Immunoactivity of Protein Conjugates of Carba Analogues from Neisseria meningitidis A Capsular Polysaccharide

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• 作者：Qi Gao ; Marta Tontini ; Giulia Brogioni ; Alberto Nilo ; Sara Filippini ; Carole Harfouche ; Laura Polito ; Maria R. Romano ; Paolo Costantino ; Francesco Berti ; Roberto Adamo ; Luigi Lay
• 刊名：ACS Chemical Biology
• 出版年：2013
• 出版时间：November 15, 2013
• 年：2013
• 卷：8
• 期：11
• 页码：2561-2567
• 全文大小：323K
• 年卷期：v.8,no.11(November 15, 2013)
• ISSN：1554-8937

文摘

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鈫?)-linked 2-acetamido-2-deoxy-伪-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.