Safety of bivalent omicron-containing mRNA-booster vaccines: a nationwide cohort study

Background Safety data to support bivalent omicron-containing mRNA-booster vaccination are lacking. Methods In a Danish nationwide cohort study from 1 January 2021 to 10 December 2022, we examined the association between bivalent omicron-containing mRNA-booster vaccination as a fourth Covid-19 vaccine dose and risk of adverse events in individuals aged ≥50 years. Using incidence rate ratios estimated with Poisson regression, we compared the rates of hospital visits for 27 different adverse events in a 28-day main risk period following vaccination with a bivalent omicron-containing mRNA-booster vaccine as a fourth dose to reference period rates from day 29 after the third or fourth vaccine dose and onward. Secondary analyses included stratifying by sex, age, and vaccine type and assessing the associations using self-controlled case series and observed vs. expected cohort analyses. Results 1,740,417 individuals (mean age 67.8 years, standard deviation 10.7) received a bivalent omicron-containing mRNA-booster vaccine as a fourth dose. Fourth dose vaccination with a bivalent omicron-containing booster did not statistically significantly increase the rate of any of the 27 adverse outcomes within 28 days, nor when analyzed according to age, sex, vaccine type, or using alternative analytical approaches. However, post-hoc analysis detected signals for myocarditis (statistically significantly so in females), although the outcome was very rare and findings were based on few cases. No risk of cerebrovascular infarction was found. Conclusions Bivalent omicron-containing mRNA-booster vaccination as a fourth dose was not associated with an increased risk of 27 different adverse events in 50+-year-olds. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement There was no specific funding for this study. ### 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 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. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes No additional data available. Owing to data privacy regulations in Denmark, the raw data cannot be shared.