School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
Tuberculosis Research Program Centenary Institute, The University of Sydney, Camperdown, NSW 2006, Australia.
Proc Natl Acad Sci U S A. 2021 Jan 26;118(4). doi: 10.1073/pnas.2013730118.
The global incidence of tuberculosis remains unacceptably high, with new preventative strategies needed to reduce the burden of disease. We describe here a method for the generation of synthetic self-adjuvanted protein vaccines and demonstrate application in vaccination against Two vaccine constructs were designed, consisting of full-length ESAT6 protein fused to the TLR2-targeting adjuvants PamCys-SK or PamCys-SK These were produced by chemical synthesis using a peptide ligation strategy. The synthetic self-adjuvanting vaccines generated powerful local CD4 T cell responses against ESAT6 and provided significant protection in the lungs from virulent aerosol challenge when administered to the pulmonary mucosa of mice. The flexible synthetic platform we describe, which allows incorporation of adjuvants to multiantigenic vaccines, represents a general approach that can be applied to rapidly assess vaccination strategies in preclinical models for a range of diseases, including against novel pandemic pathogens such as SARS-CoV-2.
全球结核病发病率仍然高得令人无法接受，需要新的预防策略来减轻疾病负担。我们在这里描述了一种用于生成合成自佐剂蛋白疫苗的方法，并展示了其在针对结核分枝杆菌的疫苗接种中的应用。两种疫苗构建体被设计出来，由全长 ESAT6 蛋白与 TLR2 靶向佐剂 PamCys-SK 或 PamCys-SK 融合而成。这些疫苗通过化学合成使用肽连接策略进行生产。所产生的合成自佐剂疫苗在针对 ESAT6 时引发了强大的局部 CD4 T 细胞反应，并在给予小鼠肺部黏膜时，在肺部从毒力气溶胶挑战中提供了显著的保护。我们描述的这种灵活的合成平台允许将佐剂纳入多抗原疫苗中，代表了一种通用方法，可用于快速评估针对一系列疾病的临床前模型中的疫苗接种策略，包括针对新型大流行病原体如 SARS-CoV-2 的策略。
