Background
The annual number of Shigella episodes worldwide has been estimated to be 164.7 million with 1.2 million deaths. Even this high burden of disease is likely to be an underestimate because of the low sensitivity of routine microbiological tests, likely underestimates in adults, and failure to account for the delayed morbidity and mortality caused by Shigella. Very little information is available about Shigella species and serotype distribution, which is essential for the implementation of appropriate vaccination programs. Case management consisting of the distribution of ORS and antibiotics is increasingly limited by the emergence of antibiotic resistance though the magnitude of resistance is not well characterized in many countries. Furthermore there is only one licensed vaccine. This vaccine is produced by the Lanzhou Institute of Vaccines and Biological Products and is available only in China.

Goals
The goals of DOMI Shigella studies are a) to provide the data and analyses necessary for rational targeting and implementation of vaccination against Shigella in endemic settings; b) to provide Phase 3 evidence of the efficacy of at least one new-generation Shigella vaccine in Shigella-endemic settings of Asia; and c) to support research on the development of additional vaccine candidates.

Projects
Shigella disease burden surveillance studies in six Asian countries (Bangladesh, China, Indonesia, Pakistan, Thailand, and Vietnam) are underway. Each study is designed to detect all treated cases of shigellosis during a two-year period in a defined catchment population. The studies quantify the burden of shigellosis in both children and adults, since shigellosis, unlike many forms of infectious diarrhea in developing countries, affects all age groups. The studies will also permit estimation of delayed morbidity and mortality due to Shigella and documentation of the distribution of Shigella species and serotypes infecting persons in developing countries. An important feature of the studies is that they employ common surveillance and microbiological methods to permit comparison of results.

The prelicensure vaccine research and development portfolio is focusing on three vaccines. First, the DOMI Program is supporting the clinical evaluation of a genetically attenuated, live oral S. Flexneri 2a strain developed by Professor Phillipe Sansonetti of the Pasteur Institute. This vaccine has shown promising results in North American adults, and Bangladeshi adults and school children. A Phase 2 trial of the vaccine in Bangladesh preschool children, conducted by investigators at the International Center for Diarrheal Disease Research, Bangladesh, has been completed and a manuscript is in preparation.

Finally, a project jointly proposed by the Walter Reed Army Institute of Medical Research in Bethesda, Maryland, and the Pasteur Institute in Paris, France revisits the development of ribosomal vaccines against Shigella. These vaccines, initially developed in the 1970s and protective in animal models, were not pursued further because of their pyrogenicity and the growing trend at that time to focus on molecular engineered, live oral vaccines. Safe and protective ribosomal vaccines would be particularly attractive for developing countries because they could be produced easily and cheaply in those countries. In this project, advantage is being taken of Shigella mutants (msbB) that have been genetically engineered to express substantially (1,000 to 10,000-fold) lower levels of endotoxin as source strains for ribosomal vaccines. The first stage of this project will produce a lot of clinical grade ribosomal vaccine that will be suitable for human testing.