Coping with genetic diversity: the contribution of pathogen and human genomics to modern vaccinology

Lemaire, D.; Barbosa, T.; Rihet, P.

The impact of in silico analysis on vaccine development can be exemplified by the first study published using this approach (8) . A capsular polysaccharide-based vaccine against Neisseria meningitidis serogroups A, C, W135, and Y is available, but not against serogroup B as its structure is identical to the polysialic acid structure present on human cells (3) . The entire genome sequence of a virulent N. meningitidis serogroup B strain, which accounts for the majority of meningococcal disease burden in the United States and Europe (9) , was analyzed to identify candidates for a new vaccine. The bacterial genome was screened using bioinformatics tools to identify relatively conserved, surface-exposed outer membrane protein antigens: 570 of 2158 open reading frames (ORFs) were thus selected. Immunoproteomics methods were then used to select the most immunogenic meningococcal antigens that would elicit a protective immunity. Five of 28 genome-derived candidate antigens are components of a rationally designed vaccine against N. meningitidis serogroup B (10) and a formulation of four of these antigens (4CMenB, Novartis, Switzerland) has induced high titers of bactericidal antibodies in a phase I/II clinical trial (11) . The multivalent vaccine formulation has been proposed to overcome the issue of antigenic diversity between strains of N. meningitidis, and it would be expected to stimulate immune responses capable of recognizing multiple antigenic variants. The promising results of this new vaccine candidate may be the critical "proof of concept" stage for this novel approach that has significantly shifted the paradigm of vaccine development from microbiological to sequence-based approaches.