Objectives: To determine whether respiratory syncytial virus (RSV) vaccination reduces the rate of all-cause moderate-to-severe acute exacerbations of COPD (AECOPD) in high-risk patients, and to characterise RSV-specific infection and immune responses in this population.

Hypothesis: RSV vaccination in COPD frequent exacerbators receiving dual long-acting bronchodilators will reduce all-cause moderate-to-severe AECOPD by at least 20-25% over 12 months.

Design and subjects: This multicentre, two-arm, open-label, prospective study will recruit 320 COPD patients with 2 moderate or severe AECOPD in the prior year despite dual long-acting bronchodilator therapy. Eligible subjects will be allocated 1:1 to receive RSV vaccination plus standard care or standard care alone and followed for 12 months.

Interventions: Participants in the vaccine arm will receive a single dose of a licensed RSV vaccine in addition to usual COPD management. Controls will receive usual care without RSV vaccination during the study period.

Main outcome measures: The primary outcome is the rate of all-cause moderate-to-severe AECOPD per patient-year. Secondary outcomes include RSV-positive AECOPD, RSV infection incidence confirmed by virological testing, severe AECOPD requiring hospitalisation, time to first moderate-to-severe AECOPD, and changes in plasma RSV-specific antibody titres over 12 months.

Data analysis and expected results: Exacerbation rates will be compared between groups using negative binomial regression with adjustment for key covariates on an intention-to-treat basis. The investigators expect RSV vaccination to achieve a clinically meaningful (20%) reduction in all-cause moderate-to-severe AECOPD and to provide mechanistic insights linking RSV immunity, RSV infection, and exacerbation risk in COPD frequent exacerbators.

Chronic obstructive pulmonary disease (COPD) is one of the most prevalent chronic respiratory diseases worldwide and a leading cause of morbidity and mortality. Global estimates suggest 212.3 million prevalent cases of COPD and 3.3 million deaths due to COPD globally in 2019. It is the fourth leading cause of death worldwide in 2021. In Hong Kong, COPD contributes significantly to respiratory morbidity, accounting for a yearly 20,000 to 23,000 hospital admissions between 2006 and 2014 in Hong Kong.

Acute exacerbation of COPD (AECOPD) represents the most important adverse event in the natural history of COPD. Exacerbations cause acute lung function deterioration, prolonged recovery, impaired quality of life, cardiovascular events, and increased mortality. Recurrent exacerbations accelerate lung function decline and define the "frequent exacerbator" phenotype, which persists over time and predicts worse outcomes. Prior exacerbation history is the strongest predictor of future events and forms the basis of GOLD risk stratification. Preventing AECOPD is thus critical for both individual prognosis and healthcare sustainability.

Despite guideline-directed therapy, AECOPD occurs in 0.5-3.5 events/patient/year. Respiratory infections trigger around 50-80% of exacerbations. Respiratory viruses predominate in up to 40% of events, especially for hospitalized and winter-clustered exacerbations. Common pathogens include rhinovirus/enterovirus (17.3%), influenza (7.4%), RSV (respiratory syncytial virus, 5.3%), and coronaviruses (3.1%). AECOPD associated with viral infection shows greater systemic inflammation and more severe courses compared to non infective events.

Community COPD cohorts report RSV in 8.7% of outpatient events over multiple seasons, with serology detecting twice as many cases as PCR alone. Hospital series show even higher impact in older COPD patients, where RSV typically causes lower respiratory disease and AECOPD rather than URTI. RSV-associated AECOPD is associated with worse outcomes than other viral triggers, including influenza. Systematic reviews confirm COPD prevalence of 30.8% among RSV inpatients, with ≥83.0% of RSV-infected COPD cases presenting as exacerbations. Adults with COPD were more likely to be hospitalized following RSV infection than those without these conditions, with an adjusted incidence rate ratio of hospitalization was 9.6-9.7 for COPD. Case fatality rates range 2.8-17.8% across studies.

