Daily Respiratory Research Analysis
Analyzed 197 papers and selected 3 impactful papers.
Summary
Analyzed 197 papers and selected 3 impactful articles.
Selected Articles
1. Intranasal DNA nanocarrier vaccines with surface-patterned antigens enhance efficacy against respiratory syncytial virus.
A rationally engineered library of DNA nanocarriers displaying patterned RSV pre-F antigens achieved strong and durable systemic and mucosal immunity in mice, matching or surpassing approved trimeric mRNA vaccines in durability. Intranasal delivery outperformed intramuscular mRNA in eliciting respiratory mucosal immunity and conferred robust protection against RSV challenge.
Impact: This work advances a generalizable design principle for intranasal vaccines that directly target mucosal immunity, addressing a key limitation of current systemic RSV vaccines.
Clinical Implications: If translated to humans, intranasal DNA nanocarrier vaccines could complement or replace systemic RSV vaccines by providing durable mucosal protection, potentially reducing transmission and severe disease.
Key Findings
- Engineered DNA nanocarriers organized pre-F monomer antigens into optimized surface patterns to maximize B cell activation.
- Intranasal vaccination induced humoral responses in mice comparable to an approved trimeric mRNA RSV vaccine, with greater durability.
- Intranasal DNA nanovaccine elicited robust respiratory mucosal immunity and provided strong protection against RSV challenge, unlike intramuscular mRNA vaccination.
Methodological Strengths
- Systematic geometric optimization with precisely controlled DNA nanocarrier dimensions and antigen functionalization.
- Direct head-to-head comparison with a clinically approved trimeric mRNA vaccine and in vivo protection readouts.
Limitations
- Preclinical mouse study; human immunogenicity, safety, and manufacturability remain unproven.
- Long-term durability and breadth across RSV strains and human mucosal compartments are unknown.
Future Directions: Advance to GLP toxicology and phase 1 trials assessing mucosal and systemic immunity, durability, and shedding/transmission endpoints; extend patterning principles to influenza, SARS-CoV-2, and pan-viral antigens.
Although injectable respiratory syncytial virus (RSV) pre-F vaccines are clinically established, effective intranasal alternatives remain elusive. Geometric and surface antigen display properties are critical for respiratory B cell activation, yet lack strategies for systematic optimization. Here we report a library of DNA nanocarriers with controlled dimensions and sizes, aiming to systemically evaluate the influence of geometric properties on intranasal retention. Taking advantage of the precise control on DNA nanocarriers and antigen functionalization, we organized the surface antigen patterns of pre-F monomers on DNA nanocarriers to maximize B cell activation. The optimized DNA nanocarrier-based vaccine elicited humoral immunity in mice comparable to that induced by the clinically approved trimeric mRNA vaccine against RSV, but with greater durability. While intramuscular mRNA vaccines failed to induce effective respiratory mucosal immunity, the intranasal DNA nanocarrier-based vaccine achieved robust local and systemic immune activation, conferring potent protection against RSV infection. This rational design of intranasal RSV vaccines may be a general strategy for testing and advancing potent intranasal vaccines for a range of infectious respiratory diseases.
2. Hypoxia-Induced Epas1-Myl9/12 Axis Shapes the Pathology of Pulmonary Hypertension.
Using Sugen/hypoxia mice and patient samples, the authors identified Myl9/12-containing microthrombi and showed that hypoxia upregulates Myl9/12 via EPAS1 in proliferating lung endothelial cells. Therapeutic anti-Myl9/12 antibody reduced microthrombus formation, inflammation, tissue hypoxia, and vascular remodeling, attenuating established PH in mice; serum Myl9 levels reflected PH severity in patients.
Impact: Reveals a previously unrecognized hypoxia–EPAS1–Myl9/12 pathway driving PH vascular lesions and demonstrates efficacy of a targeted antibody in vivo, opening a translational path to new therapies.
Clinical Implications: Serum Myl9 could serve as a severity biomarker, and anti-Myl9/12 therapeutics merit early-phase trials in PH. The findings support mechanistically targeted strategies beyond vasodilation.
Key Findings
- Myl9/12-containing microthrombi were present in PH patients and Sugen/hypoxia mice.
- Hypoxia upregulated Myl9/12 expression through EPAS1 in proliferated lung endothelial cells, releasing Myl9/12 extracellularly.
- Anti-Myl9/12 antibody attenuated established PH in mice by reducing microthrombi, inflammatory cell infiltration, hypoxia, and vascular remodeling.
- Serum Myl9 levels correlated with PH severity, whereas MYL12A/B did not.
Methodological Strengths
- Integrated in vivo (Sugen/hypoxia) and human translational analyses including serum biomarker correlations
- Therapeutic intervention with target-specific antibody demonstrating disease attenuation
Limitations
- Preclinical mouse model may not capture full heterogeneity of human PH subtypes
- Limited patient sample size and lack of interventional human data; potential off-target or safety concerns of anti-Myl9/12 remain untested in humans
Future Directions: Conduct phase I/II trials of anti-Myl9/12 in selected PH phenotypes; validate serum Myl9 as a prognostic/theranostic biomarker; map cell-type–specific EPAS1–Myl9/12 regulation in human PH.
