Daily Respiratory Research Analysis
Three impactful respiratory studies stood out today: a pooled analysis of two randomized trials showed high-dose influenza vaccine reduced hospitalizations in older adults; real-world data demonstrated very high effectiveness of the RSVpreF vaccine against severe RSV-related acute respiratory illness; and a mechanistic PNAS study identified cytosolic PCNA as a central driver of neutrophil hyperactivation in severe COVID-19 with a small-molecule inhibitor suppressing NETosis.
Summary
Three impactful respiratory studies stood out today: a pooled analysis of two randomized trials showed high-dose influenza vaccine reduced hospitalizations in older adults; real-world data demonstrated very high effectiveness of the RSVpreF vaccine against severe RSV-related acute respiratory illness; and a mechanistic PNAS study identified cytosolic PCNA as a central driver of neutrophil hyperactivation in severe COVID-19 with a small-molecule inhibitor suppressing NETosis.
Research Themes
- Respiratory vaccine effectiveness and policy
- Neutrophil-driven hyperinflammation mechanisms in COVID-19
- Prevention of severe respiratory illness in older adults
Selected Articles
1. Effectiveness of high-dose influenza vaccine against hospitalisations in older adults (FLUNITY-HD): an individual-level pooled analysis.
In a prespecified pooled analysis of two harmonized, individually randomized pragmatic trials (n=466,320; ages ≥65), high-dose inactivated influenza vaccine reduced hospitalizations for influenza or pneumonia versus standard-dose (rVE 8.8%; 95% CI 1.7–15.5). HD-IIV also reduced cardiorespiratory hospitalizations, laboratory-confirmed influenza hospitalizations, and all-cause hospitalizations, with similar mortality and safety profiles.
Impact: This large, prespecified individual-level pooled analysis provides robust randomized evidence that HD-IIV confers superior protection against severe outcomes in older adults, supporting policy shifts toward high-dose vaccination.
Clinical Implications: For adults ≥65 years, preferential use of HD-IIV could reduce hospitalizations for influenza/pneumonia and cardiorespiratory causes without compromising safety, informing vaccine program procurement and recommendations.
Key Findings
- Primary endpoint: influenza or pneumonia hospitalization reduced (0.56% HD-IIV vs 0.62% SD-IIV; rVE 8.8%, 95% CI 1.7–15.5).
- Secondary: cardiorespiratory hospitalization reduced (2.02% vs 2.16%; rVE 6.3%, 95% CI 2.5–10.0).
- Lab-confirmed influenza hospitalization reduced (0.11% vs 0.16%; rVE 31.9%, 95% CI 19.7–42.2).
- All-cause hospitalization reduced (8.54% vs 8.73%; rVE 2.2%, 95% CI 0.3–4.1); mortality similar (0.61% vs 0.62%).
- Serious adverse events were similar between groups.
Methodological Strengths
- Prespecified individual-level pooled analysis of two harmonized, randomized pragmatic trials across multiple seasons and countries.
- Large sample size (466,320) with routine healthcare databases enabling robust endpoint capture.
Limitations
- Mortality was not reduced and the effect on pneumonia alone was small; absolute risk differences were modest.
- Generalisability primarily to older adults in Denmark and Spain; results contingent on circulating strains/seasons.
Future Directions: Assess cost-effectiveness and equity impacts of switching to HD-IIV, evaluate performance across diverse regions/seasons, and integrate with coadministration strategies (e.g., RSV vaccines).
BACKGROUND: Two large-scale trials comparing high-dose inactivated influenza vaccine (HD-IIV) versus standard-dose inactivated influenza vaccine (SD-IIV) against hospitalisation outcomes have been conducted in Denmark and Spain. We aimed to analyse the pooled data from these trials to enhance generalisability and assess the relative vaccine effectiveness (rVE) of HD-IIV versus SD-IIV against severe clinical outcomes in older adults. METHODS: FLUNITY-HD was a prespecified, individual-level pooled analysis of two methodologically harmonised pragmatic, individually randomised trials comparing HD-IIV with SD-IIV in older adults. DANFLU-2 included adults aged 65 years or older and GALFLU included community-dwelling adults aged 65-79 years. DANFLU-2 was conducted during the 2022-23, 2023-24, and 2024-25 influenza seasons in Denmark, whereas GALFLU was conducted during the 2023-24 and 2024-25 seasons in Galicia, Spain. In both trials, participants were randomly assigned (1:1) to receive either HD-IIV (60 μg of haemagglutinin [HA] antigen per strain) or SD-IIV (15 μg of HA antigen per strain) and followed up for the occurrence of endpoints from 14 days after vaccination to May 31 the following year in each season.
2. Cytosolic proliferating cell nuclear antigen (PCNA) orchestrates neutrophil hyperactivation in COVID-19.
The study links elevated cytosolic PCNA in neutrophils from severe/critical COVID-19 to increased ROS and NETosis and shows that a PCNA-scaffold inhibitor (T2AA) markedly suppresses these responses, especially to SARS-CoV-2 RNA. A novel interaction between PCNA and calprotectin (S100A8/S100A9) is identified, providing a druggable axis for mitigating neutrophil-driven hyperinflammation.
Impact: Revealing a cytosolic PCNA–calprotectin axis that drives neutrophil hyperactivation is a notable mechanistic advance with immediate translational implications through a small-molecule inhibitor.
Clinical Implications: Targeting PCNA scaffolding may attenuate detrimental NETosis/oxidative bursts in severe viral pneumonias, potentially complementing anti-inflammatory therapies in COVID-19 and related conditions.
