Daily Respiratory Research Analysis
Three studies advance respiratory science across prevention and therapy: a phase 2 randomized trial shows an adjuvanted RSV vaccine elicits robust neutralizing and cellular responses in older adults; an intranasal parainfluenza-vectored SARS‑CoV‑2 vaccine induces mucosal and systemic immunity and protects hamsters against variant challenges; and a neutrophil‑targeted lipid nanoparticle co‑delivering DNase I and sivelestat reduces NETs, lung injury, and inflammation in COVID‑19 mice.
Summary
Three studies advance respiratory science across prevention and therapy: a phase 2 randomized trial shows an adjuvanted RSV vaccine elicits robust neutralizing and cellular responses in older adults; an intranasal parainfluenza-vectored SARS‑CoV‑2 vaccine induces mucosal and systemic immunity and protects hamsters against variant challenges; and a neutrophil‑targeted lipid nanoparticle co‑delivering DNase I and sivelestat reduces NETs, lung injury, and inflammation in COVID‑19 mice.
Research Themes
- Respiratory virus vaccination and immunogenicity
- Mucosal immunity via intranasal vaccination
- Targeted nanotherapies modulating neutrophil activity and NETs
Selected Articles
1. Immunogenicity, safety, and tolerability of a β-glucan-CpG-adjuvanted respiratory syncytial virus vaccine in Japanese healthy participants aged 60 to 80 years: A phase 2, randomized, double-blind, dose-finding study.
Across 342 older adults, all VN-0200 antigen/adjuvant combinations increased RSV/A and RSV/B neutralizing activity by Days 29 and 57 and boosted antigen-specific IFN-γ responses, with no serious vaccine-related TEAEs. No clear dose–response was observed, suggesting multiple dose pairs are acceptable from an immunogenicity and tolerability standpoint.
Impact: Provides randomized, double-blind evidence that a novel β-glucan–CpG-adjuvanted RSV vaccine is immunogenic and well tolerated in older adults, informing dose selection for phase 3 efficacy trials.
Clinical Implications: Supports advancing VN-0200 to efficacy trials in older adults and suggests flexible dose options given consistent immunogenicity and tolerability. Clinicians may anticipate additional RSV vaccine candidates tailored for elderly populations.
Key Findings
- All vaccine regimens increased anti-RSV/A and RSV/B neutralization GMTs from baseline by Days 29 and 57; GMFR lower 95% CI limits exceeded 1.0 in all groups.
- Anti-VAGA-9001a antibody titers and VAGA-9001a-specific IFN-γ responses rose at Days 29 and 57.
- No serious vaccine-related TEAEs or deaths; tolerability was good across all antigen/adjuvant combinations.
- No clear antigen or adjuvant dose–response relationships were observed for immunogenicity endpoints.
Methodological Strengths
- Randomized, double-blind, multicenter phase 2 design with multiple antigen/adjuvant dose levels
- Comprehensive immunogenicity endpoints (neutralization against RSV A/B, binding antibodies, IFN-γ responses) with prespecified timepoints
Limitations
- No clinical efficacy endpoints; results limited to immunogenicity and safety
- Lack of clear dose–response relationships complicates optimal dose selection
Future Directions: Proceed to phase 3 efficacy trials in diverse older adult populations; assess durability, correlates of protection, and real-world effectiveness, including coadministration strategies.
