We conducted a pilot study followed by a large clinical trial in Nepal of the use of the capsular polysaccharide of Salmonella typhi (Vi) as a vaccine to prevent typhoid fever. In the pilot study, involving 274 Nepalese, there were no significant side effects of the Vi vaccine; about 75 percent responded with a rise in serum antibodies of fourfold or more. In the clinical trial, residents of five villages were given intramuscular injections of either Vi or, as a control, pneumococcus vaccine dispensed in coded, randomly arranged, single-dose syringes. There were 6907 participants, of whom 6438 were members of the target population (5 to 44 years of age); each was visited every two days. Those with temperatures of 37.8 degrees C or higher for three consecutive days were examined and asked to give blood for culture. Typhoid was diagnosed as either blood culture-positive or clinically suspected on the basis of bradycardia, splenomegaly, and fever, with a negative blood culture. Seventeen months after vaccination, the codes were broken for the 71 patients meeting the criteria for either culture-positive or clinically suspected typhoid. The attack rate of typhoid was 16.2 per 1000 among the controls and 4.1 per 1000 among those immunized with Vi (P less than 0.00001). The efficacy of Vi was 72 percent in the culture-positive cases, 80 percent in the clinically suspected cases, and 75 percent in the two groups combined. These data provide evidence that Vi antibodies confer protection against typhoid. Surveillance continues to determine the duration of Vi-induced immunity.

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In a double-blind, randomized, and placebo-controlled previous trial, the efficacy of Vi-rEPA for typhoid fever in 2-to 5-year-olds was 89.0% for 46 months. Vi-rEPA contained 25 g of Vi and induced a greaterthan-eightfold rise in immunoglobulin G (IgG) anti-Vi in all of the vaccinees tested. In this investigation, we conducted a dosage-immunogenicity study of 5, 12.5, and 25 g of Vi-rEPA in this age group. Two doses of Vi-rEPA were injected 6 weeks apart. Blood samples were taken before and at 10 weeks (4 weeks after the second injection) and 1 year later. All postimmunization geometric mean (GM) levels were higher than the preimmune levels (P < 0.0001). At 10 weeks, the GM IgG anti-Vi level elicited by 25 g (102 EU/ml) was higher than those elicited by 12.5 g (74.7 EU/ml) and 5 g (43 EU/ml) (P < 0.004): all of the children had >3.52 EU/ml (estimated minimum protective level). One year later, the levels declined about sevenfold (13.3 and 11.3 versus 6.43 EU/ml, P < 0.0001) but remained significantly higher than the preimmune levels (P < 0.0001), and >96% of the children had a greater-than-eightfold rise. This study also confirmed the safety and consistent immunogenicity of the four lots of Vi-rEPA used in this and previous trials.The Vi capsular polysaccharide of Salmonella enterica serovar Typhi is both an essential virulence factor and a protective antigen (1, 7, 11). To improve its immunogenicity in children Ͻ5 years of age, a conjugate composed of the Vi capsular polysaccharide bound to recombinant mutant Pseudomonas aeruginosa exoprotein A (Vi-rEPA) was synthesized (8,13,14). A double blind, randomized, and placebo-controlled trial with 2-to 5-year-old Vietnamese children showed Vi-rEPA to be safe and 89.0% effective in preventing typhoid fever for 46 months (9, 10). Among 76 children selected randomly from the phase 3 trial, Vi-rEPA induced a greater-than-eightfold rise in immunoglobulin G (IgG) anti-Vi in all vaccinees tested. The conjugate contained ϳ25 g of Vi as Vi-rEPA. Because dosage-related immunogenicity has been shown for other conjugates such as the polysaccharides of Haemophilus influenzae type b and pneumococcus types, in this study the safety and immunogenicity of various dosages (5, 12.5, and 25 g) of Vi as Vi-rEPA were evaluated in 2-to 5-year-old children (2,3,5,6,12). MATERIALS AND METHODSStudy design. Two hundred forty-one children, 2 to 5 years old and evenly distributed by age and sex, were recruited from Thanh Ba District, Phu Tho Province, Vietnam. Half of the children were recruited from day care centers, and the other half were from the community of three communes. At the time of their recruitment and after informed consent was obtained from their parents or guardians, the children received identification numbers and were randomly assigned to three dosage groups (25, 12.5, and 5 g of Vi as Vi-rEPA). Two injections of the same dosage were administered 6 weeks apart. Blood samples were collected before the first injection, 4 weeks after the second injection, and 1 year after the first...

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