Purpose of the Study. To apply comparative genomic techniques for the development of a universally protective group B Streptococcus (GBS) vaccine.
Methods. The genome sequences of 8 GBS strains were compared to identify shared and strain-restricted genes. Computer algorithms were used to identify putative surface or secreted proteins. Candidates were cloned and expressed recombinantly in Escherichia coli. Purified proteins initially alone and then in combination were used to immunize groups of female mice. Immunized animals were then mated, and resulting offspring were challenged at <48 hours of age with virulent GBS. Protection was also correlated with specific antibody binding.
Results. Genomic analysis identified 1811 shared genes representing ∼80% of the genome of each strain. Of these, 589 proteins were predicted to be surface or secreted proteins (396 shared, 193 variable), and 312 of them were successfully expressed as soluble fusion proteins from E coli. Systemic screening of all 312 of these proteins revealed that 4 were capable of significant protection of GBS-challenged offspring of immunized mothers. One of these 4, Sip, was a previously described shared gene, whereas 3 were variably present in the genomes from different strains. As expected, in experiments with single-antigen vaccination, there was no protection when challenged with strains that lack the gene encoding the vaccine protein. However, protection was also variable and even absent in some strains when the gene was known to be present. However, using all 4 antigens in combination, the authors demonstrated protection against a panel of 12 challenge strains representing all 9 major pathogenic GBS serotypes ranging from 59% to 100%.
Conclusions. Multistrain genome analysis and screening represents an effective new approach for the identification of vaccine candidates that single-strain analysis would miss.
Reviewer Comments. Vaccine strategies taking into account the enormous variability at the genomic and proteomic levels that many pathogens have evolved are the best hedge against a mere “arms race” in which temporary vaccine efficacy gives way to the emergence of antigenic variants. This is a novel application of such a rational strategy. However, the extent of the challenge is underscored by the identification of only 4 targets despite a comprehensive approach. Furthermore, 3 of 4 are not part of the “core” conserved genome and are, therefore, likely to be nonessential. It remains unproven whether targeting of so few surface proteins of an encapsulated organism would prove to be a good long-term strategy. Nevertheless, this approach seems likely to be at least complementary to efforts directed to polysaccharides for encapsulated organisms.
- Copyright © 2006 by the American Academy of Pediatrics