Development of Attenuated Salmonella Strains That Express Heterologous Antigens

Abstract

The ability of attenuated strains of Salmonella to express foreign antigens—which then induce humoral, secretory, and cellular immune responses following oral ingestion—has made them attractive as a system for delivering heterologous antigens to the mammalian immune system. More recently, Salmonella has also been successfully used as a means of delivering DNA vaccines to intracellular sites (1). A number of attenuated Salmonella hosts are available, and these have been fully characterized. In using Salmonella as a delivery system, some consideration must be given to the desired final outcome, as this can be influenced by the host strain chosen. The balance of humoral vs cell-mediated immunity stimulated, for example, can depend on the nature of the attenuating lesion. It has been observed that some mutants stimulate antibody preferentially, and others generate strong humoral and cell-mediated immunity (2). Once an appropriate host has been selected, DNA capable of driving the expression of heterologous antigens can be introduced into Salmonella vaccine strains using a variety of approaches. In general, there are two common methods of expressing a foreign antigen in salmonellae: from plasmid vectors or from the bacterial chromosome. Since there are many similarities in the cellular and molecular biology of Escherichia coli and Salmonella, most of the genetic manipulations required to construct expression cassettes can be carried out in E. coli. The resulting constructs can then be introduced into the vaccine strains using simple transformation or other similar techniques. However, the laboratory manipulation of Salmonella strains should be undertaken using techniques that do not lead to the accumulation of undefined genetic lesions, which may compromise the growth and immunogenicity of Salmonella in vivo.