BACKGROUND: The SARS-CoV-2 Omicron variant continues to pose a global health burden.
PURPOSE: To assess the effectiveness, comparative effectiveness, and harms of COVID-19 vaccines in nonpregnant, nonimmunocompromised adults.
DATA SOURCES: Medline via Ovid and DynaMedex from January 2022 to September 2025.
STUDY SELECTION: Two reviewers independently selected English-language randomized controlled trials (RCTs) and nonrandomized studies of interventions (NRSIs).
DATA EXTRACTION: One reviewer extracted data and assessed the certainty of evidence (CoE), and a second reviewer verified; 2 reviewers independently assessed risk of bias.
DATA SYNTHESIS: Five RCTs and 18 NRSIs were included. In adults of all ages, Omicron-adapted vaccination probably reduces all-cause mortality (vaccine effectiveness [VE] ranged from 26.6% [95% CI, 5.5% to 42.3%] to 75.2% [CI, 70.6% to 79.9%]; moderate CoE) and COVID-19-related hospitalization (VE ranged from 16.6% [CI, 6.5% to 25.8%] to 67.8% [CI, 63.1% to 72.5%]; moderate CoE) compared with no Omicron-adapted vaccination. When administered more than 365 days after the prior vaccine, it probably reduces all-cause mortality (VE, 36.1% [CI, 14.8% to 54.1%]; moderate CoE) and COVID-19-related hospitalization (VE, 22.2% [CI, 11.4% to 32.0%]; moderate CoE). When administered earlier, it may result in no difference in COVID-19-related hospitalization. Omicron-adapted vaccination may increase myocarditis (incidence rate ratio, 2.7 [CI, 1.0 to 7.0]; low CoE) in adults aged 50 years or older. The mRNA-1283.222 bivalent vaccine probably results in no difference in all-cause mortality or serious adverse events compared with mRNA-1273.222 in adults of all ages.
LIMITATIONS: No RCTs assessed the effectiveness of Omicron-adapted versus no Omicron-adapted vaccination. Evidence on harms was limited.
CONCLUSION: Omicron-adapted vaccines improve protection compared with no Omicron-adapted vaccines, particularly when administered more than 365 days after the prior vaccination.
PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD420251136017).
| Discipline Area | Score |
|---|---|
| Infectious Disease |  |
| Public Health |  |
| Internal Medicine | |
| Family Medicine (FM)/General Practice (GP) | Coming Soon... |
| General Internal Medicine-Primary Care(US) | Coming Soon... |
Conclusions reinforce the view that COVID-19 vaccination has mortality and hospitalization benefits for adults because of the value of the Omicron-adapted vaccine given at least 365 days after a previous COVID-19 vaccination. The conclusions are strengthened by the systematic review described in the article.
