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.

Abstract

Seasonal influenza is a contagious viral respiratory illness that causes yearly epidemics. To assess the comparative effectiveness and harm of standard and newer and enhanced influenza vaccines in nonpregnant, nonimmunocompromised adults. 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. Two investigators independently selected English-language randomized controlled trials (RCTs) and nonrandomized studies of interventions (NRSIs). 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. 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). 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. 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. American College of Physicians. (PROSPERO: CRD420251114496).