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Comparative effectiveness and harm of seasonal influenza vaccines in adults who are not pregnant or immunocompromised
A rapid review for the American college of physicians
Dobrescu, A. I., Sharifan, A., Sommer, I., Neubauer-Bruckner, C. I. A., Gadinger, A., Klerings, I., Nowak, C., & Gartlehner, G. (2025). Comparative effectiveness and harm of seasonal influenza vaccines in adults who are not pregnant or immunocompromised: A rapid review for the American college of physicians. Annals of Internal Medicine. Advance online publication. https://doi.org/10.7326/ANNALS-25-04028
BACKGROUND: Seasonal influenza is a contagious viral respiratory illness that causes yearly epidemics.
PURPOSE: To assess the comparative effectiveness and harm of standard and newer and enhanced influenza vaccines in nonpregnant, nonimmunocompromised adults.
DATA SOURCES: Medline and Embase between May 2023 and July 2025, and a systematic review by the European Centre for Disease Prevention and Control (ECDC) to identify studies published before May 2023.
STUDY SELECTION: Two investigators independently selected English-language randomized controlled trials (RCTs) and nonrandomized studies of interventions (NRSIs).
DATA EXTRACTION: For newly included studies, one reviewer extracted data and assessed certainty of evidence (CoE), which was verified by a second reviewer; 2 reviewers independently assessed risk of bias. For studies from the ECDC report, original data and risk-of-bias assessments were used.
DATA SYNTHESIS: The review included 35 RCTs and 5 NRSIs. Compared with standard vaccines, high-dose vaccines reduced laboratory-confirmed influenza in adults aged 65 years or older (high CoE) but increased the risk for fever in this group (high CoE). High-dose vaccines probably caused fewer serious adverse events in all adults and those aged 65 years or older (moderate CoE). Recombinant vaccines reduced laboratory-confirmed influenza in all adults and those younger than 65 years compared with standard vaccines (high CoE). Evidence from 2 RCTs indicated that mRNA vaccines may increase serious adverse events in all adults and those younger than 65 years compared with standard vaccines (low CoE).
LIMITATIONS: RCTs evaluating laboratory-confirmed influenza and influenza-related hospitalization or death are limited. Evidence was lacking for several comparisons and outcomes. Broad definitions of serious adverse events may have inflated risk estimates.
CONCLUSION: High-dose and recombinant vaccines improve protection compared with standard vaccines, but high-dose vaccines increase fever risk. Evidence for mRNA vaccines is limited and should be cautiously interpreted.
PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD420251114496).
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