Daily Respiratory Research Analysis
Three impactful respiratory studies stood out: broadly cross-protective neuraminidase antibodies that neutralize seasonal and avian influenza (including H5N1/H7N9), a mechanistic IPF study identifying epithelial YAP-TEAD/LOX signaling as a therapeutic target reversible by verteporfin, and a cluster-randomized surveillance study showing ARI case definitions capture RSV better than ILI in older adults. Together, they advance vaccine/antibody strategies, antifibrotic targets, and public health surv
Summary
Three impactful respiratory studies stood out: broadly cross-protective neuraminidase antibodies that neutralize seasonal and avian influenza (including H5N1/H7N9), a mechanistic IPF study identifying epithelial YAP-TEAD/LOX signaling as a therapeutic target reversible by verteporfin, and a cluster-randomized surveillance study showing ARI case definitions capture RSV better than ILI in older adults. Together, they advance vaccine/antibody strategies, antifibrotic targets, and public health surveillance.
Research Themes
- Universal influenza immunity via neuraminidase-targeting antibodies
- Epithelial drivers of pulmonary fibrosis and antifibrotic repurposing
- Optimizing RSV surveillance: ARI vs ILI case definitions
Selected Articles
1. Broad neuraminidase antibodies confer protection against seasonal and avian influenza viruses.
Two human monoclonal antibodies (CAV-F6, CAV-F34) broadly inhibit neuraminidase activity, protect mice from seasonal influenza, and neutralize avian strains (H5N1, H7N9). Structural data show HCDR3 engagement of conserved active-site residues, informing NA-focused universal vaccine and therapeutic designs.
Impact: This work reveals broadly neutralizing NA antibodies with activity against zoonotic strains, a key step toward universal influenza interventions beyond HA-focused strategies.
Clinical Implications: Supports inclusion of NA antigens in next-generation influenza vaccines and development of NA-targeting therapeutics with potential pandemic utility.
Key Findings
- Identified two monoclonal antibodies (CAV-F6, CAV-F34) that inhibit NA across multiple influenza subtypes.
- Both antibodies protected female mice from seasonal influenza and neutralized avian H5N1 and H7N9 strains.
- Structural analyses showed HCDR3-mediated binding to conserved NA active-site regions, blocking sialic acid interaction.
Methodological Strengths
- Integration of enzymatic inhibition, in vivo protection studies, and high-resolution structural analysis.
- Cross-subtype assessment including zoonotic strains enhances translational relevance.
Limitations
- Protection demonstrated in mouse models; human efficacy remains to be established.
- Female mice were used for protection studies; sex-based differences were not fully explored.
Future Directions: Evaluate human prophylactic/therapeutic potential of NA bnAbs, define correlates of protection, and translate conserved NA epitopes into vaccine immunogen designs.
Neuraminidase (NA) is a critical target for universal influenza vaccines and therapeutic antibodies, yet its antigenic landscape remains incompletely understood. Here we identify two broadly cross-protective monoclonal antibodies, CAV-F6 and CAV-F34, from influenza-infected individuals. These antibodies inhibit NA enzymatic activity across multiple subtypes and confer protection against seasonal influenza in female mouse models. Importantly, the two antibodies also neutralize emerging avian strains, including recent bovine H5N1 and H7N9 strains, both with pandemic potential. Structural studies reveal that both antibodies target conserved regions of the NA active site via HCDR3, blocking sialic acid interaction. Furthermore, we observe distinct occupancy for the two antibodies on N2 tetramer, which is likely due to differences in binding affinity. Our findings provide molecular insights into NA-targeted immunity and offer a foundation for developing broadly protective influenza vaccines and therapeutics.
2. Inhibition of epithelial cell YAP-TEAD/LOX signaling attenuates pulmonary fibrosis in preclinical models.
Fibrotic AT2 cells drive matrix production and crosslinking through YAP-induced LOX. Pharmacologic YAP inhibition with verteporfin reverses AT2 reprogramming and LOX expression in murine fibrosis and human ex vivo tissue, nominating epithelial YAP-TEAD/LOX as a druggable IPF pathway.
Impact: Shifts focus to epithelial drivers of fibrosis and demonstrates reversibility via an approved photosensitizer (verteporfin), opening a tractable translational path.
Clinical Implications: Supports repurposing verteporfin and development of YAP-TEAD/LOX inhibitors targeting alveolar epithelium as potential disease-modifying therapies in IPF.
Key Findings
- Fibrotic alveolar type II cells upregulate LOX via YAP, increasing extracellular matrix crosslinking.
- Verteporfin-mediated YAP inhibition reverses AT2 reprogramming and reduces LOX expression in vivo and in human fibrotic tissue ex vivo.
- Identifies epithelial YAP-TEAD/LOX signaling as a therapeutic axis for IPF.
Methodological Strengths
- Use of complementary in vivo fibrosis models and ex vivo human fibrotic tissue.
- Mechanistic linkage from transcriptional coactivator (YAP) to enzymatic effector (LOX) with pharmacologic reversal.
