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.