%0 Journal Article %A Goran Bajic %A Max J. Maron %A Ming Tian %A Garnett Kelsoe %A Masayuki Kuraoka %A Aaron G. Schmidt %T Structure-guided molecular grafting of a complex broadly neutralizing viral epitope %D 2019 %R 10.1101/860825 %J bioRxiv %P 860825 %X Antigenic variation and viral evolution have thwarted traditional influenza vaccination strategies. The broad protection afforded by a “universal” influenza vaccine will come from immunogens that elicit humoral immune responses targeting conserved epitopes on the viral hemagglutinin (HA), such as the receptor-binding site (RBS). Here, we engineered candidate immunogens that use non-circulating, avian influenza HAs as molecular scaffolds to present the broadly neutralizing RBS epitope from historical, circulating H1 influenzas. These “resurfaced” HAs (rsHAs) remove epitopes potentially targeted by strain-specific responses in immune-experienced individuals. Through structure-guided optimization we improved two antigenically different scaffolds to bind a diverse panel of pan-H1 and H1/H3 cross-reactive bnAbs with high affinity. Subsequent serological analyses from murine prime-boost immunizations show that the rsHAs are both immunogenic and can enrich for RBS-directed antibodies. Our structure-guided, RBS grafting approach provides candidate immunogens for selectively presenting a conserved viral epitope. %U https://www.biorxiv.org/content/biorxiv/early/2019/12/02/860825.full.pdf