Prevention of Pneumococcal Disease in Mice Immunized with Conserved Surface-Accessible Proteins

Abstract

The development of a vaccine against Streptococcus pneumoniae has been complicated by the existence of at least 90 antigenically distinct capsular serotypes. Common protein-based vaccines could represent the best strategy to prevent pneumococcal infections, regardless of serotype. In the present study, the immunoscreening of an S. pneumoniae genomic library allowed the identification of a novel immune protein target, BVH-3. We demonstrate that immunization of mice with BVH-3 elicits protective immunity against experimental sepsis and pneumonia. Sequence analysis revealed that the bvh-3 gene is highly conserved within the species. Since the BVH-3 protein shows homology at its amino-terminal end with other pneumococcal proteins, it was of interest to determine if protection was due to the homologous or to the protein-specific regions. Immunoprotection studies using recombinant BVH-3 and BVH-3-related protein fragments as antigens allowed the localization of surface-exposed and protective epitopes at the protein-specific carboxyl termini, thus establishing that BVH-3 is distinct from other previously reported protective protein antigens. Immunization with a chimeric protein comprising the carboxyl-terminal regions of BVH-3 and of a BVH-3-related protein improved the protection by targeting two surface pneumococcal components. Thus, BVH-3 and the chimeric protein hold strong promise as vaccine components to control pneumococcal disease.

Transcriptional regulation, occurrence and putative role of the Pht family of Streptococcus pneumoniae

“…Results from antibodylabelling and flow cytometry experiments demonstrated that the Pht proteins are exposed on the surface of the encapsulated bacterium (Hamel et al, 2004), which is in agreement with their relevance as vaccine targets. Based on signature-tagged mutagenesis, it has been suggested that PhtA, PhtB and PhtD are involved in lung-specific virulence (Hava & Camilli, 2002), without further indication about their biological function.…”

“…In a previous study, DNA sequencing of overlapping clones from an S. pneumoniae strain SP64 genomic library (Hamel et al, 2004) and PCR analyses allowed deduction of the genomic organization of the pht genes and their neighbouring genes in this type 6B strain. The phtA and phtB genes, as well as the phtD and phtE genes, were organized as a pair.…”

“…PhtE is a longer protein, the only one with six repeats of the histidine triad motif. In mouse immunization studies, all members of the Pht family have been shown to afford a high level of protection to subsequent pneumococcal challenge with a number of different strains/serotypes Godfroid et al, 2011;Hamel et al, 2004;Ogunniyi et al, 2007;Wizemann et al, 2001;Zhang et al, 2001).…”

“…Among multiple candidates, the Pht protein family, restricted to the genus Streptococcus, is promising, as it is well conserved across pneumococcal species (Hamel et al, 2004;Zhang et al, 2001), and its members are immune targets in infected individuals and protective antigens in immunized mice upon challenge (Beghetto et al, 2006). Originally, this protein family was independently reported by three groups, and three separate denominations were used: Pht (for pneumococcal histidine triad) , Php (for pneumococcal histidine protein) (Zhang et al, 2001) and BVH (Hamel et al, 2004). Those proteins are characterized by a histidine triad motif, HxxHxH, repeated five to six times in their amino acid sequences.…”

Discovery of Immunodominant B Cell Epitopes within Surface Pneumococcal Virulence Proteins in Pediatric Patients with Invasive Pneumococcal Disease

“…Our finding that one of the two 6B isolates displayed an absence of surface binding could be attributed to the known variation in bacterial capsule thickness or to a lower expression of PhtE, PhtD, and CbpD proteins in this particular strain (38,39). Previous reports have demonstrated that surface-accessible epitopes may elicit antibody-mediated protection against pneumococcal disease (21,40,41), underlining the potential of our epitopes for the development of future vaccines. Additional studies evaluating the in vitro opsonophagocytic and in vivo protective efficacy of anti-peptide antibodies are required.…”