Oral vaccination with subunit vaccines protects animals against aerosol infection with Mycobacterium tuberculosis
Oral vaccination with subunit vaccines protects animals against aerosol infection with Mycobacterium tuberculosis
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DOI：
10.1128/iai.70.6.3111-3121.2002
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发表时间：
2002-06-01
影响因子：
3.1
通讯作者：
Andersen, P
中科院分区：
文献类型：
--
作者：
Doherty, TM;Olsen, AW;Andersen, P
对结核分枝杆菌的免疫在很大程度上依赖于细胞介导的反应的激活，而伽玛干扰素在人类和动物模型中都被证明在这一过程中发挥了关键作用。由于肺部通常是开始感染的器官，也是主要的病理部位，肺部的免疫反应在限制结核分枝杆菌初始感染方面发挥着重要作用。本研究的目的是通过靶向肠粘膜来刺激肺部的有效免疫。解毒单磷脂A(MPL)已被证明是一种相对无毒的佐剂，通过传统的皮下给药途径可以有效地促进1型反应的诱导。因此，我们将小鼠的皮下免疫与口服免疫进行了比较，方法是使用携带两种结核分枝杆菌免疫优势蛋白的模型亚单位疫苗，并结合基于MPL的佐剂。虽然用来启动应答的效果较差，但使用口服加强免疫的异种启动和加强接种策略诱导了显著的系统性1型反应，与皮下免疫方案达到的效果相当，甚至超过了皮下免疫方案。此外，观察到的增强的免疫反应与诱导对随后的强毒结核分枝杆菌气雾剂感染的实质性保护相关联，其水平与多次皮下接种所获得的水平相当或更好。这些结果表明，通过粘膜表面加强疫苗接种，通过结合有效的亚单位疫苗和强有力的佐剂MPL，可能是解决当前疫苗接种策略的一些缺点的有效方法。
Immunity against Mycobacterium tuberculosis depends largely on activation of cell-mediated responses, and gamma interferon has been shown to play a crucial role in this process in both humans and animal models. Since the lung is normally the organ in which infection is initiated and is the major site of pathology, immune responses in the lung play a significant role in restricting initial infection with M. tuberculosis. The aim of the present study was to stimulate efficient immunity in the lung by targeting the gut mucosa. Detoxified monophosphoryl lipid A (MPL) has been shown to be a relatively nontoxic adjuvant which efficiently promotes the induction of type 1 responses when it is given by the traditional subcutaneous route. We have therefore compared subcutaneous immunization of mice to oral immunization by using a model subunit vaccine carrying two immunodominant proteins from M. tuberculosis, in combination with MPL-based adjuvants. While less effective when used to prime a response, a heterologous priming and boosting vaccination strategy employing oral boosting induced significant systemic type 1 responses which equaled and surpassed those attained by subcutaneous immunization protocols. Moreover, the increased immune responses observed correlated with the induction of substantial protection against subsequent aerosol infection with virulent M. tuberculosis at levels comparable to, or better than, those obtained by multiple subcutaneous vaccinations. These results demonstrate that booster vaccinations via mucosal surfaces, by combining efficient subunit vaccines with the potent adjuvant MPL, may be an effective method of addressing some of the shortcomings of current vaccination strategies.