title: Multivalent Pneumococcal Protein Vaccines Comprising Pneumolysoid with Epitopes/Fragments of CbpA and/or PspA Elicit Strong and Broad Protection.
abstract: Immunization with the pneumococcal proteins pneumolysin (Ply), choline binding protein A (CbpA), or pneumococcal surface protein A (PspA) elicits protective responses against invasive pneumococcal disease in animal models. In this study, we used different mouse models to test the efficacy of a variety of multivalent protein-based vaccines that comprised various combinations of full-length or peptide regions of the immunogens Ply, CbpA, or PspA: Ply toxoid with the L460D substitution (referred to herein as L460D); L460D fused with protective peptide epitopes from CbpA (YPT-L460D-NEEK [YLN]); L460D fused with the CD2 peptide containing the proline-rich region (PRR) of PspA (CD2-L460D); a combination of L460D and H70 (L460D+H70), a slightly larger PspA-derived peptide containing the PRR and the SM1 region; H70+YLN; and other combinations. Each mouse was immunized either intraperitoneally (i.p.) or subcutaneously (s.c.) with three doses (at 2-week intervals) of the various antigen combinations in alum adjuvant and then challenged in mouse models featuring different infection routes with multiple Streptococcus pneumoniae strains. In the i.p. infection sepsis model, H70+YLN consistently provided significant protection against three different challenge strains (serotypes 1, 2, and 6A); the CD2+YLN and H70+L460D combinations also elicited significant protection. Protection against intravenous (i.v.) sepsis (type 3 and 6A challenge strains) was largely dependent on PspA-derived antigen components, and the most protection was elicited by H70 with or without L460D or YLN. In a type 4 intratracheal (i.t.) challenge model that results in progression to meningitis, antigen combinations that contained YLN elicited the strongest protection. Thus, the trivalent antigen combination of H70+YLN elicited the strongest and broadest protection in diverse pneumococcal challenge models.
authors.affiliation: Research Centre for Infectious Diseases, Department of Molecular and Cellular Biology, University of Adelaide, South Australia, Australia.
authors.forename: Austen
authors.initials: A
authors.lastname: Chen
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Mann
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Geli
authors.initials: G
authors.lastname: Gao
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Heath
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: King
authors.affiliation: PATH, Seattle, Washington, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Maissoneuve
authors.affiliation: PATH, Seattle, Washington, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Alderson
authors.affiliation: PATH, Seattle, Washington, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tate
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Hollingshead
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Rodney K
authors.initials: RK
authors.lastname: Tweten
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Briles
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Elaine I
authors.initials: EI
authors.lastname: Tuomanen
authors.affiliation: Research Centre for Infectious Diseases, Department of Molecular and Cellular Biology, University of Adelaide, South Australia, Australia james.paton@adelaide.edu.au.
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D007115:Immunization Schedule; D007074:Immunoglobulin G / Q000097:blood; D008586:Meningitis, Pneumococcal / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D008807:Mice, Inbred BALB C; D011008:Pneumococcal Infections / Q000276:immunology / Q000517:prevention & control*; D022242:Pneumococcal Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D011018:Pneumonia, Pneumococcal / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D018805:Sepsis / Q000382:microbiology / Q000517:prevention & control*; D013296:Streptococcus pneumoniae / Q000145:classification / Q000276:immunology*; D013301:Streptolysins / Q000276:immunology*; D014121:Toxoids / Q000276:immunology; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; C490083:CbpA protein, bacteria; D000939:Epitopes; D007074:Immunoglobulin G; D022242:Pneumococcal Vaccines; D011993:Recombinant Fusion Proteins; D013301:Streptolysins; D014121:Toxoids; D014614:Vaccines, Synthetic; C032290:plY protein, Streptococcus pneumoniae; C051592:pneumococcal surface protein A