Salmonella typhi is the etiological agent of typhoid fever, an acute, febrile enteric disease. Typhoid fever continues to be an important disease in many parts of the world. Travelers entering infected areas are at risk of contracting typhoid fever following the ingestion of contaminated food or water. Typhoid fever is considered to be endemic in most areas of Central and South America, the African continent, the Near East and the Middle East, Southeast Asia and the Indian subcontinent (3). There are approximately 500 cases of typhoid fever per year diagnosed

in the United States (4). In 62 % of these patients (data from 1975–1984) the disease was acquired outside of the United States while in 38 % of the patients the disease was acquired within the United States (5). Of 340 cases acquired in the United States between 1977 and 1979, 23% of the cases were associated with typhoid carriers, 24% were due to food outbreaks, 23% were associated with the ingestion of contaminated food or water, 6% due to household contact with an infected person and 4% following exposure to S. typhi in a laboratory setting (6).

The majority of typhoid cases respond favorably to antibiotic therapy. However, the emergence of multi-drug resistant strains has greatly complicated therapy and cases of typhoid fever that are treated with ineffective drugs can be fatal (7). Approximately 2–4% of acute typhoid cases result in the development of a chronic carrier state (8). These non-symptomatic carriers are the natural reservoir for S. typhi and can serve to maintain the disease in its endemic state or to directly infect individuals (3).

Virulent strains of S. typhi upon ingestion are able to pass through the stomach acid barrier, colonize the intestinal tract, penetrate the lumen and enter the lymphatic system and blood stream, thereby causing disease. One possible mechanism by which disease may be prevented is by evoking a local immune response in the intestinal tract.

Such local immunity may be induced by oral ingestion of a live attenuated strain of S. typhi undergoing an aborted infection. The ability of S. typhi to cause disease and to induce a protective immune response is dependent upon the bacteria possessing a complete lipopolysaccharide (1). The S. typhi Ty21a vaccine strain, by virtue of a reduction

in enzymes essential for lipopolysaccharide biosynthesis, is restricted in its ability to produce complete lipopolysaccharide (1,2). However, a sufficient quantity of complete lipopolysaccharide is synthesized to evoke a protective immune response. Despite low levels of lipopolysaccharide synthesis, the cells lyse before regaining a virulent phenotype due to the intracellular build-up of intermediates during lipopolysaccharide synthesis (1,2).

Results from clinical studies indicate that adults and children greater than 6 years of age may be protected against typhoid fever following the oral ingestion of 4 doses of Vivotif (Typhoid Vaccine Live Oral Ty21a). The efficacy of the S. typhi Ty21a strain has been evaluated in a series of randomized, double-blind, controlled field trials. Suspected typhoid cases, detected by passive surveillance, were confirmed bacteriologically either by blood or bone marrow culture. The first trial was performed in Alexandria, Egypt with a study population of 32,388 children aged 6 to 7 years. Three doses of vaccine, in the form of a freshly reconstituted suspension administered after ingestion of 1 g of bicarbonate, were given on alternate days. Immunization resulted in a 95% decrease [95% confidence interval (CI) = 77%–99%] in the incidence of typhoid fever over a 3-year period of surveillance (9). A series of field trials were subsequently performed in Santiago, Chile to evaluate efficacy when the vaccine strain was administered in the form of an acid-resistant enteric-coated capsule. The initial trial involved 82,543 school-aged children, and compared 1 or 2 doses of vaccine given one week apart. After 24 months of surveillance vaccine efficacy was 29% (95% CI = 4%–47%) for the single dose schedule and 59% (95% CI = 41%–71%) for the 2-dose schedule (10). A further field trial was performed in Santiago, Chile involving 109,594 school-aged children (11). Three doses of enteric-coated capsules were administered either on alternate days (short immunization schedule) or 21 days apart (long immunization schedule). Following 36 months of surveillance vaccination resulted in a 67% (95% CI = 47%–79%) decrease in the incidence of typhoid fever in the short immunization schedule group and a 49% reduction (95% CI = 24%–66%) in the long immunization schedule group. After 48 months of surveillance the short immunization schedule resulted in a 69% (95% CI = 55%–80%) decrease in typhoid fever (12). An undiminished level of protection was observed during the fifth year of surveillance. A field trial was next conducted in Santiago,

Chile to determine the relative efficacy of 2, 3 and 4 doses of enteric-coated vaccine administered on alternate days to school-aged children. Relative vaccine efficacy as determined by comparison of disease incidence within the three vaccinated groups was highest for the four dose regimen (13). The incidence of typhoid fever per 105 study subjects was 160.5 (95% CI = 130–191) for the three dose regimen versus 95.8 (95% CI = 71–121) for the four dose regimen (p<0.004). An additional field trial to determine vaccine efficacy was conducted in Plaju, Indonesia involving

20,543 individuals approximately 3 to 44 years of age (14). Due to logistical considerations three doses of enteric-coated capsules were administered at weekly intervals, a schedule known to provide suboptimal protection (11). After 30 months of surveillance vaccine efficacy for all age groups was 42% (95% CI = 23%–57%).

Vaccine organisms can be shed transiently in the stool of vaccine recipients (16). However, secondary transmission of vaccine organisms has not been documented. Ty21a has not been isolated from blood cultures following immunization. At present, the precise mechanism(s) by which Vivotif confers protection against typhoid fever is unknown. However, it is known that immunization of adult subjects can elicit a humoral anti-S. typhi LPS antibody response. Taking advantage of this fact, the seroconversion rate (defined as a ≥0.15 increase in optical density

units over baseline determined in an ELISA) was compared in an open study between adults living in an endemic area (Chile) and non-endemic areas (United States and Switzerland) after the ingestion of 3 doses of vaccine.

Comparable seroconversion rates were seen between these groups (15). S. typhi Ty21a cultured in medium not containing BHI induced an anti-S. typhi LPS antibody response comparable to that obtained with vaccine organisms cultured in medium containing BHI (15). Challenge studies in North American volunteers have shown that the Ty21a strain is capable of providing significant protection to an experimental challenge of S. typhi (16).

Because of the very low incidence of typhoid fever in United States citizens, efficacy studies are not currently feasible in this population. However, the above observations support the expectation that Vivotif will provide protection to recipients from non-typhoid endemic areas such as the United States.