Newer approaches to vaccine development

There are a great variety of diseases - viral, bacterial and parasitic - for which no vaccines are available. The need is great: five parasitic diseases alone affect about one-quarter of the world's population. Reasons such as the inability to grow sufficient of the organism either in vitro or in an animal, the complex nature of the infectious process (often including substantial suppressor effects), a lack of understanding of the basis of many chronic and persisting infections, all contribute to the lack of progress in vaccine development. Fortunately, techniques have become available which may overcome some of these restrictions.

Peptide-based preparations

In association with class I or II MHC antigens, specific linear amino acid sequences from foreign proteins may be recognized by the T cell receptor (TCR). By using a sufficient range of such sequences most people in an outbred population should respond. Peptide-based vaccines provide the opportunity to eliminate sequences which may cause immunosuppression or cross-react with self protein. There is great interest in this approach, but to date, no candidate vaccine based on peptides has been licensed. A putative vaccine to prevent malaria and containing several peptides from plasmodial proteins has shown moderate potential in some field trials, but was inactive in a recent trial in The Gambia.

There are fairly severe restrictions on this approach as any B cell epitopes would need to be continuous sequences and several T helper and CTI. epitopes would need to be included so that most people would respond. Special methods of presentation would be needed if a strong CTI. response was required. Generally, oligo- or polypeptides are poorly immunogenic, so usually a powerful potentiator, called an adjuvant, must be used to ensure an immune response.

Anti-idiotype preparations

A number of such preparations have been made and tested in different animal models to control either viral, bacterial or parasitic infections, and many have been relatively successful. But despite the obvious attractions of the approach, e.g. to mimic discontinuous epitopes or those composed of carbohydrate, no candidate vaccine has reached the licensing stage, and in view of the continuing developments with recombinant DNA technology, it seems unlikely that this approach will fulfill its earlier promise.

Approaches using recombinant DNA technology

The ability to manipulate DNA has transformed this area of biology. There are three main approaches with an extra one waiting in the wings. These are as follows.

1. Transfection of cells with DNA coding for the antigen(s) in question. Three classes of cells have been used - bacteria, lower eukaryotes such as yeast, and mammalian cells.

2. The construction of chimeric viruses or bacteria which, upon infection of cells, will express the inserted foreign DNA.

3. Direct immunization with a plasmid containing the foreign DNA.

4. The possibility of producing the antigens in DNA-transfected plants, such as banana, potato or tobacco.

Transfection of bacteria is appropriate for generating relatively simple proteins, such as occur in bacteria and some parasites, but limitations on post-trans-lational processing restrict this approach. Trans-fected yeast, the source of the first genetically engineered vaccine, the hepatitis B viral vaccine composed of the surface antigen (HBsAg), has also considerable promise for some other products. For some preparations, e.g. viral glycoproteins, transfected mammalian cells - either primary cells (e.g. monkey kidney), cell strains (a finite capacity to replicate) or cell lines (immortalized cells) - offer great promise. All have been used successfully for veterinary vaccines, and will find increasing use in the future for medical products.

Chimeric live vectors In this approach, DNA coding for the antigen is inserted into the genome of an appropriate live virus or bacteria (frequently an existing vaccine). Upon infection, the DNA is expressed with the production of the foreign antigen either in the chimeric virus-infected cell or in the bacterium. Table 3 lists some of the vectors used successfully for this purpose. Each has its advantages and disadvantages. Vaccinia virus has mainly been used and the list of antigens expressed by different vaccinia constructs is now quite long. Though none is yet licensed for medical use, two veterinary vaccines are in use: a vaccinia-rabies glycoprotein construct used in the field to immunize foxes and similar pests, and a vaccinia-rinderpest antigen construct used in Africa to vaccinate cattle. Several vaccinia constructs have successfully undergone clinical trials.

DNA (genetic) immunization When mice are injected intramuscularly with plasmids containing DNA coding for foreign antigens, long-lived immune responses, including both antibody and CTL, occur after a single inoculation. A modification which uses much less antigen has been to coat gold microbeads with the plasmid and inject into skin epithelia with a 'gene gun'. This technique holds great promise in many ways, e.g. the plasmids should be inexpensive to make and effective in the presence of antibody to the donor agent. The next few years should see just how good this approach may be in humans.

Plants as sources of future vaccines? There are encouraging early experiments showing that some antigens can be produced by transfected plants, and even molecules as complex as antibodies have been prepared in this way.

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