Daily Respiratory Research Analysis
Three impactful respiratory studies span mechanisms, prevention, and policy. A JCI study identifies P-selectin as a key host factor mediating SARS-CoV-2 interactions with platelets and endothelium, suggesting a novel therapeutic axis. Complementing this, an Annals systematic review and a nationwide French cohort provide converging evidence to optimize influenza vaccination strategies, supporting high-dose or recombinant vaccines in adults, especially older populations.
Summary
Three impactful respiratory studies span mechanisms, prevention, and policy. A JCI study identifies P-selectin as a key host factor mediating SARS-CoV-2 interactions with platelets and endothelium, suggesting a novel therapeutic axis. Complementing this, an Annals systematic review and a nationwide French cohort provide converging evidence to optimize influenza vaccination strategies, supporting high-dose or recombinant vaccines in adults, especially older populations.
Research Themes
- Host–virus interaction mechanisms in respiratory infection
- Comparative effectiveness of influenza vaccines in adults
- Real-world evidence informing respiratory vaccine policy
Selected Articles
1. P selectin promotes SARS-CoV-2 interactions with platelets and the endothelium.
A CRISPRa screen identified P-selectin as a host factor that increases spike-dependent binding yet protects against SARS-CoV-2 infection. P-selectin on platelets and endothelium mediates vascular interactions and homing of virus to capillary beds; synthetic mRNA–driven P-selectin expression blocks infection, and inhibiting P-selectin interactions clears pulmonary vascular virus in vivo.
Impact: This work reveals a previously unappreciated role for P-selectin in coronavirus vascular tropism and identifies a modifiable host pathway with therapeutic potential.
Clinical Implications: Targeting P-selectin–mediated interactions (e.g., with blockers or modulating expression) may reduce vascular sequestration and platelet aggregation in COVID‑19, opening avenues for adjunctive therapies alongside antivirals.
Key Findings
- CRISPR activation screening identified 34 host genes modulating infection; seven, including P-selectin, suppressed authentic SARS-CoV-2 infection.
- P-selectin increased spike-dependent binding but conferred protection from infection; synthetic mRNA–driven P‑selectin expression blocked infection.
- P-selectin mediated spike interactions on platelets and endothelium, promoting platelet aggregation and vascular homing; blockade cleared pulmonary vascular virus in vivo.
- P-selectin facilitated binding across SARS-CoV-2 variants and other pathogenic coronaviruses (SARS-CoV-1, MERS), indicating broader relevance.
Methodological Strengths
- Genome-wide CRISPRa screen followed by validation across multiple systems (cellular assays, platelets, endothelium, in vivo).
- Mechanistic breadth including binding, aggregation, vascular homing, and therapeutic mRNA/antagonist interventions.
Limitations
- Preclinical models may not fully recapitulate human vascular physiology and safety of P-selectin modulation.
- Translation to clinical outcomes requires trials to assess efficacy and thrombotic/bleeding risk balance.
Future Directions: Evaluate pharmacologic P-selectin blockers or RNA-based modulation in relevant animal models and early-phase clinical studies to test reduction of vascular viral load, thrombosis, and hypoxemia.
The physiology of SARS-CoV-2 virus/host interactions is not well understood. To better understand host/virus interactions, we performed a CRISPR activation screen to identify host genes that confer resistance to authentic SARS-CoV-2. This highlighted 34 new candidate genes that may alter the course of infection. We validated that 7 of these genes can suppress authentic SARS-CoV-2 infection, including the innate immune receptor P selectin, which increases SARS-CoV-2 spike-dependent binding to cells, while protecting from infection. P selectin also promotes binding to SARS-CoV-2 variants, SARS-CoV-1, and Middle East respiratory syndrome spike proteins, suggesting a general role for P selectin in highly pathogenic coronavirus infections. Importantly, P selectin protein expression driven by synthetic mRNA can block SARS-CoV-2 infection. Naturally, P selectin is expressed on platelets, and we show that it promotes spike-mediated platelet aggregation. P selectin is also expressed on the endothelium, where SARS-CoV-2 spike interactions are also P selectin dependent. In vivo, SARS-CoV-2 uses P selectin to home to capillary beds where the virus interacts with platelets and endothelium, and blocking this interaction can clear vascular-associated pulmonary SARS-CoV-2.
2. Comparative Effectiveness and Harm of Seasonal Influenza Vaccines in Adults Who Are Not Pregnant or Immunocompromised: A Rapid Review for the American College of Physicians.
Across 35 RCTs and 5 NRSIs, high-dose influenza vaccines reduced lab-confirmed influenza in adults ≥65 but increased fever; recombinant vaccines reduced influenza in adults, particularly <65. Limited low-certainty evidence suggested mRNA vaccines may increase serious adverse events versus standard vaccines.
Impact: This synthesis directly informs vaccine selection by age group, clarifying benefits and trade-offs among modern influenza vaccine platforms.
Clinical Implications: Prefer high-dose vaccines for adults ≥65 to maximize protection, counsel about fever risk; consider recombinant vaccines for broad adult protection, particularly <65. Exercise caution interpreting mRNA influenza vaccine safety until more data accrue.
Key Findings
- High-dose vaccines reduced lab-confirmed influenza in adults ≥65 (high certainty) but increased fever risk in this group.
- High-dose vaccines probably caused fewer serious adverse events overall and in ≥65 (moderate certainty).
- Recombinant vaccines reduced lab-confirmed influenza in all adults and <65 (high certainty).
