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Towards an understanding of the adjuvant action of aluminium
Philippa Marrack, Amy S. McKee and Michael W. Munks
Abstract | The efficacy of vaccines depends on the presence of an adjuvant in conjunction with the antigen. Of these adjuvants, the ones that contain aluminium, which were first discovered empirically in 1926, are currently the most widely used. However, a detailed understanding of their mechanism of action has only started to be revealed. In this Timeline article, we briefly describe the initial discovery of aluminium adjuvants and discuss historically important advances. We also summarize recent progress in the field and discuss their implications and the remaining questions on how these adjuvants work.
Vaccines that consist of attenuated pathogens, such as the Sabin live polio vaccine, or killed pathogens, such as the Salk inactivated polio vaccine, contain endogenous adjuvants. However, vaccines that contain purified antigens, such as the diphtheria tetanuspertussis vaccine or the hepatitis A and hepatitis B vaccines, usually require the addition of an exogenous adjuvant to
increase the immune response to the antigens following immunization.
In the early 1900s, infections by Clostridium tetani and Corynebacterium diphtheriae were serious health issues owing to the pathology that is induced by tetanus and diphtheria toxins, respectively
(Timeline). Immunization with conjugates of
toxin and antibody, which were referred to as
toxinantitoxin, yielded better protection and fewer side effects than low-dose toxin alone1,
and it was proposed that the antitoxin enhanced the immune response of the recipient by slowly releasing antigen over time.
In the following years, further improvement came with the production of toxins thathad been inactivated with formalin or heat (referred to as toxoids), which could be used for immunization2,3.
In 1926, Alexander T. Glenny and colleagues reported that precipitation of antigen onto insoluble particles of aluminium potassium sulphate (BOX 1), known as potash alum, before immunization produced better antibody responses than soluble antigen alone, providing the first clue to the adjuvant properties of aluminium salts4. Following this discovery, aluminium salts were used in vaccine preparations with tetanus and diphtheria toxoids to protect against C. tetani and C. diphtheriae, respectively, and today insoluble aluminium salts are used worldwide as the principle adjuvants in clinical vaccines.
Glenny believed that aluminium...