Group A streptococcus (GAS) species are responsible for a broad spectrum of human diseases, ranging from superficial to invasive infections, and are associated with autoimmune disorders. There is no commercial vaccine against GAS. The clinical manifestations of GAS infection may be attributable to the large repertoire of virulence factors used selectively in different types of GAS disease. Here, we selected five molecules, highly conserved among GAS serotypes, and involved in different pathogenic mechanisms, as a multicomponent vaccine, 5CP. Intranasal (i.n.) immunization with 5CP protected mice against both mucosal and systemic GAS infection across serotypes; the protection lasted at least 6 months. Immunization of mice with 5CP constrained skin lesion development and accelerated lesion recovery. Flow cytometry and enzyme-linked immunosorbent assay analyses revealed that 5CP induced Th17 and antibody responses locally and systemically; however, the Th17 response induced by 5CP resolved more quickly than that to GAS when challenge bacteria were cleared, suggesting that 5CP is less likely to cause autoimmune responses. These findings support that immunization through the i.n. route targeting multiple nonredundant virulence factors can induce immunity against different types of GAS disease and represents an alternative strategy for GAS vaccine development, with favorable efficacy, coverage, duration, and safety.IMPORTANCE GAS is among the most common human pathogens and causes a wide variety of diseases, likely more than any other microorganism. The diverse clinical manifestations of GAS may be attributable to its large repertoire of virulence factors that are selectively and synergistically involved in streptococcal pathogenesis. To date, GAS vaccines have not been successful due to multiple serotypes and postinfection sequelae associated with autoimmunity. In this study, five conserved virulence factors that are involved in GAS pathogenesis were used as a combined vaccine. Intranasal immunization with this vaccine induced humoral and cellular immune responses across GAS serotypes and protected against mucosal, systemic, and skin infections. The significance of this work is to demonstrate that the efficacy of GAS vaccines can be achieved by including multiple nonredundant critical virulence factors and inducing local and systemic immunity. The strategy also provides valuable insights for vaccine development against other pathogens.

中文翻译：

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多组分疫苗可通过血清型的A组链球菌提供针对局部和全身感染的免疫力。

A类链球菌（GAS）物种负责从浅表感染到侵入性感染的各种人类疾病，并与自身免疫性疾病相关。没有针对GAS的商业疫苗。GAS感染的临床表现可能归因于在不同类型的GAS疾病中选择性使用的大量毒力因子。在这里，我们选择了五个分子，它们是GAS血清型中高度保守的，并参与了不同的致病机制，作为多组分疫苗5CP。用5CP进行鼻内（in）免疫可保护小鼠免于跨血清型的粘膜和全身GAS感染；保护至少持续了6个月。用5CP免疫小鼠会限制皮肤病变的发展并加速病变的恢复。流式细胞仪和酶联免疫吸附试验分析表明，5CP可局部和全身诱导Th17和抗体反应。然而，当清除挑战细菌后，由5CP诱导的Th17应答比对GAS的应答更快，这表明5CP不太可能引起自身免疫应答。这些发现支持通过针对多个非冗余毒力因子的途中免疫可以诱导针对不同类型GAS疾病的免疫力，并代表了GAS疫苗开发的替代策略，具有良好的功效，覆盖范围，持续时间和安全性。常见的人类病原体并引起多种疾病，可能比其他任何微生物都多。GAS的多种临床表现可能归因于其大量的毒力因子，这些因子选择性地和协同地参与了链球菌的发病机理。迄今为止，由于多种血清型和与自身免疫有关的感染后后遗症，GAS疫苗尚未获得成功。在这项研究中，与GAS发病机理有关的五个保守毒力因子被用作联合疫苗。用这种疫苗进行鼻内免疫可诱导GAS血清型产生体液和细胞免疫应答，并能抵抗粘膜，全身和皮肤感染。这项工作的意义在于证明，可以通过包括多个非冗余关键毒力因子并诱导局部和全身免疫来实现GAS疫苗的功效。