Lassa virus glycoprotein nanoparticles elicit a neutralizing antibody that defines a new site of vulnerability

Brouwer, P. J. M.; Antanasijevic, A.; Ronk, A. J.; Mulller-Krauter, H.; Watanabe, Y.; Claireaux, M.; Lloyd, N. M.; Bijl, T. P. L.; Perrett, H. R.; Steijaert, T. H.; Burger, J. A.; van Haaren, M. M.; Sliepen, K.; van Gils, M.; Crispin, M.; Strecker, T.; Bukreyev, A.; Ward, A.; Sanders, R. W.

doi:10.1101/2022.03.28.486091

bioRxiv · 10.1101/2022.03.28.486091

Lassa virus glycoprotein nanoparticles elicit a neutralizing antibody that defines a new site of vulnerability

Brouwer, P. J. M.·Antanasijevic, A.·Ronk, A. J.·Mulller-Krauter, H.·Watanabe, Y.·Claireaux, M.·Lloyd, N. M.·Bijl, T. P. L.·Perrett, H. R.·Steijaert, T. H.·Burger, J. A.·van Haaren, M. M.·Sliepen, K.·van Gils, M.·Crispin, M.·Strecker, T.·Bukreyev, A.·Ward, A.·Sanders, R. W.

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Abstract

Lassa virus is endemic in large parts of West Africa and causes a hemorrhagic fever. Recent years have seen several serious outbreaks of Lassa fever with high mortality rates. A vaccine to curtail infection is urgently needed. 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 to stabilize GPC in a trimeric conformation and present twenty prefusion GPC trimers on the surface of an icosahedral nanoparticle. Cryo-EM studies of assembled 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 a lethal Lassa virus challenge in guinea pigs. We isolated a neutralizing antibody which was mapped to the putative receptor-binding site, revealing a novel site of vulnerability on GPC.

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Brouwer, P. J. M., Antanasijevic, A., Ronk, A. J., Mulller-Krauter, H., Watanabe, Y., Claireaux, M., Lloyd, N. M., Bijl, T. P. L., Perrett, H. R., Steijaert, T. H., Burger, J. A., van Haaren, M. M., Sliepen, K., van Gils, M., Crispin, M., Strecker, T., Bukreyev, A., Ward, A., Sanders, R. W.. 2022-03-29. Lassa virus glycoprotein nanoparticles elicit a neutralizing antibody that defines a new site of vulnerability. https://doi.org/10.1101/2022.03.28.486091

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