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Published on: July 25, 2022
Structural Characterization and Modeling of a Respiratory Syncytial Virus Fusion Glycoprotein Nanoparticle Vaccine in
Susan Krueger1, Joseph E Curtis1, Daniel R Scott2
1NIST Center for Neutron Research, National Institute of Standards and Technology, 100 Bureau Drive, Gaithersburg, Maryland 20899, United States.
Insights
The respiratory syncytial virus (RSV) fusion (F) protein nanoparticle vaccine
Area of Science:
- Structural biology
- Vaccine development
- Nanoparticle characterization
Background:
- The RSV F protein/polysorbate 80 (PS80) nanoparticle vaccine is advanced for maternal immunization.
- Understanding its structure is key to explaining vaccine efficacy.
Purpose of the Study:
- To elucidate the structural basis of the RSV F nanoparticle vaccine's efficacy.
- To characterize the nanoparticle's structure and hydrodynamic properties in solution.
Main Methods:
- Small-angle neutron scattering (SANS) and X-ray scattering (SAXS).
- Transmission electron microscopy (TEM).
- All-atom modeling of RSV F trimers.
Main Results:
- The nanoparticle comprises approximately 350 PS80 molecules forming a core with five RSV F trimers arranged around it.
- Hydrodynamic size is modulated by the PS80 to protein ratio, suggesting a growth mechanism.
- Structural models agree with scattering and TEM data.
Conclusions:
- Provides structural details of antigen presentation in the RSV F nanoparticle vaccine.
- Explains the induction of broad immunity and clinical efficacy.
- Small-angle scattering offers a strategy for characterizing other nanoparticle vaccines.
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.