Limitations
- Preclinical evidence without clinical efficacy data in IPF patients.
- Potential off-target or photodynamic effects of verteporfin require careful clinical evaluation.
Future Directions: Phase 1/2 trials of verteporfin or selective YAP-TEAD/LOX inhibitors in IPF, biomarker development (epithelial YAP/LOX signatures), and safety profiling.
Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease characterized by excessive extracellular matrix deposition. Current IPF therapies slow disease progression but do not stop or reverse it. The (myo)fibroblasts are thought to be the main cellular contributors to excessive extracellular matrix production in IPF. Here we show that fibrotic alveolar type II cells regulate production and crosslinking of extracellular matrix via the co-transcriptional activator YAP. YAP leads to increased expression of Lysl oxidase (LOX) and subsequent LOX-mediated crosslinking by fibrotic alveolar type II cells. Pharmacological YAP inhibition via verteporfin reverses fibrotic alveolar type II cell reprogramming and LOX expression in experimental lung fibrosis in vivo and in human fibrotic tissue ex vivo. We thus identify YAP-TEAD/LOX inhibition in alveolar type II cells as a promising potential therapy for IPF patients.
3. A Cluster Randomized Study to Explore Case Definitions, Clinical Course and Consequences of RSV in Community-Dwelling Adults Aged ≥ 50 Years.
In a GP-level cluster randomization (n=1431), ARI-based case definitions captured more RSV than ILI. An ARI variant including wheeze/productive cough/rhonchi/dyspnea achieved 92% sensitivity (30.8% specificity). RSV outpatient burden was substantial with 30.7% complications, 2.7% hospitalizations, and notable societal costs.
Impact: Directly informs RSV surveillance and testing strategies in older adults by demonstrating the superiority of ARI-based definitions and proposing a high-sensitivity clinical qualifier set.
Clinical Implications: Public health programs should favor ARI-based triggers (with respiratory qualifiers) over ILI for RSV testing in adults ≥50 years to avoid under-ascertainment and to better allocate diagnostics and preventive measures.
Key Findings
- ARI case definitions detected more RSV than ILI (5.8% vs 4.6%; OR 1.26; 95% CI 0.60–2.65; higher OR after excluding low-enrolling GPs).
- An ARI variant with wheeze/productive cough/rhonchi/dyspnea achieved 92.0% sensitivity and 30.8% specificity for RSV.
- Among RSV-positive outpatients, 30.7% had complications, 2.7% were hospitalized, 1.3% died; mean societal cost per case up to €899.51.
Methodological Strengths
- Cluster randomization at the GP level with pathogen testing for all enrolled subjects.
- Prospective follow-up of RSV-positive patients capturing clinical outcomes and costs.
Limitations
- Primary ARI vs ILI comparison yielded wide CIs with non-significant OR; power limited by enrollment variability.
- Specificity of the high-sensitivity ARI variant was low (30.8%), which may increase testing burden.
Future Directions: Validate refined ARI qualifiers in larger multicountry cohorts, integrate with rapid diagnostics, and assess impacts on vaccine effectiveness studies and resource allocation.
INTRODUCTION: In Europe, surveillance of respiratory syncytial virus (RSV) has been recently incorporated into existing influenza monitoring platforms that are based on influenza-like illness (ILI) or acute respiratory infection (ARI) case definitions. This study aims to compare RSV rates captured by ARI versus ILI case definitions and to describe the clinical and economic trajectories of RSV in older adults. METHODS: The study was conducted in Italy during the 2023/2024 and 2024/2025 seasons. Thirty-eight general practitioners were randomized 1:1 to enroll individuals ≥ 50 years presenting for care and meeting the European criteria for ARI or ILI, respectively. Alternative definitions were also explored. All subjects were tested for respiratory pathogens. RSV-positive individuals were followed for up to one month. RESULTS: Of 1431 patients (ARI: 741; ILI: 690) included, 5.2% tested positive for RSV. Odds of RSV in the ARI group (5.8%) was 26% higher than in the ILI group (4.6%) [odds ratio (OR) 1.26; 95% CI 0.60-2.65]. Exclusion of GPs with unexpectedly low enrollment rates increased the OR to 1.67 (95% CI 0.80-3.42). Conversely, adults in the ILI group showed higher rates of influenza A (OR 0.83; 95% CI 0.47-1.44) and SARS-CoV-2 (OR 0.57; 95% CI 0.34-0.95). A proposed alternative case definition, denoted as ARI with wheezing and/or productive cough and/or rhonchi and/or dyspnea was sensitive at 92.0% and specific at 30.8%. Among 75 RSV-positive outpatients, the case-complication, case-hospitalization and case-fatality rates were 30.7%, 2.7%, and 1.3%, respectively. The mean costs per RSV case were € 168.71 from the payer perspective and up to € 899.51 from the societal perspective. CONCLUSIONS: Compared to a highly sensitive ARI definition, ILI-based surveillance likely underestimates the incidence of RSV. Further qualifiers can enhance specificity of the ARI case definition. The study confirms a significant burden of RSV in older adults.