Synthesis of Neisseria Meningitidis A Carba Analogues as Hydrolytically Stable Antigens for Antimeningococcal Glycoconjugate Vaccines

The Gram-negative encapsulated bacterium Neisseria meningitidis type A (MenA) is a major cause of meningitis in developing countries, especially in the sub-Saharan region of Africa [1]. The development and manufacture of an efficient glycoconjugate vaccine against MenA is largely hampered by the poor stability in water of the natural capsular polysaccharide (CPS)[2], composed of (1→6)-linked 2-acetamido-2-deoxy-α-D-mannopyranosyl phosphate repeating units, with acetyl substituents. As a consequence, most of MenA glycoconjugates currently available have been licensed as lyophilisates. The availability of MenA polysaccharide mimics resistant to hydrolysis, however, is highly attractive for the development of a more stable glycoconjugate vaccine in liquid formulation. To this end, we envisaged that the replacement of the endocyclic ring oxygen with a methylene group to get a carbocyclic analogue will lead to the loss of the acetalic character of the phosphodiester and consequently to the enhancement of its chemical stability [3], [4]. 

We describe herein our synthetic approach to non-acetylated phosphodiester-linked carba oligomers of MenA CPS containing up to 7 repeating units. The increased stability of the synthetic carba oligomers was first confirmed by an accelerated stability study, then selected fragments were conjugated to CRM197 (a diphtheria toxin mutant) as a protein carrier. The immunological profile of the resulting neo-glycoconjugates was carefully investigated, with the purpose to highlight the effect of the carbohydrate chain length on the immunoactivity [5].