Aluminum adjuvants vaccines

Following intramuscular administration of aluminum hydroxide or aluminum phosphate vaccine adjuvants in rabbits, increased levels of26Al were found in the kidney, spleen, liver, heart, lymph nodes, and brain (in decreasing order of aluminum concentration) (Flarend et al. 1997). 

Flarend RE, Hem SL, White JL, et al. 1997. In vivo absorption of aluminum-containing vaccine adjuvants using 26Al. Vaccine 15 1314-1317. 

Many compounds can act as adjuvants. Their classification is made difficult by the variety in chemical composition and the overlapping, often poorly understood, mechanisms of action. Only aluminum adjuvants are approved by the FDA for use in human vaccines. Quil A is a saponin that is commonly used as an adjuvant in veterinary vaccines and is also a component of immune-stimulating complexes (ISCOM). These adjuvants are addressed in some detail below. A detailed discussion of other types of adjuvants can be found in recent books and reviews on this subject. 

Aluminum adjuvants in human vaccines are either aluminum hydroxyphosphate (commonly referred to as aluminum phosphate) or aluminum oxyhydroxide (aluminum hydroxide). Aluminum-based vaccines are prepared by adsorption of antigen to commercial aluminum hydroxide or aluminum phosphate gels or by mixing antigen with alum (potassium aluminum sulfate),... 

Aluminum adjuvants are universally used in diptheria-tetanus-pertussis (DTP) vaccines and in most hepatitis B vaccines and have an excellent safety record. They are not ideal adjuvants, however, because the enhancement of the immune response is relatively weak, they are not effective with all antigens, and, most important, they only enhance the humoral (type 2) immune response and have little effect on the cell-mediated (type 1) immune response. 

Lindblad EB. Aluminum adjuvants — in retrospect and prospect. Vaccine 2004 22 3658-3668. 

There also is a marketed Lyme disease vaccine containing recombinant OspA (31,115,116). The vaccine is a sterile suspension of a noninfectious recombinant vaccine containing an immunodominant outer surface protein of Borrelia burgdorferi known as lipoprotein OspA. The antigen is adsorbed onto aluminum hydroxide as an adjuvant. Vaccine efficacy against definite Lyme disease is 78% after three doses. 

Seeber S.J., White J.L., and Helm S.L. 1991. Predicting the adsorption of proteins by aluminum-containing adjuvants. Vaccine 9 201. 

Adjuvants are substances which can modify the immune response of an antigen (139,140). With better understanding of the functions of different arms of the immune system, it is possible to explore the effects of an adjuvant, such that the protective efficacy of a vaccine can be improved. At present, aluminum salt is the only adjuvant approved for use in human vaccines. New adjuvants such as QS-21, 3D-MPL, MF-59, and other liposome preparations are being evaluated. Several of these adjuvants have been in clinical trial, but none have been approved for human use. IL-12 has been proposed as an adjuvant which can specifically promote T-helper 1 ceU response, and can be a very promising adjuvant for future vaccine development. 

Gupta RK (1998) Aluminum compounds as vaccine adjuvants. Adv Dmg Deliv Rev 32 155-172... 

Toxoids are inactivated bacterial toxins. They retain the ability to stimulate the formation of antitoxin, which are antibodies directed against the bacterial toxin. Adjuvants are inert substances, such as aluminum salts (i.e., alum), which enhance vaccine antigenicity by prolonging antigen absorption. 

The effect of alum as adjuvant was also tested in the liposphere-vaccine formulation. In the presence of lipid A, enhanced immune response is obtained even in the absence of alum. This observation is very important because there is increasing concern about the toxic side effects of alum in the long term. Research has suggested a link between aluminum and diseases of the brain, including Alzheimer s disease. 

Very often, vaccines are formulated with certain substances to enhance the immune response. These substances are called adjuvants (from the Latin adju-vare, which means to help ). The most common adjuvants for human use are aluminum hydroxide, aluminum phosphate, and calcium phosphate. Other adjuvants being used include bacteria and cholesterol. Mineral oil emulsions are normally the adjuvants used in animal studies. The adjuvant known as Freund s complete adjuvant consists of killed tubercle bacilli in water-inmineral oil emulsion, and Freund s incomplete adjuvant is a water-in-oil emulsion. Both these adjuvants are effective in stimulating an immune response, but they cause unacceptable side effects in humans (see Table 4.2). 

A dose of vaccine containing ILf (2-2.5 pg) tetanus toxoid in aluminum phosphate adjuvant at pH 6.0 (1 1) (TT j) or a dose of adjuvant alone in a dose corresponding to the dose given with the vaccine (ADJ) is administered intramuscularly. The administration site is the left hind leg quadriceps see Note 11). 

Very often whole-killed vaccines are formulated with adjuvants, which are designed to enhance vaccine persistence and induction of immune responses. However, the only adjuvant currently approved by FDA for clinical use is alum, in the form of vaccines complexed with aluminum hydroxide or aluminum sulfate. Even with the help of alum adjuvants, inactivated vaccine antigens are presented to APC extracellularly, as opposed to intracellularly, leading to a bias toward antibody-mediated responses. Little or no cell-mediated response to whole-killed vaccines with alum adjuvant renders some vaccines ineffective. 

A wide variety of materials have been explored for their adjuvant activity, although not all are equally effective or nontoxic, especially in humans. Alum and other aluminum salts were first recognized in 1926 and remain the most effective agents licensed for human use by the FDA, although some French products also use calcium phosphate. However, in recent years it has become evident that new and improved vaccine adjuvants are needed. 

Adjuvants. Adjuvants are substances which can modify the immune response of an antigen. With better understanding of the functions of different aims of the immune system, it is possible to explore the effects of an adjuvant, such that the protective efficacy of a vaccine can be improved. At present, aluminum salt is the only adjuvant approved for use in human vaccines. 

Garcon, N. Development and evaluation of AS04, a novel and improved adjuvant system containing MPL and aluminum salt. In Schijns, V., O Hagan, D. (eds), Immunopotentiators in Modem Vaccines. Academic Press, London (2005), pp. 161-178. 

The final vaccine contains the two toxoids, as well as pertussis (whole cell or acellular), a buffer, and an adjuvant, ie, a substance that increases the response to an antigen when combined with the antigen, eg, aluminum. As noted above, the final vaccine can also contain a component that protects against Haemophilus disease. 

Aluminum, in the form of aluminum hydroxide, aluminum phosphate or aluminum potassium sulfate, is used as adjuvant in various vaccine formulations to elicit an increased immunogenic response. 

Hem, S.L. White, J.L. Structure and properties of aluminum-containing adjuvants. In Vaccine Design. The Subunit and Adjuvant Approach Powell, M.F., Newman, M.J., Eds. Plenum Press New York, 1995 249-276. 

Aluminum hydroxide adjuvant is used in parenteral human and veterinary vaccines. It activates Th2 immune responses, including IgG and IgE antibody responses. It is also used for the isolation of certain serum components such as blood clotting factors. ... 

---