Tuberculosis (TB) is the leading cause of death from infection worldwide. The only approved vaccine, BCG, has variable protective efficacy against pulmonary TB, the transmissible form of the disease. Therefore, improving this efficacy is an urgent priority. This study assessed whether heterologous prime-boost vaccine regimens in which BCG priming is boosted with either (i) protein and adjuvant (M72 plus AS01_E or H56 plus CAF01) delivered intramuscularly (IM), or (ii) replication-defective recombinant adenovirus serotype 5 (Ad5) expressing various Mycobacterium tuberculosis (Mtb) antigens (Ad5(TB): M72, ESAT-6/Ag85b, or ESAT-6/Rv1733/Rv2626/RpfD) administered simultaneously by IM and aerosol (AE) routes, could enhance blood- and lung-localized T-cell immunity and improve protection in a nonhuman primate (NHP) model of TB infection. Ad5(TB) vaccines administered by AE/IM routes following BCG priming elicited ~10–30% antigen-specific CD4 and CD8 T-cell multifunctional cytokine responses in bronchoalveolar lavage (BAL) but did not provide additional protection compared to BCG alone. Moreover, AE administration of an Ad5(empty) control vector after BCG priming appeared to diminish protection induced by BCG. Boosting BCG by IM immunization of M72/AS01_E or H56:CAF01 elicited ~0.1–0.3% antigen-specific CD4 cytokine responses in blood with only a transient increase of ~0.5–1% in BAL; these vaccine regimens also failed to enhance BCG-induced protection. Taken together, this study shows that boosting BCG with protein/adjuvant or Ad-based vaccines using these antigens, by IM or IM/AE routes, respectively, do not enhance protection against primary infection compared with BCG alone, in the highly susceptible rhesus macaque model of tuberculosis.

结核病（TB）是全球感染致死的主要原因。唯一获准使用的疫苗BCG对肺结核（该疾病的可传播形式）具有不同的保护作用。因此，提高这一功效是当务之急。这项研究评估了是否通过肌肉注射（IM）或（ii）复制缺陷的重组腺病毒血清型（i）蛋白质和佐剂（M72加AS01 _E或H56加CAF01）加强BCG引发的异源初免-加强疫苗接种方案表达各种结核分枝杆菌的5（Ad5）（Mtb）抗原（Ad5（TB）：M72，ESAT-6 / Ag85b或ESAT-6 / Rv1733 / Rv2626 / RpfD）同时通过IM和气雾剂（AE）途径给药，可以增强血液和肺局部T-细胞免疫力并在非人类灵长类动物（NHP）结核感染模型中改善保护作用。BCG引发后，通过AE / IM途径施用的Ad5（TB）疫苗在支气管肺泡灌洗（BAL）中引起约10–30％的抗原特异性CD4和CD8 T细胞多功能细胞因子反应，但与单独使用BCG相比没有提供额外的保护。此外，在接种BCG后，对Ad5（空）对照载体进行AE给药似乎减弱了BCG诱导的保护作用。通过IM免疫M72 / AS01 _E增强卡介苗或H56：CAF01引起血液中〜0.1–0.3％的抗原特异性CD4细胞因子应答，而BAL仅有短暂的〜0.5–1％升高；或 这些疫苗方案也未能增强BCG诱导的保护作用。综上所述，这项研究表明，在高度易感的猕猴中，分别使用IM或IM / AE途径分别使用这些抗原的蛋白/佐剂或基于Ad的疫苗来增强BCG，与单独使用BCG相比，并没有增强针对原发性感染的保护作用。结核模型。