SYNTHESISOF IMMUNO-ACTIVE OLIGOSACCHARIDES AND GLYCONJUGATES AS ANTIGENS FOR VACCINE FORMULATION.

Neisseria meningitidis type A (MenA) is a Gram-negative encapsulated bacterium that causes recurrent epidemics of meningitis in the sub-Saharan region of Africa. [1] The development and manufacture of an efficient glycoconjugate vaccine against MenA has to consider the poor hydrolytic stability of its capsular polysaccharide (CPS), which is made up of (16)-linked 2-acetamido-2-deoxy-α-D-mannopyranosyl phosphate repeating units. [2] Since the chemical lability of MenA CPS is a product of the inherent instability of the phosphodiester bridge, a possible solution could be the replacement of the pyranose oxygen atom with a methylene group to give carbocyclic analogues. In this way, the acetal character of the phosphodiester is lost, and the new molecules are expected to be of comparable stability to that of oligonucleotides. Previous conformational studies indicated that the carba analogues of MenA CPS could be effective structural mimics of MenA CPS fragments.[3] We herein describe our work towards the design, synthesis and preliminary immunological evaluation of carba-oligomers of MenA CPS. A straightforward strategy for preparing the phosphodiester-linked oligomers (monomer, dimer and trimer, Figure 1) has been developed. The synthetic oligomers all have 1-O-phosphodiester-linked aminopropyl spacer arm to allow conjugation with a carrier protein or multivalent support. Preliminary ELISA test showed these molecules could be promising vaccine candidates against MenA.