Background
Typhoid fever is a major cause of morbidity with an estimated global prevalence of between 16 million and 33 million cases each year. There are 500,000 to 700,000 deaths attributed to typhoid fever each year. Multidrug-resistant Salmonella typhi has spread to many parts of the world, limiting the ability to treat typhoid fever with available antibiotics. The public health importance of typhoid fever is multifaceted. It is both a waterborne and food-borne gastrointestinal infection, with high incidence approaching 1 percent of the population annually in endemic areas. In the absence of an affordable program to assure safe water and better sanitation conditions in less developed countries, efforts need to be directed towards prevention through vaccines. The widely available heat-phenol-inactivated whole cell typhoid vaccine, which provides approximately 65 percent protection, has limited usefulness because of the adverse reactions it evokes. In contrast, two new typhoid vaccines promise protection without significant side-effects. These are the live, attenuated oral vaccine, Ty21a, and the injectable subunit vaccine, Vi polysaccharide. Both Ty21a and Vi have been shown to be safe. In contrast to Ty21a, whose protective performance has been inconsistent in different geographic areas, the protective efficacy of Vi has been consistent in all field trials. Moreover, administration of Vi entails only a single dose regime, while Ty21a requires at least three doses. Furthermore, Ty21a is heat-labile and requires storage in a strict cold chain, whereas Vi vaccine is relatively heat-stable and has much less strict cold chain requirements. Finally, the technology for production of Vi has already been transferred to both Vietnam and China. For these reasons, Vi vaccine is felt by most public health experts to be the modern typhoid vaccine best suited for use in public health programs in developing countries, and, consequently, Vi vaccine has been targeted by the DOMI Program for accelerated introduction into public health programs.

Goals
The five-year goals of the Typhoid Working Group are a) to provide data for rational targeting and implementation of vaccination against typhoid; b) to generate the evidence, provide the technical assistance, and obtain the consensus and approvals necessary to accelerate the introduction and use of Vi vaccine in public heath programs of China, Indonesia, Pakistan, Vietnam, and a refugee setting; c) to provide Phase 3 evidence of the efficacy of at least one additional typhoid vaccine in a typhoid-endemic setting in Asia.

Projects
Research protocols have been developed to undertake coordinated activities across the spectrum of vaccine development, introduction, and evaluation. These include epidemiological studies, disability burden assessment, cost effectiveness analyses, technical assistance in vaccine production and regulation, policy and economic studies of vaccine introduction, and behavioral studies of vaccine acceptability.

Six core demonstration projects of Vi vaccine are under way. The projects are designed to provide sound scientific evidence on vaccine cost-effectiveness and to provide information on an affordable and replicable delivery system to children older than 2 years of age. These projects are multi-country cluster randomized effectiveness trials covering a total population of approximately 350,000. The projects will be conducted in two cities Hechi (China) and Hue (Vietnam); three slums (Karachi, Jakarta, and Dhaka); and a refugee camp in Thailand. These Vi demonstration projects will be conducted employing common surveillance and microbiology methods to permit comparisons among sites. All typhoid fever cases will be documented through the government health facilities during a period of two years. Passive surveillance systems, aiming to evaluate vaccine related side effects, will be implemented as well. Behavioral studies will be carried out with the aim of identifying community and policy determinants of implementing Vi vaccination campaigns reaching population exposed to high typhoid infection risk.

In addition, other epidemiological studies have been designed to answer important policy questions such as the magnitude of typhoid fever associated disability, the duration of Vi vaccine efficacy, the need to give a boosting Vi dose, and the possibility of reducing the Vi vaccine price by combining it with meningococcal A vaccine. The cost of an episode of typhoid fever and the disability associated is under analysis, in collaboration with All India Institute of Medical Sciences, following a further analysis of a typhoid surveillance study recently conducted in urban slums of Delhi. Long-term efficacy will be evaluated in China by analyzing retrospective data of the two individually randomized control licensure Vi trials conducted in Jiangsu (1994) and Guangxi (1995). Vi effectiveness will also be evaluated by conducting a retrospective matched case control study in Baoying County (Jiangsu, China). Evaluation of Vi in combination with meningococcal A/C will be done in Guanxi, China. Along with the above described projects, Vi technology transfer and scaling up of Vi production by local manufacturers is being facilitated in China, India, and Vietnam. Finally, Phase 2 and 3 trials of a second generation, as-yet-unlicensed Vi conjugate vaccine are being planned in Sukkur, Pakistan.