Verreck Frank A W, Vervenne Richard A W, Kondova Ivanela, van Kralingen Klaas W, Remarque Edmond J, Braskamp Gerco, van der Werff Nicole M, Kersbergen Ariena, Ottenhoff Tom H M, Heidt Peter J, Gilbert Sarah C, Gicquel Brigitte, Hill Adrian V S, Martin Carlos, McShane Helen, Thomas Alan W
Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
PLoS One. 2009;4(4):e5264. doi: 10.1371/journal.pone.0005264. Epub 2009 Apr 15.
Continuous high global tuberculosis (TB) mortality rates and variable vaccine efficacy of Mycobacterium bovis Bacille Calmette-Guérin (BCG) motivate the search for better vaccine regimes. Relevant models are required to downselect the most promising vaccines entering clinical efficacy testing and to identify correlates of protection.
Here, we evaluated immunogenicity and protection against Mycobacterium tuberculosis in rhesus monkeys with two novel strategies: BCG boosted by modified vaccinia virus Ankara expressing antigen 85A (MVA.85A), and attenuated M. tuberculosis with a disrupted phoP gene (SO2) as a single-dose vaccine. Both strategies were well tolerated, and immunogenic as evidenced by induction of specific IFNgamma responses. Antigen 85A-specific IFNgamma secretion was specifically increased by MVA.85A boosting. Importantly, both MVA.85A and SO2 treatment significantly reduced pathology and chest X-ray scores upon infectious challenge with M. tuberculosis Erdman strain. MVA.85A and SO2 treatment also showed reduced average lung bacterial counts (1.0 and 1.2 log respectively, compared with 0.4 log for BCG) and significant protective effect by reduction in C-reactive protein levels, body weight loss, and decrease of erythrocyte-associated hematologic parameters (MCV, MCH, Hb, Ht) as markers of inflammatory infection, all relative to non-vaccinated controls. Lymphocyte stimulation revealed Ag85A-induced IFNgamma levels post-infection as the strongest immunocorrelate for protection (spearman's rho: -0.60).
Both the BCG/MVA.85A prime-boost regime and the novel live attenuated, phoP deficient TB vaccine candidate SO2 showed significant protective efficacy by various parameters in rhesus macaques. Considering the phylogenetic relationship between macaque and man and the similarity in manifestations of TB disease, these data support further development of these primary and combination TB vaccine candidates.
全球结核病（TB）死亡率持续居高不下，且卡介苗（BCG）的疫苗效力参差不齐，这促使人们寻找更好的疫苗接种方案。需要相关模型来筛选出最有前景的疫苗进入临床疗效测试，并确定保护的相关因素。
在此，我们用两种新策略评估了恒河猴对结核分枝杆菌的免疫原性和保护作用：用表达抗原85A的改良安卡拉痘苗病毒（MVA.85A）加强免疫卡介苗，以及用缺失phoP基因的减毒结核分枝杆菌（SO2）作为单剂量疫苗。两种策略耐受性良好，且通过诱导特异性IFNγ反应证明具有免疫原性。MVA.85A加强免疫特异性增加了抗原85A特异性IFNγ分泌。重要的是，在用结核分枝杆菌埃尔德曼菌株进行感染攻击后，MVA.85A和SO2治疗均显著降低了病理学和胸部X光评分。MVA.85A和SO2治疗还显示平均肺细菌计数降低（分别为1.0和1.2对数，而卡介苗为0.4对数），并且通过降低C反应蛋白水平、体重减轻以及降低红细胞相关血液学参数（平均红细胞体积、平均红细胞血红蛋白含量、血红蛋白、血细胞比容）作为炎症感染标志物，相对于未接种疫苗的对照组具有显著的保护作用。淋巴细胞刺激显示感染后Ag85A诱导的IFNγ水平是保护作用最强的免疫相关因素（斯皮尔曼相关系数：-0.60）。
卡介苗/MVA.85A初免-加强方案以及新型减毒活的、phoP缺陷的结核疫苗候选物SO2在恒河猴中通过各种参数均显示出显著的保护效力。考虑到猕猴与人之间发育关系以及结核病表现的相似性，这些数据支持进一步研发这些主要的和联合的结核疫苗候选物。
