Some Aspects of Active Immunization

Development of Vaccine Adjuvants: A Historical Perspective

“…Adjuvant research began in earnest with the development of diphtheria subunit toxoid [6] vaccines due to the weak immunogenicity observed with these vaccines [7][8][9]. As noted by Freund: "Interest in promoting antibody formation by addition of unrelated substances to antigens has never been lacking" [10]. Substances such as agar, tapioca, lecithin starch oil, saponin, salts of calcium and magnesium, killed Salmonella typhi, and even bread crumbs were tested [6,11,12].…”

“…Freund demonstrated similar increased antibody responses using live TB with oils. Freund made two jumps in the technology in the 1930s with the substitution of killed TB for live TB and the use of a water-in-oil emulsion [24], inspired by repository formulation techniques being used at the time [10]. The water-in-oil emulsion was formed by the mixture of one volume of 10% Arlacel A (mannide monooleate) and 90% mineral oil with one volume of antigen solution.…”

“…The water-in-oil emulsion was formed by the mixture of one volume of 10% Arlacel A (mannide monooleate) and 90% mineral oil with one volume of antigen solution. This system became the standard for adjuvant activity when Freund demonstrated that the emulsion without killed TB was almost as potent as the emulsion with killed TB when used as an adjuvant with diphtheria toxoid and far exceeded the potency of an alum-toxoid formulation [10]. These emulsions went on to become the standard potent adjuvant systems used in preclinical settings and became known as complete Freund's adjuvant (CFA, with killed TB) and incomplete Freund's adjuvant (IFA, without TB).…”

“…It was postulated that alum worked by means of a slow-release depot system [14]. Freund attributed the activity of the water-in-oil emulsion in some part to extended antigen presentation [10]. In this era, adjuvant discovery scientists appeared to be closely involved with immunologists of the day, with adjuvant mechanisms contributing to immunological theory.…”

“…Oil-in-water emulsions judged to be ineffective when using mineral oil [10] were reexamined when Ribi and co-workers found antitumor activity with trehalose dimycolate surfaces on drakeol oil-in-water emulsions [214]. The somewhat-toxic trehalose dimycolate surface was replaced with pluronic polyol block polymer surfactants, and a correlation was established between the hydrophile-lipophile balance (HLB) and activity [215].…”