Vaccines work primarily by eliciting antibodies, even when recovery from natural infection depends on cellular immunity. Large efforts have therefore been made to identify microbial antigens that elicit protective antibodies, but these endeavors have encountered major difficulties, as witnessed by the lack of vaccines against many pathogens. This review summarizes accumulating evidence that subdominant protein regions, i.e., surface-exposed regions that elicit relatively weak antibody responses, are of particular interest for vaccine development. This concept may seem counterintuitive, but subdominance may represent an immune evasion mechanism, implying that the corresponding region potentially is a key target for protective immunity. Following a presentation of the concepts of immunodominance and subdominance, the review will present work on subdominant regions in several major human pathogens: the protozoan Plasmodium falciparum, two species of pathogenic streptococci, and the dengue and influenza viruses. Later sections are devoted to the molecular basis of subdominance, its potential role in immune evasion, and general implications for vaccine development. Special emphasis will be placed on the fact that a whole surface-exposed protein domain can be subdominant, as demonstrated for all of the pathogens described here. Overall, the available data indicate that subdominant protein regions are of much interest for vaccine development, not least in bacterial and protozoal systems, for which antibody subdominance remains largely unexplored.

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抗体反应的亚优势：对疫苗开发的影响

疫苗主要通过引发抗体起作用，即使从自然感染中恢复取决于细胞免疫。因此，已经做出了大量努力来鉴定引发保护性抗体的微生物抗原，但这些努力遇到了重大困难，正如缺乏针对许多病原体的疫苗所证明的那样。这篇综述总结了越来越多的证据，即亚优势蛋白区域，即引发相对较弱的抗体反应的表面暴露区域，对疫苗开发特别感兴趣。这个概念似乎违反直觉，但亚优势可能代表一种免疫逃避机制，暗示相应区域可能是保护性免疫的关键目标。在介绍免疫优势和亚优势的概念之后，恶性疟原虫，两种致病性链球菌，以及登革热和流感病毒。后面的部分专门介绍亚优势的分子基础、其在免疫逃避中的潜在作用以及对疫苗开发的一般意义。将特别强调一个事实，即整个表面暴露的蛋白质结构域可以是次要的，正如这里描述的所有病原体所证明的那样。总体而言，现有数据表明亚优势蛋白区域对疫苗开发很感兴趣，尤其是在细菌和原生动物系统中，抗体亚优势在很大程度上仍未被探索。