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Novel and optimized diagnostics for pediatric TB in endemic countries: NOD-pedFEND study protocol.
BACKGROUND: Pediatric tuberculosis is a major global public health challenge, with reliable diagnosis being a main obstacle to identifying and treating affected children. New and improved diagnostics, ideally on non-sputum samples, are urgently required, especially in the most vulnerable group of children under five years of age. Studies to date have been limited by small sample sizes and few bacteriologically-confirmed cases. Here, we describe the study protocol of the NIH-funded NOD-pedFEND study, which will be one of the largest diagnostic studies to date of children at greatest risk of tuberculosis. METHODS: In this prospective observational cohort study, we aim to evaluate existing and novel diagnostic assays, including pathogen- and host-based tests and combinations of tests. A consecutive cohort of children under five years of age with signs and symptoms of tuberculosis is enrolled in Uganda and Peru. All children undergo an extensive baseline workup with signs- and symptoms recording, microbiological reference tests, chest X-ray and tuberculin skin test for rigorous classification according to internationally recognized microbiological, composite reference and strict standards. An array of samples is collected for investigational tests. Follow-up visits are conducted at 2 weeks, 2 months and 6 months. A small cohort of healthy controls is enrolled to evaluate the specificity of selected diagnostics. The study has been approved by the relevant institutional review boards. DISCUSSION: With this large cohort study of children under five years of age, we aim to make an important contribution to the evaluation of new diagnostics for pediatric tuberculosis. By establishing a comprehensive biorepository, the study will also enable the assessment of novel tests as they become available during and after the study.
Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 lineages circulating in Brazil.
Several COVID-19 vaccines have shown good efficacy in clinical trials, but there remains uncertainty about the efficacy of vaccines against different variants. Here, we investigate the efficacy of ChAdOx1 nCoV-19 (AZD1222) against symptomatic COVID-19 in a post-hoc exploratory analysis of a Phase 3 randomised trial in Brazil (trial registration ISRCTN89951424). Nose and throat swabs were tested by PCR in symptomatic participants. Sequencing and genotyping of swabs were performed to determine the lineages of SARS-CoV-2 circulating during the study. Protection against any symptomatic COVID-19 caused by the Zeta (P.2) variant was assessed in 153 cases with vaccine efficacy (VE) of 69% (95% CI 55, 78). 49 cases of B.1.1.28 occurred and VE was 73% (46, 86). The Gamma (P.1) variant arose later in the trial and fewer cases (N = 18) were available for analysis. VE was 64% (-2, 87). ChAdOx1 nCoV-19 provided 95% protection (95% CI 61%, 99%) against hospitalisation due to COVID-19. In summary, we report that ChAdOx1 nCoV-19 protects against emerging variants in Brazil despite the presence of the spike protein mutation E484K.
Synovial tissue atlas in juvenile idiopathic arthritis reveals pathogenic niches associated with disease severity.
Precision application of targeted therapies is urgently needed to improve long-term clinical outcomes for children affected by inflammatory arthritis, known as juvenile idiopathic arthritis (JIA). Progress has been hampered by our limited understanding of the cellular basis of inflammation in the target tissue of the disease, the synovial membrane. Here, we analyzed biopsies from the inflamed joints of treatment-naïve children with JIA, early in the course of their disease, using single-cell RNA sequencing, multiplexed immunofluorescence, and spatial transcriptomics to establish a cellular atlas of the JIA synovium. We identified distinct spatial tissue niches, composed of specific stromal and immune cell populations. In addition, we localized genes linked to arthritis severity and disease risk to effector cell populations, including tissue resident SPP1+ macrophages and fibrin-associated myeloid cells. Combined analyses of synovial fluid and peripheral blood from matched individuals revealed differences in cellular composition, signaling pathways, and transcriptional programs across these distinct anatomical compartments. Furthermore, our analysis revealed several pathogenic cell populations that are shared with adult-onset inflammatory arthritis, as well as age-associated differences in tissue vascularity, prominence of innate immunity, and enrichment of TGF-β-responsive stromal subsets that up-regulate expression of disease risk-associated genes. Overall, our findings demonstrate the need for age-specific analyses of synovial tissue pathology to guide targeted treatment strategies in JIA.
Heterologous COVID-19 vaccine schedule with protein-based prime (NVX-CoV2373) and mRNA boost (BNT162b2) induces strong humoral responses: results from COV-BOOST trial.
