The high Lassa fever mortality rates of the recent outbreaks in several endemic West-African countries stress the need for an effective Lassavirus (LASV) vaccine. Among the several vaccine strategies that are currently being pursued, a subunit vaccine that is able to elicit broad and potent neutralizing antibodies would provide a safe and effective option to induce protective immunity. However, the LASV glycoprotein (GP) trimer is intrinsically unstable and falls apart into monomers when it is made as a soluble protein. As a result, recombinant soluble GP formulations usually only induce non-neutralizing antibodies that target the interior of LASV-GP, which is hidden on infectious pre-fusion LASV GP. Here, we have used two-component protein nanoparticles (I53-50NPs) to multivalently present twenty stabilized pre-fusion LASV-GP trimers. Pre-fusion LASV-GPs are genetically linked to the trimeric nanoparticle component to create LASV-GP-I53-50A fusion proteins (LASV-GP-I53-50A). Negative-stain electron microscopy, monoclonal antibody binding and site-specific glycan analysis indicate that the recombinant LASV-GP-trimers on I53-50A closely resemble the viral pre-fusion LASV GP conformation. When mixed with the second nanoparticle component, LASV-GP-I53-50A assembled into monodisperse, well-ordered icosahedral nanoparticles. The immunogenicity of these nanoparticles is currently being tested in rabbits of which the preliminary results will be presented at the meeting.
Philip Brouwer
A two-component nanoparticle vaccine candidate presenting stabilized Lassavirus glycoproteins
Philip J.M. Brouwer1, Tom P.L. Bijl1, Aleksandar Antanasijevic2, Yasunori Watanabe3, Thijs Steijaert1, Brooke Nickerson4, Rashmi Ravichandran4, Judith A. Burger1, Max Crispin3, Andrew B. Ward2, Neil P.King4, Rogier W. Sanders1
1 Academic Medical Center, Amsterdam, The Netherlands
2 The Scripps Research Institute, La Jolla, USA
3 University of Southampton, Southampton, UK
4 University of Washington, Seattle, USA