Vaccine Adjuvants Revisited

A huge amount of evidence has been made available on various adjuvants as immunological auxiliaries. Very few of them, however, have made it into commercial vaccines. Their defining properties and uses are discussed in the following mini-review. WHAT IS AN ADJUVANT? In Freund's words [1] an adjuvant should “evoke very abundant serum antibody production sustained for an unexpectedly long time”. In other words, it is something very practical. It must work in animals at least the size of sheep and of course in both veterinary and human vaccination. To this end it must be thoroughly biocompatible, easy to handle and to store, sterile, safe, acceptable for registration as an auxiliary in vaccination and, last but not least, must have an affordable price. “Abundant serum antibody production” moreover always seems to go hand-in-hand with a host of other beneficial cellular immunostimulatory effects. WHAT IS NOT AN ADJUVANT? The following are not adjuvants: Any soluble or insoluble substance producing antibodies only in mice (which then have to take the blame for “lying”), and also immunopotentiators (showing saturation doses) or immunomodulators (showing dose optimum and even inhibition at the high end). Examples are: water soluble muramyl peptides, saponins, liposaccharides, hormones. These one might characterize as “adjuvants for adjuvants”, or, in a word, pseudo-adjuvant. Undoubtedly they are important in special cases, but their usefulness is more remote. Whether, for instance, the glycopeptide GMDP, a powerful cellular promotor is of any real use in a vaccine unfortunately cannot be established with a few mice but requires field tests with 2000 volunteers. This typifies the vaccine adjuvant dilemma. ALUMINUM HYDROXIDE GELS A.T. Glenny [2] (1926) and his colleagues introduced the notion that the “antigenic value” of a toxoid is higher if it is not in solution, but comes attached to solid particles, and they proposed immunizing with a precipitate of aluminium hydroxide containing adsorbed diphtheria toxin. Merschheimer [3] introduced preformed, standardized alumina gels which can absorb the protein antigen in a truly industrial process. The first practically usable “Alhydrogel” was delivered to a vaccine manufacturer in 1939. *Address correspondence to this author at the Gerbu Biotechnik GmbH, D69251 Gaiberg, Germany; E-mail: [email protected] A long way from Glenny's test tube material were the salts, removed in tonnage level from the alumina precipitate, which, after heat sterilization and pH adjustment, remained economically priced. Then was a good time: alumina gels were easy to use and easy to understand, regulatory hurdles were zero. The gels could be put into the vaccine just like a special kind of buffer. So manufacturers liked to use them.