Reverse vaccinology 2.0: Human immunology instructs vaccine antigen design

Abstract

Traditionally, vaccines have been developed by cultivating infectious agents and isolating the inactivated whole pathogen or some of its purified components. 20 years ago, reverse vaccinology enabled vaccine discovery and design based on information deriving from the sequence of microbial genomes rather than via the growth of pathogens. Today, the high throughput discovery of protective human antibodies, sequencing of the B cell repertoire, and the increasing structural characterization of protective antigens and epitopes provide the molecular and mechanistic understanding to drive the discovery of novel vaccines that were previously impossible. We are entering a "reverse vaccinology 2.0" era.

Figure 1.

Interplay of B cell technology and structural biology in vaccine design. Beginning at center left, a flow path representation of how human B cell repertoire analyses enable the identification of protective Abs from vaccinated or infected subjects. (Top inset) Single B cell sorting and culturing in the presence of feeder cells allow direct screening and selection of naturally produced Abs with desired functionality and recovery of the corresponding Ig gene sequence. This approach is one of the most recent that allows for the interrogation of single-sorted B cells through direct screening of Ab functionality. In turn, repertoire analyses to understand the origin and evolution of the Abs of interest can be performed (Huang et al., 2013). Starting from the recovered sequences, further expression of the recombinant Abs of interest in the most appropriate system allows for a fine-tuned characterization of their properties. (Center right) Structural characterization of such Abs bound to their target antigen (Ag) allows for the detailed definition of the protective epitope. A molecular detail of an antigen–Ab (Fab) complex as revealed by a cocrystal structure identifying a protective epitope is represented as an example. The protective epitope (red shape) can then be engineered for presentation as an optimized immunogen in a novel format (for example, by mounting the epitope in an oriented multicopy array on a nanoparticle [orange octagon], because nanoparticles can increase an epitope-focused immune response; López-Sagaseta et al., 2016). (Bottom inset) The new antigen can be developed with the best formulation or delivery system to then be tested in humans. The figure was inspired by Fig. 3 from an earlier paper (Burton, 2002).