(A-090) Effectiveness and waning of the fourth dose mRNA COVID-19 vaccines for the prevention of severe COVID-19 related outcomes

Background: Booster vaccination programmes against the SARS-CoV-2 virus have been implemented globally aiming to prevent severe COVID-19 outcomes. However, post-authorisation studies suggest a decline in the effectiveness against COVID-19 related hospitalisation of a fourth dose of mRNA vaccines.

Objectives: To assess the effectiveness against severe COVID-19 related outcomes of a second booster dose (fourth dose) of an mRNA COVID-19 vaccine, compared to the third dose.

Methods: A multi-database, population-based, retrospective cohort study was conducted using routinely collected electronic health records from the UK, the Netherlands, and Catalonia (Spain) through DARWIN EU®. The study included individuals aged ≥12 years who had received at least three COVID-19 vaccine doses between January 2021 and June 2023. A weekly sequential 1:1 matching approach was applied using large-scale propensity scores to compare individuals receiving a fourth dose with those who had received only three doses. The primary outcomes were COVID-19-related hospitalisation and death. Hazard ratios (HR) were estimated using Cox proportional hazards models, with vaccine effectiveness (VE) defined as 1-HR. VE estimates were reported separately for each database, and pooled estimates were generated when data from all three sources were available. VE waning was assessed at monthly intervals.

Results: A total of 975,496 matched pairs were identified across the three databases, with a median age ranging from 63 to 78 years and a median follow-up duration of 8 to 21 weeks. The pooled VE against COVID-19-related death of the fourth dose compared to the third dose was 30% (95% CI: 9–46). VE against hospitalisation with COVID-19 ranged from 26% to 46%. A decline in VE was observed beginning 4–8 weeks after vaccination.

Conclusions: A fourth dose of an mRNA COVID-19 vaccine provided protection against severe COVID-19 outcomes, including hospitalisation and death. However, effectiveness declined over time, underscoring the value of continued seasonal vaccination to maintain protection in vulnerable populations. The lessons from this proof-of-concept study can inform the design of future VE studies in DARWIN EU.