From the point of view of the pathogen (starting at the lower left-hand corner and moving in a clockwise direction), vaccine candidates can be identified by analysis of the organism’s genome and/or pan-genome (the complete genetic content of the organism/species, which contains the complete repertoire of antigens that an organism/species is capable of expressing), transcriptome (the complete set of RNA transcripts expressed by an organism under a specified condition), proteome (the complete set of proteins expressed by an organism under a specified condition), surface proteome (the subset of proteins that are surface exposed), or structural genome (the 3D structure of the proteins of an organism, in particular the structural epitopes of immunogenic antigens). With respect to interactions between the pathogen and the host immune system, vaccine candidates can also be identified by analysis of the organism’s immunoproteome (the set of antigens that interact with the host immune system). The newer field of vaccinomics (the way in which individual host immune systems respond to a vaccine) will also aid in future vaccine development.

(A) Most licensed vaccines target pathogens that have low antigenic variability and pathogens for which protection depends on antibody-mediated immunity. These vaccines have typically been developed using conventional vaccinology. (B) Several pathogens are shown for which no vaccine is available, due to either their high antigenic variability and/or the need to induce T cell–dependent immunity to elicit protection. New approaches are being applied to vaccine development for these pathogens in the genome era. Vaccines/diseases shown in the figure are selected examples of each category and are not a complete list. TB, M. tuberculosis.

Preclinical development was based on a reverse vaccinology approach, in which the genome sequence of the virulent MenB strain MC58 was used to identify ORFs predicted to encode proteins that were surface exposed (i.e., secreted [S] or located in the outer membrane [OM]), which were then expressed in E. coli, purified, and used to immunize mice. Antibodies generated in mice were then used to confirm surface exposure of the vaccine candidate by FACS and to identify proteins that induced bactericidal activity. This screening process resulted in identification of several novel vaccine candidates, including GNA1870 (which is fHBP), GNA1994 (which is NadA), GNA2132, GNA1030, and GNA2091. The formulation for the comprehensive MenB vaccine consists of four components: fHBP-GNA2091 and GNA2132-GNA1030 fusion proteins, NadA, and OMV from the New Zealand MeNZB vaccine strain. Clinical development using this formulation has shown in phase I and II trials that the vaccine is well tolerated and immunogenic. The vaccine induced bactericidal activity using human complement (hSBA) with titers greater than 1:4, which indicates the generation of antibodies able to kill the bacteria at a level that correlates with protection against the bacteria, in more than 90% of infants after the fourth dose. This vaccine entered phase III clinical trials in 2008. P, periplasm; IM, inner membrane; C, cytoplasm.