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 effects of the JN.1-adapted mRNA vaccines against COVD-19 hospitalisation and death. In this study, we estimated vaccine effectiveness against COVID-19 hospitalisation and death.

METHODS

This nationwide, register-based, cohort study included all Danish residents older than 65 years on Oct 1, 2024. We used Denmark's national COVID-19 surveillance system and comprehensive population-based registers, which are updated daily and linked via the unique civil registration number assigned to all residents. To minimise differences between the comparison groups with regard to vaccination history, participants were required to have completed a primary vaccination course in 2021 and have received the 2023-24 XBB.1.5-adapted vaccine between Oct 1, 2023, and Jan 15, 2024. Participants with a recent recorded infection, or a vaccine dose since the previous season and prior to study start, were excluded. COVID-19 hospitalisation was defined as hospital admissions lasting more than 12 h, with associated ICD-10 primary diagnosis codes B342 or B972 (indicating that COVID-19 was the primary reason for admission) and occurring no earlier than 2 days before, and no later than 14 days after, a positive PCR test. Since cause-of-death data were unavailable, a COVID-19 death was defined as a death due to any cause occurring within 30 days of a positive SARS-CoV-2 PCR test. Participants were followed up from study start on Oct 1, 2024, until Jan 31, 2025, or, if earlier, until their date of death, emigration, first positive SARS-CoV-2 PCR test during follow-up, or further vaccination, whichever occurred first. Hazard ratios comparing event rates among those with and without a JN.1 booster dose during follow-up were derived using Cox regression. Vaccine effectiveness was estimated separately by vaccine brand, time since vaccination, and for the predominant circulating variants KP.3.1.1 and XEC. We used a case-only analysis to assess comparative vaccine effectiveness between the two variants.

FINDINGS

Of nearly 6 million people resident in Denmark on Oct 1, 2024, 1 247 315 were older than 65 years and 894 560 met inclusion criteria and were included in the study. Median age was 76 years (IQR 70-81); 484 735 (54·2%) of 894 560 people were female and 409 825 (45·8%) were male. Among those without JN.1 vaccination, 278 COVID-19 hospitalisations and 84 deaths were observed during 25·6 million person-days compared with 197 COVID-19 hospitalisations and 56 deaths observed during 62·9 million person-days in those vaccinated with BNT162b2 JN.1 and ten COVID-19 hospitalisations and one death observed during 9·2 million person-days in those vaccinated with mRNA-1273 JN.1. Vaccine effectiveness for BNT162b2 JN.1 was 70·2% (95% CI 62·0-76·6) against hospitalisation and 76·2% (63·4-84·5) against death. We found little evidence of waning effectiveness 4 months after vaccination. For mRNA-1273 JN.1, vaccine effectiveness was 84·9% (70·9-92·2%) against hospitalisation and 95·8% (69·2-99·4%) against death; however those vaccinated with mRNA-1273 JN.1 were younger and healthier. The BNT162b2 JN.1 vaccine effectiveness against hospitalisation was 71·7% (44·4-85·6) after infection with KP.3.1.1 and 76·8% (59·0-86·9) after infection with XEC. BNT162b2 JN.1 vaccine effectiveness against death from these variants was 90·9% (67·4-97·5) for KP.3.1.1 and 76·3% (24·7-92·6) for XEC. The case-only analysis found no differential protection.

INTERPRETATION

Both JN.1-adapted vaccines offered high levels of sustained protection for 4 months against hospitalisation and death. These findings support continued use of regularly updated variant-adapted mRNA vaccines in older adults as an effective strategy to reduce severe COVID-19 outcomes.

FUNDING

None.