While live vaccines such as the yellow fever vaccine or BCG contain their own stimuli (including endogenous toll-like receptor (TLR) ligands such as viral RNA or bacterial DNA), which stimulate the innate immune system and in effect act as their endogenous adjuvants, subunit vaccines such as recombinant protein vaccines need to be supplemented with exogenous substances to enhance their immunogenicity.
虽然黄热病疫苗或卡介苗等活疫苗含有自身的刺激物（包括内源性toll样受体（TLR）配体，如病毒RNA或细菌DNA），可以刺激先天免疫系统，并实际上充当其内源性佐剂，但重组蛋白疫苗等亚单位疫苗需要补充外源物质以增强其免疫原性。

The French veterinarian Gaston Ramon, while working at the Pasteur Institute in the 1920s, showed that coadministration of inactivated diphtheria toxin with other substances such as tapioca, lecithin, agar, oil, saponin, or breadcrumbs increased antitoxin antibody responses to diphtheria.
20世纪20年代，法国兽医Gaston Ramon在巴斯德研究所工作时发现，灭活白喉毒素与木薯、卵磷脂、琼脂、油、皂苷或面包屑等其他物质联合使用会增加对白喉的抗毒素抗体反应。

The British immunologist Alexander Glenny and colleagues, working at the Wellcome Physiological Laboratories in London, in an attempt to purify inactivated diphtheria toxin (toxoid) to make a vaccine, noticed that when aluminum sulfate was used in the purification process, the toxoid induced stronger antibody response in guinea pigs, compared to soluble toxoid. 26 , 71 This was the first demonstration of the adjuvant properties of alum, which has since been used in billions of doses of vaccines and is included in vaccines given to millions of people annually. However, despite its widespread use, for the 7 decades from its licensure in the 1920s till the late 1990s, alum remained the only adjuvant included in licensed vaccines such as the DTP or HPV vaccines. For this reason, the development of vaccine adjuvants has been described as one of the slowest processes in the history of medicine. 72 A major obstacle to the development of adjuvants is that despite the dozens of candidates that have shown promising results in preclinical models, only a small fraction has the safety profile required for licensure in humans.
英国免疫学家亚历山大-格兰尼及其同事在伦敦威康生理实验室工作时，试图提纯灭活白喉毒素（类毒素）以制成疫苗，他们注意到，在提纯过程中使用硫酸铝时，类毒素在豚鼠体内诱发的抗体反应比可溶性类毒素更强。这是明矾佐剂特性的首次展示，此后明矾被用于数十亿剂次的疫苗中，每年都有数百万人接种明矾疫苗。然而，尽管明矾被广泛使用，但从 20 世纪 20 年代获得许可到 20 世纪 90 年代末的 70 年间，明矾仍然是白喉、百日咳和破伤风三联疫苗或人类乳头瘤病毒疫苗等获得许可的疫苗中唯一使用的佐剂。因此，疫苗佐剂的开发被称为医学史上最缓慢的过程之一。佐剂开发的一个主要障碍是，尽管有数十种候选佐剂在临床前模型中显示出良好的效果，但只有一小部分具有人体许可所需的安全性特征。