Serotype-independent pneumococcal experimental vaccines that induce cellular as well as humoral immunity
Serotype-independent pneumococcal experimental vaccines that induce cellular as well as humoral immunity
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DOI：
10.1073/pnas.1121383109
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发表时间：
2012-03-06
影响因子：
11.1
通讯作者：
Anderson, Porter W.
中科院分区：
文献类型：
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作者：
Malley, Richard;Anderson, Porter W.
为了预防婴儿期肺炎链球菌（肺炎球菌）感染，蛋白偶联荚膜多糖疫苗提供了抗体型特异性、抗体介导的免疫，但不能覆盖所有90多种荚膜血清型。因此，微生物学家一直在寻找所有菌株共有的保护性非荚膜抗原。或者，我们研究了非胶囊化菌株的死亡细胞，该细胞暴露了许多此类共同抗原。鼻内给予小鼠，该疫苗增强抗体非依赖性、CD 4 + T淋巴细胞依赖性，加速细胞因子IL-17 A介导的各种血清型肺炎球菌从鼻咽的清除。这种免疫力可以复制在荚膜抗体产生之前在婴儿中发展的天然抵抗力。通过注射给予，灭活细胞疫苗诱导双功能免疫：血浆抗体保护免受致命性肺炎攻击，以及IL-17 A介导的鼻咽清除。计划通过肌肉注射对这种廉价的候选疫苗进行人体试验。细菌细胞疫苗是复杂的，这是对可重复性的挑战。然而，当删除几种已知的保护性抗原时，灭活的肺炎球菌疫苗仍然具有保护性。这种抗原冗余可以防止疫苗逃逸变异的重组损失，这是常见的肺炎球菌。还设计了具有双功能活性的生物化学定义的免疫原。这些免疫原是三组分缀合物，其中细胞壁磷壁酸（能够活化T细胞的常见抗原）与两种常见肺炎球菌蛋白的遗传融合物偶联：保护性表面抗原和肺炎球菌溶血素的衍生物，其提供TLR 4激动剂活性并诱导抗毒性免疫。这样的构建体在鼻内给予时诱导加速清除，并且在注射时诱导两种免疫机制。定义的组成允许结构-功能活性分析。
For prevention of Streptococcus pneumoniae (pneumococcus) infections in infancy, protein-conjugated capsular polysaccharide vaccines provide serotype-specific, antibody-mediated immunity but do not cover all of the 90+ capsule serotypes. Therefore, micro-biologists have sought protective noncapsular antigens common to all strains. Alternatively, we investigated killed cells of a non-capsulated strain, which expose many such common antigens. Given to mice intranasally, this vaccine elicits antibody-independent, CD4+ T lymphocyte-dependent accelerated clearance of pneumococci of various serotypes from the nasopharynx mediated by the cytokine IL-17A. Such immunity may reproduce the natural resistance that develops in infants before capsular antibodies arise. Given by injection, the killed cell vaccine induces bifunctional immunity: plasma antibodies protective against fatal pneumonia challenge, as well as IL-17A-mediated nasopharyngeal clearance. Human testing of this inexpensive candidate vaccine by intramuscular injection is planned. Bacterial cellular vaccines are complex-a challenge for reproducibility. However, when several known protective antigens were deleted, the killed pneumococcal vaccine was still protective. This antigenic redundancy may prevent vaccine escape variants by recombinational loss, which is frequent in pneumococcus. Biochemically defined immunogens with bifunctional activity have also been devised. These immunogens are three-component conjugates in which cell wall teichoic acid (a common antigen capable of T cell activation) is coupled to a genetic fusion of two common pneumococcal proteins: a protective surface antigen and a derivative of pneumolysin, which provides TLR4 agonist activity and induces antitoxic immunity. Such constructs induce accelerated clearance when given intranasally and induce both immune mechanisms when injected. The defined composition permits analysis of structure-function activity.