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.
BACKGROUND: Immunocompromised patients, especially those receiving B-cell-depleting therapy (BCDT), remain at high risk for severe coronavirus disease 2019 (COVID-19). Although monoclonal antibodies showed benefit pre-Omicron, the real-world effectiveness of the oral antivirals in BCDT recipients is unclear. METHODS: We emulated a target trial using the Cleveland Clinic electronic health record. Adult patients (≥18 years) with immune-mediated inflammatory diseases who received rituximab or ocrelizumab and tested positive for severe acute respiratory syndrome coronavirus 2 between 19 December 2021 and 30 June 2025 were eligible. The primary endpoint was hospitalization or death within 21 days; the secondary endpoint was death within 90 days. Propensity scores adjusted for confounding, and Weighted Cox regression models were used to evaluated treatment effects. RESULTS: Among 255 853 COVID-19 cases, 876 met criteria for the nirmatrelvir/ritonavir cohort (411 treated, 465 untreated) and 566 for the molnupiravir cohort (91 treated, 475 untreated). In the nirmatrelvir/ritonavir cohort, 18 (4.4%) of treated versus 43 (9.2%) of untreated patients were hospitalized or died within 21 days. After weighting, nirmatrelvir/ritonavir reduced the hazard by 44% (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.31-0.99). In the molnupiravir cohort, 6 (6.6%) of treated and 46 (9.7%) of untreated patients met the primary endpoint; the weighted HR was 0.56 (95% CI, 0.24-1.33), not statistically significant. CONCLUSIONS: Early outpatient nirmatrelvir/ritonavir significantly lowers the risk of COVID-19-related hospitalization or death in patients on BCDT. Molnupiravir showed a nonsignificant trend toward benefit. These findings support prioritizing nirmatrelvir/ritonavir for high-risk 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.
The objectives of this study were to quantify the relationship between vaccine-induced immunogenicity responses and the protection against respiratory syncytial virus (RSV) infection-related clinical outcomes, and to evaluate immunogenicity as a surrogate marker for vaccine efficacy (VE) to accelerate RSV vaccine development. Serum neutralizing activity (SNA) and cell-mediated immunity (CMI) may serve as surrogate markers for the protection against RSV infection and are evaluated as immunogenicity endpoints in clinical trials of RSV vaccine candidates. Two meta-analytical approaches were applied to data from seven randomized placebo-controlled clinical trials that investigated RSV vaccines in older adults. The primary analysis examined the relationship between SNA and VE across three different clinical severity levels: (1) acute respiratory infection, (2) RSV lower respiratory tract disease (LRTD) with ≥ 2 clinical symptoms, and (3) RSV LRTD with ≥ 3 clinical symptoms (LRTD 3+). Furthermore, the additional contribution of CMI to VE, after accounting for the effect of SNA, was explored in a secondary analysis. The results demonstrated a positive correlation between SNA and VE across three clinical severity levels. Higher CMI was associated with higher VE specifically for RSV LRTD 3+, the most severe clinical level, suggesting that CMI may be correlated with additional clinical benefits in mitigating the severity of RSV infection. These findings provided preliminary evidence for immune correlates of protection against RSV infection and may aid in accelerating the development of new RSV vaccines.
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.
SARS-CoV-2 respiratory-tract infection affects both vaccinated and unvaccinated persons suggesting factors besides adaptive immunity are operative. We investigated the role of collectin-11 (CL-11), an epithelial-secreted carbohydrate-binding lectin that drives innate immunity and eliminates pathogens by complement activation. SARS-CoV-2, despite binding CL-11 to activate complement, was resistant to lysis. Remarkably, opsonization by CL-11 enhanced virus production by infected respiratory epithelial cells independently of complement. Furthermore, infected cells expressing SARS-CoV-2 spike protein displayed enhanced vulnerability to CL-11 binding and membrane attack by complement. The mechanism of enhanced infectivity was ablated in the presence of L-fucose, which occupied the extended carbohydrate-binding cleft of CL-11 in a crystallographic analysis of complexes between L-fucose and CL-11. Our study suggests pathogenicity of SARS-CoV-2 is related to complement-resistance together with enhanced infectivity and injury of respiratory epithelial cells mediated by locally released CL-11.