Theresa E. Pankhurst, Isabelle Montgomerie, Andrew Marshall, Sarah L. Draper, Tim Bilbrough, Kaileen R. Button, Olga R. Palmer, Ian F. Hermans, Gavin F. Painter, Lisa M. Connor* and Benjamin J. Compton*,
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While such carrier-based vaccines have proven extremely successful, particularly in protecting against bacterial diseases, they can be challenging to manufacture, and repeated use can be compromised by pre-existing immunity against the carrier. One approach to reducing these complications is to recruit help from type I natural killer T (NKT) cells, which exhibit limited diversity in their antigen receptors and respond to glycolipid antigens presented by the highly conserved presenting molecule CD1d. Synthetic vaccines for universal use can, therefore, be prepared by conjugating haptens to an NKT cell agonist such as α-galactosylceramide (αGalCer, KRN7000). An additional advantage is that the quality of NKT cell help is sufficient to overcome the need for an extra immune adjuvant. However, while initial studies with αGalCer-hapten conjugate vaccines report strong and rapid antihapten antibody responses, they can fail to generate lasting memory. 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引用次数: 0
摘要
在疫苗接种过程中激发抗链肽抗体反应通常需要使用构建物,将多份链肽共价连接到更大的载体分子上。载体需要通过呈现主要组织相容性复合体(MHC)II 类分子上的肽表位来激发 T 细胞的帮助;因此,通常使用单独或复合的全尺寸蛋白质来解释人类 MHC 的显著多样性。虽然这种以载体为基础的疫苗已被证明非常成功,特别是在预防细菌性疾病方面,但它们的制造可能具有挑战性,而且重复使用可能会受到针对载体的已有免疫力的影响。减少这些并发症的一种方法是利用 I 型自然杀伤 T(NKT)细胞的帮助,这些细胞的抗原受体多样性有限,并对高度保守的呈递分子 CD1d 呈递的糖脂抗原做出反应。因此,可通过将触媒与 NKT 细胞激动剂(如 α-半乳糖甘油酰胺(αGalCer,KRN7000))共轭来制备通用的合成疫苗。另一个优点是,NKT 细胞的帮助质量足以克服额外免疫佐剂的需要。然而,尽管αGalCer-合体疫苗的初步研究报告显示了强烈而快速的抗合体抗体反应,但它们可能无法产生持久的记忆。在这里,我们展示了通过额外连接含有可结合多种 MHC II 类分子的杂合辅助性 T 细胞表位(Pan DR 表位,PADRE)的融合肽,可改善对 4-hydoxy-3-nitrophenyl acetyl (NP)合剂的抗体反应。与不含辅助表位的疫苗相比,这种αGalCer-合肽三组分疫苗能产生强而持久的抗 NP 抗体滴度,并能提高合肽亲和力。因此,三组分疫苗平台适合进一步探索有效的抗链肽免疫疗法。
A Glycolipid-Peptide-Hapten Tricomponent Conjugate Vaccine Generates Durable Antihapten Antibody Responses in Mice
Eliciting an antihapten antibody response to vaccination typically requires the use of constructs where multiple copies of the hapten are covalently attached to a larger carrier molecule. The carrier is required to elicit T cell help via presentation of peptide epitopes on major histocompatibility complex (MHC) class II molecules; as such, attachment to full-sized proteins, alone or in a complex, is generally used to account for the significant MHC diversity in humans. While such carrier-based vaccines have proven extremely successful, particularly in protecting against bacterial diseases, they can be challenging to manufacture, and repeated use can be compromised by pre-existing immunity against the carrier. One approach to reducing these complications is to recruit help from type I natural killer T (NKT) cells, which exhibit limited diversity in their antigen receptors and respond to glycolipid antigens presented by the highly conserved presenting molecule CD1d. Synthetic vaccines for universal use can, therefore, be prepared by conjugating haptens to an NKT cell agonist such as α-galactosylceramide (αGalCer, KRN7000). An additional advantage is that the quality of NKT cell help is sufficient to overcome the need for an extra immune adjuvant. However, while initial studies with αGalCer-hapten conjugate vaccines report strong and rapid antihapten antibody responses, they can fail to generate lasting memory. Here, we show that antibody responses to the hapten 4-hydoxy-3-nitrophenyl acetyl (NP) can be improved through additional attachment of a fusion peptide containing a promiscuous helper T cell epitope (Pan DR epitope, PADRE) that binds diverse MHC class II molecules. Such αGalCer-hapten-peptide tricomponent vaccines generate strong and sustained anti-NP antibody titers with increased hapten affinity compared to vaccines without the helper epitope. The tricomponent vaccine platform is therefore suitable for further exploration in the pursuit of efficacious antihapten immunotherapies.
期刊介绍:
ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology.
The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies.
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