Evaluating the Safety of Same-Day COVID-19 and Influenza Vaccination: Insights from a Large Veterans Affairs Target Trial Emulation

Highlight

• This large observational study emulated a target trial to assess 90-day adverse event risks after coadministration of updated-formulation COVID-19 vaccines with seasonal influenza vaccine compared to influenza vaccine alone.
• Analysis of over 2.5 million U.S. Veterans showed no increased risk for serious, clinically significant, or less severe adverse events after same-day vaccination across three COVID-19 vaccine variant periods (bivalent, XBB-adapted, KP-adapted).
• No statistically significant differences remained after multiple comparisons correction; nominal risk increases in syncope and slight decreases in tinnitus were noted but not clinically meaningful.
• Findings support the safety and convenience of coadministering COVID-19 and influenza vaccines, facilitating improved vaccine uptake and public health protection.

Study Background

Vaccination remains a critical tool for preventing respiratory viral illness, including influenza and COVID-19. Since 2020, COVID-19 vaccination programs have been rapidly implemented worldwide. Safety surveillance identified some adverse events associated with early COVID-19 vaccines. However, vaccine formulations have since evolved to include newer variant-updated vaccines (such as bivalent, XBB-adapted, and KP-adapted formulations), and populations have increased hybrid immunity from prior infections and vaccinations.

These dynamics necessitate updated safety evaluations to inform clinical guidance about administering COVID-19 vaccines alongside seasonal influenza vaccines, a common public health strategy designed for efficiency and enhanced protection.

Study Design

The study used a target trial emulation approach with electronic health care data from the U.S. Department of Veterans Affairs, encompassing individuals eligible for seasonal influenza and COVID-19 vaccines between September 1, 2022, and August 26, 2025.

Two cohorts were compared: those who received same-day COVID-19 and influenza vaccinations (n=705,124) versus those who received influenza vaccination only (n=1,813,205). The intervention groups spanned three COVID-19 vaccine formulation periods: bivalent, XBB-adapted, and KP-adapted.

Outcomes included 90-day risks for 46 prespecified adverse events grouped into three composite tiers based on severity: tier 1 (serious or life-threatening), tier 2 (clinically significant), and tier 3 (less severe or self-limiting), analyzed with weighted discrete-time survival models to estimate risk ratios (RR) and confidence intervals (CI).

Key Findings

The analyses revealed no increased risk of adverse events following same-day COVID-19 and influenza vaccination versus influenza vaccination alone across all severity tiers. Specifically:

• Tier 1 (serious or life-threatening): RR 1.03 (95% CI, 0.99 to 1.09) indicating no significant risk elevation.
• Tier 2 (clinically significant): RR 0.99 (95% CI, 0.96 to 1.03) consistent with no difference.
• Tier 3 (less severe or self-limiting): RR 0.99 (95% CI, 0.96 to 1.02).

Among individual adverse events, two tier-3 outcomes—syncope and tinnitus—showed nominal significance (higher risk of syncope and a slightly lower risk of tinnitus). However, no associations remained significant after correcting for multiple comparisons.

Stratified analyses across the three COVID-19 formulation periods yielded consistent results with no appreciable risk difference.

Expert Commentary

This study’s strengths include a large, real-world cohort and methodologically rigorous target trial emulation, enabling robust comparative safety assessment in a setting reflecting current vaccine formulations and hybrid immunity. The findings are reassuring for clinicians and public health officials advocating coadministration strategies, which improve vaccination rates and reduce healthcare utilization.

Limitations include reliance on Veteran population data, which may limit generalizability to younger or more diverse demographics. Residual confounding or unmeasured biases inherent in observational data also cannot be entirely excluded. Nonetheless, the consistency of null findings across outcomes and periods strengthens the evidence base.

Complementing existing data on vaccine safety, this study supports current recommendations that COVID-19 and influenza vaccines can be safely coadministered without increased short-term adverse events.

Conclusion

In conclusion, same-day administration of updated COVID-19 and seasonal influenza vaccines does not increase the risk of adverse events within 90 days post-vaccination in a large U.S. Veterans Affairs cohort. These findings endorse the safety of coadministration, facilitating integrated vaccination strategies that can enhance public health impact and efficiency.

Funding

This study was funded by the U.S. Department of Veterans Affairs.

References

1. Xie Y, Choi T, Al-Aly Z. Adverse Events After Same-Day COVID-19 and Influenza Vaccination Versus Influenza Vaccination Alone: A Target Trial Emulation. Ann Intern Med. 2026 Jun 30; PMID: 42372279.
2. Centers for Disease Control and Prevention. Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Approved or Authorized in the United States. [Accessed 2026]. Available from: https://www.cdc.gov/vaccines/covid-19/clinical-considerations/index.html.
3. Wu X, Chen Y, Nelson CA, et al. Safety of simultaneous administration of influenza and COVID-19 vaccines: A systematic review. Vaccine. 2025;43(2):233-239.