Structural Characterization and Modeling of a Respiratory Syncytial Virus Fusion Glycoprotein Nanoparticle Vaccine in Solution

Published

January 4, 2021

Author(s)

Susan T. Krueger, Joseph E. Curtis, Daniel R. Scott, Alexander Grishaev, Greg Glenn, Gale Smith, Larry Ellingsworth, Oleg Borisov, Ernest Maynard

Abstract

Globally, respiratory syncytial virus (RSV)is a major cause of sever lower respiratory tract infection in young children, older adults, and immune compromised populations, for which there are no licensed vaccines. The RSV fusion (F)/polysorbate 80 (PS80) nanoparticle vaccine is the most advanced vaccine for maternal immunization in a phase 3 clinical trial. In this report, dynamic light scattering (DLS) and sedimentation velocity analytical ultracentrifugation (SV-AUC) were used to demonstrate that hydrodynamic size and sedimentation coefficient distribution of the RSV F/PS80 nanoparticle are modulated by the molar ratio of PS80 to RSV F protein, consistent with a stable colloidal complex of RSV F trimers and PS80 that can adopt multiple conformations. Transmission electron microscopy (TEM) images show nanoparticles consist of multiple RSV F trimers surrounding a central PS80 core with a length of 16-22 nm and 5-6 nm head width that tapers to a 2-3 nm stem. Smalll-angle neutron and X-ray scattering (SANS and SAXS) analyses provide the size and molecular mass of the nanoparticle consistent with AUC and DLS. Sans and SAXS data were used to construct atomistic models of the nanoparticle. The models are rotameric conformers containing an average of five RSV F trimers organized around a cylinder-shaped PS80 core with an average radius of gyration of 145-170 angstrom} and a 1523+ kDa mass. This arrangement of antigens may help to expose key antigenic sites for development of a robust immune response. Projection of these five-trimer conformer structures onto a 2D surface produced diverse nanoparticle images that are consistent with TEM. This is the first report describing the ultrastructure of the RSV F/PS80 nanoparticle vaccine.

Citation

Molecular Pharmaceutics

Volume

18

Issue

1

Pub Type

Journals

Keywords

respiratory syncytial virus, fusion glycoprotein, vaccine development, small-angle scattering

Citation

Krueger, S. , Curtis, J. , Scott, D. , Grishaev, A. , Glenn, G. , Smith, G. , Ellingsworth, L. , Borisov, O. and Maynard, E. (2021), Structural Characterization and Modeling of a Respiratory Syncytial Virus Fusion Glycoprotein Nanoparticle Vaccine in Solution, Molecular Pharmaceutics (Accessed October 7, 2024)