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.
BACKGROUND: RSV/ΔNS2/Δ1313/I1314L (RSVt) (Sanofi) is a candidate live-attenuated intranasal respiratory syncytial virus (RSV) vaccine for infants and toddlers. METHODS: This phase I/II randomized clinical trial, conducted at sites in the United States (N=22), Chile (N=2), and Honduras (N=2), enrolled participants 6-18 months of age in four cohorts. In cohort 4, the primary cohort reported in this article, participants were randomly assigned to receive vaccinations on days 0 and 56 of either low-dose (LD) RSVt, high-dose (HD) RSVt, or placebo. Primary safety end points included: unsolicited systemic adverse events 30 minutes post vaccination, and solicited site and systemic reactions 28 days post vaccination. The primary immunogenicity end points were the geometric mean titers of RSV A serum neutralizing antibody after vaccinations 1 (day 56) and 2 (day 84) among RSV-naive participants at baseline. RESULTS: Among 180 participants (LD, N=61; HD, N=58; placebo, N=61), 115 were RSV-naive at baseline (LD, N=45; HD, N=32; placebo, N=38). No unsolicited systemic adverse events occurred within 30 minutes post vaccination in the LD or HD groups. Solicited site reactions were reported by 83.1%, 74.5%, and 68.9% of participants post vaccination 1, and 75.6%, 77.8%, and 55.6% post vaccination 2, in the LD, HD, and placebo groups, respectively. Solicited systemic reactions were reported by 79.7%, 73.2%, and 77.0% of participants post vaccination 1, and 66.7%, 66.7%, and 48.1% post vaccination 2, in the LD, HD, and placebo groups, respectively. Neutralizing antibody titers among RSV-naive participants were 83.7 (95% confidence interval (CI), 49.5 to 142.0), 79.4 (95% CI, 47.2 to 134.0), and 20.6 (95% CI, 16.4 to 25.9) post vaccination 1, and 142.0 (95% CI, 86.4 to 232.2), 107.0 (95% CI, 70.0 to 163.0), and 26.3 (95% CI, 18.8 to 37.0) post vaccination 2, in the LD, HD, and placebo groups, respectively. CONCLUSIONS: The RSVt vaccine demonstrated promising immunogenicity profiles at both LD and HD strengths among infants and toddlers, without identified safety concerns. (Funded by Sanofi; ClinicalTrials.gov number, NCT04491877).
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.
Stabilizing the RSV F protein in its prefusion conformation is crucial for effective vaccine development but has remained a significant challenge. Traditional stabilization methods, such as disulfide bonds and cavity-filling mutations, have been labor-intensive and have often resulted in suboptimal expression levels. Here, we report the design of an RSV prefusion F (preF) antigen using a proline-scanning strategy, incorporating seven proline substitutions to achieve stabilization. The resulting variant, preF7P, is structurally and biochemically validated to maintain the correct prefusion state. PreF7P demonstrates superior immunogenicity with a 1.8-fold increase in neutralizing antibody titers when compared to DS-cav2, and provides protection from clinical disease against both RSV A and B strains in female murine and female cotton rat models. In clinical development, preF7P exhibits high expression levels (~10 g/L) in clinical-grade CHO cells. The clinical-grade vaccine elicits robust immunogenic responses across female mice, female SD rats, and both male and female cynomolgus macaques, significantly boosting RSV pre-infection neutralizing antibody titers, and providing sustained protection for at least six months in female mice. This proline-scanning strategy offers a streamlined approach for stabilizing class I fusion proteins, potentially accelerating the development of vaccines for other pathogens.
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.
Genetically engineered pig lungs have not previously been transplanted into humans, leaving key questions unanswered regarding the human immune response in the context of a xenotransplanted lung and the possibility of hyperacute rejection. Here, we report a case of pig-to-human lung xenotransplantation, in which a lung from a six-gene-edited pig was transplanted into a 39-year-old brain-dead male human recipient following a brain hemorrhage. The lung xenograft maintained viability and functionality over the course of the 216 hours of the monitoring period, without signs of hyperacute rejection or infection. Severe edema resembling primary graft dysfunction was observed at 24 hours after transplantation, potentially due to ischemia-reperfusion injury. Antibody-mediated rejection appeared to contribute to xenograft damage on postoperative days 3 and 6, with partial recovery by day 9. Immunosuppression included rabbit anti-thymocyte globulin, basiliximab, rituximab, eculizumab, tofacitinib, tacrolimus, mycophenolate mofetil and tapering steroids, with adjustments made during the postoperative period based on assessments of immune status. Although this study demonstrates the feasibility of pig-to-human lung xenotransplantation, substantial challenges relating to organ rejection and infection remain, and further preclinical studies are necessary before clinical translation of this procedure.