Design of a Candida albicans Disaccharide Conjugate Vaccine by Reverse Engineering a Protective Monoclonal Antibody

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• 作者：David R. Bundle ; Corwin Nycholat ; Casey Costello ; Robert Rennie ; Tomasz Lipinski
• 刊名：ACS Chemical Biology
• 出版年：2012
• 出版时间：October 19, 2012
• 年：2012
• 卷：7
• 期：10
• 页码：1754-1763
• 全文大小：548K
• 年卷期：v.7,no.10(October 19, 2012)
• ISSN：1554-8937

文摘

A disaccharide-chicken serum albumin conjugate vaccine against Candida albicans infections has been developed by reverse engineering a protective monoclonal antibody, C3.1. The binding site of C3.1 binds short oligosaccharides of 尾1,2-linked mannopyranose residues present in the fungal cell wall phosphomannan. By delineating the fine detail of the molecular recognition of the cell wall 尾-mannan antigen, a disaccharide epitope was deduced to be the minimum size epitope that should induce the formation of protective antibody. Sequential functional group replacement of disaccharide hydroxyl groups to yield a series of monodeoxy and mono-O-methyl 尾1,2-linked mannobioside congeners established that three hydroxyl groups are essential for binding. Two of these, O-3 and O-4, are located on the internal mannose residue of the disaccharide, and a third, O-3鈥? is located on the terminal mannose. Synthesis of a series of trisaccharides that mandate binding of either the reducing or nonreducing disaccharide epitopes provided the final indication that a disaccharide protein conjugate should have the potential to induce protective antibody. When disaccharide was conjugated to chicken serum albumin this vaccine produced antibodies in rabbits that recognized the native cell wall phosphomannan. In proof of concept protection experiments, three immunized rabbits showed a reduction in fungal burden when challenged with live C. albicans.