Structural Vaccinology for Viral Vaccine Design

Abstract

Although vaccines have proven pivotal against arrays of infectious viral diseases, there are still no effective vaccines against many viruses. New structural insights into the viral envelope, protein conformation, and antigenic epitopes can guide the design of novel vaccines against challenging viruses such as human immunodeficiency virus (HIV), hepatitis C virus, enterovirus A71, and dengue virus. Recent studies demonstrated that applications of this structural information can solve some of the vaccine conundrums. This review focuses on recent advances in structure-based vaccine design, or structural vaccinology, for novel and innovative viral vaccine design.

Keywords: epitope; protein structure; structural vaccinology; vaccine design; virus.

FIGURE 1

Structural vaccinology for vaccine design. (A) Basic methods and tools for structural vaccinology. (B) Irreversible conformational change (immunogenic to non-immunogenic) of viral antigens occurred spontaneously during recombinant antigen expression. To overcome this problem, the three-dimensional structure of the antigen (II) will be determined using structural biology techniques such as X-ray crystallography, cryo-electron microscopy (cryo-EM), and nuclear magnetic resonance (NMR). Based on the structure, the antigen will be re-engineered to produce an optimal antigen adopting a specific immunogenic conformation (I). Next, the re-engineered antigen could be incorporated into one of the vaccine platforms such as the recombinant protein vaccine platform. Thereafter, the safety and efficacy of the candidate vaccine should be tested in animal models. The antigen could be re-designed based on the animal testing evaluations to improve its immunogenicity and efficacy. RSV F glycoprotein was used as an illustrative example. PDB IDs: 4MMU and 3RKI.

FIGURE 2

Targeting the prefusion F glycoprotein of respiratory syncytial virus (RSV). (A) Surface representation of the DS-Cav1 F glycoprotein variant (PDB ID: 4MMU). DS-Cav1 adopted the prefusion F glycoprotein conformation. The antigenic site ø is shown in black. (B) Surface representation of the trimeric postfusion F glycoprotein (PDB ID: 3RKI). The disrupted antigenic site ø caused by structural rearrangement from the prefusion to postfusion F is shown in black.

FIGURE 3

Resurfaced domain III of the envelope glycoprotein. Cartoon representation of domain III of DENV2 envelope glycoprotein. The residues in the FG loop and AB loop that were mutated in the rsDIII-Ala30 are shown as spheres and labeled. PDB ID: 1OAN.

FIGURE 4

VP1 of EV-A71 and CV-A16. (A,B) Cartoon representation of VP1 (amino acids 76–276) of EV-A71 (PDB ID: 3VBS) and CV-A16 (PDB ID: 5C4W). The BC loop and SP70 region are shown in black and labeled. (C) Sequence alignment of SP70 segments of EV-A71 and CV-A16. Amino acids that are not conserved between the two viruses are highlighted in light gray.