Efficacy of one or two doses of Ty21a Salmonella typhi vaccine in enteric-coated capsules in a controlled field trial. Chilean Typhoid Committee. Safety and immunogenicity of Salmonella typhi Ty21a vaccine in young Thai children. A controlled field trial of liver oral typhoid vaccine Ty21a. The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five-year-old children. Large-scale field trial of Ty21a live oral typhoid vaccine in enteric-coated capsule formulation. Clinical and serological responses following primary and booster immunization with Salmonella typhi Vi capsular polysaccharide vaccines. Efficacy trial of Vi polysaccharide vaccine against typhoid fever in south-western China. Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi. A preliminary report. Comparison of enteric-coated capsules and liquid formulation of Ty21a typhoid vaccine in randomised controlled field trial. [Efficacy and side effects following immunization with Salmonella typhi Vi capsular polysaccharide vaccine]. Safety and immunogenicity of Salmonella typhi Ty21a liquid formulation vaccine in 4- to 6-year-old Thai children. Protective activity of Vi capsular polysaccharide vaccine against typhoid fever. Oral immunisation against typhoid fever in Indonesia with Ty21a vaccine.
Typhoid fever remains an important public health problem in many areas of the world and an effective, non-reactogenic vaccine would be useful to control this disease. An attenuated Salmonella typhi strain (Ty21a), which has shown promise in previous trials, was evaluated in a controlled field trial in Santiago, Chile. In this trial, 82,543 schoolchildren were randomly assigned to receive one or two doses of Ty21a vaccine in enteric-coated capsules or placebo. The enteric-coated vaccine formulation was well tolerated and practical for mass oral immunization. In the first two years of surveillance, 213 cases of bacteriologically-confirmed typhoid fever were found in schoolchildren participating in the trial; annual rates in the placebo group were 139 and 227 per 100,000. Vaccine efficacy in the first two years after vaccination was 59% for two doses and 29% for one dose; no efficacy was found 3-5 years after vaccination. These results indicate that it will be necessary to identify a vaccine formulation and schedule for Ty21a S. typhi that is practical and provides high level protection for greater than 2 years. Salmonella typhi Ty21a vaccine in a liquid formulation was evaluated in 634 Thai children 2 to 6 years of age. The seroconversion rate was 69% for those who received vaccine versus 14% for those who received placebo (P < 0.005). The immune responses among vaccine recipients ranged from 60% in 3-year-olds to 81% for 6-year-olds. A controlled field trial of a live oral typhoid vaccine was carried out in Alexandria, Egypt, in 1978-79. A total of 32 388 children were included in the study. They were divided in two comparable groups, one given 3 doses of the vaccine and the other 3 doses of the placebo. Each active dose contained 1 x 10(9)-8 x 10(9) live Ty21a bacteria. From March 1978 to March 1979, the population studied was followed up and suspected typhoid cases were investigated bacteriologically and serologically. The effectiveness of the vaccine was assessed by analysis of the incidence of typhoid fever in the two groups. The results of the follow-up indicate that, in the dosage schedule used, the Ty21a mutant strain, found previously to be stable and safe, is protective against typhoid fever for at least one year. Typhoid fever is common in developing countries. The licensed typhoid vaccines confer only about 70 percent immunity, do not protect young children, and are not used for routine vaccination. A newly devised conjugate of the capsular polysaccharide of Salmonella typhi, Vi, bound to nontoxic recombinant Pseudomonas aeruginosa exotoxin A (rEPA), has enhanced immunogenicity in adults and in children 5 to 14 years old and has elicited a booster response in children 2 to 4 years old.
                In a double-blind, randomized trial, we evaluated the safety, immunogenicity, and efficacy of the Vi-rEPA vaccine in children two to five years old in 16 communes in Dong Thap Province, Vietnam. Each of the 11,091 children received two injections six weeks apart of either Vi-rEPA or a saline placebo. Cases of typhoid, diagnosed by the isolation of S. typhi from blood cultures after 3 or more days of fever (a temperature of 37.5 degrees C or higher), were identified by active surveillance over a period of 27 months. We estimated efficacy by comparing the attack rate of typhoid in the vaccine group with that in the placebo group.
