Protection of Omicron XBB.1.5 vaccine, previous infection, and their induced neutralizing antibodies against symptomatic SARS-CoV-2 infection during Omicron KP.3 wave

BACKGROUND: Data are limited on the protection of Omicron XBB.1.5 vaccine, previous infection, and their induced neutralizing antibodies against Omicron KP.3 infection. METHODS: Among 1826 tertiary hospital staff in Tokyo who had received three or more doses of COVID-19 mRNA vaccines and provided blood samples in June 2024, we prospectively examined the associations of XBB.1.5 vaccination and previous infection (classified by the timing of the last infection as pre-Omicron XBB, Omicron XBB, or Omicron JN.1 waves) with the risk of symptomatic SARS-CoV-2 infection during the Omicron KP.3 wave (June to September 2024). In a nested case-control analysis, we compared pre-infection live-virus KP.3.3-neutralizing antibody titers between cases and 1: 1 propensity-score matched controls. RESULTS: XBB.1.5 vaccination was not associated with measurable protection against symptomatic infection (4%, 95% CI, -88 to 51). Previous infection conferred protection that increased with its recency: 26% (95% CI, -26 to 56) for pre-Omicron XBB, 44% (95% CI, 2 to 68) for Omicron XBB, and 89% (95% CI, 52 to 97) for Omicron JN.1 waves. Pre-infection KP.3.3-neutralizing titers tended to be lower in cases than in matched controls (GMT ratio 0.68, 95% CI, 0.35 to 1.33); KP.3.3-neutralizing activity was only modestly elevated by XBB.1.5 vaccination but markedly higher after recent JN.1 infection. CONCLUSIONS: During the Omicron KP.3 wave, when an updated vaccine was unavailable, XBB.1.5 vaccination administered approximately 7 months earlier conferred no measurable neutralizing activity or protection against symptomatic KP.3 infection. Previous SARS-CoV-2 infection, particularly recent JN.1-wave infection, affords substantial neutralizing titers and protection.