Baek J Y, Geissner A, Rathwell D C K, Meierhofer D, Pereira C L, Seeberger P H
Max Planck Institute of Colloids and Interfaces , 14476 Potsdam , Germany . Email:
Freie Universität Berlin , Department of Chemistry and Biochemistry , 14195 Berlin , Germany.
Chem Sci. 2017 Dec 11;9(5):1279-1288. doi: 10.1039/c7sc04521b. eCollection 2018 Feb 7.
The first glycoconjugate vaccine using isolated glycans was licensed to protect children from serotype b (Hib) infections. Subsequently, the first semisynthetic glycoconjugate vaccine using a mixture of antigens derived by polymerization targeted the same pathogen. Still, a detailed understanding concerning the correlation between oligosaccharide chain length and the immune response towards the polyribosyl-ribitol-phosphate (PRP) capsular polysaccharide that surrounds Hib remains elusive. The design of semisynthetic and synthetic Hib vaccines critically depends on the identification of the minimally protective epitope. Here, we demonstrate that an octasaccharide antigen containing four repeating disaccharide units resembles PRP polysaccharide in terms of immunogenicity and recognition by anti-Hib antibodies. Key to this discovery was the development of a modular synthesis that enabled access to oligosaccharides up to decamers. Glycan arrays containing the synthetic oligosaccharides were used to analyze anti-PRP sera for antibodies. Conjugates of the synthetic antigens and the carrier protein CRM197, which is used in licensed vaccines, were employed in immunization studies in rabbits.
首款使用分离聚糖的糖缀合物疫苗被批准用于保护儿童免受b型流感嗜血杆菌（Hib）感染。随后，首款使用通过聚合衍生的抗原混合物的半合成糖缀合物疫苗针对的是同一种病原体。然而，关于寡糖链长度与针对包围Hib的多聚核糖醇磷酸（PRP）荚膜多糖的免疫反应之间的相关性，仍缺乏详细的了解。半合成和合成Hib疫苗的设计关键取决于最小保护表位的识别。在此，我们证明，含有四个重复二糖单元的八糖抗原在免疫原性和被抗Hib抗体识别方面类似于PRP多糖。这一发现的关键在于开发了一种模块化合成方法，该方法能够获得长达十聚体的寡糖。含有合成寡糖的聚糖阵列用于分析抗PRP血清中的抗体。合成抗原与许可疫苗中使用的载体蛋白CRM197的缀合物被用于兔免疫研究。