No approved RSV antivirals exist for adults. Management of RSV associated AECOPD therefore remains supportive and indistinguishable from the management of non RSV exacerbations, relying on bronchodilators, systemic corticosteroids, antibiotics when indicated, and ventilatory support. In this context, prevention is the most promising strategy to reduce RSV related disease burden. Recent landmark trials published in 2023 demonstrated that RSV vaccines reduce lower respiratory tract disease (LRTD) by 80-90% in the first RSV season, and sustained 60 to 80% over two to three RSV seasons. These pivotal trials included adults with chronic lung diseases, including COPD, and subgroup analyses suggest that vaccine efficacy against RSV-related LRTD is preserved in these high risk groups. Reflecting these data, the Global Initiative for Obstructive Lung Disease (GOLD) committee and several national advisory bodies (e.g. US ACIP, UK NHS) now recommend RSV vaccination for adults with chronic lung disease, including COPD. However, COPD patients have been underrepresented in phase 3 trial populations (5-9%), and these pivotal trials measured RSV-LRTD, not AECOPD. No direct evidence exists that RSV vaccination reduces the burden of AECOPD, despite biological plausibility.

The situation contrasts with the more mature evidence base for influenza and pneumococcal vaccination in COPD. Only a few studies have evaluated exacerbations. A systematic review showed that influenza vaccination reduces AECOPD by 36% and hospitalizations by 49%, primarily by preventing late exacerbations and influenza-like illness. Pneumococcal vaccination reduces the risk of community-acquired pneumonia (OR 0.62) and AECOPD (OR 0.60), although no evidence indicates that vaccination reduced the risk of confirmed pneumococcal pneumonia, which was a relatively rare event. Therefore, AECOPD benefits exceed pathogen-specific reductions, suggesting that vaccines attenuate broader respiratory infection burden or inflammation that triggers exacerbations. By analogy, RSV vaccination may reduce all-cause AECOPD via preventing RSV-LRTD, secondary bacterial events, and inflammatory amplification. No trial has tested this hypothesis, particularly in frequent exacerbators who drive most healthcare costs.

Policy recommendations for RSV vaccination in COPD are currently extrapolated from overall vaccine efficacy against RSV LRTD and from the recognized high burden of RSV disease in COPD, rather than from direct data demonstrating a reduction in AECOPD rates. For payers and guideline panels, particularly in health systems like Hong Kong's where RSV vaccination is not subsidized and must be self funded, robust data on AECOPD reduction, hospital utilization, and safety in real world COPD populations would greatly strengthen the case for prioritizing RSV vaccination in this group.

The investigators propose a pragmatic trial in frequent COPD exacerbators (≥2 moderate or ≥1 severe AECOPD in prior year) to test if RSV vaccination and standard-of-care (SOC) reduces all-cause moderate-severe AECOPD versus SOC over 12 months. The investigators target patients with recent AECOPD and a high baseline risk of future exacerbations, in whom any preventive effect of RSV vaccination is most likely to translate into clinically meaningful reductions in events and hospitalizations. The investigators hypothesize that RSV vaccination, when added to guideline-directed COPD therapy (SOC) in frequent exacerbators, will reduce the rate of all-cause moderate-to-severe AECOPD over one year compared with SOC without RSV vaccination.

Inclusion Criteria:

• Age 50 years or older
• Spirometry evidence of airflow obstruction (post-bronchodilator FEV1/FVC <0.70)
• Current or former smoker who had accrued a ≥10 pack-year smoking history
• Frequent COPD exacerbator, as defined by at least ≥2 moderate or ≥1 severe AECOPD in the 12 months prior to screening [31,32]
• On dual LABD (LABA and LAMA) using the same inhaler/device for ≥8 weeks
• Up-to-date influenza and pneumococcal vaccination received at least 1 month prior to screening

Exclusion Criteria:

• Coexisting significant pulmonary disease predominating the respiratory symptoms (e.g. asthma, bronchiectasis)
• Life expectancy shorter than 1 year due to serious or unstable chronic illness (e.g. advanced lung cancer)
• Refused to receive RSV vaccine (for the RSV group only)
• Received RSV vaccine of any brand before
• Immunocompromised or long-term steroid user (≥10mg/day prednisolone or equivalent for ≥2 weeks), which may affect the RSV vaccine efficacy
• History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine
• Pregnant or lactating (females not yet menopausal must have a negative pregnancy test before receiving the RSV vaccination)
• Unable to provide informed consent