Vaccines, reverse vaccinology, and bacterial pathogenesis

Abstract

Advances in genomics and innovative strategies such as reverse vaccinology have changed the concepts and approaches to vaccine candidate selection and design. Genome mining and blind selection of novel antigens provide a novel route to investigate the mechanisms that underpin pathogenesis. The resulting lists of novel candidates are revealing new aspects of pathogenesis of target organisms, which in turn drives the rational design of optimal vaccine antigens. Here we use the discovery, characterization, and exploitation of fHbp, a vaccine candidate and key virulence factor of meningococcus, as an illustrative case in point. Applying genomic approaches to study both the pathogen and host will ultimately increase our fundamental understanding of pathogen biology, mechanisms responsible for the development of protective immunity, and guide next-generation vaccine design.

Figure 1.

Interactions between microbial pathogenesis and vaccine development. Historically, the understanding of microbial mechanisms of pathogenesis have driven vaccine development, with empirical vaccinology approaches being based on inactivating, attenuating, and/or targeting and interrupting the function of virulence factors, such as capsule polysaccharides, toxins, and other surface proteins. However, with new technologies and vaccine approaches, the focus has shifted to functionally blind antigen discovery based on high-throughput screening of the pathogen’s genome and proteome. These approaches have identified many promising vaccine candidates, which have subsequently been found to be involved in the pathogenic process, such as colonization of the host or serum resistance.

Figure 2.

The meningococcal fHbp antigen as an example of how vaccine development has led to an increased understanding of pathogenesis. Genome-derived Neisseria antigen 1870 (GNA1870) was identified as a novel vaccine antigen from the genome sequence of N. meningitidis by reverse vaccinology. Since then it has been studied extensively for vaccine development (top panel) in terms of its distribution and sequence variation, as well as its ability to induce cross-protective bactericidal antibodies. This information has also been used to engineer meningococcal strains overexpressing fHbp for outer membrane vesicle (OMV) vaccines. In addition, structural studies have been used for epitope mapping and the generation of a chimeric fHbp antigen that is able to induce broad cross protection. Parallel to this work, the understanding of meningococcal pathogenesis has greatly advanced by studying this antigen (bottom panel). GNA1870 was renamed as factor H-binding protein (fHbp) owing to the discovery of its functional role in binding human factor H (fH), which increases serum resistance. This role has also led to increased understanding of meningococcal host specificity and the development of transgenic mice models expressing human fH. Furthermore, human fH alleles have been identified that increase host susceptibility to meningococcal disease.

Figure 3.

Key areas of next-generation vaccine development. High-throughput (HTP) DNA sequencing and screening technologies are leading to a better understanding of the genetic variation of both pathogens and the human host, which in turn is improving the fundamental understanding of the pathogen and the immune response, respectively. This information can be exploited to enable identification of protective antigens from the pathogen as well as the signatures in the host immune response that lead to protection. These two parallel fields of vaccinology, combined with improving vaccine formulation and delivery technologies, are key components of next-generation vaccine development.