biostudies-literatureKim DNIAID NIH HHSNIH HHS12https://www.ebi.ac.uk/biostudies/studies/S-EPMC12468577biostudies-literatureUnknown7(1)Influenza has been a global health concern for the past century. Current seasonal influenza vaccines primarily elicit an antibody response that targets the immunodominant head domain of the viral glycoprotein hemagglutinin (HA), which consistently mutates due to selective pressure. To circumvent this problem, we introduce a "tethered antigenic suppression" strategy to shield the HA head domain and refocus the immune response towards the conserved but immunosubdominant stalk domain of HA. Specifically, we tethered an antibody fragment (Fab) that recognizes the Sb antigenic site in the HA head domain to the HA protein with a linker. We immunized separate groups of female mice with the Fab-tethered HA or regular HA and characterized the elicited antibody response. We demonstrate that shieldinChemistry (Basel, Switzerland)Tethered Antigenic Suppression Shields the Hemagglutinin Head Domain and Refocuses the Antibody Response to the Stalk Domain.PMC12468577R01 AI168408P51 OD011132Kim DHariharan VKane RSMurali SHu YLoeffler KArsiwala AFrey SMoreno AfalseTethered Antigenic Suppression Shields the Hemagglutinin Head Domain and Refocuses the Antibody Response to the Stalk Domain.Influenza has been a global health concern for the past century. Current seasonal influenza vaccines primarily elicit an antibody response that targets the immunodominant head domain of the viral glycoprotein hemagglutinin (HA), which consistently mutates due to selective pressure. To circumvent this problem, we introduce a "tethered antigenic suppression" strategy to shield the HA head domain and refocus the immune response towards the conserved but immunosubdominant stalk domain of HA. Specifically, we tethered an antibody fragment (Fab) that recognizes the Sb antigenic site in the HA head domain to the HA protein with a linker. We immunized separate groups of female mice with the Fab-tethered HA or regular HA and characterized the elicited antibody response. We demonstrate that shieldin2025-01-01T00:00:00Z2025 Feb2026-06-03T23:22:50.8Z2026-05-03T03:11:21.009ZS-EPMC124685774101790710.3390/chemistry7010012