期刊
CELL HOST & MICROBE
卷 30, 期 12, 页码 1759-+出版社
CELL PRESS
DOI: 10.1016/j.chom.2022.10.018
关键词
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资金
- Rubicon fellowship from the Netherlands Organisation for Scientific Research [452020226 NWO]
- Vici fellowship from the Netherlands Organisation for Scientific Research (NWO)
- Fondation Dormeur, Vaduz
- Bill and Melinda Gates Foundation [OPP1170236]
- amfAR Mathilde Krim Fellowship in Biomedical Research [110182-69-RKVA]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [197785619/SFB1021]
- International AIDS Vaccine Initiative (IAVI) through the Collaboration for AIDS Vaccine Discovery (CAVD) - Bill and Melinda Gates Foundation [INV-008352/OPP1153692]
The use of two-component protein nanoparticles to stabilize the Lassa virus glycoprotein complex (GPC) trimers has shown promising results in vaccine development, inducing potent immune responses and protection against the lethal Lassa virus challenge in animal models.
The Lassa virus is endemic in parts of West Africa, and it causes hemorrhagic fever with high mortality. The development of a recombinant protein vaccine has been hampered by the instability of soluble Lassa virus glycoprotein complex (GPC) trimers, which disassemble into monomeric subunits after expression. Here, we use two-component protein nanoparticles consisting of trimeric and pentameric subunits to stabilize GPC in a trimeric conformation. These GPC nanoparticles present twenty prefusion GPC trimers on the surface of an icosahedral particle. Cryo-EM studies of GPC nanoparticles demonstrated a well-ordered structure and yielded a high-resolution structure of an unliganded GPC. These nanoparticles induced potent humoral immune responses in rabbits and protective immunity against the lethal Lassa virus challenge in guinea pigs. Additionally, we isolated a neutralizing antibody that mapped to the putative receptor-binding site, revealing a previously undefined site of vulnerability. Collectively, these findings offer potential approaches to vaccine and therapeutic design for the Lassa virus.
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