title: Mutant lipooligosaccharide-based conjugate vaccine demonstrates a broad-spectrum effectiveness against Moraxella catarrhalis.
abstract: There is no licensed vaccine available against Moraxella catarrhalis, an exclusive human pathogen responsible for otitis media in children and respiratory infections in adults. We previously developed conjugate vaccine candidates based on lipooligosaccharides (LOSs) of M. catarrhalis serotypes A, B, and C, each of which was shown to cover a portion of the clinical strains. To generate conserved LOS antigens and eliminate a potential autoimmune response to a similar epitope between M. catarrhalis LOS moiety Galα1-4Galβ1-4Glc and human P(k) antigen, two LOS mutants from strain O35E were constructed. Mutant O35Elgt5 or O35EgalE revealed a deletion of one or two terminal galactose residues of wild type O35E LOS. Each LOS molecule was purified, characterized, detoxified, and coupled to tetanus toxoid (TT) to form conjugates, namely dLOS-TT. Three subcutaneous immunizations using dLOS-TT from O35Elgt5 or O35EgalE elicited significant increases (a 729- or 1263-fold above the preimmune serum levels) of serum immunoglobulin (Ig)G against O35E LOS in rabbits with an adjuvant or without an adjuvant (an 140- or 140-fold above the preimmune serum levels). Rabbit antisera demonstrated elevated complement-mediated bactericidal activities against the wild type strain O35E. The rabbit sera elicited by O35Elgt5 dLOS-TT were further examined and showed cross bactericidal activity against all additional 19 M. catarrhalis strains and clinical isolates studied. Moreover, the rabbit sera displayed cross-reactivity not only among three serotype strains but also clinical isolates in a whole-cell enzyme-linked immunosorbent assay (ELISA), which was further confirmed under transmission electron microscopy. In conclusion, O35Elgt5 dLOS-TT may act as a vaccine against most M. catarrhalis strains and therefore can be used for further in vivo efficacy studies.
authors.affiliation: Vaccine Research Section, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Rockville, MD 20850, USA.
authors.forename: Dabin
authors.initials: D
authors.lastname: Ren
authors.forename: Shengqing
authors.initials: S
authors.lastname: Yu
authors.forename: Song
authors.initials: S
authors.lastname: Gao
authors.forename: Daxin
authors.initials: D
authors.lastname: Peng
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Petralia
authors.forename: Artur
authors.initials: A
authors.lastname: Muszynski
authors.forename: Russell W
authors.initials: RW
authors.lastname: Carlson
authors.forename: John B
authors.initials: JB
authors.lastname: Robbins
authors.forename: Chao-Ming
authors.initials: CM
authors.lastname: Tsai
authors.forename: David J
authors.initials: DJ
authors.lastname: Lim
authors.forename: Xin-Xing
authors.initials: XX
authors.lastname: Gu
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D001770:Blood Bactericidal Activity; D003165:Complement System Proteins / Q000276:immunology; D003429:Cross Reactions; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007117:Immunization, Secondary / Q000379:methods; D007074:Immunoglobulin G / Q000097:blood; D007279:Injections, Subcutaneous; D008070:Lipopolysaccharides / Q000235:genetics / Q000276:immunology*; D001936:Moraxella catarrhalis / Q000235:genetics / Q000276:immunology*; D045828:Moraxellaceae Infections / Q000276:immunology / Q000517:prevention & control*; D011817:Rabbits; D013745:Tetanus Toxoid / Q000008:administration & dosage / Q000276:immunology; D014611:Vaccination / Q000379:methods; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D001428:Bacterial Vaccines; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D013745:Tetanus Toxoid; D018074:Vaccines, Conjugate; C023023:lipid-linked oligosaccharides; D003165:Complement System Proteins