Antibodies, vaccines and adjuvants - Pharmaceutical Biotechnology: Concepts and Aapplications - page 416

aluminium-based products display poor/no adjuvanticity when combined with some antigen (e.g.
typhoid or Haemophilus infl uenzae type b capsular polysaccharides).

13.5.3 Oil-based emulsion adjuvants

The adjuvanticity of oil emulsions was fi rst recognized in the early 1900s. However, the fi rst such
product to gain widespread attention was Freund's complete adjuvant (FCA), developed in 1937.
This product essentially contained a mixture of paraffi n (i.e. mineral) oil with dead mycobacteria,
formulated to form a water-in-oil emulsion. Arlacel A (mannide mono-oleate) is usually added as
an emulsifi er.
Freund's incomplete adjuvant (FIA) is a similar product. It differs from FCA in that it lacks the
mycobacterial component and, consequently, displays somewhat lesser adjuvanticity. The mode
of action of FIA is largely attributed to depot formation. The mycobacterial components in FCA
have additional direct immunostimulatory activities. Although it is one of the most potent adjuvant
substances known, FCA is too toxic for human use.
Latterly, some oil-in-water adjuvants have been developed. Many are squalene-in-water emul-
sions. Emulsifi ers most commonly used include polyalcohols, such as Tween and Span. In some
cases, immunostimulatory molecules (including MDP and TDM; see Section 13.5.4) have also
been incorporated in order to enhance adjuvanticity. These continue to be carefully assessed and
may well form a future family of useful adjuvant preparations.

13.5.4 Bacteria/bacterial products as adjuvants

Selected microorganisms have been identifi ed that can trigger particularly potent immunological
responses. The immunostimulatory properties of these cells have generated interest in their poten-
tial application as adjuvants. Examples include various mycobacteria, Corynebacterium parvum ,
Corynebacterium granulosum and B. pertussis . Although some such microorganisms are used
as antigens in vaccines, they are considered too toxic to be used solely in the role of adjuvant.
Researchers have thus sought to identify the specifi c microbial biomolecules responsible for the
observed immunostimulatory activity. It was hoped that these substances, when purifi ed, might
display lesser/no toxic side effects while retaining their immunostimulatory capacity.
Fractionation of mycobacteria resulted in the identifi cation of two cellular immunostimulatory
components, namely TDM and MDPs. Both are normally found in association with the mycobac-
terial cell wall. TDM is composed of a molecule of trehalose (a disaccharide consisting of two
molecules of 1-1 glycosidic bond), linked to two molecules of my-

colic acid (a long-chain aliphatic hydrocarbon-based acid) found almost exclusively in association
with mycobacteria. TDM, although retaining its adjuvanticity, is relatively non-toxic.
The structure of the native immunostimulatory MDPs was found to be N -acetyl muramyl- L -
alanyl- D -isoglutamine. ( N -Acetyl muramic acid is a base component of bacterial peptidoglycan.)
Native TDM is a potent pyrogen and is too toxic for general use as an adjuvant. The molecular
basis underlining MDP's adjuvanticity remains to be fully elucidated. Administration of MDP,
however, is known to activate a number of cell types that play direct/indirect roles in immune
function, and induces the secretion of various immunomodulatory cytokines (Table 13.14).

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