BACKGROUND: Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by vascular remodeling, abnormal vasoconstriction of small lung arteries, and right heart failure. Hypoxia causes vascular damage, leading to vessel stenosis or occlusion by aberrant endothelial cells, hypertrophy of the tunica media, and thrombus formation. But the precise molecular mechanisms underlying the pathology of PH have been uncertain. METHODS: To investigate the pathogenic role of Myl (myosin light chain) 9/12 in PH, we utilized the Sugen/hypoxia mouse model, generated by administration of the VEGF (vascular endothelial growth factor) receptor inhibitor SU5416 under hypoxic conditions (10% O
3. Community-based tuberculosis screening with computer-aided detection technology alone and in combination with point-of-care C-reactive protein testing: a paired screen-positive trial.
In a pragmatic within-person community trial across Lesotho and South Africa, CAD chest x-ray screening alone identified more TB cases than CAD followed by point-of-care CRP and at lower cost. The CAD+CRP strategy failed non-inferiority (−12.3% case yield; 95% CI −23.0 to −1.6) and was 37.3% more expensive per detected case.
Impact: Provides high-quality, programmatically relevant evidence that simplifies community TB screening by favoring CAD alone, optimizing yield and cost in high-burden settings.
Clinical Implications: TB programs should prioritize CAD-only chest x-ray screening workflows over adding CRP in community case-finding to maximize detection and cost-effectiveness.
Key Findings
- CAD-only detected 94.5% (69/73) of paired screen-positive TB cases vs 82.2% (60/73) with CAD+CRP; non-inferiority not met (difference −12.3%, 95% CI −23.0 to −1.6).
- Cost per detected case was lower with CAD-only (US$5,454) than CAD+CRP (US$7,486), a 37.3% increase with CRP addition.
- Large community enrollment (n=20,023) with high HIV prevalence (22.6%) supports external relevance to high-burden settings.
Methodological Strengths
- Pragmatic, within-person paired screen-positive design reduces between-person confounding.
- Integrated cost-effectiveness analysis alongside diagnostic yield in real-world community settings.
Limitations
- Primary outcome set was relatively small (n=73 paired cases) due to design and eligibility constraints.
- Generalizability beyond the two districts may vary; not a randomized parallel-arm trial.
Future Directions: Assess CAD-only algorithms across diverse settings and integrate AI threshold optimization, linkage-to-care metrics, and radiation safety; evaluate adjuncts targeted to subgroups where incremental value is plausible.
BACKGROUND: Active tuberculosis case-finding in communities is crucial for early disease detection and disruption of transmission; however, it is complex and costly. A thorough analysis of tuberculosis screening strategies is essential, particularly because the health systems affected often have limited resources. We aimed to compare two community screening approaches in terms of tuberculosis case yield and cost. METHODS: This pragmatic community trial, with a paired screen-positive design (ie, within-person comparison), was conducted in the Butha-Buthe District in Lesotho and the uMgungundlovu District in South Africa. All household members aged at least 18 years were eligible to participate, except those who were seriously ill, had a condition that prevented their safe and full participation, were receiving tuberculosis treatment, or were pregnant (Lesotho only). We compared two screening approaches: the use of computer-aided detection (CAD) software on digital chest x-rays alone (the CAD4TBv7 approach) and the use of CAD followed by a C-reactive protein (CRP) test if the CAD score was in a particular range (the CAD4TBv7-CRP approach). A confirmatory Xpert MTB/RIF Ultra test was conducted when required by the algorithm of one or both approaches. Coprimary outcomes were to establish whether the CAD4TBv7-CRP approach was non-inferior to the CAD4TBv7 approach (non-inferiority margin -10%) and to conduct a comparative cost analysis between the two approaches. FINDINGS: Among 20 023 enrolled participants, the median age was 42 years (IQR 29-60); 12 387 (61·9%) participants were female, 7625 (38·1%) were male, and 11 (0·1%) were intersex. 4534 (22·6%) of 20 023 participants were living with HIV, 1547 (7·7%) had a history of tuberculosis, and 1545 (7·7%) reported at least one of the four main symptoms of tuberculosis. The primary outcome set, defined as participants who were identified as having tuberculosis according to at least one of the two approaches and had complete data for both approaches, comprised 73 participants: the CAD4TBv7 approach identified 69 (94·5%) of these cases of tuberculosis and the CAD4TBv7-CRP approach identified 60 (82·2%) cases. The difference of -12·3% (95% CI -23·0 to -1·6) indicates that the non-inferiority criterion was not met. The cost per detected case of tuberculosis was US$5454 (95% uncertainty interval 4294-6777) for the CAD4TBv7 approach and $7486 (5948-9246) for the CAD4TBv7-CRP approach, making the CAD4TBv7-CRP approach 37·3% more expensive. INTERPRETATION: In active tuberculosis case-finding in our community setting, the combination of CAD followed by CRP testing offered no advantage over CAD alone owing to its inferior case yield and higher cost. CAD alone, however, has the potential to be an effective and economically viable tuberculosis screening strategy in areas with high disease burden.