呼吸道合胞病毒(RSV)感染超过60%的婴儿在其生命的第一年。自从1960年代测试的实验性福尔马林灭活(FI)RSV疫苗引起了增强的呼吸系统疾病(ERD),很少有人尝试给婴儿接种疫苗。ERD的特征是Th2偏倚的反应,肺部炎症,保护性免疫记忆力差.先天性免疫记忆在再刺激时显示出增加的非特异性效应子功能,一个叫做训练免疫的过程,或者在再刺激时抑制的效应器功能,一个叫做宽容的过程,参与宿主防御和炎性疾病。出生时给予牛分枝杆菌卡介苗(BCG)可以诱导训练有素的免疫力以及异源Th1反应。我们推测,出生时给予卡介苗,随后给予FI-RSV可能通过促进训练的免疫力和平衡的Th免疫记忆来减轻ERD并增强保护作用。新生小鼠在出生时给予BCG,然后用FI-RSV+Al(OH)3接种。BCG/FI-RSV+Al(OH)3诱导的训练巨噬细胞,组织驻留记忆T细胞(TRM),和特异性细胞毒性T淋巴细胞(CTL)在肺和抑制Th2和Th17细胞免疫记忆,所有这些都有助于抑制ERD并增加保护作用.值得注意的是,FI-RSV+Al(OH)3诱导的耐受巨噬细胞,而BCG/FI-RSV+Al(OH)3通过促进训练的巨噬细胞来阻止先天耐受。此外,ERD的抑制归因于肺中训练过的巨噬细胞或TRM,而非脾中的记忆T细胞.因此,出生时给予BCG以调节训练有素的免疫力和TRM可能是开发针对年轻婴儿的安全有效的RSV灭杀疫苗的新策略。重要性RSV是婴儿严重下呼吸道感染的主要原因。ERD,以Th2偏向反应为特征,炎症,免疫记忆力差,已成为开发安全有效的灭活RSV疫苗的障碍。先天免疫记忆参与宿主防御和炎症性疾病。出生时给予的BCG可以诱导训练的免疫以及异源Th1应答。我们的结果表明,BCG/FI-RSV+Al(OH)3诱导训练的巨噬细胞,TRM,特异性CTL,和平衡的Th细胞免疫记忆,这有助于抑制ERD和增加保护。值得注意的是,FI-RSV+Al(OH)3诱导的耐受巨噬细胞,而BCG/FI-RSV+Al(OH)3通过促进训练的巨噬细胞来阻止耐受性。此外,ERD的抑制归因于肺中训练过的巨噬细胞或TRM,而非脾中的记忆T细胞.出生时BCG作为佐剂调节训练免疫和TRM可能是开发安全有效的婴幼儿RSV灭活疫苗的新策略。
Respiratory syncytial virus (RSV) infects more than 60% of infants in their first year of life. Since an experimental formalin-inactivated (FI) RSV vaccine tested in the 1960s caused enhanced respiratory disease (ERD), few attempts have been made to vaccinate infants. ERD is characterized by Th2-biased responses, lung inflammation, and poor protective immune memory. Innate immune memory displays an increased nonspecific effector function upon restimulation, a process called trained immunity, or a repressed effector function upon restimulation, a process called tolerance, which participates in host defense and inflammatory disease. Mycobacterium bovis bacillus Calmette-Guérin (BCG) given at birth can induce trained immunity as well as heterologous Th1 responses. We speculate that BCG given at birth followed by FI-RSV may alleviate ERD and enhance protection through promoting trained immunity and balanced Th immune memory. Neonatal mice were given BCG at birth and then vaccinated with FI-RSV+Al(OH)3. BCG/FI-RSV+Al(OH)3 induced trained macrophages, tissue-resident memory T cells (TRM), and specific cytotoxic T lymphocytes (CTL) in lungs and inhibited Th2 and Th17 cell immune memory, all of which contributed to inhibition of ERD and increased protection. Notably, FI-RSV+Al(OH)3 induced tolerant macrophages, while BCG/FI-RSV+Al(OH)3 prevented the innate tolerance through promoting trained macrophages. Moreover, inhibition of ERD was attributed to trained macrophages or TRM in lungs but not memory T cells in spleens. Therefore, BCG given at birth to regulate trained immunity and TRM may be a new strategy for developing safe and effective RSV killed vaccines for young infants. IMPORTANCE RSV is the leading cause of severe lower respiratory tract infection of infants. ERD, characterized by Th2-biased responses, inflammation, and poor immune memory, has been an obstacle to the development of safe and effective killed RSV vaccines. Innate immune memory participates in host defense and inflammatory disease. BCG given at birth can induce trained immunity as well as heterologous Th1 responses. Our results showed that BCG/FI-RSV+Al(OH)3 induced trained macrophages, TRM, specific CTL, and balanced Th cell immune memory, which contributed to inhibition of ERD and increased protection. Notably, FI-RSV+Al(OH)3 induced tolerant macrophages, while BCG/FI-RSV+Al(OH)3 prevented tolerance through promoting trained macrophages. Moreover, inhibition of ERD was attributed to trained macrophages or TRM in lungs but not memory T cells in spleens. BCG at birth as an adjuvant to regulate trained immunity and TRM may be a new strategy for developing safe and effective RSV killed vaccines for young infants.