Cleavage-intermediate Lassa virus trimer elicits neutralizing responses, identifies neutralizing nanobodies, and reveals an apex-situated site-of-vulnerability
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Published:2024-01-04
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Gorman JasonORCID, Cheung Crystal Sao-Fong, Duan Zhijian, Ou Li, Wang Maple, Chen XuejunORCID, Cheng Cheng, Biju Andrea, Sun Yaping, Wang PengfeiORCID, Yang Yongping, Zhang Baoshan, Boyington Jeffrey C., Bylund Tatsiana, Charaf Sam, Chen Steven J., Du Haijuan, Henry Amy R., Liu Tracy, Sarfo Edward K.ORCID, Schramm Chaim A.ORCID, Shen Chen-Hsiang, Stephens Tyler, Teng I-Ting, Todd John-Paul, Tsybovsky YaroslavORCID, Verardi RaffaelloORCID, Wang DanyiORCID, Wang ShuishuORCID, Wang Zhantong, Zheng Cheng-Yan, Zhou TongqingORCID, Douek Daniel C.ORCID, Mascola John R., Ho David D., Ho MitchellORCID, Kwong Peter D.ORCID
Abstract
AbstractLassa virus (LASV) infection is expanding outside its traditionally endemic areas in West Africa, posing a pandemic biothreat. LASV-neutralizing antibodies, moreover, have proven difficult to elicit. To gain insight into LASV neutralization, here we develop a prefusion-stabilized LASV glycoprotein trimer (GPC), pan it against phage libraries comprising single-domain antibodies (nanobodies) from shark and camel, and identify one, D5, which neutralizes LASV. Cryo-EM analyses reveal D5 to recognize a cleavage-dependent site-of-vulnerability at the trimer apex. The recognized site appears specific to GPC intermediates, with protomers lacking full cleavage between GP1 and GP2 subunits. Guinea pig immunizations with the prefusion-stabilized cleavage-intermediate LASV GPC, first as trimer and then as a nanoparticle, induce neutralizing responses, targeting multiple epitopes including that of D5; we identify a neutralizing antibody (GP23) from the immunized guinea pigs. Collectively, our findings define a prefusion-stabilized GPC trimer, reveal an apex-situated site-of-vulnerability, and demonstrate elicitation of LASV-neutralizing responses by a cleavage-intermediate LASV trimer.
Funder
Division of Intramural Research, National Institute of Allergy and Infectious Diseases
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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