Traditional vaccination approaches (e.g. live attenuated or killed microorganisms) are among the most effective means to prevent the spread of infectious diseases. These approaches, nevertheless, have failed to yield successful vaccines against many important pathogens. To overcome this problem, methods have been developed to identify microbial components, against which protective immune responses can be elicited. Subunit antigens identified by these approaches enable the production of defined vaccines, with improved safety profiles. However, they are generally poorly immunogenic, necessitating their administration with potent immunostimulatory adjuvants. Since few safe and effective adjuvants are currently used in vaccines approved for human use, with those available displaying poor potency, or an inability to stimulate the types of immune responses required for vaccines against specific diseases (e.g. cytotoxic lymphocytes (CTLs) to treat cancers), the development of new vaccines will be aided by the availability of characterized platforms of new adjuvants, improving our capacity to rationally select adjuvants for different applications. One such approach, involves the addition of microbial components (pathogen-associated molecular patterns; PAMPs), that can stimulate strong immune responses, into subunit vaccine formulations. The conjugation of PAMPs to subunit antigens provides a means to greatly increase vaccine potency, by targeting immunostimulation and antigen to the same antigen presenting cell. Thus, methods that enable the efficient, and inexpensive production of antigen-adjuvant fusions represent an exciting mean to improve immunity towards subunit antigens. Herein we review four protein-based adjuvants (flagellin, bacterial lipoproteins, the extra domain A of fibronectin (EDA), and heat shock proteins (Hsps)), which can be genetically fused to antigens to enable recombinant production of antigen-adjuvant fusion proteins, with a focus on their mechanisms of action, structural or sequence requirements for activity, sequence modifications to enhance their activity or simplify production, adverse effects, and examples of vaccines in preclinical or human clinical trials.

传统的疫苗接种方法（例如减毒或杀死的活微生物）是预防传染病传播的最有效手段。然而，这些方法未能成功产生针对许多重要病原体的疫苗。为了克服这个问题，已经开发了鉴定微生物成分的方法，针对微生物成分可以引发保护性免疫应答。通过这些方法鉴定的亚基抗原能够生产确定的疫苗，并具有改进的安全性。但是，它们通常免疫原性差，因此需要与有效的免疫刺激佐剂一起给药。由于目前在批准用于人类的疫苗中很少使用安全有效的佐剂，而可用佐剂的功效却很差，或无法刺激针对特定疾病的疫苗（例如，用于治疗癌症的细胞毒性淋巴细胞（CTL））所需的免疫应答类型，新疫苗的开发将得益于新佐剂特征性平台的提供，从而提高了我们的能力。合理选择适合不同应用的佐剂。一种这样的方法涉及在亚单位疫苗制剂中添加微生物成分（病原相关的分子模式； PAMP），这些成分可以刺激强烈的免疫反应。通过将免疫刺激和抗原靶向同一抗原呈递细胞，PAMP与亚基抗原的缀合提供了一种大大提高疫苗效力的方法。因此，可以有效，抗原-佐剂融合物的廉价生产是提高针对亚基抗原的免疫力的令人兴奋的手段。本文中，我们综述了四种基于蛋白质的佐剂（鞭毛蛋白，细菌脂蛋白，纤连蛋白的额外域A（EDA）和热休克蛋白（Hsps）），可以将它们遗传融合到抗原上，从而重组产生抗原-佐剂融合蛋白，重点关注它们的作用机理，活性的结构或序列要求，增强其活性或简化生产的序列修饰，不良作用以及临床前或人类临床试验中的疫苗实例。