Sequential reinfection with Omicron variants elicits broader neutralizing antibody profiles in booster vaccinees and reduces the duration of viral shedding.

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The constant emergence of breakthrough infections with Omicron variants poses an escalating challenge to the current vaccination strategy. In this study, we investigated the distinct neutralization activities and clinical characteristics of the booster vaccinees with Omicron reinfection compared with single breakthrough infection and homologous booster vaccination. Our results demonstrate that neutralizing antibody GMTs for WT and other four subvariants (BA.2.2, BA.5.2, BF.7, and XBB.1) differ greatly between breakthrough infection and homologous booster cohorts. Sequential reinfection with Omicron variants elicits broader and high-titer variant-specific neutralizing antibody profiles against Omicron variants. It could also dampen the hyperactivation of WT-specific neutralization induced by previous WT-based vaccination. Moreover, the clinical characteristics from reinfection demonstrated that repeated stimulation by Omicron variants could reduce the duration of viral shedding. By considering reinfection with the Omicron variant as a representative model of repeated immunogen exposures, our results thus illustrate the potential superiority of repeated Omicron stimuli and provide additional evidence supporting the Omicron immunogen as a more effective vaccine candidate to mitigate the transmission of emerging variants.