Live attenuated Salmonella hold great potential as vaccine vectors to deliver antigens from a variety of pathogenic organisms to elicit a protective immune response. While strategies devised using attenuated Salmonella enterica serovar Typhimurium strains administered to mice has demonstrated this potential, when these same strategies are transferred to Salmonella enterica serovar Typhi, the resulting strains are often reactogenic or poorly immunogenic when administered to humans. One weakness of the existing oral S. Typhimurium/mouse model or the intranasal S. Typhi/mouse model is that neither detects nor predicts reactogenic vaccines. The lack of a reliable oral animal model to study S. Typhi reactogenicity has hampered vaccine development in this field. Rabbits have been used to a limited extent to evaluate reactogenicity, but none of the current models involve oral administration of the vaccine to adult rabbits. We observed that some attenuated host restricted Salmonella serovars are reactogenic when orally administered to adult rabbits. Based on this observation, we will develop an oral adult rabbit model to detect reactogenicity of host-restricted Salmonella vaccine vectors, such as S. Typhi. We will establish specific parameters and correlates to define reactogenicity in Salmonella vaccines. This oral rabbit model can also be used to evaluate the immunogenicity of Salmonella vaccines and may provide a better picture of immunogenicity in humans than the mouse intranasal model. We will establish and define correlates between immune responses in orally immunized rabbits with historical data on human immune responses observed in clinical trials. This animal model will expand our current knowledge of S. Typhi vaccines by providing a means to test the effects of a wide variety of genetic manipulations on reactogenicity and immunogenicity prior to testing in humans.
While effective live, orally administered recombinant attenuated Salmonella vaccines expressing heterologous antigen genes hold the promise of providing low cost life-long protection against a variety of diseases, many of the vaccine strains are reactogenic and/or are poorly immunogenic in human volunteers. These issues have surfaced largely due to the lack of animal models to study reactogenicity and immunogenicity of these vaccines. The goal of this project is to develop an oral animal model to provide an accurate means to evaluate reactogenicity and to get a more relevant picture of the immunogenicity of live attenuated Salmonella vaccines prior to testing in clinical trials.