The aluminium salts, aluminium hydroxide and aluminium phosphate, are still the only adjuvants licensed for human use in the United States (Heimlich et al 1999; Kovarik & Siegrist 1998; Vogel 1998), and the only ones in the paediatric vaccines licensed for use in Australia (NHMRC 2000a), although France still favours the use of calcium phosphate (Léry 1994). There are limitations with the use of aluminium adjuvants, and so the potential of many other formulations is being examined (Gupta et al 1993; Gupta & Siber 1995). Some are candidates for human use, and a selection of these will be briefly discussed later.
In their favour, aluminium salts are credited with a good safety record. They fit the criteria of low reactogenicity and induction of good antibody response, although some local reactions do occur and increase with subsequent exposure. Their long history of use makes them difficult to replace. They are also inexpensive (Cox & Coulter 1997).
A significant problem with the preparation of aluminium adjuvants is that they are difficult to manufacture in a “physico-chemically reproducible way, thus resulting in batch to batch variations” (Gupta, 1998, p 156). A review in the 1960’s revealed that:
. . . specifications are practically nonexistent for controlling the chemical purity of the aluminium compounds used in the preparation of adjuvants for biologic products. (Piersma 1966, p 353)
To overcome this, in 1989, the World Health Organisation chose Alhydrogel, an aluminium hydroxide compound from Superfos Biosector in Denmark, as the standard preparation for inclusion in vaccines (Gupta et al 1995).
Another limitation of aluminium salts is that they are not active with all immunogens (Audibert & Lise 1993), and do not promote a cell mediated Th1 or cytotoxic T- lymphocyte response. They promote only a humoral, or Th2 lymphocyte response in both mice and humans, which is accompanied by the generation of IgE-mediated allergic reactions. This
. . . Th2 driving activity of aluminium salts is, therefore, a major
disadvantage for infant vaccines aiming at the induction of Th1 and CTL [cytotoxic T lymphocyte] responses to viral/bacterial agents. Such Th1 responses, which are difficult to elicit in early life, will be, furthermore, driven towards Th2 responses in the presence of aluminium salts. This could be of significant importance for certain new vaccines as the priming effect of this Th2-polarizing alum formulation could only be partially reverted even by boosting at adulthood with a strong Th1-driving adjuvant. (Kovarik & Seigrist 1998, p 226)
Particular care needs to be taken with this issue when multiple vaccines are
administered simultaneously. An example of this problem is found in the Australian Childhood Immunisation Schedule (NHMRC 2000a) where the aluminium salts, aluminium hydroxide and aluminium phosphate, are used as adjuvants in both the whole cell and acellular DTP vaccines. These are administered simultaneously with OPV which requires a Th1 or cell mediated response to promote protective
immunity. Further to this, the promotion of related IgE responses has relevance to the development of atopic or allergic conditions as will be discussed in Chapter 7.
Another concern with the use of aluminium adjuvants is their association with neurological conditions. Aluminium plays no known biological role in the body, and tends to accumulate in the tissues of the liver, kidney, spleen, bone, brain, heart and hair (Allen & Cumming 1998).
Aluminium has long been associated with neurological changes, especially Alzheimer’s disease. Aluminium causes changes in neuron structure and a breakdown of electrochemical neuro-transmission. Most of the research was done with Alzheimer’s patients and autopsies of brain tissue of affected individuals. It is only reasonable to suspect the immature brain structure of a small baby to be extremely vulnerable to aluminium compounds injected
into its system. (Griffin 1998, p 103)
The Provisional Tolerable Weekly Intake (PTWI) of aluminium as set by the Joint Expert Committee on Food Additives (World Health Organisation 1989) is 7mg of aluminium per kg of body weight.
The usual dose of aluminium used for human vaccines is around 0.5 mg. The upper allowable limit of aluminium adjuvants for injection in humans is 1.25 mg as per World Health Organisation regulations and 0.85 to 1.25 mg aluminium as per United States Food and Drug Administration guidelines. (Gupta 1998, p 161)
In the Australian Immunisation Handbook (NHMRC 1997) the conjugate Hib vaccine PedavaxHIB from CSL/Merck, Sharp & Dohme is noted as containing 225
g of aluminium per dose. Four injections (at 2,4,6 and 12 months) are required to
μ
complete the schedule.
The DTP whole cell vaccine (Triple Antigen by CSL) is adsorbed onto aluminium phosphate, and the DTP acellular vaccine (Infanrix by SmithKline Beecham) is adsorbed onto aluminium hydroxide. Although no mention is made of the amount of aluminium included in each dose either in the Handbook or in the product inserts for these vaccines, presumably it is within the WHO guidelines. Five injections (at 2,4,6 and 18 months, and at 4-5 years) are required to complete the schedule.
The Hepatitis B vaccine (Engerix-B by SmithKline Beecham) contains 0.5 mg/ml pf aluminium hydroxide. The paediatric dose is 0.5 ml, providing 0.25 mg aluminium. The schedule requires three injections. The initial dose is followed by another one a month later, and a final one six months later. Hepatitis B has been endorsed for all infants at birth (with follow up injections at 1 and 6-12 months) and is “strongly recommended” (NHMRC 2000a, frontispiece) if the mother is HBsAg+ [hepatitis B surface-antigen positive] and/or if the mother belongs to a group with a carrier rate of over 2%. This is a large proportion of the world’s population including Aboriginal
and Torres Strait Islanders, people from Asia, Africa, Oceania, Central and South America, Eastern Europe and the Mediterranean (NHMRC 2000a).
The cumulative total of aluminium in the paediatric schedule is therefore only a few grams and “minor compared to that of diet and medications, such as antacids” (Gupta 1998, p 165). However a major difference lies in the route of administration.
With the oral route, only a small percentage of the total ingested aluminium is absorbed into the body. The amount of aluminium absorbed from the
gastrointestinal tract may be influenced by a variety of factors including the
. . . overall composition of the diet and potential moderating effects of particular ions such as citrates, silicates, fluoride and phosphates and other substances . . . (Allen & Cumming 1998, p 11)
The details of this influence are not clearly understood, however, it is known that
. . . not all forms of dietary aluminium are available for absorption and that potential sites of absorption will differ throughout the gastro-intestinal tract. .
In vivo measurements suggested that only a small portion of aluminium is
potentially available for absorption throughout the small bowel . . . (Allen & Cumming 1998, p 54)
In contrast, when a dose of vaccine is injected into muscle tissue, all the aluminium present must be dealt with by the body. It is the lymphatic system, rather than the gastrointestinal tract that would be called upon to disperse and eliminate the aluminium in this situation. However, many aluminium compounds, including aluminium hydroxide and aluminium phosphate, are insoluble (Penney 1995) and are not biodegradable (Gupta 1998). Aluminium adjuvants have been found at the injection site in mice and guinea pigs up to one year later (Gupta 1998).
. . . studies suggest that children who had primary immunization with aluminium-adsorbed vaccines are more likely to develop antigen specific Ig E and higher frequency of local reactions on booster injection with soluble or aluminium adsorbed vaccines than children who had primary
immunization with unadsorbed vaccines. (Gupta 1998, p 165)
Findings such as these, and the connection of the systemic accumulation of aluminium with nervous system disorders and bone diseases have led some scientists (such as Gupta 1998; Mark et al 1975) to suggest the “need to re- evaluate aluminium compounds as vaccine adjuvants” (Gupta 1998, p 165).