title: Structure-guided antigen engineering yields pneumolysin mutants suitable for vaccination against pneumococcal disease.
abstract: Pneumolysin (PLY) is a cholesterol-binding, pore-forming protein toxin. It is an important virulence factor of Streptococcus pneumoniae and a key vaccine target against pneumococcal disease. We report a systematic structure-driven approach that solves a long-standing problem for vaccine development in this field: detoxification of PLY with retention of its antigenic integrity. Using three conformational restraint techniques, we rationally designed variants of PLY that lack hemolytic activity and yet induce neutralizing antibodies against the wild-type toxin. These results represent a key milestone toward a broad-spectrum protein-based pneumococcal vaccine and illustrate the value of structural knowledge in formulating effective strategies for antigen optimization.
authors.affiliation: sanofi pasteur, Toronto, Ontario M2R 3T4, Canada. eliud.oloo@sanofipasteur.com
authors.forename: Eliud O
authors.initials: EO
authors.lastname: Oloo
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Yethon
authors.forename: Martina M
authors.initials: MM
authors.lastname: Ochs
authors.forename: Bruce
authors.initials: B
authors.lastname: Carpick
authors.forename: Raymond
authors.initials: R
authors.lastname: Oomen
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial; D001426:Bacterial Proteins / Q000009:adverse effects / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002152:Calorimetry, Differential Scanning; D002478:Cells, Cultured; D002942:Circular Dichroism; D006461:Hemolysis / Q000187:drug effects; D016297:Mutagenesis, Site-Directed; D011008:Pneumococcal Infections / Q000276:immunology* / Q000517:prevention & control*; D022242:Pneumococcal Vaccines / Q000276:immunology*; D017433:Protein Structure, Secondary; D012756:Sheep; D013301:Streptolysins / Q000009:adverse effects / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D022242:Pneumococcal Vaccines; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae