The Influenza-Specific Immunoglobulin Repertoire - Nimble Yet Steeped in Tradition

Influenza virus has circulated in the human population and co-evolved with us for centuries or longer, shaping our immune repertoires through a continuous host-virus arms race. Across individuals, antibodies repeatedly converge on shared solutions for capturing this shape-shifting virus by precisely targeting conserved sites of vulnerability-sites the virus cannot alter without functional cost-through structural features encoded directly by germline immunoglobulin genes. These recurring public antibodies, termed multi-donor class antibodies, have been pivotal for understanding human anti-influenza immunity and in guiding vaccine strategies that may shift the balance of the host-virus arms race. As single-cell biology, structural biology, and computational approaches mature, previously uncharted areas of our immune repertoires are coming into view. Here, we review the current understanding of the influenza-specific immune repertoire, focusing on antibodies and multi-donor antibody classes directed toward antigenic supersites on viral hemagglutinin and neuraminidase-the two major targets of protective antibodies-and discuss how these insights may advance the development of game-changing influenza vaccines.