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Development of an Efficacious, Semisynthetic Glycoconjugate Vaccine Candidate against Streptococcus pneumoniae Serotype 1
ACS Central Science ( IF 18.2 ) Pub Date : 2018-03-14 00:00:00 , DOI: 10.1021/acscentsci.7b00504
Benjamin Schumann 1, 2 , Katrin Reppe 3 , Paulina Kaplonek 1, 2 , Annette Wahlbrink 1 , Chakkumkal Anish 1 , Martin Witzenrath 3 , Claney L. Pereira 1 , Peter H. Seeberger 1, 2
Affiliation  

Infections with Streptococcus pneumoniae are a major health burden. Glycoconjugate vaccines based on capsular polysaccharides (CPSs) successfully protect from infection, but not all pneumococcal serotypes are covered with equal potency. Marketed glycoconjugate vaccines induce low levels of functional antibodies against the highly invasive serotype 1 (ST1), presumably due to the obscuring of protective epitopes during chemical activation and conjugation to carrier proteins. Synthetic oligosaccharide antigens can be designed to carry linkers for site-selective protein conjugation while keeping protective epitopes intact. Here, we developed an efficacious semisynthetic ST1 glycoconjugate vaccine candidate. A panel of synthetic oligosaccharides served to reveal a critical role of the rare aminosugar, 2-acetamido-4-amino-2,4,6-trideoxy-d-galactose (d-AAT), for ST1 immune recognition. A monovalent ST1 trisaccharide carrying d-AAT at the nonreducing end induced a strong antibacterial immune response in rabbits and outperformed the ST1 component of the multivalent blockbuster vaccine Prevenar 13, paving the way for a more efficacious vaccine.

中文翻译:

对抗肺炎链球菌血清型1的高效,半合成糖共轭疫苗候选人的发展。

与感染肺炎链球菌是主要的健康负担。基于荚膜多糖(CPS)的糖缀合物疫苗可成功预防感染,但并非所有肺炎球菌血清型都具有相同的效力。市售的糖缀合物疫苗诱导出针对高侵入性血清型1(ST1)的低水平功能性抗体,这可能是由于在化学激活和与载体蛋白结合过程中保护性表位的模糊化所致。合成的低聚糖抗原可以设计成带有接头,用于位点选择性蛋白质偶联,同时保持保护性表位完整。在这里,我们开发了一种有效的半合成ST1糖缀合物疫苗候选物。合成寡糖的面板供应以显示罕见氨基糖中起关键作用,2-乙酰氨基-4-氨基-2,4,6-三脱氧d半乳糖(d -AAT),用于ST1免疫识别。在非还原端带有d -AAT的单价ST1三糖在兔中诱导了强大的抗菌免疫反应,并且胜过了多价重磅炸弹疫苗Prevenar 13的ST1成分,为更有效的疫苗铺平了道路。
更新日期:2018-03-14
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