A genomics-based approach to biodefence preparedness

Abstract

The anthrax letter attacks in October 2001, followed by the SARS outbreak in early 2003, dramatically illustrated our vulnerability to both deliberate and natural outbreaks of infectious disease. The availability of pathogen genome sequences and high-throughput methods for studying the biology of both pathogens and their hosts have provided new insights into the mechanisms of pathogenesis and host defence. As infectious disease research expands to include major bioterror agents, genomics-based approaches will provide one of the cornerstones of efforts to develop more accurate diagnostics, new therapeutics and vaccines, and further capabilities for microbial forensics.

Figure 1. Reverse vaccinology: a genomics-enabled approach to vaccine development.

The reverse vaccinology strategy was first successfully used in the search for vaccine candidates against serogroup B Neisseria meningitidis (MenB). The first step in this process is the completion of the genome sequence of the pathogen of interest. In the case of MenB, this took approximately 18 months from the time when it was undertaken in 1998–1999. Today, the complete genome sequence of a pathogen can be obtained in a matter of days to weeks. Several algorithms are used to identify putative cell-surface or secreted proteins that could potentially elicit antibody responses in a human host. For MenB, 570 potential vaccine candidates were identified by bioinformatics approaches. The next step in the process was to produce recombinant proteins in Escherichia coli; approximately 350 proteins were expressed at high levels, purified and used as immunogens in mice. Immune sera were collected and assayed for their ability to bind to the surface of MenB cells and for their bactericidal activity in vitro. Seven proteins had high titres in all of the assays that were carried out and were taken into the final stage of evaluation, which assessed the extent of protein sequence variability in these proteins across large numbers of MenB isolates. From this large-scale screening process, two new vaccine candidates emerged that met all of the criteria. These vaccine candidates are now in Phase I clinical trials. Modified with permission from Ref. © Macmillan Magazines Ltd (2000).