                S. typhi was isolated from 4 of the 5525 children who were fully vaccinated with Vi-rEPA and from 47 of the 5566 children who received both injections of placebo (efficacy, 91.5 percent; 95 percent confidence interval, 77.1 to 96.6; P<0.001). Among the 771 children who received only one injection, there was 1 case of typhoid in the vaccine group and 8 cases in the placebo group. Cases were distributed evenly among all age groups and throughout the study period. No serious adverse reactions were observed. In all 36 children studied four weeks after the second injection of the vaccine, levels of serum IgG Vi antibodies had increased by a factor of 10 or more.
                The Vi-rEPA conjugate typhoid vaccine is safe and immunogenic and has more than 90 percent efficacy in children two to five years old. The antibody responses and the efficacy suggest that this vaccine should be at least as protective in persons who are more than five years old. Three doses, given within one week, of Ty21a attenuated Salmonella typhi oral vaccine in an enteric-coated formulation provided 67% efficacy for at least 3 years in a randomised, placebo-controlled field trial involving 109,000 schoolchildren in Santiago, Chile. Increasing the interval between doses to twenty-one days did not enhance protection. Significantly less protection followed administration of vaccine in gelatin capsules with sodium bicarbonate. Ty21a provides the same level of protection as the heat/phenol-inactivated whole cell parenteral vaccine but differs in not causing adverse reactions. Ty21a may now be regarded as a practical public health tool. Clinical and serum antibody responses following intramuscular injection of two formulations of Salmonella typhi Vi capsular polysaccharide (Vi) were assessed in a double-blind evaluation. Healthy adults were randomly assigned to receive a 25 micrograms dose of liquid (Vi-Liq; n = 182) or freeze-dried Vi vaccine (Vi-Lyoph; n = 55), or placebo (n = 86). Erythema and/or induration > or = 1 cm in diameter at the injection site developed in 13/182 (7%) of Vi-Liq and 3/55 (5%) of Vi-Lyoph recipients (not significant, n.s.). Fever (oral temperature > or = 100 degrees F (37.8 degrees C)) occurred in < 2% of vaccinees. The frequencies of rises of fourfold or greater and of maximal Vi antibody levels were similar in the two vaccine groups. Fourfold or greater rises in serum Vi antibody levels (RIA) developed in 53% of Vi-Lyoph and 60% of Vi-Liq recipients by 1 week (n.s.), and 98 and 93%, respectively, by 1 month (n.s.). The frequencies of adverse reactions and mean Vi antibody levels following booster immunization with Vi-Liq 27 to 34 months after primary immunization (n = 55) were similar to those observed following primary immunization, although subjects given a booster dose were more likely to develop local reactions > or = 1 cm in diameter than those given a first dose (10/55 versus 13/182, p = 0.013 by the chi 2 test). Primary and booster immunizations with the Vi vaccines are well tolerated in healthy adults; mean Vi antibody levels remain significantly elevated for up to 34 months after primary immunization. To test the efficacy of locally produced Vi vaccine over a time period of longer than one year.
                A double-blinded, randomized field trial was performed in Guangxi Zhuang Autonomous Region in south-western China, using 30 micrograms doses of locally produced Vi. Enrolled subjects were 3-50 years of age, although the majority (92%) were school-aged children, who have the highest rate of typhoid fever in this setting. A total of 131,271 people were systematically allocated a single dose of 30 micrograms of Vi polysaccharide or saline placebo. The study population was followed for 19 months, with passive surveillance conducted in the Ministry of Health and the Regional Health and Anti-epidemic Centre (HAEC). Clinically suspected cases of typhoid fever were confirmed by blood culture, or by serological reaction with O-antigen (Widal tests).
                After 19 months, there were 23 culture-confirmed cases of typhoid fever in the placebo group versus 7 cases in the Vi group (Protective efficacy (PE) = 69%; 95% CI = 28%, 87%). Most of the isolates were from school-aged children: 22 cases in the placebo group versus 6 in the Vi group (PE = 72%; 95% CI = 32%, 82%). No serious post-injection reactions were observed. The locally produced Vi polysaccharide vaccine showed levels of protective efficacy similar to those for Vi vaccine produced in industrial countries.