BACKGROUND: Heterologous schedules of booster vaccines for COVID-19 following initial doses of mRNA or adenoviral vector vaccines have been shown to be safe and immunogenic. There are few data on booster doses following initial doses of protein nanoparticle vaccines. METHODS: Participants of the phase 3 clinical trial of the COVID-19 vaccine NVX-CoV2373 (EudraCT 2020-004123-16) enrolled between September 28 and November 28, 2020, who received 2 doses of NVX-CoV2373 administered 21 days apart were invited to receive a third dose booster vaccine of BNT162b2 (wild type mRNA vaccine) as a sub-study of the COV-BOOST clinical trial, and were followed up for assessment of safety, reactogenicity and immunogenicity to day 242 post-booster. RESULTS: The BNT162b2 booster following two doses of NVX-COV2373 was well-tolerated. Most adverse events were mild to moderate, with no serious vaccine-related adverse events reported. Immunogenicity analysis showed a significant increase in spike IgG titres and T-cell responses post-third dose booster. Specifically, IgG levels peaked at day 14 with a geometric mean concentration (GMC) of 216,255 ELISA laboratory units (ELU)/mL (95% CI 191,083-244,743). The geometric mean fold increase from baseline to day 28 post-boost was 168.6 (95% CI 117.5-241.8). Spike IgG titres were sustained above baseline levels at day 242 with a GMC of 58,686 ELU/mL (95% CI 48,954-74,652), with significant decay between days 28 and 84 (geometric mean ratio 0.58, 95% CI 0.53-0.63). T-cell responses also demonstrated enhancement post-booster, with a geometric mean fold increase of 5.1 (95% CI 2.9-9.0) at day 14 in fresh samples and 3.0 (95% CI 1.8-4.9) in frozen samples as measured by ELISpot. In an exploratory analysis, participants who received BNT162b2 after two doses of NVX-COV2373 exhibited higher anti-spike IgG at Day 28 than those who received homologous three doses of BNT162b2, with a GMR of 5.02 (95% CI: 3.17-7.94). This trend remained consistent across all time points, indicating a similar decay rate between the two schedules. CONCLUSIONS: A BNT162b2 third dose booster dose in individuals primed with two doses of NVX-COV2373 is safe and induces strong and durable immunogenic responses, higher than seen in other comparable studies. These findings support the use and investigation of heterologous booster strategies and early investigation of heterologous vaccine technology schedules should be a priority in the development of vaccines against new pathogens.
Respiratory syncytial virus hospitalisation by chronological month of age and by birth month in infants
Understanding the distribution of respiratory syncytial virus (RSV) disease burden by more granular age bands in infants is necessary for optimising infant RSV immunisation strategies. Using a Bayesian model, we synthesised published data from a systematic literature review and unpublished data shared by international collaborators for estimating the distribution of infant RSV hospitalisations by month of age. Based on local RSV seasonality data, we further developed and validated a web-based prediction tool for estimating infant RSV hospitalisation distribution by birth month. Although RSV hospitalisation burden mostly peaked at the second month of life and was concentrated in infants under six months globally, substantial variations were noted in the age distribution of RSV hospitalisation among infants born in different months. Passive immunisation strategies should ideally be tailored to the local RSV disease burden distribution by age and birth month to maximise their per-dose effectiveness before a universal immunisation can be achieved.
High propensity for multidrug-resistant pneumococcal shedding among adults living with HIV on stable antiretroviral therapy in Malawi
Abstract Background People living with HIV (PLHIV) on antiretroviral therapy (ART) are still at risk of pneumococcal disease and have over two-fold higher pneumococcal carriage prevalence than HIV-uninfected adults (HIV- adults). Carriage is a risk factor for pneumococcal disease, antimicrobial resistance (AMR) emergence, and transmission. Therefore, we tested whether the high prevalence of pneumococcal carriage in PLHIV on ART is associated with increased bacterial density, shedding and AMR. Methods We recruited asymptomatic PLHIV on ART for more than one year (PLHIV-ART>1yr) and HIV- adults. Nasopharyngeal swabs were collected on days 3, 7, 14, 21, and 28, followed by monthly collections for 12 months, while shedding samples were collected on days 3, 21, and 28. Peripheral blood was collected on day 3 to measure CD4 count and HIV viral load. Pneumococcal carriage density and shedding were assessed using standard bacterial culture, and multiple carriage was detected through whole plate sweep sequencing. AMR profiling was conducted using disk diffusion and E-test. Findings PLHIV-ART>1yr had a higher propensity for high-density carriage (adjusted Odds Ratio 1.67, 95% CI 1.07-2.60, p=0.023). Moreover, PLHIV-ART>1yr are more likely to shed pneumococci than HIV- adults (aOR 2.52, 95% CI 1.06-6.00, p=0.037), with carriage density identified as an important risk factor for shedding (aOR 3.35, 95% CI 1.55-7.24, p=0.002). Aerosol shed isolates from PLHIV-ART>1yr were mostly multidrug-resistant (62% 18/29, 95% CI 48%-77%). Interpretation These findings indicate that PLHIV-ART>1yr remain at high risk of pneumococcal disease and could also be an important reservoir for shedding multidrug-resistant pneumococci.
Electroencephalogram Features Distinguish Cases of Cerebral Malaria Among Malawian Children With Fever and Coma.
