- Background Despite its high worldwide morbidity and mortality, there is yet no licensed vaccine for shigellosis. We reported the safety and immunogenicity of Shigella O-specific polysaccharide–protein conjugates in adults and young children and efficacy of Shigella sonnei conjugate in young adults. Methods A double-blinded, randomized and vaccine-controlled Phase 3 evaluation of S. sonnei and Shigella flexneri 2a O-SP–rEPA conjugates, 25 μg, injected IM twice, 6 weeks apart, into healthy 1–4 years old, is reported. The children were followed for 2 years by telephone every other week and stool cultures were obtained for each episode of acute diarrhea (≥3 loose stools/day or a bloody/mucous stool). Sera were taken randomly from 10% of the participants for IgG anti-LPS and anti-carrier levels. Results Of the 2799 enrollees, 1433 received S. sonnei and 1366 S. flexneri 2a conjugates; 2699 (96.4%) completed the 2-year follow-up. Local reactions occurred in ∼5% and ∼4% had temperatures ≥38.0 °C lasting 1–2 days. There were no serious adverse events attributable to the vaccines. Of the 3295 stool cultures obtained, 125 yielded S. sonnei and 21 S. flexneri 2a. Immunogenicity and efficacy were age-related. The overall efficacy of the S. sonnei conjugate was 27.5%; 71.1% ( P = 0.043) in the 3–4 years old. The numbers for S. flexneri 2a were too few for meaningful analysis. Cross-protection by S. flexneri 2a for non-vaccine S. flexneri types was found, but the numbers were too few for statistical significance. There was an age-related rise of vaccine-specific IgG anti-LPS in both groups, peaking at about 10 weeks and declining thereafter, but remaining ≥4-fold higher than in the controls 2 years after the second dose. Conclusions Shigella conjugates are safe and immunogenic in 1–4 years old. The S. sonnei conjugate elicited 71.1% efficacy in the 3–4 years old and can be predicted to be efficacious in individuals older than 3 years of age. These results urge studies with our improved conjugates.