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 Mycobacterium tuberculosis. Two vaccine constructs were designed, consisting of full-length ESAT6 protein fused to the TLR2-targeting adjuvants Pam₂Cys-SK₄ or Pam₃Cys-SK₄. 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 M. tuberculosis 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合成自佐剂蛋白疫苗的生成方法，并展示了在结核分枝杆菌疫苗接种中的应用。_{设计了两种疫苗构建体，由与 TLR2 靶向佐剂 Pam 2} Cys-SK ₄或 Pam ₃ Cys-SK ₄融合的全长 ESAT6 蛋白组成。这些是通过使用肽连接策略的化学合成产生的。合成的自佐剂疫苗产生强大的局部 CD4 ⁺T 细胞对 ESAT6 的反应并在对小鼠肺黏膜给药时对肺部产生显着的保护，使其免受毒性结核分枝杆菌气溶胶攻击。我们描述的灵活合成平台允许在多抗原疫苗中加入佐剂，它代表了一种通用方法，可用于快速评估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 .