Objectives To estimate the effectiveness and waning immunity of the bivalent BA.4-5 or BA.1 mRNA booster vaccine against Covid-19-related hospital admission and death in immunocompromised individuals. Design Nationwide cohort analyses using a matched cohort design. Setting Denmark, Finland, and Sweden, from 1 September 2022 to 31 October 2023. Participants All individuals aged 18 years or above with medical history of at least one immunocompromised condition, residency in Denmark, Finland or Sweden, no history of Covid-19-related hospitalization, and receipt of at least three Covid-19 vaccine doses as of study start, 1 September 2022. Individuals boosted with a BA.4-5 or BA.1 vaccine were matched 1:1 with unboosted individuals. Main outcome measures Country-combined vaccine effectiveness (VE) estimates against Covid-19 hospitalization and Covid-19-related death at day 270 of follow-up. Potential waning was assessed in 45-day intervals. Results A total of 352,762 BA.4-5 and 191,070 BA.1 booster vaccine doses were administered to immunocompromised individuals. At day 270, the comparative VE against Covid-19 hospitalization was 34.2% (95% CI, 7.1% to 61.3%) for the bivalent BA.4-5 vaccine (696 vs 1,128 events, risk difference [RD] per 100,000, -223.7, 95% CI, -411.5 to -36.0) and 42.6% (95% CI, 31.3% to 53.9%) for the BA.1 vaccine (395 vs 740 events, RD per 100,000, -385.0, -673.4 to -96.6) compared with matched unboosted. The comparative VE against Covid-19 death was 53.9% (95% CI, 38.6% to 69.3%) for the bivalent BA.4-5 vaccine (203 vs 457 events, RD per 100,000, -138.7, 95% CI, -195.5 to -81.9) and 57.9% (95% CI, 48.5% to 67.4%) for the BA.1 vaccine (112 vs 302 events, RD per 100,000, -220.6, -275.9 to -165.4). The VE estimates were highest in the first 45 days since eight days after vaccination (52.8% and 72.8% for bivalent BA.4-5 vaccine against Covid-19-related hospitalization and death, and 62.2% and 84.2% for bivalent BA.1 vaccine) and waned gradually during the 270 days of follow-up. Conclusions In immunocompromised individuals, vaccination with a bivalent BA.4-5 or BA.1 booster lowered the risk of Covid-19-related hospitalization and death over a follow-up period of 9 months. The effectiveness was highest during the first months since vaccination with subsequent gradual waning.

EP reports receiving a unrelated grant from Finnish Medical Foundation. RL reports receiving grants from Sanofi Aventis paid to his institution outside the submitted work; and receiving personal fees from Pfizer outside the submitted work. NP and RL are employed at the Swedish Medical Products Agency, Uppsala, Sweden. The views expressed in this paper do not necessarily represent the views of the Government agency. AH reports receiving unrelated grants from Independent Research Fund Denmark, the Lundbeck Foundation and the Novo Nordisk Foundation. AH reports acting as a scientific board member for VAC4EU.

This research was supported by the European Medicines Agency. The funders had no role in considering 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.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Denmark: 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. Finland: 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, https://www.finlex.fi/en/laki/kaannokset/2016/en20161227.pdf). Neither specific ethical approval of this study nor informed consent from the participants were needed. Sweden: 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.

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