Vordermeier H Martin, Villarreal-Ramos Bernardo, Cockle Paul J, McAulay Martin, Rhodes Shelley G, Thacker Tyler, Gilbert Sarah C, McShane Helen, Hill Adrian V S, Xing Zhou, Hewinson R Glyn
TB Research Group, VLA-Weybridge, New Haw, Addlestone, Surrey, United Kingdom.
Infect Immun. 2009 Aug;77(8):3364-73. doi: 10.1128/IAI.00287-09. Epub 2009 Jun 1.
Previous work with small-animal laboratory models of tuberculosis has shown that vaccination strategies based on heterologous prime-boost protocols using Mycobacterium bovis bacillus Calmette-Guérin (BCG) to prime and modified vaccinia virus Ankara strain (MVA85A) or recombinant attenuated adenoviruses (Ad85A) expressing the mycobacterial antigen Ag85A to boost may increase the protective efficacy of BCG. Here we report the first efficacy data on using these vaccines in cattle, a natural target species of tuberculous infection. Protection was determined by measuring development of disease as an end point after M. bovis challenge. Either Ad85A or MVA85A boosting resulted in protection superior to that given by BCG alone: boosting BCG with MVA85A or Ad85A induced significant reduction in pathology in four/eight parameters assessed, while BCG vaccination alone did so in only one parameter studied. Protection was particularly evident in the lungs of vaccinated animals (median lung scores for naïve and BCG-, BCG/MVA85A-, and BCG/Ad85A-vaccinated animals were 10.5, 5, 2.5, and 0, respectively). The bacterial loads in lymph node tissues were also reduced after viral boosting of BCG-vaccinated calves compared to those in BCG-only-vaccinated animals. Analysis of vaccine-induced immunity identified memory responses measured by cultured enzyme-linked immunospot assay as well as in vitro interleukin-17 production as predictors of vaccination success, as both responses, measured before challenge, correlated positively with the degree of protection. Therefore, this study provides evidence of improved protection against tuberculosis by viral booster vaccination in a natural target species and has prioritized potential correlates of vaccine efficacy for further evaluation. These findings also have implications for human tuberculosis vaccine development.
以往对结核病小型动物实验模型的研究表明，基于异源初免-加强方案的疫苗接种策略，即使用卡介苗（BCG）进行初免，并用表达结核分枝杆菌抗原Ag85A的改良安卡拉痘苗病毒株（MVA85A）或重组减毒腺病毒（Ad85A）进行加强免疫，可能会提高卡介苗的保护效力。在此，我们报告了在牛（结核感染的自然宿主物种）中使用这些疫苗的首个效力数据。通过在牛分枝杆菌攻击后，将疾病发展情况作为终点指标来确定保护效果。Ad85A或MVA85A加强免疫均产生了优于单独使用卡介苗的保护效果：用MVA85A或Ad85A加强卡介苗免疫后，在评估的8项指标中有4项的病理变化显著减少，而单独接种卡介苗仅在1项研究指标中出现这种情况。接种疫苗动物的肺部保护效果尤为明显（未接种疫苗、接种卡介苗、接种卡介苗/MVA85A和接种卡介苗/Ad85A的动物肺部评分中位数分别为10.5、5、2.5和0）。与仅接种卡介苗的动物相比，卡介苗接种的犊牛经病毒加强免疫后，淋巴结组织中的细菌载量也有所降低。对疫苗诱导免疫的分析确定，通过培养酶联免疫斑点试验测量的记忆反应以及体外白细胞介素-17的产生可作为疫苗接种成功的预测指标，因为在攻击前测量的这两种反应均与保护程度呈正相关。因此，本研究提供了证据，表明在自然宿主物种中通过病毒加强免疫可提高对结核病的保护效果，并确定了疫苗效力的潜在相关指标以便进一步评估。这些发现也对人类结核病疫苗的研发具有启示意义。
