Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection

Philip J M Brouwer; Aleksandar Antanasijevic; Adam J Ronk; Helena Müller-Kräuter; Yasunori Watanabe; Mathieu Claireaux; Hailee R Perrett; Tom P L Bijl; Marloes Grobben; Jeffrey C Umotoy; Angela I Schriek; Judith A Burger; Khadija Tejjani; Nicole M Lloyd; Thijs H Steijaert; Marlies M van Haaren; Kwinten Sliepen; Steven W de Taeye; Marit J van Gils; Max Crispin; Thomas Strecker; Alexander Bukreyev; Andrew B Ward; Rogier W Sanders

doi:10.1016/j.chom.2022.10.018

Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection

Cell Host Microbe. 2022 Dec 14;30(12):1759-1772.e12. doi: 10.1016/j.chom.2022.10.018. Epub 2022 Nov 17.

Authors

Philip J M Brouwer¹, Aleksandar Antanasijevic², Adam J Ronk³, Helena Müller-Kräuter⁴, Yasunori Watanabe⁵, Mathieu Claireaux⁶, Hailee R Perrett⁷, Tom P L Bijl⁶, Marloes Grobben⁶, Jeffrey C Umotoy⁶, Angela I Schriek⁶, Judith A Burger⁶, Khadija Tejjani⁶, Nicole M Lloyd³, Thijs H Steijaert⁶, Marlies M van Haaren⁶, Kwinten Sliepen⁶, Steven W de Taeye⁶, Marit J van Gils⁶, Max Crispin⁵, Thomas Strecker⁴, Alexander Bukreyev³, Andrew B Ward⁸, Rogier W Sanders⁹

Affiliations

¹ Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands; Department of Integrative, Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
² Department of Integrative, Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
³ Department of Pathology, University of Texas Medical Branch, Galveston, TX 77550, USA; Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550, USA.
⁴ Institute of Virology, Philipps University Marburg, 35043 Marburg, Germany.
⁵ School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK.
⁶ Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands.
⁷ Department of Integrative, Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁸ Department of Integrative, Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: andrew@scripps.edu.
⁹ Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA. Electronic address: r.w.sanders@amsterdamumc.nl.

Abstract

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.

Keywords: Lassa virus; antibody; challenge study; cryo-EM; nanoparticles; vaccine.

MeSH terms

Animals
Antibodies, Neutralizing
Glycoproteins
Guinea Pigs
Lassa Fever* / prevention & control
Lassa virus / chemistry
Nanoparticles*
Rabbits
Vaccines, Synthetic

Substances

Antibodies, Neutralizing
Glycoproteins
Vaccines, Synthetic