Male and female mice achieve equivalent protection against heterologous SARS-CoV-2 infection through divergent immune mechanisms

Kenney, D.; Matsuo, M.; Pantelias, A.; Leger, J.; Kaplan, A.; Cerbo, F.; Chen, D.-Y.; Adams, S.; Unali, G.; Wallace, D.; Saeed, M.; Belkina, A.; Harly, C.; Douam, F.

doi:10.64898/2026.09.28.755090

bioRxiv · 10.64898/2026.09.28.755090

Male and female mice achieve equivalent protection against heterologous SARS-CoV-2 infection through divergent immune mechanisms

Kenney, D.·Matsuo, M.·Pantelias, A.·Leger, J.·Kaplan, A.·Cerbo, F.·Chen, D.-Y.·Adams, S.·Unali, G.·Wallace, D.·Saeed, M.·Belkina, A.·Harly, C.·Douam, F.

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Abstract

Biological sex is a major determinant of antiviral immunity, yet how it shapes lung-resident antiviral immunity remains poorly understood. We report that prior mild SARS-CoV-2 BA.1 infection protects mice from lethal heterologous Delta challenge through distinct sex-biased immune mechanisms. Although heterologous protection is clinically equivalent between sexes, T- and B-cell depletions before BA.1 exposure abrogate protection only in males. Depletion with anti-CD4, but not anti-CD8, abolishes protection in both sexes, but co-depletion with anti-CD4/anti-CD8 partially restores protection in females only. Further, females exhibit enhanced IFN-gamma-associated myeloid inflammation upon secondary Delta infection. Using lymphoid-deficient mice that display female-biased resistance to Delta infection, IFN-gamma treatment provides partial protection to naive males against Delta. Female resistance is lost after previous BA.1 exposure, highlighting the importance of lymphoid-mediated inflammatory regulation. Together, equivalent antiviral protection against heterologous respiratory viral infection is governed by sexually dimorphic mechanisms, with significant implications for designing mucosal vaccines and immunotherapies.

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Kenney, D., Matsuo, M., Pantelias, A., Leger, J., Kaplan, A., Cerbo, F., Chen, D.-Y., Adams, S., Unali, G., Wallace, D., Saeed, M., Belkina, A., Harly, C., Douam, F.. 2026-10-03. Male and female mice achieve equivalent protection against heterologous SARS-CoV-2 infection through divergent immune mechanisms. https://doi.org/10.64898/2026.09.28.755090

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