Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA.
Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Nat Commun. 2022 Aug 2;13(1):4234. doi: 10.1038/s41467-022-31709-2.
Respiratory syncytial virus is a leading cause of morbidity and mortality in children, due in part to their distinct immune system, characterized by impaired induction of Th 1 immunity. Here we show application of cationic adjuvant formulation CAF08, a liposomal vaccine formulation tailored to induce Th 1 immunity in early life via synergistic engagement of Toll-like Receptor 7/8 and the C-type lectin receptor Mincle. We apply quantitative phosphoproteomics to human dendritic cells and reveal a role for Protein Kinase C-δ for enhanced Th1 cytokine production in neonatal dendritic cells and identify signaling events resulting in antigen cross-presentation. In a murine in vivo model a single immunization at birth with CAF08-adjuvanted RSV pre-fusion antigen protects newborn mice from RSV infection by induction of antigen-specific CD8 T-cells and Th1 cells. Overall, we describe a pediatric adjuvant formulation and characterize its mechanism of action providing a promising avenue for development of early life vaccines against RSV and other respiratory viral pathogens.
呼吸道合胞病毒是导致儿童发病和死亡的主要原因,部分原因是他们独特的免疫系统,其特征是 Th1 免疫诱导受损。在这里,我们展示了阳离子佐剂制剂 CAF08 的应用,这是一种脂质体制剂,旨在通过协同激活 Toll 样受体 7/8 和 C 型凝集素受体 Mincle,在生命早期诱导 Th1 免疫。我们应用定量磷酸蛋白质组学研究人类树突状细胞,并揭示蛋白激酶 C-δ在增强新生儿树突状细胞产生 Th1 细胞因子中的作用,并确定导致抗原交叉呈递的信号事件。在一项小鼠体内模型研究中,在出生时用 CAF08 佐剂的 RSV 融合前抗原进行单次免疫接种,可以通过诱导抗原特异性 CD8 T 细胞和 Th1 细胞来保护新生小鼠免受 RSV 感染。总的来说,我们描述了一种儿科佐剂制剂,并对其作用机制进行了表征,为开发针对 RSV 和其他呼吸道病毒病原体的生命早期疫苗提供了有希望的途径。