American Chemical Society, ACS Chemical Biology, 11(8), p. 2561-2567, 2013
DOI: 10.1021/cb400463u
Full text: Download
Neisseria meningitidis type A (MenA) is a Gram-negative encapsulated bacterium, which 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 is 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 get a carbocyclic analogue leads to the 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, which possessed in vitro bactericidal activity, although in lesser extent than pentadecamer and hexamer oligomers obtained from mild acid hydrolysis of the native polysaccharide and conjugated to the same protein carrier. This study represents the first proof-of-concept that hydrolytically stable structural analogues of saccharide antigens could be used for the development of efficacious anti-microbial preventative therapies. Conjugates with longer carbocyclic oligomers and/or precise acetylation pattern could further increase the induced immune response in order to be comparable to the commercially available anti-meningococcal glycoconjugate vaccines.