Adjuvants: The problem with peptides and the DCtag advantage

Vaxine's Nikolai Petrovsky says peptide vaccines work well in highly inbred laboratory mice, but have consistently failed in clinical trials over the past two decades because humans are an outbred species.

The problem lies with the rich, individual variation in the genes of the human leukocyte antigen (HLA) complex on chromosome 6, which determine how antigen-presenting dendritic cells will dissect alien proteins and present their peptide fragments for recognition by the immune system's humoral and cytotoxic arms.

The dendritic cells of any two individuals are likely to produce quite different set of peptide fragments from the same viral or bacterial protein. Even if immunologists select a particular, conserved peptide fragment from a target protein, it may be strongly immunogenic in 5 per cent of the population, but ineffectual in the other 95 per cent.

Petrovsky says evidence suggests most peptides are weakly immunogenic simply because they are too small for the immune system to detect -- and adjuvants, while they may help, are unlikely to be enough to overcome the problem. The selected peptides in any one vaccine preparation are usually mismatched to all but a few of our species' huge repertoire of antigen-presenting HLA molecules.

To be effective, a peptide vaccine would need to contain an "horrendously expensive" mish-mash of thousands of different peptide fragments derived from the same protein.

Researchers are experimenting with peptides conjugated to large proteins, but none have yet reached the clinic.

The upside to being outbred, says Petrovsky, is that it provides insurance policy against devastating viral epidemics that have wiped out genetically isolated, inbred populations in the past.

The DCtag advantage

Recently, Australian Biotechnology News described how Dr Magda Plebanski's team at the Austin Research Institute showed that the simple technique of presenting antigens on virus-sized (~40m) particles rouses dendritic cells to vigorous action, generating powerful humoral and cytotoxic responses.

The Austin team has presented its commercial collaborator, Prima BioMed (ASX:PRR), with what may be the most significant advance in adjuvant technology in decades.

DCtag (dendritic cell-tag) technology, which has been licensed to Prima subsidiary Panvax, opens the way for the rational design of vaccines that will optimise the immune response against different classes of pathogens -- viruses, bacteria or parasites -- or tumours.