Pneumococcal strains used in this study.

Despite the implementation of conjugate vaccines in several countries, S. pneumoniae continues to pose a great burden worldwide, causing around 1 million annual deaths. Pneumococcal proteins have long been investigated as serotype-independent vaccines against this pathogen, with promising results. However, it is a consensus that one antigen alone will not be sufficient to provide long-term protection with wide coverage. Amongst the most well studied pneumococcal proteins are PspA and pneumolysin (Ply), two major virulence factors required by the bacterium for successful invasion of host tissues. PspA is highly immunogenic and protective, but it is structurally variable; pneumolysin is conserved among different pneumococci, but it is toxic to the host. To overcome these limitations, N-terminal PspA fragments have been genetically fused to non-toxic pneumolysin derivatives (PlD) to create PspA_PlD chimeras. Mouse immunization with these fusions confers protection against pneumococcal strains expressing heterologous PspAs, which correlates with antibody-induced complement C3 deposition on the surface of multiple pneumococcal strains. Analysis of mutant strains lacking PspA or Pneumolysin shows that both proteins contribute to the antibody-mediated enhancement in complement deposition induced by the fusion. These results expand previous data evaluating PspA_PlD and demonstrate that the fusion combines the protective traits of both proteins, inducing antibodies that efficiently promote complement deposition on multiple strains and cross-protection.

尽管多个国家已推行结合疫苗（conjugate vaccines）的免疫接种计划，肺炎链球菌（Streptococcus pneumoniae，S. pneumoniae）仍在全球范围内造成沉重疾病负担，每年导致约100万人死亡。长期以来，肺炎链球菌蛋白作为针对该病原菌的血清型独立疫苗（serotype-independent vaccines）被广泛研究，并取得了颇具前景的研究成果。然而学界普遍达成共识：单一抗原无法提供兼具广谱覆盖性的长期保护。目前研究最为深入的肺炎链球菌蛋白包括PspA与肺炎溶血素（pneumolysin, Ply），二者均为该细菌成功侵袭宿主组织所必需的主要毒力因子（virulence factors）。PspA具有极强的免疫原性与保护效力，但其结构存在较高变异性；肺炎溶血素在不同肺炎链球菌菌株中保守性良好，却会对宿主产生毒性。为克服上述局限，研究人员将N端PspA片段与无毒性的肺炎溶血素衍生物（PlD）进行基因融合，构建得到PspA_PlD嵌合蛋白。小鼠免疫实验显示，该融合蛋白可对表达异源PspA的肺炎链球菌菌株提供保护，这一效应与抗体介导的补体C3（complement C3）在多种肺炎链球菌菌株表面的沉积密切相关。对缺失PspA或肺炎溶血素的突变菌株进行分析后发现，这两种蛋白均可增强融合蛋白诱导的抗体介导补体沉积过程。本研究结果拓展了此前针对PspA_PlD嵌合蛋白的研究数据，证实该融合蛋白兼具两种蛋白的保护特性，可诱导能够高效促进多种菌株表面补体沉积的抗体，从而实现交叉保护。