjunctive low-dose oral corticosteroids are found to be beneficial, this easily scalable intervention would significantly reduce the currently high mortality associated with community acquired pneumonia. Pan-African Clinical Trials Registry: PACTR202111481740832; ISRCTRN registry: ISRCTN36138594
Magnetic resonance enterography to predict subsequent disabling Crohn's disease in newly diagnosed patients (METRIC-EF)-multivariable prediction model, multicentre diagnostic inception cohort.
ObjectivesMagnetic resonance enterography (MRE) is a first-line investigation to diagnose Crohn's disease (CD), but its role for prognostication is unknown. Accordingly, we assessed the predictive ability of prognostic models including MRE scores (MRE Global Score (MEGS), simplified MR Index of Activity (sMARIA), and Lémann index (LI)) against models using clinical predictors alone for the development of modified Beaugerie disabling CD (MBDD) within 5 years of diagnosis.MethodsThis was a multicentre, diagnostic inception cohort of patients with newly diagnosed CD across 9 UK hospitals, followed for 4 years or more. We censored development of MBDD ≤ 90 days from diagnosis, and used time-to-event models using Royston-Parmer flexible parametric models.ResultsWe included 194 patients, median age 29, IQR 22-44 years, 52% female. Within 5 years of diagnosis, 42% (81/194) developed MBDD. In univariable analysis, initial steroid requirement was associated with increased risk of developing MBDD (HR 2.11 (95% CI 1.36, 3.26). The baseline clinical model had 49% (39, 60) sensitivity and 66% (57, 74) specificity for predicting the top 40% of patients with the greatest risk of developing MBDD, and 86% (77, 92) sensitivity and 35% (27, 45) specificity for predicting the development of MBDD in patients with an absolute risk of ≥ 10%. There was no significant difference in sensitivity when the MEGS, sMARIA, or LI were added to the baseline clinical model.ConclusionsAddition of MRE scores at diagnosis to a multivariable model comprising clinical predictors did not improve prediction of MBDD within 5 years of diagnosis.Key pointsQuestion Magnetic resonance enterography (MRE) is important for diagnosing and monitoring Crohn's disease (CD), but primary research evaluating its prognostic role is lacking. Findings Adding MRE findings at diagnosis to a multivariable model comprising clinical predictors did not improve the prediction of disabling CD within 5 years of diagnosis. Clinical relevance When tested in a prospective, multicentre trial, current MRE activity and damage scores at diagnosis did not reliably predict whether patients would subsequently develop disabling CD. Notwithstanding this finding, MRE remains an essential tool for diagnosis and monitoring.
How useful is Nanopore adaptive sampling for sequencing Schistosoma mansoni miracidia?
Background Whole-genome sequencing (WGS) is now widely used in Schistosoma genomics. Whilst adult worms typically provide sufficient DNA for molecular analyses, their inaccessibility in live definitive hosts presents a challenge for population studies. Larval stages, such as miracidia can be collected non-invasively and preserved on Whatman FTA cards, however these samples typically yield low quantities of DNA and have high levels of contamination, particularly when obtained from stool samples. To counteract contamination, multiple washing steps prior to placement onto Whatman FTA cards can be performed, but this is labour-intensive and can limit the number of larvae collected. Methods Nanopore sequencing technologies includes an “adaptive sampling” feature, which enables selective enrichment or depletion of target DNA sequences during sequencing. In this study, we evaluated the potential of adaptive sampling to selectively enrich S. mansoni DNA from both washed and unwashed larval stage miracidia. We used Kraken2 to characterise sample contamination and assessed sequencing breadth and depth of genome coverage to determine whether adaptive sampling could provide sufficient S. mansoni DNA for WGS. Results and conclusion Our results demonstrate that washed samples contained a higher proportion of S. mansoni DNA, validating the effectiveness of washing for contamination removal. However, adaptive sampling failed to generate sufficient S. mansoni reads for effective WGS. These findings suggest that, at present, washing remains critical for maximising S. mansoni DNA purity as adaptive sampling alone is insufficient for enrichment. Alternative enrichment strategies will be necessary to improve sequencing efficiency and data quality for S. mansoni WGS.