Tailored design of protein nanoparticle scaffolds for multivalent presentation of viral glycoprotein antigens

By G. Ueda, A. Antanasijevic, J. Fallas, W. Sheffler, Jeffrey Copps, Daniel Ellis, Geoffrey B. Hutchinson, A. Moyer, A. Yasmeen, Y. Tsybovsky and 15 more. 2020

147 citations recorded by the source corpus.

The adaptive immune system is highly sensitive to arrayed antigens, and multivalent display of viral glycoproteins on symmetric scaffolds has been found to substantially increase the elicitation of antigen-specific antibodies. Motivated by the considerable promise of this strategy for next-generation anti-viral vaccines, we set out to design new self-assembling protein nanoparticles with geometries specifically tailored to scaffold ectodomains of different viral glycoproteins. We first designed and characterized homo-trimers from designed repeat proteins with N-terminal helices positioned to match the C termini of several viral glycoprotein trimers. Oligomers found to experimentally adopt the designed configuration were then used to generate nanoparticles with tetrahedral, octahedral, or icosahedral symmetry. Examples of all three target symmetries were experimentally validated by cryo-electron microscopy and several were assessed for their ability to display viral glycoproteins via genetic fusion. Electron microscopy and antibody binding experiments demonstrated that the designed nanoparticles display conformationally intact native-like HIV-1 Env, influenza hemagglutinin, and prefusion RSV F trimers in the predicted geometries. This work demonstrates that novel nanoparticle immunogens can be designed from the bottom up with atomic-level accuracy and provides a general strategy for precisely controlling epitope presentation and accessibility.

Subfields: Ecology, Molecular Biology, Radiology, Nuclear Medicine and Imaging

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Ecology

In Molecular Biology

In Radiology, Nuclear Medicine and Imaging

Citations in the corpus

Generation of ordered protein assemblies using rigid three-body fusion (2020, unknown): “T is considerable interest in the design of novel protein assemblies, for example, to develop cryogenic electron microscopy (cryo-EM) scaffolds to aid in structure determination (1, 2) and protein nanoparticle vaccines (3, 4).”
Elicitation of broadly protective immunity to influenza by multivalent hemagglutinin nanoparticle vaccines (2020, methodology): “Several potential factors may contribute to this effect, such as the geometric relationship between neighboring HAs on the nanoparticle surface 33,42,45 , preferential antigen uptake or retention kinetics by macrophages and follicular dendritic cells 63 , or the presence of T helper epitopes…”