Abstract
SARS-CoV-2 Delta and Omicron are globally relevant variants of concern (VOCs). While individuals infected with Delta are at risk to develop severe lung disease, Omicron infection often causes milder symptoms, especially in vaccinated individuals1,2. The question arises whether the current rampant spread of Omicron could lead to future cross-variant protection, accelerating the end of the pandemic. Here we show that without vaccination, infection with Omicron induces a limited humoral immune response in mice and humans. Sera from mice overexpressing the human ACE2 receptor and infected with Omicron neutralize only Omicron, but no other VOCs, while Delta infection elicits broad cross-variant neutralization. This is not observed with the WA1 ancestral isolate, although exposure to both, WA1 and Delta, but not Omicron, cause high-level viral replication, pro-inflammatory cytokine expression, exhaustion of lung-resident T cells and severe disease in infected animals. Analysis of human sera from unvaccinated, Omicron-infected individuals confirms limited neutralization of other variants besides Omicron itself, while sera from Omicron breakthrough cases show robust cross-variant neutralization in vaccinated individuals. Together, our results indicate that Omicron infection enhances preexisting immunity elicited by vaccines, but on its own may not confer broad protection against Non-Omicron variants in unvaccinated individuals.
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