Vaccine Manual 5
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PART 1 Overview: the present state of veterinary vaccine development Vaccine manual 5 uct of irnunity by veteir irnUn prop'.ylactic W.I. Morrison Infectious disease continues to be one of developments in the application of DNA the most important constraints on the technology, now provide a strong con- efficient production of farm livestock in ceptual framework for the rational devel- both developing and developed countries. opment of new vaccines. While vaccination and the therapeutic or This chapter will consider recent de- prophylactic use of drugs both play an velopments in immunology that are important role in animal disease control, pertinent to understanding how the vaccination is increasingly being viewed immune system controls infections as the more sustainable option. This view and will discuss their implications for is influenced not only by the potential that contemporary approaches to vaccine vaccination offers for greater economic development. efficiency but also by the concerns that have been raised about the selection of APPROACHES TO VACCINE DEVELOPMENT drug-resistant pathogens and the potential Most of the current veterinary vaccines are harmful effects of drug residues in animal based on the use of either killed organisms products and the environment. Vaccination or their products or live attenuated has had a major impact on the control of organisms. The development of these epidemic viral diseases of livestock such vaccines has not relied on knowledge of as foot-and-mouth disease and rinderpest. the immune responses that mediate However, there are many other important immunity. Significant advances have been diseases for which efforts to develop made primarily by the development of new effective methods of vaccination have been culture techniques, improved attenuation unsuccessful. procedures and better adjuvants. While The advent of recombinant DNA there is some scope for further efforts to technology in the early 1980s created develop vaccines along these lines, there exciting new opportunities to produce are many diseases for which the more vaccines based on the use of expressed empirical methods are unlikely to be products of cloned genes. However, only a successful. few such vaccines have been successfully Two main approaches to vaccine design developed. In retrospect, it can be seen can be considered using modern molecular that the immediate expectations of the new technologies, namely the production of technology were unrealistically high, given attenuated mutant organisms by deliber- the limited knowledge of the immunology ate molecular manipulation and the of many of the target diseases and of how identification of antigenic components of antigens are processed and recognized by pathogens that can be used to induce the immune system. In the intervening protective immune responses (these decade there have been major advances in components are known as subunit immunology which, coupled with further vaccines). Unlike the traditional vaccine 6 The induction of immunity by veterinary immunoprophylactics strategies, the ability to exploit these new Recognition of antigen by B and T approaches to vaccine development is lymphocytes dependent on an intimate knowledge of The antigen recognition structures on B the molecular structure of the target and T lymphocytes, namely immuno- pathogens and an understanding of the globulin (Ig) and the T cell receptor (TCR) mechanisms of immunity. are both generated by a process of gene rearrangement whereby each of the two PROCESSING AND RECOGNITION OF chains that make up the molecules is ANTIGENS produced by bringing together two or three Immune effector mechanisms variable sequences, from a pre-existing Studies in laboratory animal model library of variable genes, with a constant systems have demonstrated that the sequence to form a functional gene (Cooper immune system can respond in a number and Burrows, 1989; Davis and Bjorkman, of different ways to control an infection. 1988). This mechanism, together with the The type of response elicited by a pathogen further diversity created by a combination depends largely on the nature of the of different variable regions in Ig heavy organism and its site of replication within and light chains and TCR alpha and beta the host. In general, organisms that chains facilitates the generation of a very establish systemic infections and replicate large repertoire of B lymphocytes and extracellularly are controlled by antibody T lymphocytes, each with a unique antigen responses. recognition specificity. Secretory antibody responses also play Despite the similarity in structure of Ig an important role in the control of infec- and TCR molecules, B and T lymphocytes tions at mucosal surfaces. By contrast, cell- differ fundamentally in the way they mediated immune responses are generally recognize antigen. Immunoglobulins, more important in controlling organisms whether on the surface of B lymphocytes which replicate intracellularly. The T lym- or as secreted antibodies interact directly phocytes that participate in cell-mediated with foreign antigen, usually in the form immune responses may exert their effector in which it is initially encountered by the function in a number of differentways. host, i.e. as an intact organismor as They may kill infected cellsor release molecules released from the organism. cytokines, which inhibit growth of intra- Recognition of antigens by antibody is, cellular organisms or which recruit and therefore, often dependent on thecon- .activate accessory cells such as macro- formational integrity of the molecules. By phages, to perform these functions. Indeed, contrast, T lymphocytes only recognize a number of different mechanisms may antigens after they have been degraded operate against the same organism. Stimu- and presented on the surface of other cells lation of T lymphocyteresponses is also (Brodsky and Guagliardi, 1991). These essential to provide help, again in the form antigen-bearing cells rnay be cells infected of cytokines, for the production of antibody with foreign organisms or "professional" by B lymphocytes. Hence, T lymphocytes antigen-presenting cells, such as macro- have a pivotal role in the induction of phages and dendritic cells, which have virtually all specific immuneresponses. ingested antigen. The processed antigen, The way in which antigen is processed which is in the form of short peptides of and recognized by the immune system less than 20 amino acids, is associated with determines the type of T cellresponse that major histocompatibility complex (MHC) is induced. molecules on the surface of the antigen- Vaccine manual 7 presenting cell (Bodmer, 1984). The T cell although the antigenic peptides that receptor does not react with antigen alone associate with class II are longer (13 to 17 but rather recognizes a combination of the amino acids) than those bound to class I antigenic peptide and the associated MHC (eight to ten amino acids). Much of the molecule (Townsend and Bodmer, 1989). sequencepolymorphismin MHC molecules occurs in and around the The special role of MHC molecules peptide-binding region and, although this The MHC consists of a set of closely linked variation does not affect the overall genes, many of which encode molecules structure of the peptide-binding groove, it involved in antigen processing and results in subtle differences that influence presentation (Trowsdale, 1993). There are the nature of the peptides that each two main types of MHC molecules, namely molecule will bind. Thus, each individual class I and class II. The most striking class I molecule tends to bind a different feature of these MHC molecules is the high repertoire of peptides (Sette et al., 1987; degree of polymorphism they display Rothbard and Gefter, 1991), so that T cells among individuals of a species (Bodmer, from animals expressing different MHC 1984; Trowsdale, 1993). Class I molecules molecules will often recognize different are heterodimers composed of a poly- epitopes from the same pathogen, and in morphic heavy chain and a non-poly- some cases these epitopes may be on morphic light chain (j32-microglobulin), the different proteins. latter encoded outside the MHC. They are Although this variation might be expect- expressed on most cells of the body. Class ed to result in quantitative differences in II molecules are also heterodimers, both the immune response to pathogens, and polypeptides being encoded within the hence differences in susceptibility to MHC, but their expression in healthy disease, there are relatively few well- animals is confined mainly to "profes- documented examples of strong asso- sional" antigen-presenting cells, namely ciations of MHC with susceptibility to macrophages, dendritic cells and B lym- infectious disease in outbred species. This phocytes. In most mammalian species probably reflects the large number of examined, each class is encoded by two potential T cell epitopes in most pathogens gene loci and, in each instance,both alleles and the fact that most animals in an are expressed. outbred population will be heterozygous While it has been recognized since the and therefore will express several class I early 1970s that class I and class II or class II molecules. Variations inthe molecules are involved in presenting epitopes that are selected in individual antigen to T cells, the precise molecular animals may, however, affect the strain and structural basis of presentation was specificity of the T cell response if some of not elucidated until the late