Structure-based antigen design: a strategy for next generation vaccines

Abstract

Vaccine design is progressing from empiricism towards the increasingly rational presentation of the targets of protective immunity. Nevertheless, most current vaccine antigens are essentially the native macromolecules of pathogens. These molecules are adapted to evade, not induce, immunity. High resolution structures reveal the electrostatic surfaces recognized by neutralizing antibodies and the architectures underlying these surfaces, thereby identifying which substructures must be left intact and which can be changed to optimize biochemical and immunologic performance. Armed with detailed structural information, we can engineer optimized antigens that are more stable, homogeneous, and efficiently produced, making immunization more practical and affordable. Understanding the structural basis for immunogenicity and immunodominance will allow us to improve vaccine efficacy and broaden the range of vaccine-preventable diseases.

Figure 1

Flow chart of the structural vaccinology approach.

Figure 2

Parainfluenza virus fusion protein rearrangements. The F glycoprotein is a major target of antibodies that neutralize parainfluenza viruses. (a) Pre-fusion F. (b) Post-fusion F. During the rearrangement, a coiled-coil tipped by the fusion peptide extends from the purple domain, and the helices that make up the pre-fusion coiled-coil separate and pack between the new extension to form a six-helix bundle. This rearrangement brings the cellular and viral membranes into close apposition and extensively alters the solvent exposed surface of F. Red indicates the fusion peptide. The other colors indicate structural domains. The drawing is based on structures presented in and .

Figure 3

Rotavirus spike protein VP4 rearrangements. VP4 is made up of discrete, compactly folded domains that undergo rearrangements during membrane penetration. The trimeric molecule is thought to progress from an initial state in which all three subunits are flexible (not shown); to (a), a primed state in which two subunits are rigid and the third remains flexible; and then to (b), a folded back state. The grey receptor binding head and the green and red antigen domain contain all known neutralizing epitopes on VP4. The red patch depicts the hydrophobic apex of the antigen domain, which is thought to interact with host membranes to effect entry. Motions and alternative packings of flexible elements, such as the cyan foot and stalk domains, drive the rearrangements of the rigid domains. Produced by Digizyme, Inc. and originally published in .