BACKGROUND: In febrile comatose patients living in malaria-endemic areas, overlapping symptoms and limited laboratory capacity make it difficult to distinguish parasitic, bacterial, and viral central nervous system infections. We evaluated electroencephalography (EEG) as a biomarker to differentiate the microbiologic etiology of pediatric febrile coma at a major referral center in Malawi. METHODS: This was a retrospective case-control study comparing EEG recordings of Malawian children with cerebral malaria to those with febrile coma of nonmalarial cause (bacterial meningitis, viral encephalitis, or unknown cause). Participants were admitted to Queen Elizabeth Central Hospital (Blantyre, Malawi) between 2013 and 2021. Inclusion criteria were fever, coma (Blantyre Coma Score ≤2), and coma etiology (malarial or nonmalarial) defined by laboratory testing. Four supervised machine learning algorithms were used to train a balanced ensemble classifier, SuperLearner, generating test characteristics of the diagnostic ability of EEG features. RESULTS: Two hundred three children with cerebral malaria and 87 children with nonmalarial coma were included. Univariate analysis of qualitative (visual) EEG interpretations revealed higher voltage, slower background frequency, more sleep elements, less variability, more abnormal organization, and less continuity in cerebral malaria. Quantitative waveform analysis showed greater power in cerebral malaria. Both quantitative and qualitative EEG interpretation distinguished coma etiology (area under the receiver operating characteristic curve [AUROC] = 0.85 and 0.86, respectively). Combining qualitative and quantitative interpretation methods, the test characteristic improved (AUROC = 0.90). CONCLUSIONS: EEG features distinguish malarial from nonmalarial coma in febrile Malawian children. This technology may aid in distinguishing the microbiologic etiology of febrile coma in malaria-endemic areas.
Using Electroencephalography to Assess Coma Etiology in Children with Retinopathy-Negative Cerebral Malaria.
Autopsy studies of children dying of cerebral malaria (CM) have revealed that those with malarial retinopathy exhibited high levels of sequestration in the cerebral vasculature, whereas children with retinopathy-negative CM exhibited lower sequestration levels and possible nonmalarial causes of death. This suggests that children dying of retinopathy-negative CM have nonmalarial coma etiologies with concomitant incidental parasitemia, which is common in high malaria transmission areas. Subsequent studies have challenged this assertion, positing that retinopathy-negative CM and retinopathy-positive CM are variants of the same disease pathophysiology or host biology, both caused by acute malaria infection. We recently determined that electroencephalography (EEG) can be used to discriminate between a malarial coma (CM) and a nonmalarial coma. To better understand the contribution of acute malaria infection in the pathophysiology of retinopathy-negative CM, we compared qualitative and quantitative EEG findings from 30-minute EEG recordings of Malawian children aged 3 months to 14 years hospitalized at Queen Elizabeth Central Hospital with retinopathy-negative CM, retinopathy-positive CM, and nonmalarial coma. Neither qualitative nor quantitative EEG interpretation methods allow for the discrimination between children with retinopathy-positive CM and those with retinopathy-negative CM. Conversely, quantitative EEG readily differentiated children with retinopathy-negative CM from those with nonmalarial coma (area under the receiving operating characteristic [AUROC] curve of 0.83). When combining qualitative and quantitative EEG interpretation methods, the ability of EEG to distinguish retinopathy-negative CM from nonmalarial EEG increases (AUROC of 0.87). The EEGs of children with retinopathy-negative CM are similar to those of children with retinopathy-positive CM and significantly different from those of children with nonmalarial coma, supporting the hypothesis that acute malarial infection is pathophysiologically important in retinopathy-negative CM.
Early Cardiac Dysfunction in Adolescents With Low Vigorous Physical Activity.
BACKGROUND: Adverse left ventricular diastolic function (LVDF) is an early marker of cardiac dysfunction that worsens with age and can lead to heart failure. It is unclear when this deterioration begins and whether physical activity (PA) influences it. We assessed the independent relationships of adverse LVDF in adolescents with different PA intensities, compared to the association with adiposity. The impact of adverse LVDF from low PA on cardiorespiratory fitness was examined. METHODS: In 127 adolescents (aged 11-18 years), we assessed LVDF by echocardiography, 7-day PA by wrist-worn accelerometry, adiposity Z scores by bioimpedance, and peak oxygen consumption by cardiopulmonary exercise testing (OxSOCRATES [Oxfordshire Sedentariness, Obesity, and Cardiometabolic Risk in Adolescents: A Trial of Exercise in Schools] study; NCT04118543). Adverse LVDF was defined using a body surface area-adjusted septal early diastolic tissue peak velocity Z score (
The molecular reach of antibodies crucially underpins their viral neutralisation capacity.
Key functions of antibodies, such as viral neutralisation, depend on high-affinity binding. However, viral neutralisation poorly correlates with antigen affinity for reasons that have been unclear. Here, we use a new mechanistic model of bivalent binding to study >45 patient-isolated IgG1 antibodies interacting with SARS-CoV-2 RBD surfaces. The model provides the standard monovalent affinity/kinetics and new bivalent parameters, including the molecular reach: the maximum antigen separation enabling bivalent binding. We find large variations in these parameters across antibodies, including reach variations (22-46 nm) that exceed the physical antibody size (~15 nm). By using antigens of different physical sizes, we show that these large molecular reaches are the result of both the antibody and antigen sizes. Although viral neutralisation correlates poorly with affinity, a striking correlation is observed with molecular reach. Indeed, the molecular reach explains differences in neutralisation for antibodies binding with the same affinity to the same RBD-epitope. Thus, antibodies within an isotype class binding the same antigen can display differences in molecular reach, substantially modulating their binding and functional properties.