Comparison of Omicron Breakthrough Infection Versus Monovalent SARS-CoV-2 Intramuscular Booster Reveals Differences in Mucosal and Systemic Humoral Immunity.

Our understanding of the quality of cellular and humoral immunity conferred by coronavirus disease 2019 (COVID-19) vaccination alone versus vaccination plus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough (BT) infection remains incomplete. While the current (2023) SARS-CoV-2 immune landscape of Canadians is complex, in late 2021 most Canadians had either just received a third dose of COVID-19 vaccine, or had received their two dose primary series and then experienced an Omicron BT. Herein we took advantage of this coincident timing to contrast cellular and humoral immunity conferred by three doses of vaccine versus two doses plus BT. Our results show that mild BT infection induces cell-mediated immune responses to variants comparable to an intramuscular vaccine booster dose. In contrast, BT subjects had higher salivary IgG and IgA levels against the Omicron spike and enhanced reactivity to the ancestral spike for the IgA isotype, which also reacted with SARS-CoV-1. Serum neutralizing antibody levels against the ancestral strain and the variants were also higher after BT infection. Our results support the need for vaccines that emulate the enhanced mucosal and humoral immunity induced by Omicron BT without exposing individuals to the risks associated with SARS-CoV-2 infection. One Sentence Summary Omicron breakthrough elicits cross-reactive systemic and mucosal immune responses in vaccinated adults.

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