Omicron Breakthrough Infection Elicits Superior Humoral and Mucosal Immunity to SARS-CoV-2 Variants than Booster Doses

Abstract In light of ongoing booster vaccination campaigns, one recurring question is whether individuals infected with SARS-CoV-2 should still receive a booster dose if they were infected after completing their primary series. We aimed to assess the intensity of functional humoral and cellular immune responses induced by breakthrough infections during the B.1.1.529 wave in Canada compared to individuals who received three doses of vaccine. Because hybrid immunity has been shown to induce particularly potent immunity, we hypothesized that breakthrough infections could induce superior immune response to variants than booster doses. To address this important public health question, we analyzed samples from two cohorts of individuals naïve to SARS-CoV-2 or who were primary infected before vaccination. We compared responses 45 days after a third vaccine dose or an Omicron breakthrough infection. Our results show that mild breakthrough infection induces cell-mediated immune response to variants comparable to a vaccine booster dose. In contrast, breakthrough 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 breakthrough infection, especially in individuals naïve to the infection prior to vaccination. Altogether our results demonstrate that an Omicron breakthrough infection can substitute a booster dose of vaccine, while also supporting the need for mucosal vaccine boosts to potentially replicate the improvement on mucosal and humoral immunity without the risks associated to being infected with SARS-CoV-2. Research supported by grants from the Canadian Institutes of Health Research, Public Health Agency of Canada and the Ontario COVID-19 Rapid Research Fund through Ontario Together.