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

Linling He, Anshul Chaudhary, Xiaohe Lin, Cindy Sou, Tanwee Alkutkar, Sonu Kumar, Timothy Ngo, Ezra Kosviner, Gabriel Ozorowski, Robyn L. Stanfield, Andrew B. Ward, Ian A. Wilson () and Jiang Zhu ()
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Linling He: The Scripps Research Institute
Anshul Chaudhary: The Scripps Research Institute
Xiaohe Lin: The Scripps Research Institute
Cindy Sou: The Scripps Research Institute
Tanwee Alkutkar: The Scripps Research Institute
Sonu Kumar: The Scripps Research Institute
Timothy Ngo: The Scripps Research Institute
Ezra Kosviner: The Scripps Research Institute
Gabriel Ozorowski: The Scripps Research Institute
Robyn L. Stanfield: The Scripps Research Institute
Andrew B. Ward: The Scripps Research Institute
Ian A. Wilson: The Scripps Research Institute
Jiang Zhu: The Scripps Research Institute

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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 (HR1C) regions to GP metastability. Specific stalk and HR1C modifications in a mucin-deleted form (GPΔmuc) increase trimer yield, whereas alterations of HR1C exert a more complex effect on thermostability. Crystal structures are determined to validate two rationally designed GPΔmuc trimers in their unliganded state. We then display a modified GPΔmuc 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.

Date: 2021
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DOI: 10.1038/s41467-021-22867-w

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