title: Immunoactivity of protein conjugates of carba analogues from Neisseria meningitidis a capsular polysaccharide.
abstract: Neisseria meningitidis type A (MenA) is a Gram-negative encapsulated bacterium that is a major cause of epidemic meningitis, especially in the sub-Saharan region of Africa. The development and manufacture of a liquid glycoconjugate vaccine against MenA are hampered by the poor hydrolytic stability of its capsular polysaccharide (CPS), consisting of (1→6)-linked 2-acetamido-2-deoxy-α-d-mannopyranosyl phosphate repeating units. The replacement of the ring oxygen with a methylene group to generate a carbocyclic analogue leads to enhancement of its chemical stability. Herein, we report conjugation of carbocyclic analogue monomer, dimer, and trimer to the protein carrier CRM197. After immunization in mice, only the conjugated trimer was able to induce specific anti-MenA polysaccharide IgG antibodies with in vitro bactericidal activity, although to a lesser extent than pentadecamer and hexamer oligomers obtained from mild acid hydrolysis of the native polysaccharide conjugated to the same protein carrier. This study represents the first proof-of-concept that hydrolytically stable structural analogues of saccharide antigens can be used for the development of efficacious antimicrobial preventative therapies. Conjugates with longer carbocyclic oligomers and/or precise acetylation patterns could further increase the induced immune response to a level comparable with those of commercially available anti-meningococcal glycoconjugate vaccines.
authors.affiliation: Dipartimento di Chimica and ISTM-CNR, Università degli Studi di Milano , via Golgi 19, I-20133 Milano, Italy.
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.forename: Marta
authors.initials: M
authors.lastname: Tontini
authors.forename: Giulia
authors.initials: G
authors.lastname: Brogioni
authors.forename: Alberto
authors.initials: A
authors.lastname: Nilo
authors.forename: Sara
authors.initials: S
authors.lastname: Filippini
authors.forename: Carole
authors.initials: C
authors.lastname: Harfouche
authors.forename: Laura
authors.initials: L
authors.lastname: Polito
authors.forename: Maria R
authors.initials: MR
authors.lastname: Romano
authors.forename: Paolo
authors.initials: P
authors.lastname: Costantino
authors.forename: Francesco
authors.initials: F
authors.lastname: Berti
authors.forename: Roberto
authors.initials: R
authors.lastname: Adamo
authors.forename: Luigi
authors.initials: L
authors.lastname: Lay
mesh_terms: D000146:Acids, Carbocyclic / Q000737:chemistry* / Q000276:immunology; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D016667:Bacterial Capsules / Q000276:immunology*; D001426:Bacterial Proteins / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009345:Neisseria meningitidis / Q000737:chemistry / Q000276:immunology; D011135:Polysaccharides, Bacterial / Q000276:immunology*; D014611:Vaccination
chemical_list: D000146:Acids, Carbocyclic; D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D007074:Immunoglobulin G; D011135:Polysaccharides, Bacterial; C028581:CRM197 (non-toxic variant of diphtheria toxin)