PT  - JOURNAL ARTICLE
AU  - Bajic, Goran
AU  - Maron, Max J.
AU  - Tian, Ming
AU  - Kelsoe, Garnett
AU  - Kuraoka, Masayuki
AU  - Schmidt, Aaron G.
TI  - Structure-guided molecular grafting of a complex broadly neutralizing viral epitope
AID  - 10.1101/860825
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 860825
4099  - http://biorxiv.org/content/early/2019/12/02/860825.short
4100  - http://biorxiv.org/content/early/2019/12/02/860825.full
AB  - 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.