Limited cross-variant immunity from SARS-CoV-2 Omicron without vaccination

SARS-CoV-2 Delta and Omicron are globally relevant variants of concern. Although individuals infected with Delta are at risk of developing severe lung disease, infection with Omicron often causes milder symptoms, especially in vaccinated individuals. The question arises of whether widespread Omicron infections could lead to further 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 can neutralize Omicron but not other variants of concern, whereas broader immunity can be induced with live Delta. Notably, we found that Omicron infections led to reduced expression of pro-inflammatory cytokines and activation of lung-resident T cells. Sera from vaccinated and infected animals exhibited enhanced neutralization of Omicron compared with Delta. In contrast, Omicron breakthrough infections conferred overall higher neutralization titers against all variants of concern. Our results demonstrate that Omicron infection enhances pre-existing immunity elicited by vaccines but, on its own, may not confer broad protection against non-Omicron variants in unvaccinated individuals.

Rahul K. Suryawanshi, Irene P. Chen, Tongqiu M. Syed, Abdullah M. Syed, Noah Brazer, Prachi Sahil, Camille R. Simoneau, Aliston Cling, M. K. Khalid, Bharath Sreekumar, Pei-Yi Chen, G. Renuka Kumar, Mauricio Montano, Ronne Gascon, Chia-Lin Tsou, Miguel A. Garcia-Knight, Alicia Sotomayor-Gonzalez, Venice Servellita, Amelia Gilwa, Jenny Nguyen, Ines Silva, Bilal Mibes, Noah Kojima, Victoria Hess, Maria Shaevitz, Lauren Lopez, Matthew Brobeck, Fred Turner, Frank W. Stowe, Ashley F. George, Xiaohui Fang, Mazharul Mashan, Michael Matthys, Mary Kate Morris, Debra Wafford, Carl Hanson, Warren C. Greene, Raul Andino, Lee Spraggy, Nadia R. Roan, Charles Y. Chiu, Jennifer A. Doudna, Melanie Ott