title: Discovery of a novel class of highly conserved vaccine antigens using genomic scale antigenic fingerprinting of pneumococcus with human antibodies.
abstract: Pneumococcus is one of the most important human pathogens that causes life-threatening invasive diseases, especially at the extremities of age. Capsular polysaccharides (CPSs) are known to induce protective antibodies; however, it is not feasible to develop CPS-based vaccines that cover all of the 90 disease-causing serotypes. We applied a genomic approach and described the antibody repertoire for pneumococcal proteins using display libraries expressing 15-150 amino acid fragments of the pathogen's proteome. Serum antibodies of exposed, but not infected, individuals and convalescing patients identified the ANTIGENome of pneumococcus consisting of approximately 140 antigens, many of them surface exposed. Based on several in vitro assays, 18 novel candidates were preselected for animal studies, and 4 of them showed significant protection against lethal sepsis. Two lead vaccine candidates, protein required for cell wall separation of group B streptococcus (PcsB) and serine/threonine protein kinase (StkP), were found to be exceptionally conserved among clinical isolates (>99.5% identity) and cross-protective against four different serotypes in lethal sepsis and pneumonia models, and have important nonredundant functions in bacterial multiplication based on gene deletion studies. We describe for the first time opsonophagocytic killing activity for pneumococcal protein antigens. A vaccine containing PcsB and StkP is intended for the prevention of infections caused by all serotypes of pneumococcus in the elderly and in children.
authors.affiliation: Intercell AG, 1030 Vienna, Austria.
authors.forename: Carmen
authors.initials: C
authors.lastname: Giefing
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Meinke
authors.forename: Markus
authors.initials: M
authors.lastname: Hanner
authors.forename: Tamás
authors.initials: T
authors.lastname: Henics
authors.forename: Minh Duc
authors.initials: MD
authors.lastname: Bui
authors.forename: Dieter
authors.initials: D
authors.lastname: Gelbmann
authors.forename: Urban
authors.initials: U
authors.lastname: Lundberg
authors.forename: Beatrice M
authors.initials: BM
authors.lastname: Senn
authors.forename: Michael
authors.initials: M
authors.lastname: Schunn
authors.forename: Andre
authors.initials: A
authors.lastname: Habel
authors.forename: Birgitta
authors.initials: B
authors.lastname: Henriques-Normark
authors.forename: Ake
authors.initials: A
authors.lastname: Ortqvist
authors.forename: Mats
authors.initials: M
authors.lastname: Kalin
authors.forename: Alexander
authors.initials: A
authors.lastname: von Gabain
authors.forename: Eszter
authors.initials: E
authors.lastname: Nagy
mesh_terms: D000328:Adult; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D000906:Antibodies; D000942:Antigens, Bacterial / Q000737:chemistry; D002648:Child; D000939:Epitopes / Q000737:chemistry; D006801:Humans; D007070:Immunoglobulin A / Q000737:chemistry; D007074:Immunoglobulin G / Q000737:chemistry; D051379:Mice; D008875:Middle Aged; D011008:Pneumococcal Infections / Q000517:prevention & control*; D022242:Pneumococcal Vaccines / Q000737:chemistry*; D011134:Polysaccharides / Q000737:chemistry; D013296:Streptococcus pneumoniae / Q000235:genetics* / Q000276:immunology*
chemical_list: D000596:Amino Acids; D000906:Antibodies; D000942:Antigens, Bacterial; D000939:Epitopes; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D022242:Pneumococcal Vaccines; D011134:Polysaccharides