VN-0200 is an investigational β-glucan-CpG-adjuvanted respiratory syncytial virus (RSV) vaccine (antigen: VAGA-9001a [RSV F glycoprotein], adjuvant: MABH-9002b). This multicenter, randomized, double-blind, dose-finding phase 2 study explored the optimal VN-0200 dose and confirmed its humoral and cellular immunity and safety. In total, 342 healthy Japanese participants aged 60 to 80 years were randomized to one of 10 vaccination groups, each receiving a different combination of VAGA-9001a and MABH-9002a. VN-0200 was administered intramuscularly on Day 1 and Day 29. Geometric mean titer (GMT) and geometric mean fold rise (GMFR) of neutralization activity for anti-RSV subgroups A (RSV/A) and B (RSV/B), anti-VAGA-9001a antibody titer, and VAGA-9001a-specific interferon (IFN)-γ response were evaluated. Safety was monitored throughout the study. GMTs of serum anti-RSV/A neutralization activity increased from baseline to Day 57 and lower limits of the 95% confidence intervals of the corresponding GMFRs were >1.0 relative to baseline in all treatment groups (primary endpoint). Findings were similar for anti-RSV/A (Day 29) and anti-RSV/B (Day 29 and Day 57) neutralization activity, anti-VAGA-9001a antibody titer (Day 29 and Day 57), and VAGA-9001a-specific IFN-γ response (Day 29 and Day 57) (secondary endpoints). There was no clear influence of adjuvant or dose - response relationship of the antigen or adjuvant for any of the study endpoints. There were no serious vaccine-related treatment-emergent adverse events (TEAEs) or vaccine-related TEAEs leading to death. All antigen/adjuvant dose combinations of VN-0200 were well tolerated and elicited an increase in anti-RSV/A and anti-RSV/B neutralization activity from baseline to Day 29 and Day 57.
2. Lipid nanoparticles target neutrophils to reduce SARS-CoV-2-induced lung injury and inflammation.
A neutrophil-targeted LNP co-delivering DNase I and sivelestat accumulated in lung neutrophils, degraded NETs, and, at lower doses than free drugs, reduced SARS‑CoV‑2–induced NETs, inflammation, epithelial injury, and collagen deposition in K18‑hACE2 mice. Treatment during the symptomatic phase still improved outcomes, highlighting translational relevance.
Impact: Introduces a cell-specific, dual‑cargo nanotherapy targeting a central pathomechanism (NETs) in severe COVID-19, with demonstrated in vivo efficacy and dose sparing.
Clinical Implications: If translated, neutrophil-targeted NET inhibition could complement antivirals and steroids to reduce lung injury and post-acute sequelae in severe viral pneumonias. Dosing during symptomatic phases may still confer benefit.
Key Findings
- LNPs loaded with DNase I and sivelestat preferentially accumulated in lung neutrophils and efficiently degraded NETs in vitro and in vivo.
- In K18-hACE2 mice, DPNLNPs inhibited SARS‑CoV‑2–induced NET formation at doses lower than free drugs.
- Treatment reduced lung and systemic inflammation, epithelial injury, and collagen deposition.
- Administration limited to the symptomatic phase still improved outcomes, underscoring timing flexibility.
Methodological Strengths
- Cell-type targeted delivery with dual therapeutics validated in vitro and in vivo
- Use of K18-hACE2 SARS-CoV-2 model with histologic, inflammatory, and fibrotic endpoints
Limitations
- Preclinical animal model; human pharmacokinetics, safety, and efficacy remain unknown
- Potential immunogenicity or off-target effects of LNPs not fully characterized
Future Directions: Conduct GLP toxicology, biodistribution, and dose-ranging studies; evaluate in large-animal models and initiate early-phase clinical trials assessing safety, NET biomarkers, and pulmonary outcomes.
The need to understand key players driving pulmonary inflammation and fibrosis in COVID-19 patients leading to effective preventive strategies is imminent. Excessive neutrophil activation, including extracellular trap (NET) formation, is associated with severe COVID-19 and long-term sequelae. However, the clinical applications of neutrophil-targeting therapies are challenging due to short bioavailability and lack of cell-type specificity. This study presents a lipid nanoparticle (LNP) platform designed to deliver two established NET inhibitors, DNase I and Sivelestat (Siv) referred to as DPNLNPs, specifically to lung neutrophils. In vitro and in vivo experiments demonstrate that DPNLNPs preferentially accumulate in the lung neutrophils and degrade NETs as efficiently as the free DNase I and Siv. Additionally, administration of DPNLNPs in K18-hACE2 mice significantly inhibited SARS-CoV-2-induced NETs at a much lower dose than the free drugs and correlated with reduced lung and systemic inflammation, lung epithelium injury, and collagen deposition. Importantly, DPNLNP treatment only during the symptomatic phase of infection improved SARS-CoV-2 outcome revealing the complex role of NETs in COVID-19 pathogenesis. Together, this study serves as a proof-of-concept for adapting the LNP platform to deliver more than one immunomodulatory drug in a cell-specific manner to manage NET-associated complications in COVID-19 and other respiratory diseases.
