Daily Respiratory Research Analysis
Three papers substantially advance respiratory science and care: a phase I/II randomized trial shows a live-attenuated intranasal RSV vaccine is immunogenic and well-tolerated in infants; a mechanistically innovative prefusion-stabilized RSV F antigen (preF7P) achieves high expression and robust protection across animal models; and a first-in-human pig-to-human lung xenotransplantation demonstrates 9-day graft viability, defining key rejection challenges.
Summary
Three papers substantially advance respiratory science and care: a phase I/II randomized trial shows a live-attenuated intranasal RSV vaccine is immunogenic and well-tolerated in infants; a mechanistically innovative prefusion-stabilized RSV F antigen (preF7P) achieves high expression and robust protection across animal models; and a first-in-human pig-to-human lung xenotransplantation demonstrates 9-day graft viability, defining key rejection challenges.
Research Themes
- Pediatric RSV vaccination and mucosal immunization
- Structure-guided antigen stabilization for respiratory vaccines
- Feasibility and immunologic barriers in lung xenotransplantation
Selected Articles
1. Live-Attenuated Intranasal RSV Vaccine in Infants and Toddlers.
In a multicenter phase I/II randomized trial, the live-attenuated intranasal RSV vaccine (RSVt) elicited substantially higher RSV A neutralizing titers versus placebo after both doses in RSV-naïve infants and toddlers, with no unsolicited systemic adverse events within 30 minutes. Solicited local/systemic reactions were common but acceptable.
Impact: Demonstrates immunogenicity and early safety of an intranasal, live-attenuated RSV vaccine directly in the target pediatric population, addressing a longstanding unmet need.
Clinical Implications: Supports advancing to efficacy trials; intranasal live-attenuated vaccination may induce mucosal immunity and simplify pediatric deployment, potentially reducing RSV hospitalization burden.
Key Findings
- RSV-naïve participants had markedly higher RSV A neutralizing GMTs with RSVt vs placebo after dose 1 (LD 83.7; HD 79.4; placebo 20.6) and dose 2 (LD 142.0; HD 107.0; placebo 26.3).
- No unsolicited systemic adverse events occurred within 30 minutes post-vaccination; solicited local/systemic reactions were frequent but similar across doses.
- Both low- and high-dose regimens showed promising immunogenicity profiles in infants/toddlers across three countries.
Methodological Strengths
- Randomized, multicenter phase I/II design with prespecified immunogenicity endpoints and CIs
- Direct enrollment of target population (6–18 months) across diverse geographies
Limitations
- Phase I/II trial not powered for clinical efficacy outcomes
- Short follow-up centered on early immunogenicity and solicited reactions
Future Directions: Proceed to phase III efficacy trials including assessment of mucosal immunity, durability, and real-world effectiveness against RSV hospitalization.
2. Highly scalable prefusion-stabilized RSV F vaccine with enhanced immunogenicity and robust protection.
A seven–proline substitution “preF7P” RSV F antigen maintains the prefusion state, increases neutralizing titers by ~1.8× versus DS‑cav2, protects against RSV A and B in mice/cotton rats, and achieves ~10 g/L expression in clinical-grade CHO. It robustly boosts neutralization in rodents and primates, with ≥6-month protection in mice.
Impact: Introduces a generalizable, scalable stabilization strategy for class I fusion antigens with immediate translational relevance for RSV vaccines and broader pathogen targets.
Clinical Implications: Enables manufacturable, potent RSV vaccine candidates that could improve durability and breadth; supports rapid progression to human trials and platform extension to other respiratory viruses.
Key Findings
- Proline-scanning with seven substitutions stabilized RSV F in the prefusion state (preF7P) with structural/biochemical validation.
- PreF7P increased neutralizing titers ~1.8× versus DS‑cav2 and protected mice and cotton rats against RSV A and B clinical disease.
- Clinical-grade CHO production achieved ~10 g/L; robust immunogenicity observed in rodents and cynomolgus macaques with ≥6 months protection in mice.
Methodological Strengths
- Multi-species validation (mice, cotton rats, cynomolgus macaques) with structural and biochemical confirmation of antigen state
- Demonstrated high-yield clinical-grade CHO expression supporting scalability
Limitations
- Preclinical models; human safety and efficacy not yet established
- Protection durability characterized primarily in mice; broader durability data pending
Future Directions: Advance to phase I human trials assessing safety, mucosal/serologic immunity, and cross-lineage protection; apply proline scanning to other class I fusion vaccine targets.
3. Pig-to-human lung xenotransplantation into a brain-dead recipient.
A six–gene-edited pig lung was transplanted into a brain-dead human and functioned for 216 hours without hyperacute rejection or infection. Early edema likely from ischemia-reperfusion injury and episodic antibody-mediated injury (POD 3 and 6) occurred, with partial recovery by day 9 under intensive, adaptive immunosuppression.
Impact: First demonstration of sustained pig lung function in a human milieu delineates key barriers (edema, antibody-mediated injury) and informs immunosuppression strategies, a foundational step toward clinical lung xenotransplantation.
Clinical Implications: Establishes feasibility and clarifies acute injury patterns to target (IRI, AMR), guiding protocol development for future feasibility trials while highlighting infection/rejection risks.
Key Findings
- No hyperacute rejection or infection; xenograft viability and function sustained for 216 hours.
- Severe edema at 24 hours consistent with ischemia–reperfusion injury; antibody-mediated rejection contributed to injury on POD 3 and 6 with partial recovery by day 9.
- Adaptive multi-agent immunosuppression (e.g., ATG, basiliximab, rituximab, eculizumab, tacrolimus, mycophenolate) guided by immune assessments.
Methodological Strengths
- First-in-human surgical and immunologic feasibility with continuous physiologic and immunologic monitoring
- Detailed characterization of injury phenotypes and responsive immunosuppression adjustments
Limitations
- Single brain-dead recipient; results may not extrapolate to living recipients
- Short observation window (9 days) with confounders inherent to brain death physiology
Future Directions: Iterative gene edits and targeted complement/B-cell modulation to mitigate AMR; longer-duration preclinical/compassionate studies to refine protocols and infection control.