SHIGELLA LIVE VECTOR-BASED MULTIVALENT VACCINE

The goal of this proposal is to construct a vaccine that is broadly protective against multiple enteropathogens of public health importance to the U.S. population. These include Shigella, enterotoxigenic E. coli (ETEC) and the emerging pathogens Shiga toxin producing E. coli (STEC and enteroaggregative E. coli (EAEC). Such a multivalent vaccine would also provide protection against emerging pathogens that have acquired new virulence factors such as the Shiga toxin-expressing EAEC German outbreak strain. These enteropathogens are all Category B risk agents of biodefense concern. A vaccine with broad coverage against this group would be beneficial to multiple segments of the US population, including: 1) adult and child travelers who visit less developed countries where these infections are hyperendemic; 2) children in certain high risk areas of the US; 3) and for mass immunization in the face a natural or deliberate outbreak scenario. Immunization by the mucosal route is an effective method for induction of mucosal and systemic immune responses, believed to be important in protection against these enteropathogens. Our successful completion of 5 attenuated Shigella live vector strains during the Mid- Atlantic RCE (MARCE) funding period, provides the platform for the expression of protective antigens from each enteropathogen. Chromosomal insertion technology and autotransporter-based surface expression of heterologous antigens will ensure stability of vaccine constructs and optimal presentation to the host. In order to confirm the safety, immunogenicity and protective capacity of the multivalent vaccine, we have recruited expert collaborators who have developed innovative, relevant animal models for each component enteropathogen. These studies will constitute preclinical evaluations necessary for advancement to clinical trials. The multivalent vaccine will be tested in the neonatal mouse model in order to assess its utility in the very young thus expanding the potential target population age range. At the completion of these studies, we expect to have completed the construction and testing of a multivalent vaccine consisting of a mixture of live attenuated Shigella strains expressing critical antigens from ETEC, STEC and EAEC that will be broadly protective against enteric infections with these pathogens. The genetic related of these pathogens makes them well suited for grouping in this vaccine strategy that represents an important part of the overall program to develop an Immunoprophylactic Strategy to Control Emerging Enteric Infections.