Augmenting Influenza-Specific T Cell Memory Generation with a Natural Killer T Cell-Dependent Glycolipid-Peptide Vaccine
Augmenting Influenza-Specific T Cell Memory Generation with a Natural Killer T Cell-Dependent Glycolipid-Peptide Vaccine
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DOI：
10.1021/acschembio.7b00845
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发表时间：
2017-11-01
影响因子：
4
通讯作者：
Painter, Gavin F.
中科院分区：
文献类型：
--
作者：
Anderson, Regan J.;Li, Jasmine;Painter, Gavin F.
开发不需要季节性调整的甲型流感病毒（IAV）通用疫苗是一项长期的卫生目标，特别是在新的全球大流行病威胁日益增加的背景下。特异性诱导T细胞应答的疫苗受到相当大的关注，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。从实践的角度来看，这种疫苗应该诱导具有持久记忆的T细胞应答，同时也易于制造和具有成本效益。在这里，我们描述了基于固相肽合成和生物正交缀合方法的疫苗平台的合成和评价。化学方法包括将来自病毒相关蛋白的合成长肽共价连接到强大的佐剂分子α-半乳糖神经酰胺（α-GalCer）上。菌株促进的叠氮化物-炔环加成被用作一种简单而有效的缀合方法，并且伪脯氨酸方法被用于提高肽合成的效率。α-GalCer是刺激NKT细胞的糖脂，NKT细胞是一群淋巴驻留免疫细胞，其可以向参与驱动肽特异性T细胞的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，疫苗诱导T细胞应答，提供有效的预防性保护以对抗IAV感染，病毒清除的速度大于从先前的病毒暴露中看到的速度。这些发现是重要的，因为疫苗是高度确定的，快速合成，易于表征，因此适合于大规模负担得起的生产。
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, alpha-galactosylceramide (alpha-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. alpha-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.