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bioRxiv · 10.1101/860825

Structure-guided molecular grafting of a complex broadly neutralizing viral epitope

Bajic, G.·Maron, M. J.·Tian, M.·Kelsoe, G.·Kuraoka, M.·Schmidt, A. G.
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Abstract

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.

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Bajic, G., Maron, M. J., Tian, M., Kelsoe, G., Kuraoka, M., Schmidt, A. G.. 2019-12-02. Structure-guided molecular grafting of a complex broadly neutralizing viral epitope. https://doi.org/10.1101/860825

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