Vaccine effectiveness across the Omicron evolutionary spectrum (BA.2, BA.5, XBB, JN.1, KP.3): a systematic review of studies published 2022–2025

BACKGROUND: Since late 2021, the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone rapid evolutionary diversification, giving rise to successive subvariants with increasing immune escape. In response, coronavirus disease 2019 (COVID-19) vaccination strategies transitioned from ancestral-strain vaccines to variant-adapted formulations. Real-world evidence on the effectiveness and durability of these updated vaccines across the full Omicron evolutionary spectrum remains fragmented. OBJECTIVES: To synthesise real-world evidence on the effectiveness of COVID-19 vaccines against SARS-CoV-2 infection and severe clinical outcomes across successive Omicron subvariants from 2022 to 2025, with particular emphasis on variant-adapted vaccine formulations and waning immunity over time. METHODS: A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and registered in PROSPERO. MEDLINE (via PubMed), Embase, CINAHL, Scopus, and Web of Science Core Collection were systematically searched for peer-reviewed observational studies published between January 2022 and December 2025. Eligible studies assessed vaccine effectiveness during periods dominated by Omicron subvariants including BA.2, BA.5, XBB, BA.2.86/JN.1, and KP lineages. Findings were synthesised narratively due to substantial heterogeneity. RESULTS: Thirty observational studies from North America, Europe, and East Asia were included. Across Omicron subvariants, vaccine effectiveness against SARS-CoV-2 infection was generally modest and short-lived, with rapid waning within months after vaccination and estimates frequently approaching null during later subvariant periods. In contrast, updated and variant-adapted vaccines consistently provided meaningful protection against severe COVID-19 outcomes, including hospitalization and death. Protection was highest during BA.4/BA.5 and early XBB-dominant periods and declined with increasing time since vaccination, especially during JN.1- and KP-predominant periods and among the oldest age groups. Importantly, substantial protection against severe outcomes persisted within the first 1–3 months following vaccination, with effectiveness against hospitalization and death generally ≥ 50%, although effectiveness declined over time during later Omicron subvariant periods. CONCLUSION: Updated and variant-adapted COVID-19 vaccines continue to confer substantial protection against severe COVID-19 outcomes across successive Omicron subvariants, despite limited and rapidly waning effectiveness against SARS-CoV-2 infection. These findings support prioritisation of periodic booster vaccination for older adults and other high-risk populations, with vaccine performance primarily evaluated using protection against severe clinical outcomes. CLINICAL TRIAL NUMBER: Not applicable.