- Two RCTs suggested mRNA vaccines may increase serious adverse events versus standard vaccines (low certainty).
Methodological Strengths
- Comprehensive synthesis of 35 RCTs with risk of bias assessment and certainty grading.
- Pre-registered protocol (PROSPERO) and dual-review processes for selection and quality.
Limitations
- Few RCTs assessed hospitalization or mortality; outcome gaps for some comparisons.
- Broad serious adverse event definitions may overestimate harms.
Future Directions: Head-to-head RCTs powered for severe outcomes across age strata and rigorous safety monitoring for emerging platforms (e.g., mRNA).
BACKGROUND: Seasonal influenza is a contagious viral respiratory illness that causes yearly epidemics. PURPOSE: To assess the comparative effectiveness and harm of standard and newer and enhanced influenza vaccines in nonpregnant, nonimmunocompromised adults. DATA SOURCES: Medline and Embase between May 2023 and July 2025, and a systematic review by the European Centre for Disease Prevention and Control (ECDC) to identify studies published before May 2023. STUDY SELECTION: Two investigators independently selected English-language randomized controlled trials (RCTs) and nonrandomized studies of interventions (NRSIs). DATA EXTRACTION: For newly included studies, one reviewer extracted data and assessed certainty of evidence (CoE), which was verified by a second reviewer; 2 reviewers independently assessed risk of bias. For studies from the ECDC report, original data and risk-of-bias assessments were used. DATA SYNTHESIS: The review included 35 RCTs and 5 NRSIs. Compared with standard vaccines, high-dose vaccines reduced laboratory-confirmed influenza in adults aged 65 years or older (high CoE) but increased the risk for fever in this group (high CoE). High-dose vaccines probably caused fewer serious adverse events in all adults and those aged 65 years or older (moderate CoE). Recombinant vaccines reduced laboratory-confirmed influenza in all adults and those younger than 65 years compared with standard vaccines (high CoE). Evidence from 2 RCTs indicated that mRNA vaccines may increase serious adverse events in all adults and those younger than 65 years compared with standard vaccines (low CoE). LIMITATIONS: RCTs evaluating laboratory-confirmed influenza and influenza-related hospitalization or death are limited. Evidence was lacking for several comparisons and outcomes. Broad definitions of serious adverse events may have inflated risk estimates. CONCLUSION: High-dose and recombinant vaccines improve protection compared with standard vaccines, but high-dose vaccines increase fever risk. Evidence for mRNA vaccines is limited and should be cautiously interpreted. PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD420251114496).
3. Relative Effectiveness of High-Dose vs. Standard-Dose Influenza Vaccines in Preventing Hospitalizations: A National Retrospective Cohort Study in France, 2022/2023 Season.
In over 3.3 million matched French older adults, high-dose influenza vaccine reduced influenza-related hospitalizations by 27.4% versus standard-dose in 2022/23, with the strongest benefit in those ≥85. Findings support preferential use of high-dose vaccines to mitigate severe respiratory outcomes.
Impact: Provides robust, nation-scale real-world evidence aligning with trial syntheses, directly informing seasonal vaccine policy for older adults.
Clinical Implications: Adopt preferential high-dose influenza vaccination in adults ≥65, especially ≥85, to reduce hospitalization risk; incorporate into national immunization recommendations and payer coverage decisions.
Key Findings
- High-dose influenza vaccine showed a 27.4% rVE versus standard-dose for influenza-related hospitalizations in 2022/23.
- Benefit was consistent across age strata, with the largest effect in adults ≥85 years.
- Large national matched cohort (675,412 HD vs 2,701,648 SD) supports generalizability.
Methodological Strengths
- Nationwide administrative dataset with very large sample and propensity score matching.
- Predefined analytic window (≥14 days post-vaccination to season end) minimizing misclassification.
Limitations
- Observational design susceptible to residual confounding (e.g., health-seeking behavior, frailty).
- Outcome and exposure misclassification possible in administrative coding; single-season analysis.
Future Directions: Extend multi-season analyses, stratify by comorbidity/frailty and vaccine brand, and integrate virological confirmation to refine effectiveness estimates.
BACKGROUND: A French cohort study (2021/2022 influenza season) found the high-dose influenza vaccine (HD) more effective than standard-dose vaccines (SDs) in preventing influenza-related hospitalizations in the elderly. The study continued to refine results and validate these findings. METHODS: Data from community-dwelling 65+ adults who received HD or SD during the 2022/2023 vaccination campaign were extracted from the National Health database. Hospitalizations were recorded from 14 days postvaccination until June 30, 2023. HD and SD recipients were matched using a propensity score. Associations between vaccines and hospitalizations were assessed by estimating incidence rate ratios and converting them to HD vs. SD vaccine relative effectiveness (rVE). RESULTS: A total of 675,412 HD recipients were matched to 2,701,648 SD recipients. The rVE for influenza-related hospitalizations was 27.4% [95% CI: 19.8; 34.3]. It ranged from 22.7% [9.8; 33.6] to 33.6% [21.2; 44.0] across age groups, indicating that HD consistently outperformed SDs in preventing influenza-related hospitalizations, with the highest effect observed in 85+. CONCLUSIONS: Our study is the first to publish rVE data comparing HD and SDs in a real-world setting in France for the 2022/2023 influenza season. Its findings reaffirm the benefit of HD vs. SDs. HD could help reduce the burden of severe respiratory infections in the elderly.