Principles and practical applications of structure-based vaccine design

Abstract

Viral proteins fold into a variety of structures as they perform their functions. Structure-based vaccine design aims to exploit knowledge of an antigen's architecture to stabilize it in a vulnerable conformation. We summarize the general principles of structure-based vaccine design, with a focus on the major types of sequence modifications: proline, disulfide, cavity-filling, electrostatic and hydrogen-bond substitution, as well as domain deletion. We then review recent applications of these principles to vaccine-design efforts across five viral families: Coronaviridae, Orthomyxoviridae, Paramyxoviridae, Pneumoviridae, and Filoviridae. Outstanding challenges include continued application of proven design principles to pathogens of interest, as well as development of new strategies for those pathogens that resist traditional techniques.

Figure 1

Examples of stabilizing amino acid substitutions. Each panel shows structural models representing one type of amino acid substitution. Source references are listed within each panel. Proline: prefusion (pale rainbow) and postfusion (bright rainbow) SARS-CoV-2 S, colored from N-terminal (blue) to C-terminal (red). The inset shows a zoomed view of the K986P and V987P substitutions. Disulfide: prefusion influenza HA. Domains HA1 and HA2 are colored blue and cyan, respectively. The inset shows a zoomed view of the cysteine substitutions at positions 30 and 47, which covalently bond HA1 to HA2. Cavity-filling: prefusion RSV F (pink) with a S190F mutation. The experimental electron-density map (2Fo–Fc) is shown as transparent gray contours. Electrostatic: HIV-1 Env. Individual chains are shown as shades of yellow. Hydrogen bond: prefusion RSV F. A substitution near the C-terminus of the ectodomain forms a ring of hydrogen bonds, which are indicated as cyan dashed lines. Individual RSV F protomers are colored in shades of orange and red.