During experimentation

with tetanus and diphtheria toxoids in horses, Ramon observed that the addition of bread crumbs, tapioca this website (both starches) or saponin increased the yields of serum antibodies. In 1926, Glenny formulated the first adjuvanted vaccine by precipitation of diphtheria antigen onto particles of aluminium potassium sulphate. It was believed that aluminium compounds enhanced the response to antigens by extending the time during which antigen is available in the tissue (the so-called depot effect). It is known today that aluminium, like many of the new adjuvants described below, acts by direct activation of the innate immune cells. First use of adjuvants Adjuvants were initially developed for use in animals to increase the yield of serum antibodies for antitoxins. Water-in-oil emulsions as adjuvants were first introduced by Jules Freund in the 1930s. Like aluminium, this adjuvant

was designed to release antigen over an extended time period at the injection site, acting as an antigen carrier. The emulsion induced potent immune responses, but the high reactogenicity observed in humans was unacceptable. It was later established that the reactogenicity observed was due to impurities present in the mineral oil, and new formulations lacking impurities were subsequently developed. As mentioned GW-572016 in vivo above, aluminium salts work well for traditional bacterial toxoids and many of the currently available vaccines for which antibodies are the main correlate of protection. The induction of complex, integrated immune responses for diseases such as human immunodeficiency virus (HIV), has reignited the search for new classes of adjuvants, including improved water-in-oil emulsions with a less reactogenic profile than Freund’s original adjuvant. Table 4.1 shows several adjuvanted vaccines currently available in Europe and the USA, some of which contain single novel adjuvants or a combination of adjuvants.

Pathogens contain intrinsic triggers of immune defence, PAMPs, which are recognised by cells of the innate immune system and are necessary to elicit a robust immune response (see Chapter 2 – Vaccine immunology). Some inactivated and subunit vaccines lose part or most those of the pathogen’s intrinsic immunostimulatory ability due to the inactivation or purification processes. These vaccines therefore require adjuvants in order to enhance an antigen-specific adaptive immune response. Expected benefits of adjuvants 1. Stronger immune priming: – Faster immune response Sentinel immune cells are equipped with innate receptors, the so-called pattern recognition receptors (PRRs). These recognise PAMPs and allow them to distinguish between different broad types of organism such as bacteria, viruses and parasites (see Chapter 2 – Vaccine immunology). Possible impact of adjuvants on immune mechanisms 1.