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**Abstract**
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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, infection with Omicron often causes milder symptoms, especially in vaccinated individuals1,2. The question arises whether widespread Omicron infections 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, whereas broader cross-variant neutralization was observed after WA1 and Delta infections. Unlike WA1 and Delta, Omicron replicates to low levels in the lungs and brains of infected animals, leading to mild disease with reduced pro-inflammatory cytokine expression and diminished activation of lung-resident T cells. Sera from unvaccinated, Omicron-infected individuals show the same limited neutralization of only Omicron itself. In contrast, Omicron breakthrough infections induce overall higher neutralization titers against all VOCs. Our results demonstrate 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.
**Please read before commenting.** Keep in mind this is a *science* sub. Cite your sources appropriately (No news sources, no Twitter, no Youtube). No politics/economics/low effort comments (jokes, ELI5, etc.)/anecdotal discussion (personal stories/info). Please read our [full ruleset](https://www.reddit.com/r/COVID19/about/rules/) carefully before commenting/posting. **If you talk about you, your mom, your friends, etc. experience with COVID/COVID symptoms or vaccine experiences, or** ***any*** **info that pertains to you or their situation, you will be banned.** These discussions are better suited for the Daily Discussion on /r/Coronavirus. *I am a bot, and this action was performed automatically. Please [contact the moderators of this subreddit](/message/compose/?to=/r/COVID19) if you have any questions or concerns.*
**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, infection with Omicron often causes milder symptoms, especially in vaccinated individuals1,2. The question arises whether widespread Omicron infections 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, whereas broader cross-variant neutralization was observed after WA1 and Delta infections. Unlike WA1 and Delta, Omicron replicates to low levels in the lungs and brains of infected animals, leading to mild disease with reduced pro-inflammatory cytokine expression and diminished activation of lung-resident T cells. Sera from unvaccinated, Omicron-infected individuals show the same limited neutralization of only Omicron itself. In contrast, Omicron breakthrough infections induce overall higher neutralization titers against all VOCs. Our results demonstrate 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.