Daily Respiratory Research Analysis

OBJECTIVE: To evaluate the safety and efficacy of VPM1002 and Immuvac in reducing the incidence of microbiologically confirmed tuberculosis (TB; pulmonary TB and extrapulmonary TB), development of latent TB infection, and immunogenicity. DESIGN: Phase 3 randomised clinical trial (PreVenTB trial). SETTING: 18 sites across six states of India. PARTICIPANTS: 12 717 healthy household contacts (aged ≥6 years) of patients with a smear positive TB test. INTERVENTIONS: Participants were randomly assigned in a 1:1:1 ratio (using block randomisation with variable sample size) to receive an intradermal injection of VPM1002, Immuvac, or placebo in both arms. After one month, a second dose was administered in one arm to 11 829 healthy participants. OUTCOME MEASURES: The primary outcome was efficacy against confirmed TB (pulmonary TB and extrapulmonary TB) over 38 months of follow-up. Secondary outcomes were development of latent TB infection, adverse and serious adverse events, efficacy in predefined age groups, and immunogenicity. Exploratory outcomes were efficacy when considering tuberculin skin test status, and post hoc analyses of efficacy in participants aged 6-14 and according to body mass index. RESULTS: 252 and 227 participants developed microbiologically confirmed TB in modified intention-to-treat and per protocol groups, respectively. The per protocol analysis showed 65 (1.68%), 80 (2.09%), and 82 (2.13%) participants developed TB in the VPM1002, Immuvac, and placebo groups, respectively. Of these, 12 (0.31%), 16 (0.42%), and 24 (0.62%) developed extrapulmonary TB in the VPM1002, Immuvac, and placebo groups, respectively. In the per protocol analysis, VPM1002 showed vaccine efficacy of 21.4% (95% confidence interval (CI) -8.9% to 43.2%), 19.5% (-14.6% to 43.4%), and 50.4% (0.8% to 75.2%) against all TB, pulmonary TB, and extrapulmonary TB, respectively. Immuvac showed vaccine efficacy of 33.2% (-25.9% to 64.5%) against extrapulmonary TB. VPM1002 and Immuvac showed vaccine efficacy of 64.9% (-2% to 90.1%) and 66.3% (1.9% to 90.5%) against extrapulmonary TB in participants with tuberculin skin test positivity. Both vaccines were well tolerated with mild local reactions in about a third of participants. VPM1002 and Immuvac induced CONCLUSIONS: Both vaccines were safe but did not show any efficacy against all forms of microbiologically confirmed TB or pulmonary TB. VPM1002 showed considerable efficacy against extrapulmonary TB. Both vaccines showed efficacy against extrapulmonary TB in participants who had a positive tuberculin skin test. TRIAL REGISTRATION: Clinical Trials Registry India CTRI/2019/01/017026.

Respiratory syncytial virus (RSV), discovered in 1956 and identified in children in 1957, is the major respiratory pathogen of infants and children under the age of 5 worldwide. RSV remains a significant challenge, despite recent advancements of vaccine development and monoclonal antibody prophylaxis. While specific antiviral agents have shown success as therapeutics for many other viruses, viral mutations inevitably develop, making these therapeutic interventions ineffective due to viral resistance. This unavoidable obstacle warrants alternative approaches to targeting host cellular factors that are essential for viral replication regardless of viral mutations. Our goal was to assess the feasibility of this approach. In doing so, we sought to determine the cellular enzymes and functions that are required for RSV replication. Here, we demonstrate that inhibiting human telomerase reduced or abolished viral protein production. Further, we showed that RNA helicase eIF4A is essential for RSV protein and progeny production. Lastly, targeting nuclear transport receptor reduces RSV RNAs and proteins synthesis, suggesting a role of host nucleus for viral replication. Overall, the inhibition of virus replication-dependent host functions may be an effective means to combat viral infections and would sidestep the inevitable resistance that emerges with virus-specific strategies.

Acute exacerbation of idiopathic pulmonary fibrosis is a life-threatening condition characterized by neutrophilic inflammation. S100A8/A9, an alarmin released by activated neutrophils and monocytes/macrophages, plays a pivotal role in regulating inflammatory responses. However, its specific involvement in acute exacerbations of pulmonary fibrosis remains unclear. This study evaluated the role of S100A8/A9 in the pathogenesis of acute exacerbations of pulmonary fibrosis. S100A8/A9 levels were measured in bronchoalveolar lavage fluid and serum from patients with idiopathic interstitial pneumonia, with and without acute exacerbations. To model acute exacerbations of pulmonary fibrosis, mice were intratracheally administered bleomycin followed by lipopolysaccharide. Subsequently, inflammatory cell infiltration, cytokine levels, morphological changes, and fibrosis marker levels in lung tissue and airways were analyzed. S100A8/A9 levels were significantly higher in the bronchoalveolar lavage fluid and serum of patients with idiopathic interstitial pneumonia experiencing acute exacerbations relative to those without; these levels were correlated with patient prognosis. In an experimental mouse model, intratracheal administration of bleomycin followed by lipopolysaccharide resulted in a significant increase in airway S100A8/A9 levels compared with bleomycin alone and control mouse. Anti-S100A8/A9 neutralizing antibody Ab45 mitigated airway inflammation and lung fibrosis in mice with acute exacerbations of pulmonary fibrosis, reducing S100A8/A9 levels and neutrophil extracellular traps. In vitro, recombinant S100A8/A9 or lipopolysaccharide and neutrophils activated and differentiated fibroblasts; these effects were inhibited by anti-S100A8/A9 neutralizing antibody Ab45 and the humanized form of Ab45 (HuAb45). These findings highlight S100A8/A9 as a potential prognostic biomarker and therapeutic target for acute exacerbations of pulmonary fibrosis.