Reverse vaccinology: developing vaccines in the era of genomics

Abstract

The sequence of microbial genomes made all potential antigens of each pathogen available for vaccine development. This increased by orders of magnitude potential vaccine targets in bacteria, parasites, and large viruses and revealed virtually all their CD4(+) and CD8(+) T cell epitopes. The genomic information was first used for the development of a vaccine against serogroup B meningococcus, and it is now being used for several other bacterial vaccines. In this review, we will first summarize the impact that genome sequencing has had on vaccine development, and then we will analyze how the genomic information can help further our understanding of immunity to infection or vaccination and lead to the design of better vaccines by diving into the world of T cell immunity.

Figure 1. Schematic Diagram Summarizing the Pathway of Vaccine Development Starting from Reverse Vaccinology

(1) First, computer analysis of the whole genome identifies the genes coding for predicted antigens and eliminates antigens with homologies to human proteins. (2) Then the identified antigens are screened for expression by the pathogen and for immunogenicity during infection. (3) The selected antigens are then used to immunize animals and test whether immunization induces a protective response. (4) Protective antigens are then tested for their presence and conservation in a collection of strains representative of the species (molecular epidemiology). (5) Finally, selected antigens are manufactured in large scale for clinical trials, and candidate vaccines are tested for safety and protective immunity in humans using established correlates of protection or efficacy studies. (6) Scientific, clinical, and technical information is then analyzed and approved by regulatory agencies, such as the Food and Drug Administration (FDA) or the European Medicinal Agency (EMA). (7) Policy-making bodies, such as the ACIP and equivalent bodies from other nations, make the recommendation on how the vaccine should be used. (8) The approved vaccine is then commercialized and used in large scale. At this point, phase IV clinical studies confirm safety.