Cleavage-intermediate Lassa virus trimer elicits neutralizing responses, identifies neutralizing nanobodies, and reveals an apex-situated site-of-vulnerability

Jason Gorman, Crystal Sao-Fong Cheung, Zhijian Duan, Li Ou, Maple Wang, Xuejun Chen, Cheng Cheng, Andrea Biju, Yaping Sun, Pengfei Wang, Yongping Yang, Baoshan Zhang, Jeffrey C. Boyington, Tatsiana Bylund, Sam Charaf, Steven J. Chen, Haijuan Du, Amy R. Henry, Tracy Liu, Edward K. Sarfo, Chaim A. Schramm, Chen-Hsiang Shen, Tyler Stephens, I-Ting Teng, John-Paul Todd, Yaroslav Tsybovsky, Raffaello Verardi, Danyi Wang, Shuishu Wang, Zhantong Wang, Cheng-Yan Zheng, Tongqing Zhou, Daniel C. Douek, John R. Mascola, David D. Ho (), Mitchell Ho () and Peter D. Kwong ()
Additional contact information
Jason Gorman: National Institutes of Health
Crystal Sao-Fong Cheung: National Institutes of Health
Zhijian Duan: National Institutes of Health
Li Ou: National Institutes of Health
Maple Wang: Columbia University Vagelos College of Physicians and Surgeons
Xuejun Chen: National Institutes of Health
Cheng Cheng: National Institutes of Health
Andrea Biju: National Institutes of Health
Yaping Sun: National Institutes of Health
Pengfei Wang: Columbia University Vagelos College of Physicians and Surgeons
Yongping Yang: National Institutes of Health
Baoshan Zhang: National Institutes of Health
Jeffrey C. Boyington: National Institutes of Health
Tatsiana Bylund: National Institutes of Health
Sam Charaf: National Institutes of Health
Steven J. Chen: National Institutes of Health
Haijuan Du: National Institutes of Health
Amy R. Henry: National Institutes of Health
Tracy Liu: National Institutes of Health
Edward K. Sarfo: National Institutes of Health
Chaim A. Schramm: National Institutes of Health
Chen-Hsiang Shen: National Institutes of Health
Tyler Stephens: Frederick National Laboratory for Cancer Research
I-Ting Teng: National Institutes of Health
John-Paul Todd: National Institutes of Health
Yaroslav Tsybovsky: Frederick National Laboratory for Cancer Research
Raffaello Verardi: National Institutes of Health
Danyi Wang: National Institutes of Health
Shuishu Wang: National Institutes of Health
Zhantong Wang: National Institutes of Health
Cheng-Yan Zheng: National Institutes of Health
Tongqing Zhou: National Institutes of Health
Daniel C. Douek: National Institutes of Health
John R. Mascola: National Institutes of Health
David D. Ho: Columbia University Vagelos College of Physicians and Surgeons
Mitchell Ho: National Institutes of Health
Peter D. Kwong: National Institutes of Health

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Lassa 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.

Date: 2024
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DOI: 10.1038/s41467-023-44534-y

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