Abstract
This cohort study investigates the association between booster vaccinations containing the JN.1 lineage and 29 serious adverse events in Denmark.
Introduction
Updated mRNA COVID-19 vaccines targeting the SARS-CoV-2 Omicron JN.1 lineage were recently authorized in the US and Europe1,2 and made available as the 2024-2025 season booster dose in many countries. Data to support their safety are scarce. This nationwide cohort study investigated the association between vaccination with JN.1-containing vaccines and the risk of 29 serious adverse events.
Methods
The study cohort was established through linkage of individual-level data from nationwide health care registers. Danish law exempts register-based research in Denmark from informed consent and ethics committee approval. This study is reported following the STROBE reporting guideline.
All adults in Denmark recommended to receive the 2024-2025 JN.1-containing booster vaccine (ie, those aged ≥65 years or individuals in high-risk groups) who had previously received 3 or more COVID-19 vaccine doses were included. The study period ran from May 1, 2024, to March 31, 2025. Vaccination status during follow-up was classified as a time-varying variable (eTable in Supplement 1).
We analyzed 29 adverse outcomes adapted from prioritized lists of adverse events of special interest to COVID-19 vaccines. Each adverse event was analyzed separately. Adverse events were identified as the first hospital contact with a recorded outcome diagnosis, with the date of diagnosis considered the event date (eTable in Supplement 1).3,4,5,6 During the study period, individuals were followed up until first outcome event while censoring upon emigration, death, or the end of the study period. Outcome rates during the first 28 days after JN.1-containing vaccine administration (ie, the risk period) were compared with outcome rates during the remaining period (ie, the reference period, with follow-up from the study start or ≥43 days after any prior dose or the JN.1-containing vaccine dose) as previously described (eFigure in Supplement 1).5,6 If uncensored, individuals could contribute person-time to 28-day risk and reference periods. We compared risk and reference period outcome rates using Poisson regression to estimate incidence rate ratios adjusted for sex, age, region, vaccination priority group, calendar time, and number of comorbidities. Statistical tests were 2-sided and conducted in R statistical software version 4.1.1 (R Project for Statistical Computing). Associations were considered statistically significant if the 95% CI did not overlap 1.
Results
The cohort totaled 1 585 883 individuals (mean [SD] age, 66.8 [14.5] years; 862 585 female [54.4%]), of whom 1 012 400 individuals (mean [SD] age, 73.5 [10.3] years) received updated mRNA COVID-19 vaccines containing the JN.1 lineage vaccine during follow-up (Table). No statistically significant increases in the rate of hospital contacts for any of 29 adverse events were observed during the 28-day risk period after receipt of a JN.1-containing mRNA vaccine compared with reference period rates (Figure). For example, the incidence rate ratio was 0.84 (95% CI, 0.76-0.94) for ischemic cardiac events, 0.92 (95% CI, 0.76-1.13) for intracranial bleeding, and 1.12 (95% CI, 0.41-3.10) for myocarditis.
Table. Study Cohort Characteristics.
| Characteristica | Individuals, No. (%) | ||
|---|---|---|---|
| Entire study cohort (N = 1 585 883) | Vaccinated with JN.1-containing vaccine (n = 1 012 400) | Not vaccinated with JN.1-containing vaccine at study end (n = 573 483) | |
| Age, mean (SD), y | 66.8 (14.5) | 73.5 (10.3) | 60.6 (17.1) |
| Sex | |||
| Female | 862 585 (54.4) | 547 550 (54.1) | 315 035 (54.9) |
| Male | 723 298 (45.6) | 464 850 (45.9) | 258 447 (45.1) |
| Region of residency | |||
| Capital Region of Denmark | 437 167 (27.6) | 274 017 (27.1) | 163 150 (28.4) |
| Central Denmark Region | 358 459 (22.6) | 233 305 (23.0) | 125 154 (21.8) |
| Northern Denmark Region | 173 947 (11.0) | 110 645 (10.9) | 63 302 (11.0) |
| Region Zealand | 255 036 (16.1) | 166 728 (16.5) | 88 308 (15.4) |
| Region of Southern Denmark | 361 232 (22.8) | 227 693 (22.5) | 133 539 (23.3) |
| Region not specified | 42 (<0.1) | 12 (<0.1) | 30 (<0.1) |
| Vaccination priority groups | |||
| Age priority | 1 145 608 (72.2) | 877 529 (86.7) | 268 079 (46.7) |
| High-risk priority | 440 275 (27.8) | 134 871 (13.3) | 305 404 (53.3) |
| Comorbidities | |||
| Asthma | 54 596 (3.4) | 31 099 (3.1) | 23 497 (4.1) |
| Chronic respiratory disorder | 64 802 (4.1) | 46 563 (4.6) | 18 239 (3.2) |
| Chronic cardiac disorder | 298 513 (18.8) | 205 581 (20.3) | 92 932 (16.2) |
| Kidney disorder | 26 021 (1.6) | 16 877 (1.7) | 9144 (1.6) |
| Diabetes | 111 169 (7.0) | 64 944 (6.4) | 46 225 (8.1) |
| Autoimmune disorder | 158 145 (10.0) | 85 931 (8.5) | 72 214 (12.6) |
| Epilepsy | 15 493 (1.0) | 9957 (1.0) | 5536 (1.0) |
| Malignant neoplasm | 157 967 (10.0) | 100 085 (9.9) | 57 882 (10.1) |
| Psychiatric disorder | 113 395 (7.2) | 61 245 (6.0) | 52 150 (9.1) |
The start of the study period was May 1, 2024, while the rollout of the JN.1-containing booster vaccine was initiated at approximately the start of October 2024, and the study period ended on March 31, 2025.
Figure. Risk of Adverse Events After Booster Vaccination With JN.1-Containing Vaccines.
The figure shows adjusted incidence rate ratios (IRRs) for 29 adverse events of special interest to COVID-19 vaccines; rates observed during the 28-day risk period after booster vaccination with updated mRNA COVID-19 vaccines containing the SARS-CoV-2 Omicron JN.1 lineage (KP.2 strain) are compared with rates during the reference period. Each outcome was studied separately, resulting in potential differences in denominators due to varying exclusions. IR indicates crude incidence rate; NE, not estimable; TC, thrombocytopenia; TIA, transient ischemic attack.
Discussion
In this nationwide cohort study, no increased risk of 29 adverse events was observed after vaccination with the updated COVID-19 mRNA vaccine containing the SARS-CoV-2 Omicron JN.1 lineage in approximately 1 million adults. Limitations include that residual confounding and health care use bias cannot be excluded even with the use of within-individual comparisons. Additionally, although we analyzed a nationwide cohort, some outcomes, such as erythema multiforme, occurred very rarely during follow-up, with consequently lower statistical precision, and some outcomes, such as transverse myelitis, could not be statistically compared. Notably, the upper bound of the CI for 19 of 29 adverse events examined was inconsistent with moderate to large increases in relative risks of more than 1.5.
eTable. Eligibility criteria, outcome, and covariate definitions
eFigure. Schematic figure of the study design
eReferences.
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable. Eligibility criteria, outcome, and covariate definitions
eFigure. Schematic figure of the study design
eReferences.
Data Sharing Statement
