Effectiveness of the BNT162b2 and mRNA-1273 JN.1-adapted vaccines against COVID-19-associated hospitalisation and death: a Danish nationwide register-based cohort study

BACKGROUND

Little epidemiological evidence exists on the protective effect of the JN.1-adapted mRNA vaccines. This study estimated vaccine effectiveness (VE) against COVID-19 hospitalisation and death.

METHODS

Linking national civil, vaccine, microbiology and hospital patient registries, we conducted a retrospective cohort study from October 1, 2024 to January 31, 2025 in a population of 894,560 people aged >65 years with primary vaccinations in 2021 and a booster dose the previous season. Participants with a recent recorded infection, or a vaccine dose since the previous season and prior to study start, were excluded. Hazard ratios comparing event rates among those with and without a JN.1 booster dose during follow-up were derived using Cox regression. 11.2% (91,461/728,768) of those vaccinated during the study received the mRNA-1273 JN.1 vaccine while participating in an influenza vaccine trial; the remainder received the BNT162b2 JN.1 vaccine. VE was estimated separately by vaccine brand, time since vaccination, and for the predominant circulating variants KP.3.1.1 and XEC. A case-only analysis assessed comparative VE between the two variants.

FINDINGS

Among the 1,247,315 individuals aged over 65 years, 894,560 met the eligibility criteria and were included in the analysis (484,735 females and 409,825 males). Among those without JN.1 vaccination, 278 COVID-19 hospitalisations and 84 deaths were observed during 25.6M person-days compared with 197 COVID-19 hospitalisations and 56 deaths observed during 62.9M person-days in BNT162b2 JN.1 vaccinated, and 10 COVID-19 hospitalisations and 1 death observed during 9.2M person-days in mRNA-1273 JN.1 vaccinated. VE for BNT162b2 JN.1 was 70.2% (95% CI 62.0–76.6%) against hospitalisation and 76.2% (63.4–84.5%) against death. There was little evidence of waning effectiveness four months post-vaccination. For mRNA-1273 JN.1, VE was 84.9% (70.9–92.2%) and 95.8% (69.2–99.4%) against hospitalisation and death, respectively, however those vaccinated with mRNA-1273 JN.1 were younger and healthier on average. The BNT162b2 JN.1 VE against hospitalisation following infection with KP.3.1.1 and XEC was 71.7% (44.4–85.6%) and 76.8% (59.0–86.9%), respectively. BNT162b2 JN.1 VE against death from these variants was 90.9% (67.4–97.5%) and 76.3% (24.7–92.6%), respectively. The case-only analysis found no differential protection.

INTERPRETATION

Both JN.1-adapted vaccines offered high levels of sustained protection over four months against hospitalisation and death. These findings support the continued use of regularly updated variant-adapted mRNA vaccines in older adults as an effective strategy to reduce severe COVID-19 outcomes.