Background
Shigellosis or bacterial dysentery, causes, according to one estimate, more than 164 million illnesses and 1.1 million deaths worldwide each year. 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. In addition, before the establishment of the DOMI Program, little information was available about Shigella species and serotype distribution, which is essential to informing decisions on the development of appropriate Shigella vaccines. 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, which is produced by the Lanzhou Institute of Vaccines and Biological Products ("FS" vaccine) and is not available outside of China.

Goals
The ultimate goal of the DOMI Shigellosis Program is to accelerate the development and introduction of a safe and protective Shigella vaccine to control epidemic and endemic disease. To achieve this goal, the DOMI Shigellosis Program has focused on providing support for clinical evaluations of newer-generation experimental vaccines and facilitating the introduction of these newer vaccines by providing data on the disease burden, epidemiology and cost of shigellosis, population perceptions about the disease and potential demand for a vaccine.

The specific objectives of the program are to:

• Measure the disease burden of shigellosis in six Asian sites through prospective population-based surveillance;
• Explore the perceptions of at-risk communities and health care providers towards shigellosis and a potential shigellosis vaccine;
• Estimate the costs-of-illness from shigellosis and the economic implications of introducing a Shigella vaccine;
• Accelerate the development and evaluation of Shigella vaccines.

Projects

Prospective population-based surveillance studies
To assess the magnitude of the disease burden in Asia, the program conducted prospective population-based disease burden studies in selected low-income sites in six Asian countries (Dhaka, Bangladesh; Zhending, China; North Jakarta, Indonesia; Saraburi Province, Thailand; Karachi and rural villages in Pakistan; and Nha Trang, Vietnam), using standardized epidemiological and laboratory methods. Each study was designed to detect all treated cases of shigellosis during a two or more year period in a defined catchment population, in order to obtain population incidence rates. To increase the sensitivity of the surveillance, surveys of health care use were conducted in each study site to estimate the number of people likely to be missed by treatment-center-based surveillance. Highly sensitive, polymerase chain reaction (PCR) tests were used to estimate the proportion of infections missed through the use of traditional culture methods.

The findings of this multi-country study were published in the on-line journal, Plos Medicine in 2006 and the results of the study in Thailand were published in Epidemiological Infections in 2005. Key findings from this study include the following:

• High rates of stool culture-confirmed shigellosis were found in children under five years of age in all six study sites. Annualized rates in 0-4 year olds ranged from 46/1,000 in the Dhaka, Bangladesh settlement site to 16-19/1,000 in Hebei, China; the mixed rural/urban study sites in and near Karachi, Pakistan and North Jakarta, Indonesia and to 4-5/1,000 in the Thailand and Vietnam sites. Incidence rates of all ages ranged from 8/1,000 in Dhaka to 0.6/1,000 in Thailand and Vietnam.

• PCR detection of Shigella DNA from a sub-sample of fecal specimens collected in all six countries also found evidence of Shigella in more than 40% of the culture-negative stool samples. This suggests that the culture-proven incidence greatly under-estimates the true proportion of all treated episodes of diarrhea that are due to Shigella, which, in the case of the site in Vietnam, could be as high as 35%.

• While children less than 10 years of age and especially those 0-4 years old are at highest risk of getting the disease, shigellosis incidence increases steadily after the age of 40. Persons 70 and over had the second highest rate in the overall study population after 0-4 year olds. The elderly in China and Vietnam were especially vulnerable to the disease. These findings suggest that vaccinating children only will not completely address the burden of shigellosis in developing countries and that parallel vaccination of young children and the elderly may be required in some countries, such as China.

• Considerable heterogeneity of Shigella species and serotypes was observed among the study sites. In five sites, S. flexneri was the most frequently isolated Shigella species, while in Thailand 80% of shigellosis cases was caused by S. sonnei. In Bangladesh, more than 20% of isolated Shigella belonged to S. boydii species, which is not commonly observed either in developed or developing countries. The studies also detected significant differences in the distribution of S. flexneri serotypes from country to country and even from year to year in the same country, posing a significant challenge for the development of effective Shigella vaccines. Since immunity against Shigella is thought to be species and serotype specific, a Shigella vaccine will need to comprise a broad "cocktail" of different Shigella organisms in order to have an important epidemiological impact.

• Thirty-five to 88 percent of Shigella isolates in all six sites were found to be resistant to the first-line antibiotics, ampicillin and cotrimoxozole. Resistance to naladixic acid - an indication of reduced effectiveness of quinolones, such as ciprofloxacin, often used as a second-line treatment - was found in nearly all specimens in China and nearly one-half of those in Bangladesh. Rising rates of antibiotic resistant Shigella, increases the difficulty and costs of treating shigellosis patients and strengthens the case for vaccination of endemic populations.

• The clinical course of the disease appeared less severe than in previous, mostly hospital-based studies. In fact, only one-third of culture-proven cases presented with dysentery. However, shigellosis was also found to be considerably more common in impoverished Asian populations than previously thought. The study concluded that the prevention of shigellosis through vaccination and other measures could exert an immediate benefit by substantially reducing the overall diarrhea burden in the region and by preventing the spread of pan-resistant Shigella strains.

Social behavioral studies of population knowledge, perceptions and beliefs regarding dysentery
Population-based surveys of community perceptions regarding dysentery and interest in future vaccines were imbedded in the disease surveillance studies in all six study sites. A cross-country analysis published in Vaccine in 2006 found that there would be uniformly high demand for a vaccine against dysentery for children across study sites and that interest in adult vaccination was also considerable, but varied by location.A separate paper on the survey results in China were also published in Vaccine in 2006.

Economic studies of shigellosis
Studies to estimate the cost-of-illness from culture-confirmed shigellosis have been conducted at all six study sites. A paper summarizing the results is being prepared.

Clinical trials of Shigella vaccine candidates
DOMI supported the clinical evaluation of a live, genetically attenuated oral S. flexneri 2a vaccine developed by the Pasteur Institute, which had shown promising results in North American adults. A Phase II trial of the vaccine in preschool children was conducted in Bangladesh by the International Center for Diarrheal Disease Research, Bangladesh (ICDDR,B). The study found poor colonization and immunogenicity in young children. These findings indicate that live oral Shigella vaccines may be less effective at inducing strong immune responses in Shigella-endemic populations that likely have high levels of pre-existing natural immunity, which may prevent intestinal colonization by the vaccine organism.

Shigella vaccine development
IVI has been developing in its laboratories a subunit Shigella vaccine by purifying ribosomes from Shigella bacteria, in the aim of developing and transferring the technology of a low-cost vaccine capable of eliciting T-cell-dependent immune responses similar to those elicited by conjugate vaccines.

Last updated: May 2007