Single-component multilayered self-assembling nanoparticles presenting rationally designed glycoprotein trimers as Ebola virus vaccines

Ebola virus (EBOV) glycoprotein (GP) can be recognized by neutralizing antibodies (NAbs) and is the main target for vaccine design. Here, we first investigate the contribution of the stalk and heptad repeat 1-C (HR1(C)) regions to GP metastability. Specific stalk and HR1(C) modifications in a mucin-deleted form (GP Delta muc) increase trimer yield, whereas alterations of HR1(C) exert a more complex effect on thermostability. Crystal structures are determined to validate two rationally designed GP Delta muc trimers in their unliganded state. We then display a modified GP Delta muc trimer on reengineered protein nanoparticles that encapsulate a layer of locking domains (LD) and a cluster of helper T-cell epitopes. In mice and rabbits, GP trimers and nanoparticles elicit cross-ebolavirus NAbs, as well as non-NAbs that enhance pseudovirus infection. Repertoire sequencing reveals quantitative profiles of vaccine-induced B-cell responses. This study demonstrates a promising vaccine strategy for filoviruses, such as EBOV, based on GP stabilization and nanoparticle display. Ebola virus glycoprotein (GP) is a major target for vaccine design. Here, the authors identify mutations to improve GP stability and yield, design two multilayered nanoparticle carriers, and demonstrate good immunogenicity of the modified GP on nanoparticles in mice and rabbits.

Automated summary

The study identifies mutations to improve GP stability and yield, designs two multilayered nanoparticle carriers, and demonstrates good immunogenicity of the modified GP on nanoparticles in mice and rabbits.