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Adverse Events After Same-Day COVID-19 and Influenza Vaccination Versus Influenza Vaccination Alone : A Target Trial
Yan Xie1, Taeyoung Choi2, Ziyad Al-Aly3
1Clinical Epidemiology Center, Research and Development Service, VA St. Louis Health Care System, St. Louis; Veterans Research and Education Foundation of St. Louis, St. Louis; Division of Pharmacoepidemiology, Clinical Epidemiology Center, Research and Development Service, VA St. Louis Health Care System, St. Louis; and Department of Surgery, Washington University School of Medicine, St. Louis, Missouri (Y.X.).
Background:
Safety studies of the COVID-19 vaccine have identified some adverse events. Yet newer variant-updated formulations, along with increased hybrid immunity, may change these risks. Early-era safety data may not reflect experience with updated formulations in more immune-experienced populations.
Objective:
To evaluate 90-day risks for adverse events after coadministration of COVID-19 and influenza vaccines compared with influenza vaccination alone, across bivalent, XBB-adapted, and KP-adapted COVID-19 vaccine periods.
Design:
Target trial emulation using electronic health care data.
Setting:
U.S. Department of Veterans Affairs.
Participants:
Participants receiving both COVID-19 and seasonal influenza vaccines (n = 705 124) and those receiving only an influenza vaccine (n = 1 813 205) between 1 September 2022 and 26 August 2025.
Intervention:
Receipt of both COVID-19 and seasonal influenza vaccines versus receipt of only an influenza vaccine.
Measurements:
90-day risks for 46 prespecified individual adverse events grouped into 3 composite outcomes (tier 1, serious or life-threatening; tier 2, clinically significant; tier 3, less severe or self-limiting), using weighted discrete-time survival models.
Results:
For all 3 composite outcomes, risks were similar between groups: tier 1 (risk ratio [RR], 1.03 [95% CI, 0.99 to 1.09]), tier 2 (RR, 0.99 [CI, 0.96 to 1.03]), and tier 3 (RR, 0.99 [CI, 0.96 to 1.02]). Of the 46 individual adverse events, 2 tier-3 risks had nominal statistical significance: syncope (RR, 1.09 [CI, 1.02 to 1.17]) and tinnitus (RR, 0.95 [CI, 0.92 to 0.99]); no risks were statistically significant after correcting for multiple comparisons. For all risks in tier 1 or tier 2, confidence bounds included 1.0 (no effect). In period-stratified analyses, neither composite (tier) nor individual event estimates supported differences in risks between groups.
Limitation:
Generalizability and potential unmeasured confounding.
Conclusion:
Same-day coadministration of COVID-19 and influenza vaccines was not associated with an increased risk for adverse events in 3 updated-formulation periods. These findings support the short-term safety of coadministration.
Primary Funding Source:
U.S. Department of Veterans Affairs.
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