1. Cleavage-intermediate Lassa virus trimer elicits neutralizing responses, identifies neutralizing nanobodies, and reveals an apex-situated site-of-vulnerability
- Author
-
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
- Subjects
Science - 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.
- Published
- 2024
- Full Text
- View/download PDF