Effectiveness and waning of the fourth dose mRNA COVID-19 vaccines for the prevention of SARS-CoV2 infection related hospitalisations and deaths

BACKGROUND: Real-world data studies suggest that the vaccine effectiveness (VE) of a fourth mRNA vaccine dose against SARS-CoV2 infection related hospitalisation wanes after a few months, potentially warranting consideration of additional booster doses. METHODS: A multi-data source cohort study was conducted through the Data Analysis and Real World Interrogation Network (DARWIN EU®) using routinely collected electronic health records from the UK (CPRD GOLD), the Netherlands (IPCI), and Spain (SIDIAP) from January 2021 to June 2023. The study included individuals aged 12 and above, vaccinated with at least three doses. We matched fourth-dose to third-dose vaccinated individuals using a weekly sequential approach, defining the date of the last dose received by the exposed individual as the index date. Primary outcomes were SARS-CoV2 infection related death and hospitalisation. Hazard ratios (HR) were estimated using Cox proportional hazard models, with VE defined as the percentage of 1 minus HR. Waning of VE was assessed at monthly intervals. FINDINGS: =0). VE against SARS-CoV2 infection related hospitalisation was 26% (19% to 33%) in Spain (SIDIAP, median follow-up 8 weeks), and 46% (15% to 66%), in the Netherlands (IPCI, median follow-up 21 weeks) respectively. VE of a fourth dose started waning at 4-8 weeks after vaccination. INTERPRETATION: A fourth dose of a mRNA COVID-19 vaccination was effective against SARS-CoV2 infection related death and hospitalisation. However, effectiveness waned over time. Periodic revaccination should be considered, with recommendations regarding booster timing taking into account circulating variants, patterns of viral transmission, and population uptake. FUNDING: European Medicines Agency.