..
JAMA. Published online February 26, 2024. doi:10.1001/jama.2024.1036
The monovalent Omicron XBB.1.5–containing COVID-19 mRNA vaccines were authorized in the US and Europe for use in autumn and winter 2023-2024.1,2 In Denmark, the XBB.1.5-containing vaccines were recommended as a fifth COVID-19 vaccine dose to individuals aged 65 years and older beginning October 1, 2023. However, data to support safety evaluations are lacking.
We investigated the association between the XBB.1.5-containing vaccine administered as a fifth COVID-19 vaccine dose and the risk of 28 adverse events.
A study cohort of all individuals in Denmark aged 65 and older who had received 4 COVID-19 vaccine doses was established by cross-linking nationwide health care and demography registers on an individual level. The study period was September 15, 2022 (ie, the national rollout date of the fourth dose), to January 8, 2024, and vaccination status was classified in a time-varying manner (the eTable in Supplement 1 provides further details). The 28 adverse events were adapted from prioritized lists of adverse events of special interest to COVID-19 vaccines (eTable in Supplement 1).3–5 Each outcome was studied separately and identified as any first hospital contact where an outcome diagnosis was recorded. The diagnosis date served as the event date.
Individuals were followed up from day 43 after the fourth dose (days 29-42 considered a buffer period) until first outcome event while censoring upon emigration, death, receipt of a sixth vaccine dose (as such a dose was not rolled out to the general Danish population during the study period), or end of the study period (eFigure in Supplement 1). Outcome rates within the risk period of 28 days following XBB.1.5-containing vaccine administration as a fifth dose was compared with reference period rates from day 43 after a fourth or fifth dose and onward as previously described; the number of events and person-time from the 2 reference periods were aggregated.5 Individuals could contribute person-time both during the 28-day risk period and the 2 reference periods; individuals not receiving the XBB.1.5-containing vaccine only contributed to reference period person-time. Using Poisson regression, the risk and reference period outcome rates were compared by incidence rate ratios, adjusted for sex, age, region of residence, considered at high risk of severe COVID-19, health care worker, calendar time, and number of comorbidities. Statistical tests were 2-sided and conducted in R (version 4.1.1; R Project for Statistical Computing). A 95% CI that did not cross 1 was defined as statistically significant. Analysis was performed as surveillance activities as part of the advisory tasks of the governmental institution Statens Serum Institut (SSI), which monitors the spread of disease in accordance with §222 of the Danish Health Act, for the Danish Ministry of Health. According to Danish law, national surveillance activities conducted by SSI do not require approval from an ethics committee.
Among the 1 076 531 included individuals (mean [SD] age, 74.7 [7.4] years; 53.8% female), 902 803 received an XBB.1.5-containing vaccine as a fifth dose during follow-up (Table).
Receipt of an XBB.1.5-containing vaccine was not associated with a statistically significant increased rate of hospital contacts for any of the 28 different adverse events within 28 days after vaccination compared with the reference period rates (Figure). For example, the incidence rate ratio was 0.96 (95% CI, 0.87-1.07) for an ischemic cardiac event, 0.87 (95% CI, 0.79-0.96) for a cerebral infarction, and 0.60 (95% CI, 0.14-2.66) for myocarditis. Some outcomes were very rare during follow-up (eg, cerebral venous thrombosis), resulting in lower statistical precision; however, for 18 of the 28 adverse events examined, the upper bound of the CI was inconsistent with moderate to large increases in relative risk of 1.4 or greater.
In a nationwide cohort of more than 1 million adults aged 65 years and older, no increased risk of 28 adverse events was observed following vaccination with a monovalent XBB.1.5-containing vaccine.
Limitations of this study include potential residual confounding; differences in ascertainment of adverse events between compared periods cannot be excluded, but, in contrast to what was observed, would bias toward increased risks if present. This was mitigated by comparing the 28-day risk period rates following a fifth dose vaccination with an XBB.1.5-containing vaccine with reference period rates from 43 days or more after the fourth and fifth vaccine dose as opposed to never vaccinated period rates. Additionally, analyses were not adjusted for multiple testing, and some results showed lower risk for XBB.1.5-containing vaccines; yet, a time-varying healthy vaccinee effect cannot be excluded. Also, no medical record review of cases was done, but any outcome misclassification would most likely be nondifferential.
Section Editors: Kristin Walter, MD, and Jody W. Zylke, MD, Deputy Editors; Karen Lasser, MD, Senior Editor.
https://jamanetwork.com/journals/jama/fullarticle/2815787?s=09
..
weehingthong 