Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection

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. [Display omitted] •Lassa virus glycoprotein complex (GPC) trimer stabilization by fusion to a trimeric protein nanoparticle component•Efficient assembly of two-component nanoparticles presenting twenty GPC trimers•GPC nanoparticles induce antibody responses in rabbits and protect guinea pigs from Lassa fever•Isolated NAb from GPC nanoparticle-immunized rabbit defines site of vulnerability on GPC There is no vaccine against Lassa fever. Brouwer et al. generate stabilized Lassa virus glycoproteins presented on two-component protein nanoparticles. In vivo characterization of these nanoparticle vaccines revealed that they induce potent antibody responses in rabbits, one targeting a previously undefined epitope, and protect guinea pigs from the Lassa virus challenge.