Daily Respiratory Research Analysis
Three studies advance respiratory-related science and practice: serial CSF ctDNA monitoring via Ommaya reservoirs in leptomeningeal metastases from lung adenocarcinoma enables highly sensitive, dynamic response assessment; an oropharyngeal adenoviral spray booster in macaques elicits strong mucosal immunity with near-sterilizing protection against Omicron EG.5.1.1; and human monoclonal antibodies against clade 2.3.4.4b H5N1 show potent cross-reactivity, in vivo protection, and a conserved HA hea
Summary
Three studies advance respiratory-related science and practice: serial CSF ctDNA monitoring via Ommaya reservoirs in leptomeningeal metastases from lung adenocarcinoma enables highly sensitive, dynamic response assessment; an oropharyngeal adenoviral spray booster in macaques elicits strong mucosal immunity with near-sterilizing protection against Omicron EG.5.1.1; and human monoclonal antibodies against clade 2.3.4.4b H5N1 show potent cross-reactivity, in vivo protection, and a conserved HA head epitope by cryo-EM.
Research Themes
- CSF liquid biopsy for leptomeningeal metastases in lung cancer
- Mucosal vaccine strategies to block respiratory virus transmission
- Pandemic preparedness via cross-reactive H5N1 monoclonal antibodies
Selected Articles
1. Serial monitoring of cerebrospinal fluid in patients with leptomeningeal metastases in lung cancer via the Ommaya reservoir as a predictive indicator of therapeutic efficacy and clinical prognosis.
In 125 LM-LUAD patients (301 CSF samples), CSF ctDNA had a 99.2% baseline detection rate versus 57.6% in plasma. A 20% change in CSF ctDNA aligned with clinical response at >90% consistency, enabling a prognostic map and multi-feature model to predict response and outcomes. Findings support CSF ctDNA as a highly sensitive, dynamic biomarker for treatment guidance.
Impact: This is the most systematic, large-scale evaluation of serial CSF ctDNA monitoring in LM-LUAD, defining a practical 20% change threshold that tracks clinical response and building a robust prognostic model.
Clinical Implications: For LM-LUAD, integrate serial CSF ctDNA monitoring via Ommaya reservoirs into routine response assessments; a ≥20% change can inform early therapy adjustments, outperforming plasma ctDNA detection.
Key Findings
- Baseline CSF ctDNA detection was 99.2% versus 57.6% in plasma.
- A 20% dynamic change in CSF ctDNA achieved >90% concordance with clinical response assessments across intervals.
- A CSF ctDNA-based prognostic map and multi-feature predictive model accurately assessed responses and prognosis.
Methodological Strengths
- Serial, intra-patient CSF sampling (301 samples from 125 patients) enabling dynamic analyses.
- Direct comparison to plasma ctDNA and development of a multi-feature predictive model.
Limitations
- Observational design without interventional adaptation based on ctDNA.
- Dependence on Ommaya reservoir access may limit generalizability; external validation not detailed.
Future Directions: Prospective interventional trials using ctDNA-guided treatment adjustments and external validation across centers and CNS metastasis types.
2. Human monoclonal antibodies that target clade 2.3.4.4b H5N1 hemagglutinin.
Sixteen fully human anti-HA mAbs to H5N1 clade 2.3.4.4b were generated; 14 neutralized in vitro, and the strongest HI mAbs conferred prophylactic and therapeutic protection in mice. Cryo-EM revealed a conserved motif binding a hydrophobic groove on the HA head, supporting cross-reactivity across clade variants and informing therapeutic and vaccine design.
Impact: This study delivers cross-reactive human mAbs with in vivo efficacy and structurally defines a conserved HA head epitope for clade 2.3.4.4b, directly supporting pandemic preparedness for H5N1.
Clinical Implications: These mAbs could be advanced for prophylaxis or treatment in H5N1 outbreaks; the conserved HA head groove motif may guide broadly protective antibody and vaccine development.
Key Findings
- Generated 16 fully human anti-HA mAbs against H5N1 clade 2.3.4.4b; 14/16 neutralized in vitro.
- HI-strong mAbs showed superior neutralization and provided prophylactic and therapeutic protection in a murine H5N1 challenge.
- Cryo-EM identified a conserved cross-clonotype motif targeting a hydrophobic groove on the HA head, supporting cross-reactivity across clade variants.
Methodological Strengths
- Integration of in vitro neutralization, in vivo murine protection, and cryo-EM structural mapping.
- Use of humanized immunoglobulin mice to generate fully human monoclonal antibodies.
Limitations
- Efficacy demonstrated in murine models; human pharmacology and clinical efficacy remain untested.
- Antigenic evolution could reduce binding; breadth against future variants requires ongoing evaluation.
Future Directions: Advance lead mAbs to GMP production and phase 1 trials; assess breadth versus evolving H5N1; explore epitope-focused immunogen design leveraging the conserved HA head groove.
3. Adenoviral vector oropharyngeal spray immunization elicits mucosal immunity and protects against heterologous SARS-CoV-2 infection.
In mRNA-primed macaques, an oropharyngeal adenoviral vector booster elicited robust mucosal IgA and T-cell responses and conferred near-sterilizing protection against Omicron EG.5.1.1, comparable to heterologous Delta infection. Live-attenuated spray did not achieve similar mucosal immunity.
Impact: Demonstrates a practical mucosal boosting strategy capable of blocking upper and lower respiratory tract infection by an immune-escape Omicron variant in a primate model.
Clinical Implications: An oropharyngeal adenoviral mucosal booster could be advanced to clinical trials to reduce transmission by enhancing airway immunity, particularly as a post-mRNA booster strategy.
Key Findings
- In mRNA-primed macaques, adenoviral oropharyngeal spray and Delta infection induced strong mucosal IgA and T-cell responses; LAV spray did not.
- Upon Omicron EG.5.1.1 challenge, adenoviral spray and Delta infection groups showed almost no upper or lower respiratory tract infection.
- Adenoviral mucosal booster achieved protection comparable to heterologous natural infection, supporting transmission-blocking potential.
Methodological Strengths
- Head-to-head comparison of three mucosal antigen exposures in a nonhuman primate model with direct heterologous challenge.
- Comprehensive mucosal and systemic immune readouts (IgA, mucosal T cells, systemic IgG) and virological outcomes.
Limitations
- Preclinical primate study with likely small group sizes; durability and safety profiles over time are not established here.
- Specific LAV platform performance may not generalize across live-attenuated constructs.
Future Directions: Phase 1/2 trials of oropharyngeal adenoviral boosters post-mRNA vaccination; durability and safety studies; assessment against diverse Omicron lineages and other respiratory viruses.