Augmenting Influenza-Specific T Cell Memory Generation with a Natural Killer T Cell-Dependent Glycolipid–Peptide Vaccine,ACS Chemical Biology

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Augmenting Influenza-Specific T Cell Memory Generation with a Natural Killer T Cell-Dependent Glycolipid–Peptide Vaccine
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-10-27 00:00:00 , DOI: 10.1021/acschembio.7b00845
Regan J. Anderson ₁ , Jasmine Li ₂ , Lukasz Kedzierski ₂ , Benjamin J. Compton ₁ , Colin M. Hayman ₁ , Taryn L. Osmond ₃ , Ching-wen Tang ₃ , Kathryn J. Farrand ₃ , Hui-Fern Koay _{4,

5} , Catarina Filipa Dos Santos Sa E. Almeida _{4,

5} , Lauren R. Holz ₄ , Geoffrey M. Williams ₆ , Margaret A Brimble _{6,

7} , Zhongfang Wang ₄ , Marios Koutsakos ₄ , Katherine Kedzierska ₄ , Dale I. Godfrey _{4,

5} , Ian F. Hermans _{3,

7,

8} , Stephen J. Turner ₂ , Gavin F. Painter _{1,

8}

Affiliation

The development of a universal vaccine for influenza A virus (IAV) that does not require seasonal modification is a long-standing health goal, particularly in the context of the increasing threat of new global pandemics. Vaccines that specifically induce T cell responses are of considerable interest because they can target viral proteins that are more likely to be shared between different virus strains and subtypes and hence provide effective cross-reactive IAV immunity. From a practical perspective, such vaccines should induce T cell responses with long-lasting memory, while also being simple to manufacture and cost-effective. Here we describe the synthesis and evaluation of a vaccine platform based on solid phase peptide synthesis and bio-orthogonal conjugation methodologies. The chemical approach involves covalently attaching synthetic long peptides from a virus-associated protein to a powerful adjuvant molecule, α-galactosylceramide (α-GalCer). Strain-promoted azide–alkyne cycloaddition is used as a simple and efficient method for conjugation, and pseudoproline methodology is used to increase the efficiency of the peptide synthesis. α-GalCer is a glycolipid that stimulates NKT cells, a population of lymphoid-resident immune cells that can provide potent stimulatory signals to antigen-presenting cells engaged in driving proliferation and differentiation of peptide-specific T cells. When used in mice, the vaccine induced T cell responses that provided effective prophylactic protection against IAV infection, with the speed of viral clearance greater than that seen from previous viral exposure. These findings are significant because the vaccines are highly defined, quick to synthesize, and easily characterized and are therefore appropriate for large scale affordable manufacture.

中文翻译：

用天然杀伤性T细胞依赖性糖脂肽疫苗增强流感特异性T细胞记忆的产生

一项长久以来的健康目标是开发一种不需要季节性修改的通用A型流感病毒疫苗（IAV），尤其是在新的全球大流行威胁日益增加的背景下。特异性诱导T细胞反应的疫苗备受关注，因为它们可以靶向更可能在不同病毒株和亚型之间共享的病毒蛋白，从而提供有效的交叉反应性IAV免疫力。从实践的角度来看，此类疫苗应诱导T细胞反应并具有长期记忆，同时还应易于制造且具有成本效益。在这里，我们描述了基于固相肽合成和生物正交偶联方法的疫苗平台的合成和评估。化学方法涉及将与病毒相关的蛋白质合成的长肽共价结合到强大的佐剂分子α-半乳糖苷神经酰胺（α-GalCer）上。应变促进的叠氮化物-炔烃环加成反应是一种简单而有效的偶联方法，而伪脯氨酸方法则用于提高肽合成的效率。α-GalCer是一种糖脂，可刺激NKT细胞，这是一种淋巴驻留免疫细胞，可以向参与驱动肽特异性T细胞增殖和分化的抗原呈递细胞提供有效的刺激信号。当在小鼠中使用时，该疫苗可诱导T细胞反应，从而为IAV感染提供有效的预防性保护，其病毒清除速度要比以前的病毒暴露速度快。

更新日期：2017-10-27

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