Open-label, Multicenter Trial of RSV Vaccination to Reduce Moderate-to-severe Exacerbations in COPD Frequent Exacerbators: Clinical Effectiveness and RSV-specific Immune Responses

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.