Key Findings
- Cytosolic PCNA is elevated in neutrophils from severe/critical COVID-19 and correlates with enhanced ROS generation and NET formation.
- T2AA, a PCNA-scaffold inhibitor, suppresses NADPH oxidase activation and NET release, especially in response to SARS-CoV-2 RNA.
- Previously unrecognized interaction between PCNA and S100A8/S100A9 (calprotectin) identified in hyperactivated neutrophils.
Methodological Strengths
- Multi-pronged approach integrating patient-derived neutrophils, pathway interrogation, and pharmacologic inhibition.
- Mechanistic dissection identifying a specific protein–protein interaction as a therapeutic target.
Limitations
- Sample sizes and patient cohort details are not provided in the abstract; external validation needed.
- Translational efficacy and safety of T2AA or related inhibitors in vivo clinical settings remain untested.
Future Directions: Validate the PCNA–S100A8/S100A9 axis across cohorts, define structural interfaces for drug design, and test PCNA-scaffold inhibitors in relevant in vivo models and early-phase clinical trials.
Neutrophils are central mediators of the hyperinflammatory response in severe SARS-CoV-2 infection. We report elevated cytosolic levels of proliferating cell nuclear antigen (PCNA) in neutrophils from patients with severe and critical COVID-19, correlating with enhanced NADPH oxidase-dependent reactive oxygen species (ROS) generation and neutrophil extracellular trap (NET) formation. Using T2AA, a small-molecule inhibitor of the PCNA scaffold, we demonstrate potent suppression of NADPH oxidase activation and NET release, particularly in response to SARS-CoV-2 RNA. Mechanistically, we identify a previously unrecognized interaction between PCNA and the heterodimeric S100A8/S100A9 (calprotectin), predominantly enriched in CD16
3. Estimated Vaccine Effectiveness for Respiratory Syncytial Virus-Related Acute Respiratory Illness in Older Adults: Findings From the First Postlicensure Season.
In a retrospective test-negative study including 8,965 ARI ED visits/hospitalizations among adults ≥60 years, RSVpreF vaccination ≥21 days prior was associated with 92% VE (95% CI 64–98) against RSV-related ARI. High VE persisted in high-risk individuals, those ≥75 years, and for critical outcomes (e.g., ICU admission, mechanical ventilation, respiratory failure, vasopressors, or death).
Impact: This is the first postlicensure season effectiveness estimate showing very high protection of RSVpreF in older adults across severe endpoints, supporting implementation and uptake in high-risk populations.
Clinical Implications: Clinicians and health systems can confidently recommend RSVpreF to adults ≥60 years, particularly those ≥75 or with comorbidities, to prevent severe RSV-related ARI requiring ED care or hospitalization.
Key Findings
- Adjusted VE against RSV-related ARI ED visits/hospitalizations was 92% (95% CI 64–98).
- High VE in patients with risk conditions (92%), in those ≥75 years (95%), and for critical outcomes (90%).
- Only 0.3% of RSV-positive cases vs 3.6% of controls had received RSVpreF ≥21 days prior.
Methodological Strengths
- Test-negative design reduces bias from healthcare-seeking behavior and differential testing.
- Large integrated health system with laboratory-confirmed outcomes and multivariable adjustment.
Limitations
- Retrospective observational design subject to residual confounding and potential misclassification.
- Single health system and one season limit generalizability; vaccine uptake and timing may bias estimates.
Future Directions: Evaluate durability across seasons, comparative effectiveness with other RSV vaccines, and effect on long-term outcomes (e.g., post-viral complications) across diverse populations.
BACKGROUND: Respiratory syncytial virus (RSV) is an important cause of severe respiratory illness among older adults. Previously, we showed that the RSVpreF vaccine (Abrysvo; Pfizer) prevents RSV-related lower respiratory tract disease-related emergency department (ED) visits/hospitalizations in older adults. Here, we evaluate its effectiveness against additional acute respiratory illness (ARI) end points, including severe disease, among high-risk persons. METHODS: This was a retrospective test-negative case-control study of adults aged ≥60 years at Kaiser Permanente Southern California with ARI ED visits/hospitalizations, defined by International Classification of Diseases, Tenth Revision discharge code, from 24 November 2023 to 9 April 2024. Case patients tested positive for RSV. Controls in the primary analysis tested negative for RSV, human metapneumovirus, influenza, and severe acute respiratory syndrome coronavirus 2 and positive for a non-vaccine-preventable pathogen. The exposure was RSVpreF receipt ≥21 days before ARI diagnosis. Vaccine effectiveness (VE) was calculated from adjusted odds ratios via multivariable logistic regression. RESULTS: Overall, 8965 ARI ED visits/hospitalizations with RSV testing were included; 7.8% of patients were RSV positive, among whom 0.3% had received RSVpreF, compared with 3.6% of controls. The adjusted VE was 92% (95% confidence interval, 64%-98%). We estimated similar VE among patients with risk conditions (92% [95% confidence interval: 65%-98%]), the oldest subgroup (age ≥75 years; 95% [60%-99%]), those with critical outcomes (intensive care unit admission, mechanical ventilation, respiratory failure, vasopressor use, or death; 90% [16%-99%]), and those with severe disease (defined as ED visit or hospitalization requiring oxygen; 92% [35%-99%]). CONCLUSIONS: Among older adults, RSVpreF demonstrated high VE against RSV-related ARI hospitalization or ED visits, including among high-risk subgroups, and against severe outcomes. RSV vaccination programs can protect groups at the highest risk of severe disease.