3. Intranasal parainfluenza virus-vectored vaccine expressing SARS-CoV-2 spike protein of Delta or Omicron B.1.1.529 induces mucosal and systemic immunity and protects hamsters against homologous and heterologous challenge.
Intranasal B/HPIV3 vectors expressing stabilized spike from ancestral, Delta, or Omicron variants replicated in the airways, induced anti‑S IgA/IgG, and conferred lung protection in hamsters against matched and heterologous WA1, Delta, and BA.1 challenges after a single dose. Antibodies elicited by ancestral/Delta S showed broader cross-reactivity than Omicron S.
Impact: Demonstrates robust mucosal and systemic immunity with single‑dose intranasal vaccination and cross-variant lung protection, informing design of pediatric mucosal vaccines that match circulating strains.
Clinical Implications: Supports development of intranasal HPIV3‑vectored SARS‑CoV‑2 vaccines to provide mucosal protection and reduce lower respiratory tract disease; strain selection should consider broader antigenic breadth (ancestral/Delta S outperformed Omicron S in breadth).
Key Findings
- Single intranasal dose induced airway replication of vectors and robust mucosal (IgA) and serum (IgG) anti‑S responses.
- Conferred lung protection against homologous and heterologous WA1/2020, Delta, and BA.1 challenges; residual URT virus was low in few animals.
- Antibodies elicited by ancestral/Delta S had greater antigenic breadth across 20 variants than Omicron S.
- Omicron S vaccine induced lower cross-neutralization, aligning with slightly reduced cross-protection against BA.1 challenges.
Methodological Strengths
- Head-to-head evaluation of spike antigens from multiple variants with homologous and heterologous challenge
- Assessment of both mucosal and systemic immunity and histopathologic/inflammatory outcomes
Limitations
- Hamster model results may not fully translate to humans, especially children
- Upper respiratory tract sterilizing immunity was incomplete in a subset
Future Directions: Advance to nonhuman primate and early human studies to evaluate safety, dosing, durability, and transmission impact; optimize antigen selection for breadth.
The continuous emergence of new SARS-CoV-2 variants requires that COVID vaccines be updated to match circulating strains. We generated B/HPIV3-vectored vaccines expressing 6P-stabilized S protein of the ancestral, B.1.617.2/Delta, or B.1.1.529/Omicron variants as pediatric vaccines for intranasal immunization against HPIV3 and SARS-CoV-2 and characterized these in hamsters. Following intranasal immunization, these B/HPIV3 vectors replicated in the upper and lower respiratory tract and induced mucosal and serum anti-S IgA and IgG. B/HPIV3 expressing ancestral or B.1.617.2/Delta-derived S-6P induced serum antibodies that effectively neutralized SARS-CoV-2 of the ancestral and B.1.617.2/Delta lineages, while the cross-neutralizing potency of B.1.1.529/Omicron S-induced antibodies was lower. Despite the lower cross-neutralizing titers induced by B/HPIV3 expressing S-6P from B.1.1.529/Omicron, a single intranasal dose of all three versions of B/HPIV3 vectors was protective against matched or heterologous WA1/2020, B.1.617.2/Delta or BA.1 (B.1.1.529.1)/Omicron challenge; hamsters were protected from challenge virus replication in the lungs, while low levels of challenge virus were detectable in the upper respiratory tract of a small number of animals. Immunization also protected against lung inflammatory response after challenge, with mild inflammatory cytokine induction associated with the slightly lower level of cross-protection of WA1/2020 and B.1.617.2/Delta variants against the BA.1/Omicron variant. Serum antibodies elicited by all vaccine candidates were broadly reactive against 20 antigenic variants, but the antigenic breadth of antibodies elicited by B/HPIV3-expressed S-6P from the ancestral or B.1.617.2/Delta variant exceeded that of the S-6P B.1.1.529/Omicron expressing vector. These results will guide development of intranasal B/HPIV3 vectors with S antigens matching circulating SARS-CoV-2 variants.