Comparative effectiveness of the monovalent XBB.1.5-containing covid-19 mRNA vaccine across three Nordic countries

Objective To estimate the effectiveness of vaccination with a monovalent XBB.1.5-containing covid-19 mRNA vaccine against severe covid-19 across three Nordic countries. Design Nationwide cohort studies, using target trial emulation. Setting Denmark, Finland, and Sweden, from 1 October 2023 to 29 February 2024. Participants Individuals aged ≥65 years who had previously received at least four covid-19 vaccine doses. Main outcome measures: Cumulative incidences of covid-19 hospital admission and death for 12 weeks after immunisation (defined as 1 week after vaccination) among recipients of an XBB.1.5-containing covid-19 mRNA vaccine and matched non-recipients. Cumulative incidences were used to calculate comparative vaccine effectiveness (1-risk ratio) and risk differences. Results During autumn and winter 2023-2024, a total of 1,867,448 1:1 matched pairs of XBB-containing covid-19 mRNA vaccine recipients and non-recipients were included (mean age 75.4 years, standard deviation 7.4 years). The comparative vaccine effectiveness was 60.6% (95% confidence interval, 46.1% to 75.1%) against covid-19 hospital admission (930 v 2,551 events) and 77.9% (69.2% to 86.7%) against covid-19 related death (301 v 1,326 events) at 12 weeks of follow-up. This corresponded to 191.1 (95% confidence interval, 50.2 to 332.1) covid-19 hospital admissions and 109.2 (100.2 to 118.1) deaths prevented per 100,000 individuals vaccinated with an XBB.1.5-containing vaccine. The comparative vaccine effectiveness was similar across sex, age (65-74/≥75 years), number of previous covid-19 vaccine doses received, and seasonal influenza vaccination co-administration subgroups and periods of either omicron XBB- or BA.2.86-sublineage dominance. While the protection was highest during the first weeks after vaccination, it was well-preserved at end of week 12 of follow-up. Conclusion Among adults aged ≥65 years, vaccination with a monovalent XBB.1.5-containing covid-19 mRNA vaccine reduced the rates of covid-19 related hospital admission and death during autumn and winter 2023-2024 across three Nordic countries. ### Competing Interest Statement All authors declare support from the European Medicines Agency; NA reports unrelated grants from Independent Research Fund Denmark, Helsefonden, Dagmar Marshall Foundation, Gangstedfonden, A.P. Moeller and Chastine Mc-Kinney Moeller Foundation, Broedrende Hartmanns fond, Snedkermester Sophus Jacobsen of hustru Astrid Jacobsens fond, Axel Muusfeldts fond, Arvid Nilssons fond, and Aase og Ejnar Danielsens fond; EP reports receiving a grant from Finnish Medical Foundation; AH reports unrelated grants from Independent Research Fund Denmark, the Novo Nordisk Foundation, and the Lundbeck Foundation; AH is a scientific board member of VAC4EU; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. ### Funding Statement This research was supported by the European Medicines Agency. The funders had no role in deciding the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. This document expresses the opinion of the authors of the paper and may not be understood or quoted as being made on behalf of, or reflecting the position of, the European Medicines Agency or one of its committees or working parties. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Danish analyses were performed as surveillance activities analyses as part of the advisory tasks of the governmental institution Statens Serum Institut (SSI) for the Danish Ministry of Health. SSI's purpose is to monitor and fight the spread of disease in accordance with section 222 of the Danish Health Act. According to Danish law, national surveillance activities conducted by SSI do not require approval from an ethics committee. Both the Danish Governmental law firm and the compliance department of SSI have approved that the study is fully compliant with all legal, ethical, and IT-security requirements and there are no further approval procedures required for such studies. For the Finnish analyses, by Finnish law, the Finnish Institute for Health and Welfare (THL) is the national expert institution to carry out surveillance of the impact of vaccinations in Finland (Communicable Diseases Act, ). Neither specific ethical approval of this study nor informed consent from the participants were needed. The Swedish analyses were conducted under the Swedish Ethical Review Authority approval 2020-06859, 2021-02186 and conformed to the principles embodied in the Declaration of Helsinki. Register-based studies (like this) in Sweden are exempt from obtaining consent to participate. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. 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