Abstract Background Assessing variant-specific COVID-19 vaccine effectiveness (VE) and severity can inform public health risk assessments and decisions about vaccine composition. BA.2.86 and its descendants, including JN.1 (referred to collectively as “JN lineages”), emerged in late 2023 and exhibited substantial divergence from co-circulating XBB lineages. Methods We analyzed patients hospitalized with COVID-19–like illness at 26 hospitals in 20 U.S. states admitted October 18, 2023–March 9, 2024. Using a test-negative, case-control design, we estimated effectiveness of an updated 2023–2024 (Monovalent XBB.1.5) COVID-19 vaccine dose against sequence-confirmed XBB and JN lineage hospitalization using logistic regression. Odds of severe outcomes, including intensive care unit (ICU) admission and invasive mechanical ventilation (IMV) or death, were compared for JN versus XBB lineage hospitalizations using logistic regression. Results 585 case-patients with XBB lineages, 397 case-patients with JN lineages, and 4,580 control-patients were included. VE in the first 7–89 days after receipt of an updated dose was 54.2% (95% CI = 36.1%–67.1%) against XBB lineage hospitalization and 32.7% (95% CI = 1.9%–53.8%) against JN lineage hospitalization. Odds of ICU admission (adjusted odds ratio [aOR] 0.80; 95% CI = 0.46–1.38) and IMV or death (aOR 0.69; 95% CI = 0.34–1.40) were not significantly different among JN compared to XBB lineage hospitalizations. Conclusions Updated 2023–2024 COVID-19 vaccination provided protection against both XBB and JN lineage hospitalization, but protection against the latter may be attenuated by immune escape. Clinical severity of JN lineage hospitalizations was not higher relative to XBB.

Effectiveness of Updated 2023–2024 (Monovalent XBB.1.5) COVID-19 Vaccination Against SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 Lineage Hospitalization and a Comparison of Clinical Severity—IVY Network, 26 Hospitals, October 18, 2023–March 9, 2024