Structural and Computational Biology in the Design of Immunogenic Vaccine Antigens

Abstract

Vaccination is historically one of the most important medical interventions for the prevention of infectious disease. Previously, vaccines were typically made of rather crude mixtures of inactivated or attenuated causative agents. However, over the last 10-20 years, several important technological and computational advances have enabled major progress in the discovery and design of potently immunogenic recombinant protein vaccine antigens. Here we discuss three key breakthrough approaches that have potentiated structural and computational vaccine design. Firstly, genomic sciences gave birth to the field of reverse vaccinology, which has enabled the rapid computational identification of potential vaccine antigens. Secondly, major advances in structural biology, experimental epitope mapping, and computational epitope prediction have yielded molecular insights into the immunogenic determinants defining protective antigens, enabling their rational optimization. Thirdly, and most recently, computational approaches have been used to convert this wealth of structural and immunological information into the design of improved vaccine antigens. This review aims to illustrate the growing power of combining sequencing, structural and computational approaches, and we discuss how this may drive the design of novel immunogens suitable for future vaccines urgently needed to increase the global prevention of infectious disease.

Figure 1

A simplified pipeline for a vaccine development project. Contributions from modern, mainly SV approaches are indicated in blue, while red dots indicate steps aided or made possible by computational methods.

Figure 2

Broad coverage chimeric fHbp generated by rational design as described in [21]. The surface of variant 1 fHbp used as a scaffold is shown in brown. The engineered area carrying heterologous epitopes is colored in dark red (residues in common between variant 2 (V2) and variant 3 (V3)) and in green (variant 3-specific residues).

Figure 3

Development of a respiratory syncytial virus (RSV) F scaffold antigen. (a) RSV F Motavizumab epitope is conserved in both pre- and postfusion conformations and a peptide epitope in complex with Motavizumab was shown to have a similar conformation as the epitope in RSV F (PDB ID: 2IXT) [29]. This information was used to design scaffolds presenting the epitope of which the best, MES1 (PDB ID: 3QWO), bound Motavizumab with high affinity but failed to induce protection in mice upon immunization [30] FFL_001 was the first example of a computationally designed scaffold that when used in immunization of macaques induced protection against the virus (PDB ID: 4JLR) [31]. FFL_001 was obtained through a computational de novo epitope scaffold design approach called “Fold From Loops” aimed at faithfully reproducing the epitope with strong immunogenic properties. The epitope on RSV F and the residues responsible for interaction with Motavizumab on the antigen constructs are shown in red. (b) Overlay of the RSV F epitope from prefusion F and the epitope region from FFL_001 illustrates the faithful reproduction of the epitope in FFL_001. Epitope residues important for Motavizumab binding from RSV F are shown in red and the corresponding residues from FFL_001 in gray.