Daily Respiratory Research Analysis
Three impactful respiratory papers stand out today: a target trial emulation shows early nirmatrelvir/ritonavir reduces hospitalization or death in B-cell–depleted patients with COVID-19; a model-based meta-analysis across seven RCTs identifies serum neutralizing activity and cell-mediated immunity as immune correlates of protection for RSV vaccines in older adults; and a mechanistic PNAS study reveals collectin-11 enhances SARS-CoV-2 infectivity and complement-mediated epithelial injury, mitiga
Summary
Three impactful respiratory papers stand out today: a target trial emulation shows early nirmatrelvir/ritonavir reduces hospitalization or death in B-cell–depleted patients with COVID-19; a model-based meta-analysis across seven RCTs identifies serum neutralizing activity and cell-mediated immunity as immune correlates of protection for RSV vaccines in older adults; and a mechanistic PNAS study reveals collectin-11 enhances SARS-CoV-2 infectivity and complement-mediated epithelial injury, mitigated by L-fucose.
Research Themes
- Outpatient COVID-19 antivirals in immunocompromised patients
- Immune correlates of protection for RSV vaccines
- Innate lectin–virus interactions driving respiratory pathogenesis
Selected Articles
1. Effectiveness of Nirmatrelvir/Ritonavir or Molnupiravir Use in Immunocompromised Patients on B-Cell-Depleting Therapy With COVID-19: A Target Trial Emulation Study.
In a target trial emulation among patients receiving B-cell–depleting therapy, early nirmatrelvir/ritonavir reduced the 21-day risk of hospitalization or death by 44% compared with no treatment, while molnupiravir showed a nonsignificant trend. These data support prioritizing nirmatrelvir/ritonavir for high-risk immunocompromised patients.
Impact: This study provides high-quality real-world evidence for antiviral prioritization in a uniquely vulnerable population where randomized trials are difficult. It informs clinical decision-making during ongoing SARS-CoV-2 circulation.
Clinical Implications: For patients on B-cell–depleting therapy who test positive for SARS-CoV-2, initiate nirmatrelvir/ritonavir promptly if eligible, as it significantly reduces short-term hospitalization or death. Molnupiravir may be considered when nirmatrelvir/ritonavir is contraindicated, acknowledging weaker evidence.
Key Findings
- Nirmatrelvir/ritonavir reduced 21-day hospitalization or death (weighted HR 0.56; 95% CI 0.31–0.99).
- In the treated vs untreated nirmatrelvir cohort, events were 4.4% vs 9.2%.
- Molnupiravir showed a nonsignificant reduction (weighted HR 0.56; 95% CI 0.24–1.33).
- Secondary endpoint (90-day mortality) framework established; emphasis on early outpatient initiation.
Methodological Strengths
- Target trial emulation with propensity score weighting and weighted Cox regression.
- Large multi-year EHR dataset with clear time windows (21-day and 90-day endpoints).
Limitations
- Observational design susceptible to residual confounding and treatment selection bias.
- Limited power for molnupiravir comparisons; changing variants and prior immunity may influence effect sizes.
Future Directions: Prospective pragmatic trials or larger multi-system emulations to refine subgroup effects (e.g., timing, concomitant immunosuppression) and comparative effectiveness among antivirals in immunocompromised populations.
2. Establishing Immune Correlates of Protection Against Respiratory Syncytial Virus Infection to Accelerate Vaccine Development: A Model-Based Meta-Analysis.
Across seven randomized trials in older adults, serum neutralizing activity correlated positively with vaccine efficacy across clinical severities, and cell-mediated immunity added predictive value for the most severe RSV lower respiratory tract disease (LRTD 3+). These findings provide preliminary immune correlates of protection that can inform accelerated RSV vaccine development.
Impact: Establishing immune correlates is crucial for efficient vaccine development and regulatory decision-making, especially in older adults where large efficacy trials are challenging.
Clinical Implications: Serum neutralizing titers and T-cell responses may serve as surrogate endpoints for RSV vaccine trials in older adults, enabling smaller or shorter studies while preserving predictive validity for severe LRTD.
Key Findings
- Serum neutralizing activity (SNA) positively correlated with vaccine efficacy across ARI, RSV LRTD (≥2 symptoms), and RSV LRTD 3+.
- Cell-mediated immunity (CMI) contributed additional explanatory power for vaccine efficacy specifically in the most severe endpoint (LRTD 3+).
- Model-based meta-analysis across seven randomized placebo-controlled trials in older adults supports preliminary immune correlates of protection.
Methodological Strengths
- Model-based meta-analysis integrating seven randomized placebo-controlled trials.
- Severity-stratified evaluation and joint assessment of humoral and cellular immunity.
Limitations
- Population limited to older adults; generalizability to other age groups unknown.
- Correlates are preliminary and may be affected by assay variability and trial heterogeneity.
Future Directions: Prospective validation of SNA and CMI thresholds as correlates of protection and exploration of combined immunologic endpoints to support regulatory acceptance.
3. Glycan recognition by collectin-11 drives SARS-CoV-2 infectivity and membrane injury of respiratory epithelial cells.
Collectin-11 bound SARS-CoV-2, activated complement, and yet the virus remained lysis-resistant. CL-11 opsonization increased viral production by respiratory epithelial cells independently of complement, and infected cells were more susceptible to complement-mediated membrane attack; L-fucose blocked this by occupying CL-11’s carbohydrate-binding cleft (shown by crystallography).
Impact: Reveals a previously unrecognized pro-viral role of an innate lectin and provides a structural basis for therapeutic blockade (e.g., L-fucose) to mitigate epithelial injury and infectivity.
Clinical Implications: Targeting CL-11–glycan interactions (e.g., with fucosylated ligands) could attenuate SARS-CoV-2 infectivity and complement-mediated epithelial injury, suggesting adjunctive strategies beyond adaptive immunity.
Key Findings
- CL-11 binds SARS-CoV-2 and activates complement, yet the virus resists lysis.
- CL-11 opsonization enhances virus production by infected respiratory epithelial cells independently of complement.
- Infected cells show increased susceptibility to CL-11 binding and complement membrane attack.
- L-fucose abrogates enhanced infectivity by occupying CL-11’s carbohydrate-binding cleft (crystallographic evidence).
Methodological Strengths
- Multimodal approach combining virology, complement assays, and crystallography.
- Relevant respiratory epithelial cell models demonstrating functional effects.
Limitations
- Primarily in vitro mechanistic data without in vivo validation.
- Translational applicability and safety of fucose-based interventions remain to be established.
Future Directions: In vivo validation of CL-11 blockade strategies and exploration of glycan-modulating therapies as adjuncts to reduce epithelial injury and viral load.