Daily Respiratory Research Analysis
Three impactful respiratory papers span vaccines, antivirals, and lung cancer therapy. An engineered SARS‑CoV‑2 virus lacking E/M open-reading frames shows robust protection in hamsters and strong CD8 responses, supporting a new live-attenuated vaccine platform. A phase 2 randomized trial reports significantly longer PFS with anlotinib plus docetaxel in advanced NSCLC, while a human-derived TMPRSS2 inhibitor (Trypstatin) demonstrates broad in vivo antiviral efficacy against coronaviruses and inf
Summary
Three impactful respiratory papers span vaccines, antivirals, and lung cancer therapy. An engineered SARS‑CoV‑2 virus lacking E/M open-reading frames shows robust protection in hamsters and strong CD8 responses, supporting a new live-attenuated vaccine platform. A phase 2 randomized trial reports significantly longer PFS with anlotinib plus docetaxel in advanced NSCLC, while a human-derived TMPRSS2 inhibitor (Trypstatin) demonstrates broad in vivo antiviral efficacy against coronaviruses and influenza.
Research Themes
- Live-attenuated SARS-CoV-2 vaccine engineering
- Broad-spectrum host-targeted antivirals (TMPRSS2 inhibitors)
- Second-line combination therapy in advanced NSCLC
Selected Articles
1. SARS-CoV-2 virus lacking the envelope and membrane open-reading frames as a vaccine platform.
An engineered E/M-deleted SARS‑CoV‑2 (ΔEM) replicates only in complementing cells, induces robust CD8 responses, and protects hamsters against Delta and Omicron XBB variants. As a booster after mRNA vaccination, ΔEM outperformed mRNA booster in protecting respiratory tissues.
Impact: Introduces a genetically contained live-attenuated SARS‑CoV‑2 platform with cross-variant protection and booster utility, addressing durability and breadth limitations of current vaccines.
Clinical Implications: If safety translates to humans, ΔEM could serve as a heterologous booster or primary vaccine to broaden and deepen mucosal and systemic immunity against evolving variants.
Key Findings
- E/M open-reading frame deletion yields a replication-competent virus only in E/M-complementing cells, enhancing biosafety.
- ΔEM vaccination induces CD8 T-cell responses to spike and nucleocapsid and protects hamsters from Delta and Omicron XBB.
- As a booster after mRNA vaccination, ΔEM provided superior protection of respiratory tissues compared to mRNA booster.
Methodological Strengths
- Rational genetic attenuation with dual structural deletions and cell-complemented production for containment
- In vivo efficacy across distinct variants and demonstration of heterologous booster performance
Limitations
- Preclinical animal study; human safety, shedding, and durability unknown
- Manufacturing and regulatory pathways for E/M-complemented production must be established
Future Directions: Advance to phase 1 safety/immunogenicity trials, assess mucosal immunity and transmission blocking, and test heterologous prime-boost strategies versus current platforms.
2. Trypstatin as a Novel TMPRSS2 Inhibitor with Broad-Spectrum Efficacy against Corona and Influenza Viruses.
Trypstatin, a human Kunitz-type protease inhibitor, potently inhibits TMPRSS2 and blocks entry of multiple coronaviruses and influenza viruses. In primary airway epithelia and in SARS‑CoV‑2–infected hamsters, intranasal Trypstatin reduced viral titers and alleviated disease.
Impact: Demonstrates a human-derived biologic that broadly targets TMPRSS2-dependent respiratory viruses with in vivo efficacy, supporting a host-targeted antiviral class resilient to viral antigenic drift.
Clinical Implications: Trypstatin could be developed as an intranasal prophylactic or early therapeutic against SARS‑CoV‑2 and influenza, potentially complementing vaccines and direct-acting antivirals.
Key Findings
- Trypstatin inhibits TMPRSS2 and related proteases at nanomolar IC50, comparable to camostat.
- Blocks spike- and hemagglutinin-mediated viral entry across SARS-CoV-1/2/MERS/NL63 and influenza A/B.
- Reduces SARS‑CoV‑2 replication in primary human airway epithelial cultures and retains activity in mucus.
- Intranasal administration in hamsters lowers viral titers and improves clinical outcomes.
Methodological Strengths
- Comprehensive profiling across multiple viruses, cell systems, and primary airway epithelia
- Demonstration of in vivo efficacy with intranasal dosing in a relevant animal model
Limitations
- Human safety, pharmacokinetics, and dosing not established
- Potential immunogenicity and delivery challenges for peptide/protein therapeutics
Future Directions: Advance to GLP toxicology and phase 1 trials, optimize intranasal formulation, and assess efficacy against emerging variants and in combination with existing antivirals.
3. Anlotinib in combination with docetaxel for advanced nonsmall cell lung cancer after failure of platinum-based treatment: A phase 1/2 trial.
In platinum-pretreated advanced NSCLC, anlotinib plus docetaxel significantly improved PFS (median 5.39 vs 2.56 months; HR 0.36) and response rate versus docetaxel alone, with manageable hematologic toxicity. Overall survival difference was not statistically significant.
Impact: Provides randomized phase 2 evidence supporting an antiangiogenic TKI plus docetaxel regimen after platinum failure, with substantial PFS benefit and acceptable safety.
Clinical Implications: For patients with advanced NSCLC progressing after platinum, anlotinib plus docetaxel may be considered to improve PFS and response rates pending confirmatory phase 3 trials.
Key Findings
- MTD of anlotinib with docetaxel established at 10 mg in phase 1.
- Significant PFS improvement with combination vs docetaxel alone (5.39 vs 2.56 months; HR 0.36; p=0.0002).
- Higher objective response rate with combination (26.32% vs 6.45%).
- No significant OS difference; hematologic AEs (neutropenia, leukopenia) were most common.
Methodological Strengths
- Randomized phase 2 design with predefined MTD from phase 1
- Clinically meaningful endpoints (PFS, ORR, OS) and hazard ratios reported
Limitations
- Phase 2 sample size limits power for OS; p=0.7114 for OS
- Potential open-label biases (blinding not specified)
Future Directions: Conduct phase 3 trials to confirm OS benefit, define biomarkers of benefit, and optimize sequencing with immunotherapy.