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

View ORCID ProfileGoran Bajic, Max J. Maron, Ming Tian, Garnett Kelsoe, Masayuki Kuraoka, View ORCID ProfileAaron G. Schmidt
doi: https://doi.org/10.1101/860825
Goran Bajic
1Laboratory of Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
2Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
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  • ORCID record for Goran Bajic
Max J. Maron
3Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA
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Ming Tian
4Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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Garnett Kelsoe
5Duke Human Vaccine Institute, Duke University, Durham, NC 27710, USA
6Department of Immunology, Duke University, Durham, NC 27710, USA
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Masayuki Kuraoka
6Department of Immunology, Duke University, Durham, NC 27710, USA
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Aaron G. Schmidt
3Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA
7Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
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  • For correspondence: aschmidt@crystal.harvard.edu
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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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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 02, 2019.
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Structure-guided molecular grafting of a complex broadly neutralizing viral epitope
Goran Bajic, Max J. Maron, Ming Tian, Garnett Kelsoe, Masayuki Kuraoka, Aaron G. Schmidt
bioRxiv 860825; doi: https://doi.org/10.1101/860825
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Structure-guided molecular grafting of a complex broadly neutralizing viral epitope
Goran Bajic, Max J. Maron, Ming Tian, Garnett Kelsoe, Masayuki Kuraoka, Aaron G. Schmidt
bioRxiv 860825; doi: https://doi.org/10.1101/860825

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