title: A semisyntheticStreptococcus pneumoniaeserotype 8 glycoconjugate vaccine.
abstract: Glycoconjugate vaccines based on capsular polysaccharides (CPSs) of pathogenic bacteria such asStreptococcus pneumoniaesuccessfully protect from disease but suffer from incomplete coverage, are troublesome to manufacture from isolated CPSs, and lack efficacy against certain serotypes. Defined, synthetic oligosaccharides are an attractive alternative to isolated CPSs but require the identification of immunogenic and protective oligosaccharide antigens. We describe a medicinal chemistry strategy based on a combination of automated glycan assembly (AGA), glycan microarray-based monoclonal antibody (mAb) reverse engineering, and immunological evaluation in vivo to uncover a protective glycan epitope (glycotope) forS. pneumoniaeserotype 8 (ST8). All four tetrasaccharide frameshifts of ST8 CPS were prepared by AGA and used in glycan microarray experiments to identify the glycotopes recognized by antibodies against ST8. One tetrasaccharide frameshift that was preferentially recognized by a protective, CPS-directed mAb was conjugated to the carrier protein CRM197. Immunization of mice with this semisynthetic glycoconjugate followed by generation and characterization of a protective mAb identified protective and nonprotective glycotopes. Immunization of rabbits with semisynthetic ST8 glycoconjugates containing protective glycotopes induced an antibacterial immune response. Coformulation of ST8 glycoconjugates with the marketed 13-valent glycoconjugate vaccine Prevnar 13 yielded a potent 14-valentS. pneumoniaevaccine. Our strategy presents a facile approach to develop efficient semisynthetic glycoconjugate vaccines.
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany.|Freie Universität Berlin, Arnimallee 22, 14195 Berlin, Germany.
authors.forename: Benjamin
authors.identifier: 0000-0001-5504-0147
authors.initials: B
authors.lastname: Schumann
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany.|Freie Universität Berlin, Arnimallee 22, 14195 Berlin, Germany.
authors.forename: Heung Sik
authors.identifier: 0000-0003-2326-7923
authors.initials: HS
authors.lastname: Hahm
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany.
authors.forename: Sharavathi G
authors.identifier: 0000-0003-2785-6063
authors.initials: SG
authors.lastname: Parameswarappa
authors.affiliation: Division of Pulmonary Inflammation, Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Reppe
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany.
authors.forename: Annette
authors.identifier: 0000-0002-0739-0748
authors.initials: A
authors.lastname: Wahlbrink
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany.
authors.forename: Subramanian
authors.identifier: 0000-0002-8536-756X
authors.initials: S
authors.lastname: Govindan
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany.|Freie Universität Berlin, Arnimallee 22, 14195 Berlin, Germany.
authors.forename: Paulina
authors.identifier: 0000-0001-9459-5946
authors.initials: P
authors.lastname: Kaplonek
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Montefiore Medical Center and Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Liise-Anne
authors.initials: LA
authors.lastname: Pirofski
authors.affiliation: Division of Pulmonary Inflammation, Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Martin
authors.identifier: 0000-0002-9787-5633
authors.initials: M
authors.lastname: Witzenrath
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany.
authors.forename: Chakkumkal
authors.initials: C
authors.lastname: Anish
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany. peter.seeberger@mpikg.mpg.de claneylebev.pereira@vaxxilon.com.
authors.forename: Claney L
authors.identifier: 0000-0003-1972-7907
authors.initials: CL
authors.lastname: Pereira
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany. peter.seeberger@mpikg.mpg.de claneylebev.pereira@vaxxilon.com.|Freie Universität Berlin, Arnimallee 22, 14195 Berlin, Germany.
authors.forename: Peter H
authors.identifier: 0000-0003-3394-8466
authors.initials: PH
authors.lastname: Seeberger
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000907:Antibodies, Bacterial / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D016667:Bacterial Capsules / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D006001:Glycoconjugates / Q000737:chemistry / Q000276:immunology*; D054794:Glycomics; D018922:HL-60 Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022242:Pneumococcal Vaccines / Q000276:immunology*; D011134:Polysaccharides / Q000378:metabolism; D011817:Rabbits; D065288:Serogroup; D013296:Streptococcus pneumoniae / Q000276:immunology*; D018074:Vaccines, Conjugate / Q000276:immunology*
chemical_list: C538862:13-valent pneumococcal vaccine; D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D006001:Glycoconjugates; D022242:Pneumococcal Vaccines; D011134:Polysaccharides; D018074:Vaccines, Conjugate