Structural Characterization and Modeling of a Respiratory Syncytial Virus Fusion Glycoprotein Nanoparticle Vaccine in Solution
Year: 2020
Type: article
Abstract: The respiratory syncytial virus (RSV) fusion (F) protein/polysorbate 80 (PS80) nanoparticle vaccine is the most clinically advanced vaccine for maternal immunization and protection of newborns against RSV infection. It is composed of a near-full-length RSV F glycoprotein, with an intact membrane domain, formulated into a stable nanoparticle with PS80 detergent. To understand the structural basis for the efficacy of the vaccine, a comprehensive study of its structure and hydrodynamic properties in solution was performed. Small-angle neutron scattering experiments indicate that the nanoparticle contains an average of 350 PS80 molecules, which form a cylindrical micellar core structure and five RSV F trimers that are arranged around the long axis of the PS80 core. All-atom models of full-length RSV F trimers were built from crystal structures of the soluble ectodomain and arranged around the long axis of the PS80 core, allowing for the generation of an ensemble of conformations that agree with small-angle neutron and X-ray scattering data as well as transmission electron microscopy (TEM) images. Furthermore, the hydrodynamic size of the RSV F nanoparticle was found to be modulated by the molar ratio of PS80 to protein, suggesting a mechanism for nanoparticle assembly involving addition of RSV F trimers to and growth along the long axis of the PS80 core. This study provides structural details of antigen presentation and conformation in the RSV F nanoparticle vaccine, helping to explain the induction of broad immunity and observed clinical efficacy. Small-angle scattering methods provide a general strategy to visualize surface glycoproteins from other pathogens and to structurally characterize nanoparticle vaccines.
Source: Molecular Pharmaceutics
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1689194922, SI2-CHE: CCP-SAS - Collaborative Computational Project for advanced analyses of structural data in chemical biology and soft condensed matter, The NIST/NSF Center for High Resolution Neutron Scattering, G2979162315, G3054295802, G3108985476, G3537589354, G4310665315, G434337789, G4981905393, G5214689270, G525358847, G5586684623, SI2-CHE: CCP-SAS - Collaborative Computing consortium for advanced analyses of structural data in chemical biology and soft condensed matter, World class Science and Innovation with Neutrons in Europe 2020 – SINE2020, G6271517897, IMR-MIP DANSE - Distributed Data Analysis for Neutron Scattering Experiments - CNST, G8380713174, G8594747244, G8786941285
OpenAlex ID: W3110755157