                The slightly higher dose of vaccine did not seem to alter efficacy significantly in China. 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. In a randomised, double-blind, controlled field trial in Santiago, Chile, 81,621 schoolchildren aged 5-19 years received three doses, within a week, of attenuated Salmonella typhi oral vaccine Ty21a in enteric-coated capsules or in a new liquid suspension, or placebo. Over 36 months of surveillance, the liquid formulation (76.9% vaccine efficacy) was significantly superior to the enteric-coated capsules (33.2% vaccine efficacy). The liquid formulation protected young children (5-9 years) (efficacy 82.3%) as well as older children (efficacy 69.3%), whereas the capsules significantly protected only older children. The liquid suspension was easy to prepare by mixing lyophilised vaccine with buffer in water and was easily administered, even to the youngest children. Thus, the liquid formulation of Ty21a is preferable to enteric-coated capsules. Efficacy and side effects following the immunization with Salmonella typhi Vi capsular polysaccharide vaccine (Vi) were assessed. The diluted solution (DS) of Vi was used as placebo. A total number of 777 children and adults were observed for side effect response. Mild and moderate fever appeared 16.93% and 0.05% in Vi group, 15.01% and 0.03% in DS group, respectively (statistically significant). Two cases with mild local reaction were observed in Vi group. A total number of 81,506 vaccinees were investigated on the efficacy of Vi vaccine, using positive blood culture of Salmonolla typhi as a diagnostic criterion. The protective rate and index of vaccine were 71.35% and 3.49% respectively. If 2 cases of positive Widal's test were included in, the protective rate would come up to 78.17% with a protective index 4.85. Clinical data showed that fever seen in the cases in Vi group was much lower than that of DS group. The systematic and local reaction of Vi vaccine were mild. The vaccine is safe and has high protective rate. It can also decrease the degree of fever with only one single dose as primary immunization. We believe Vi vaccine may serve as a vaccine of new generation to be promoted. nan The protective efficacy against typhoid fever of a single intramuscular injection of 25 micrograms of the Vi capsular polysaccharide (CPS) was assessed in a randomised double-blind controlled trial. Vaccination of 11,384 children was followed by 21 months' surveillance. 47 blood-culture-proven cases of typhoid occurred in children who received meningococcal A + C CPS vaccine and 19 cases in those vaccinated with Vi CPS. Protective efficacy was 60% calculated from the day of vaccination and 64% from 6 weeks after vaccination. Surveillance also included 11,691 unvaccinated children; 173 cases occurred in this group. Protective efficacy in relation to the unvaccinated group was 77.4% and 81.0% after 21 months, calculated immediately and 6 weeks after vaccination, respectively. Vaccination was associated with minimum local side-effects, and an increase in anti-Vi antibodies occurred, as measured by radioimmunoassay and enzyme-linked immunosorbent assay. Antibody levels remained significantly raised at 6 and 12 months post vaccination. Vi CPS is thus a safe and effective means of typhoid vaccination. When tested under conditions of moderate transmission of typhoid fever, a liquid formulation of the oral typhoid fever vaccine Ty21a had a protective efficacy of 96% in Egypt, and an enteric coated capsule formulation had an efficacy of 67% in Chile. We compared the two formulations under conditions of intense transmission of typhoid fever in Indonesia in a randomised, double-blind trial. 20,543 subjects (age range 3-44 years) received either three doses of enteric coated capsules containing placebo or live Ty21a, or three doses of lyophilised placebo or live Ty21a reconstituted with phosphate buffer. During 30 months of follow-up, the rate of blood-culture-positive typhoid fever among controls was 810/100,000 per year. Rates of typhoid fever were 379/100,000 per year for subjects who received the liquid formulation of vaccine and 468/100,000 per year for subjects who received enteric coated capsules. The protective efficacies of the liquid and enteric coated formulations were 53% and 42%, respectively. Neither formulation protected against infection with Salmonella paratyphi A. No major side-effects were noted, but the overall incidence of side-effects was greater in the vaccine groups. Under conditions of intense transmission, Ty21a protected against typhoid fever; however, because Ty21a will not protect all individuals, there is a need for additional approaches to prevent the disease.