Structure-Guided Molecular Grafting of a Complex Broadly Neutralizing Viral Epitope.

Autor:	Bajic G; Laboratory of Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States.; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, United States., Maron MJ; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, United States., Caradonna TM; Laboratory of Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States.; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, United States., Tian M; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States., Mermelstein A; Department of Chemistry and Biochemistry, Swarthmore College, Swarthmore, Pennsylvania 19081, United States., Fera D; Department of Chemistry and Biochemistry, Swarthmore College, Swarthmore, Pennsylvania 19081, United States., Kelsoe G; Duke Human Vaccine Institute, Duke University, Durham, North Carolina 27710, United States.; Department of Immunology, Duke University, Durham, North Carolina 27710, United States., Kuraoka M; Department of Immunology, Duke University, Durham, North Carolina 27710, United States., Schmidt AG; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, United States.; Department of Microbiology, Harvard Medical School, Boston, Massachusetts 02115, United States.
Jazyk:	angličtina
Zdroj:	ACS infectious diseases [ACS Infect Dis] 2020 May 08; Vol. 6 (5), pp. 1182-1191. Date of Electronic Publication: 2020 Apr 20.
DOI:	10.1021/acsinfecdis.0c00008
Abstrakt:	Antigenic variation and viral evolution have thwarted traditional influenza vaccination strategies. The broad protection afforded by a "universal" influenza vaccine may 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 noncirculating, 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 and single germinal center B cell analyses from murine prime-boost immunizations show that the rsHAs are both immunogenic and can augment the quality of elicited RBS-directed antibodies. Our structure-guided, RBS grafting approach provides candidate immunogens for selectively presenting a conserved viral epitope.
Databáze:	MEDLINE
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