LigB subunit vaccine confers sterile immunity against challenge in the hamster model of leptospirosis

Neglected tropical diseases, including zoonoses such as leptospirosis, have a major impact on rural and poor urban communities, particularly in developing countries. This has led to major investment in antipoverty vaccines that focus on diseases that influence public health and thereby productivity. While the true, global, impact of leptospirosis is unknown due to the lack of adequate laboratory diagnosis, the WHO estimates that incidence has doubled over the last 15 years to over 1 million cases that require hospitalization every year. Leptospirosis is caused by pathogenic Leptospira spp. and is spread through direct contact with infected animals, their urine or contaminated water and soil. Inactivated leptospirosis vaccines, or bacterins, are approved in only a handful of countries due to the lack of heterologous protection (there are > 250 pathogenic Leptospira serovars) and the serious side-effects associated with vaccination. Currently, research has focused on recombinant vaccines, a possible solution to these problems. However, due to a lack of standardised animal models, rigorous statistical analysis and poor reproducibility, this approach has met with limited success. We evaluated a subunit vaccine preparation, based on a conserved region of the leptospiral immunoglobulin-like B protein (LigB(131–645)) and aluminium hydroxide (AH), in the hamster model of leptospirosis. The vaccine conferred significant protection (80.0–100%, P < 0.05) against mortality in vaccinated animals in seven independent experiments. The efficacy of the LigB(131–645)/AH vaccine ranged from 87.5–100% and we observed sterile immunity (87.5–100%) among the vaccinated survivors. Significant levels of IgM and IgG were induced among vaccinated animals, although they did not correlate with immunity. A mixed IgG1/IgG2 subclass profile was associated with the subunit vaccine, compared to the predominant IgG2 profile seen in bacterin vaccinated hamsters. These findings suggest that LigB(131–645) is a vaccine candidate against leptospirosis with potential ramifications to public and veterinary health.

被忽视的热带病（Neglected Tropical Diseases），包括钩端螺旋体病（leptospirosis）这类人兽共患病（zoonoses），对农村及贫困城市社区造成严重影响，在发展中国家尤为突出。这使得针对影响公共卫生进而制约生产力的疾病的抗贫困疫苗研发获得了大规模投入。由于缺乏足够的实验室诊断手段，钩端螺旋体病的全球真实影响尚不明确，但世界卫生组织（World Health Organization, WHO）估计，过去15年间其发病率已翻倍，每年需住院治疗的病例超过100万例。钩端螺旋体病由致病性钩端螺旋体属（Leptospira spp.）病原菌引起，可通过直接接触受感染动物、其尿液或受污染的水与土壤传播。由于缺乏交叉保护（heterologous protection，目前已发现超过250种致病性钩端螺旋体血清型（serovars））且接种该疫苗会引发严重不良反应，灭活钩端螺旋体疫苗（inactivated leptospirosis vaccines，或称菌苗（bacterins））仅在少数国家获批使用。当前，研究已转向重组疫苗（recombinant vaccines），以期解决上述问题。然而，由于缺乏标准化动物模型（standardised animal models）、严谨的统计分析方法且可重复性较差，该策略收效甚微。本研究在钩端螺旋体病仓鼠模型（hamster model）中，评估了基于钩端螺旋体免疫球蛋白样B蛋白（leptospiral immunoglobulin-like B protein）保守区域（LigB(131–645)）与氢氧化铝（aluminium hydroxide, AH）佐剂的亚单位疫苗（subunit vaccine）制剂。在7项独立实验中，该疫苗可为接种动物提供显著的死亡保护（保护率达80.0%~100%，P < 0.05）。LigB(131–645)/AH疫苗的保护效力介于87.5%~100%之间，且我们在接种存活动物中观察到了无菌免疫（sterile immunity，发生率为87.5%~100%）。接种动物体内可诱导产生高水平的免疫球蛋白M（IgM）与免疫球蛋白G（IgG），但该抗体水平与免疫保护并无关联。与菌苗接种仓鼠体内以IgG2为主的抗体亚型谱不同，亚单位疫苗诱导产生的是IgG1/IgG2混合亚型谱。上述研究结果表明，LigB(131–645)是一款抗钩端螺旋体病的候选疫苗，其在公共卫生与兽医卫生领域均具有潜在应用价值。