MacLennan CA, Gondwe EN, Msefula CL, et al. J Clin Invest. 2008;118(4):1553–1562 PURPOSE OF THE STUDY. To investigate whether specific antibody protects against nontyphoidal Salmonella (NTS) bacteremia. POPULATION STUDIED AND METHODS. Admissions for NTS bacteremia during 1 year were reviewed (N = 352). Sera from 65 healthy Malawian children (median age, 24 months: range, 3–107 months) was used for in vitro NTS-killing assays. Purified immunoglobulin G (IgG) from patient sera was used to delineate the role of antibody versus complement. Immunoglobulin and complement deposition on bacteria was also assessed by flow cytometry. Complement dependency was tested by heat inactivation and by using C9-deficient serum. RESULTS. Overall, 82% of the children with NTS bacteremia were <36 months old, but there was a nonuniform distribution with fewer-than-expected cases in children <4 months old (actual: 9.7% vs 16.7%), suggesting a role for passive humoral immunity. From healthy donors, 9 of 25 children <16 months of age had serum with normal in vitro killing, whereas 40 of 40 children >16 months of age did so. NTS killing in vitro was complement and membrane attack complex dependent. Effective killing corresponded to a specific IgG or IgM Salmonella titer of 1.5 U and was associated with the deposition of complement (C3 and C9) measured by flow cytometry. Resistance to killing by alternative complement activation was mediated by long-chain lipopolysaccharide and the rck gene product. CONCLUSIONS. Salmonella-specific antibody that overcomes the complement resistance of NTS develops by 2 years of life in Malawian children and is mediated by specific IgG or IgM antibody. REVIEWER COMMENTS. NTS is the most common cause of bacteremia in Malawi and much of tropical Africa and is associated with high rates of mortality even with appropriate culture facilities and access to antibiotics. The finding that specific antibody is protective against this invasive, facultative intracellular pathogen supports the importance of vaccine development for this pathogen.