Brandt Lise, Skeiky Yasir A W, Alderson Mark R, Lobet Yves, Dalemans Wilfried, Turner Oliver C, Basaraba Randall J, Izzo Angelo A, Lasco Todd M, Chapman Philip L, Reed Steven G, Orme Ian M
Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins 80523, USA.
Infect Immun. 2004 Nov;72(11):6622-32. doi: 10.1128/IAI.72.11.6622-6632.2004.
A tuberculosis vaccine candidate consisting of a 72-kDa polyprotein or fusion protein based upon the Mtb32 and Mtb39 antigens of Mycobacterium tuberculosis and designated Mtb72F was tested for its protective capacity as a potential adjunct to the Mycobacterium bovis BCG vaccine in the mouse and guinea pig models of this disease. Formulation of recombinant Mtb72F (rMtb72F) in an AS02A adjuvant enhanced the Th1 response to BCG in mice but did not further reduce the bacterial load in the lungs after aerosol challenge infection. In the more stringent guinea pig disease model, rMtb72F delivered by coadministration with BCG vaccination significantly improved the survival of these animals compared to BCG alone, with some animals still alive and healthy in their appearance at >100 weeks post-aerosol challenge. A similar trend was observed with guinea pigs in which BCG vaccination was boosted by DNA vaccination, although this increase was not statistically significant due to excellent protection conferred by BCG alone. Histological examination of the lungs of test animals indicated that while BCG controls eventually died from overwhelming lung consolidation, the majority of guinea pigs receiving BCG mixed with rMtb72F or boosted twice with Mtb72F DNA had mostly clear lungs with minimal granulomatous lesions. Lesions were still prominent in guinea pigs receiving BCG and the Mtb72F DNA boost, but there was considerable evidence of lesion healing and airway remodeling and reestablishment. These data support the hypothesis that the coadministration or boosting of BCG vaccination with Mtb72F may limit the lung consolidation seen with BCG alone and may promote lesion resolution and healing. Collectively, these data suggest that enhancing BCG is a valid vaccination strategy for tuberculosis that is worthy of clinical evaluation.
一种基于结核分枝杆菌的Mtb32和Mtb39抗原组成的72 kDa多聚蛋白或融合蛋白的结核病候选疫苗，命名为Mtb72F，在该疾病的小鼠和豚鼠模型中作为牛分枝杆菌卡介苗（BCG）疫苗的潜在辅助剂测试其保护能力。重组Mtb72F（rMtb72F）与AS02A佐剂配制可增强小鼠对BCG的Th1反应，但在气溶胶攻击感染后并未进一步降低肺部的细菌载量。在更严格的豚鼠疾病模型中，与单独使用BCG相比，rMtb72F与BCG疫苗联合给药可显著提高这些动物的存活率，在气溶胶攻击后100周以上，一些动物仍存活且外观健康。在通过DNA疫苗加强BCG疫苗接种的豚鼠中也观察到类似趋势，尽管由于单独使用BCG提供的出色保护，这种增加在统计学上不显著。对试验动物肺部的组织学检查表明，虽然BCG对照组最终死于严重的肺实变，但大多数接受BCG与rMtb72F混合或用Mtb72F DNA加强两次的豚鼠肺部大多清晰，肉芽肿病变极少。在接受BCG和Mtb72F DNA加强的豚鼠中病变仍然明显，但有大量证据表明病变愈合以及气道重塑和重建。这些数据支持以下假设：BCG疫苗接种与Mtb72F联合给药或加强接种可能会限制单独使用BCG时出现的肺实变，并可能促进病变消退和愈合。总体而言，这些数据表明加强BCG是一种有效的结核病疫苗接种策略，值得进行临床评估。
