Molecular design versus empirical discovery in peptide-based vaccines. Coming to terms with fuzzy recognition sites and ill-defined structure-function relationships in immunology.

In view of our increased understanding of the molecular basis of immunological recognition, it is commonly believed that it should be possible to apply molecular design strategies to the development of peptide-based vaccines. The stated aim is to transform the development of a vaccine from a trial and error empirical operation into a so-called rational, structure-based process. In the present review, it is argued that it is misleading to oppose rational and empirical approaches in vaccine research since both are needed in the practice of experimental science. Many reasons are given for the view that the molecular design of synthetic vaccines is not a realistic scientific enterprise. The capacity of a peptide to induce a protective immune response depends on many extrinsic factors and regulatory mechanisms of the recipient host which are not amenable to molecular design of the peptide immunogen. It seems safe to predict that the development of peptide-based vaccines will continue to be driven by empirical discovery rather than by so-called rational design.