Weekly Respiratory Research Analysis
This week’s respiratory research highlights durable advances in prevention, mechanistic immunology, and neural control of breathing. A multi-season phase 3 trial shows an RSVPreF3 OA vaccine provides sustained protection across three RSV seasons in older adults. Mechanistic human immunology links systemic inflammation to impaired myelopoiesis and type I IFN responses, informing immunomodulatory strategies in sepsis and acute respiratory failure. Preclinical work identifies MC4R-expressing parafa
Summary
This week’s respiratory research highlights durable advances in prevention, mechanistic immunology, and neural control of breathing. A multi-season phase 3 trial shows an RSVPreF3 OA vaccine provides sustained protection across three RSV seasons in older adults. Mechanistic human immunology links systemic inflammation to impaired myelopoiesis and type I IFN responses, informing immunomodulatory strategies in sepsis and acute respiratory failure. Preclinical work identifies MC4R-expressing parafacial neurons as a druggable target to abolish sleep apneas in obese mice, opening a pharmacologic approach to sleep-disordered breathing.
Selected Articles
1. Efficacy, safety, and immunogenicity of the AS01
In a multinational, randomized, observer-blind, placebo-controlled phase 3 trial (AReSVi-006) of adults ≥60 years, a single dose of RSVPreF3 OA produced cumulative efficacy of ~62.9% against RSV lower respiratory tract disease across three consecutive seasons (median follow-up ~30.6 months). Efficacy was shown against RSV A and B, waned over time, and a revaccination at 1 year produced efficacy within a similar range. Safety was acceptable with <1% investigator-attributed serious adverse events.
Impact: Provides one of the first rigorous demonstrations of multi-season durability for an RSV vaccine in older adults, directly informing immunization policy, expected protection duration, and revaccination planning.
Clinical Implications: Supports implementation of RSVPreF3 OA vaccination for adults ≥60 years with expectation of multi-season protection; clinicians should anticipate waning effectiveness and follow evolving guidance on optimal revaccination intervals.
Key Findings
- Single-dose RSVPreF3 OA showed cumulative efficacy ≈62.9% against RSV-LRTD over three seasons (median follow-up ~30.6 months).
- Efficacy observed against both RSV A (≈69.8%) and RSV B (≈58.6%).
- Efficacy waned over time; revaccination at 1 year had efficacy within the same range as single-dose; safety profile clinically acceptable.
2. Systemic inflammation impairs myelopoiesis and interferon type I responses in humans.
Using a controlled human LPS endotoxemia model that captures hyperinflammatory and immunosuppressive phases, single-cell RNA sequencing revealed an inflammatory CD163+ population and showed that systemic inflammation impairs myelopoiesis and type I interferon signaling. The study provides mechanistic cellular maps that link clinical phenotypes of immunoparalysis to pathways amenable to biomarker development and immunomodulatory intervention.
Impact: Bridges clinical hyperinflammation/immunosuppression phenotypes and cellular programs with high-resolution single-cell data in humans, guiding biomarker strategies and timing/targets for immunotherapies in sepsis and ARDS.
Clinical Implications: Supports stratification of critically ill patients by immune axis (myelopoiesis/IFN‑I) and rational timing of immunomodulators; suggests candidate cellular biomarkers for trials and precision therapy in sepsis/acute respiratory failure.
Key Findings
- Controlled human LPS model captured both hyperinflammatory and late immunosuppressive phases.
- Single-cell RNA-seq identified an inflammatory CD163+ cellular population during the acute phase.
- Systemic inflammation impaired myelopoiesis and type I interferon responses in humans.
3. Targeting melanocortin 4 receptor to treat sleep-disordered breathing in mice.
In obese mice, MC4R agonist setmelanotide increased minute ventilation across sleep and wake states, enhanced the hypercapnic ventilatory response, and abolished sleep apneas. Mechanistic mapping identified parafacial MC4R+ neurons as critical mediators: chemogenetic activation reproduced effects, and targeted ablation eliminated drug responses, positioning MC4R agonism as a potential pharmacologic approach to sleep-disordered breathing.
Impact: Identifies a discrete brainstem neuronal population as a druggable node for sleep-disordered breathing and provides preclinical proof that MC4R agonism can normalize breathing during sleep, paving the way for human translational studies.
Clinical Implications: Supports early-phase clinical evaluation of MC4R agonists (e.g., setmelanotide) for obesity-associated sleep-disordered breathing with physiologic endpoints (apnea–hypopnea index, hypercapnic response) and safety monitoring.
Key Findings
- Setmelanotide increased minute ventilation and augmented the hypercapnic ventilatory response in obese mice.
- Sleep apneas were abolished after MC4R agonist administration.
- Parafacial MC4R+ neurons mediated the effect (chemogenetic activation reproduced, ablation abolished the response).