Adjuvant technology: a powerful brew

Shakespeare's witches, in 'Macbeth', were concocting mischief, not some nostrum to ward off plague, but some of the things that imbue today's vaccines with immunogenic fizz would not have been misplaced among the eldritch ingredients in their cauldron.

The list of exotica in modern adjuvants ranges from versatile alum and extracts from dahlia tubers and the bark of obscure South American trees, to the lipophilic creations of latter-day alchemists.

An adjuvant's role is to awaken the immune system to the antigens in a new vaccine -- as one Australian immunologist describes it, not with a kiss, but a toxic slap across the face.

Sometimes the immune system slumbers on, or opens only one eye, mounting an ineffectual antibody response when the situation calls for a strong cytoxic T-cell response to weed out cancerous or infected cells.

Many promising new vaccines, including the peptide vaccines that were expected to revolutionise protection against infectious disease and cancer, have failed because, while they showed promise in inbred laboratory mice, they didn't work in outbred humans.

Even some trusted conventional vaccines don't elicit a fully protective response in some individuals.

Flinders Medical Centre endocrinologist and immunologist Prof Nikolai Petrovsky says health authorities tend to avoid mentioning the shortcomings of current influenza vaccines when recommending an annual jab for people with chronic heart or lung disorders.

Petrovsky, who is also professor of medical informatics at the University of Canberra, and chairman and scientific director of Canberra-based vaccine developer Vaxine, says an adjuvant typically boosts antibody production by a hundredfold or more, but most attenuated-virus influenza vaccines are made without an adjuvant.

Some 40 per cent of individuals who submit to an annual flu jab may not realise they may be completely protected against current epidemic strains of the virus represented in the latest vaccine.

Up to 90 per cent of the vaccine consists of purified haemagglutinin protein, which is not highly immunogenic. The basic problem, says Petrovsky, is that the standard adjuvant, alum, doesn't work in conventional influenza vaccines.

In a minority of individuals, the antibody response may be insufficient to prevent influenza. Like many vaccines, the flu' vaccines also fail to elicit a strong cytotoxic T-cell response to destroy virus-infected cells lining the respiratory tract.

Petrovsky says decades of research have yielded only a limited choice of proven adjuvant. Only three, including alum, are approved for human use. Another 200-odd compounds work well in laboratory rodents, but toxicity precludes their use in human vaccines.

Chiron Corp had well-publicised quality-control problems last year, with the flu vaccines produced by its UK plant, which lack an adjuvant. In Italy, another Chiron facility makes a flu vaccine containing a proprietary adjuvant, but the vaccine is only licensed in a small number of countries.

Petrovsky says that if Vaxine's Advax adjuvant can boost the immunogenicity of influenza vaccines, manufacturers could reduce the level of viral proteins in their vaccines, allowing production facilities to produce up to twice as many doses from the same number of embryonated eggs.

Many adjuvants are products of suck-it-and-see experimentation. 'Designer' adjuvants, based on insights into the way the immune system recognises and processes alien antigens, have remained an elusive goal -- until now.

Vaccine technology may have vaulted from black art to solid science with the discovery by Dr Magda Plebanski's research team at Melbourne's Austin Research Institute that dendritic cells -- the immune system's forward sentries -- are uniquely adapted to process virus-sized antigenic particles.

The magical measure is around 40 microns. Dendritic cells, when presented with antigens bound to synthetic particles of this size, send the immune system into overdrive, dramatically boosting both humoral and cell-mediated immunity. Melbourne vaccine developer PanVax, a subsidiary of Perth-based biomedical investment company Prima BioMed (ASX:PRR), is commercialising the discovery (see 'Adjuvants: The problem with peptides and the DCtag advantage',).

See: "Adjuvants: the players" for a who's who of adjuvant research in Australia