Developing vaccines in the era of genomics: a decade of reverse vaccinology.

Vaccines have a significant impact on public health, and vaccinology in the era of genomics is taking advantage of new technologies to tackle diseases for which vaccine development has so far been unsuccessful. Almost all existing vaccines were developed based on traditional vaccinology methods, which relied on empirical screening of a few candidates at a time, based on known features of the pathogen. However, the ability to sequence a pathogen's genome provides access to its entire antigenic repertoire. As such, genomics has catalysed a shift in vaccine development towards sequence-based 'Reverse Vaccinology' approaches, which use high-throughput in silico screening of the entire genome of a pathogen to identify genes that encode proteins with the attributes of good vaccine targets. Furthermore, the increasing availability of genome sequences has led to the development and application of additional technologies to vaccine discovery, including comparative genomics, transcriptomics, proteomics, immunomics and structural genomics. Vaccine candidates identified from a pathogen's genome or proteome can then be expressed as recombinant proteins and tested in appropriate in vitro or in vivo models to assess immunogenicity and protection. The process of reverse vaccinology has been applied to several pathogens, including serogroup B Neisseria meningitidis, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus pneumoniae and pathogenic Escherichia coli, and has provided scores of new candidate antigens for preclinical and clinical investigation. As novel genome-based technologies continue to emerge, it is expected that new vaccines for unmet diseases will be within reach.

Factor H-binding protein is important for meningococcal survival in human whole blood and serum and in the presence of the antimicrobial peptide LL-37.

Factor H-binding protein (fHBP; GNA1870) is one of the antigens of the recombinant vaccine against serogroup B Neisseria meningitidis, which has been developed using reverse vaccinology and is the basis of a meningococcal B vaccine entering phase III clinical trials. Binding of factor H (fH), an inhibitor of the complement alternative pathway, to fHBP enables N. meningitidis to evade killing by the innate immune system. All fHBP null mutant strains analyzed were sensitive to killing in ex vivo human whole blood and serum models of meningococcal bacteremia with respect to the isogenic wild-type strains. The fHBP mutant strains of MC58 and BZ83 (high fHBP expressors) survived in human blood and serum for less than 60 min (decrease of >2 log(10) CFU), while NZ98/254 (intermediate fHBP expressor) and 67/00 (low fHBP expressor) showed decreases of >1 log(10) CFU after 60 to 120 min of incubation. In addition, fHBP is important for survival in the presence of the antimicrobial peptide LL-37 (decrease of >3 log(10) CFU after 2 h of incubation), most likely due to electrostatic interactions between fHBP and the cationic LL-37 molecule. Hence, the expression of fHBP by N. meningitidis strains is important for survival in human blood and human serum and in the presence of LL-37, even at low levels. The functional significance of fHBP in mediating resistance to the human immune response, in addition to its widespread distribution and its ability to induce bactericidal antibodies, indicates that it is an important component of the serogroup B meningococcal vaccine.