Pharmaceutics and Drug Delivery Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
PLoS One. 2013 May 10;8(5):e63344. doi: 10.1371/journal.pone.0063344. Print 2013.
Pulmonary vaccination is a promising route for immunization against tuberculosis because the lung is the natural site of infection with Mycobacterium tuberculosis. Yet, adjuvants with a suitable safety profile need to be found to enhance mucosal immunity to recombinant antigens. The aim of this study was to evaluate the immunogenicity, the safety and the protective efficacy of a subunit vaccine composed of the immunodominant mycolyl-transferase antigen 85A (Ag85A) and one of three powerful mucosal adjuvants: the oligodeoxynucleotide containing unmethylated cytosine-phosphate-guanine motifs (CpG), the monophosphoryl lipid A of Salmonella minnesota (MPLA) or the B subunit of heat-labile enterotoxin of Escherichia coli (LTB). BALB/c mice were vaccinated in the deep lungs. Our results showed that lung administration of these adjuvants could specifically induce different types of T cell immunity. Both CpG and MPLA induced a Th-1 type immune response with significant antigen-specific IFN-γ production by spleen mononuclear cells in vitro and a tendency of increased IFN-γ in the lungs. Moreover, MPLA triggered a Th-17 response reflected by high IL-17A levels in the spleen and lungs. By contrast, LTB promoted a Th-2 biased immune response, with a production of IL-5 but not IFN-γ by spleen mononuclear cells in vitro. CpG did not induce inflammation in the lungs while LTB and MPLA showed a transient inflammation including a neutrophil influx one day after pulmonary administration. Pulmonary vaccination with Ag85A without or with MPLA or LTB tended to decrease bacterial counts in the spleen and lungs following a virulent challenge with M. tuberculosis H37Rv. In conclusion, CpG and MPLA were found to be potential adjuvants for pulmonary vaccination against tuberculosis, providing Th-1 and Th-17 immune responses and a good safety profile.
肺部接种是一种有前途的结核病免疫接种途径，因为肺部是结核分枝杆菌感染的天然部位。然而，需要找到具有合适安全性的佐剂来增强对重组抗原的黏膜免疫。本研究的目的是评估由免疫优势的分枝杆菌酰基转移酶抗原 85A（Ag85A）和三种强大的黏膜佐剂之一组成的亚单位疫苗的免疫原性、安全性和保护效力：含有未甲基化胞嘧啶-磷酸-鸟嘌呤基序（CpG）的寡脱氧核苷酸、单核细胞增生李斯特菌的单磷酰脂质 A（MPLA）或大肠杆菌不耐热肠毒素的 B 亚单位（LTB）。BALB/c 小鼠在深部肺部接种疫苗。我们的结果表明，这些佐剂在肺部的给药可以特异性诱导不同类型的 T 细胞免疫。CpG 和 MPLA 均诱导 Th1 型免疫应答，体外脾单核细胞产生显著的抗原特异性 IFN-γ，且肺内 IFN-γ有增加趋势。此外，MPLA 引发 Th17 应答，反映为脾和肺中高水平的 IL-17A。相比之下，LTB 促进 Th2 偏向免疫应答，体外脾单核细胞产生 IL-5，但不产生 IFN-γ。CpG 不会在肺部引起炎症，而 LTB 和 MPLA 在肺部给药后一天会引起短暂的炎症，包括中性粒细胞浸润。用 Ag85A 进行肺部接种，不添加或添加 MPLA 或 LTB，在受到结核分枝杆菌 H37Rv 强毒力攻击后，脾脏和肺部的细菌计数有减少趋势。总之，CpG 和 MPLA 被认为是肺部结核病疫苗接种的潜在佐剂，可提供 Th1 和 Th17 免疫应答以及良好的安全性。
