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Vaccination against Salmonella Typhi using the Vi capsular polysaccharide, a T-cell independent antigen, can protect from the development of typhoid fever. This implies that antibodies to Vi alone can protect in the absence of a T cell-mediated immune response; however, protective Vi antibodies have not been well-characterized. We hypothesized that variability in the biophysical properties of vaccine-elicited antibodies, including subclass distribution and avidity, may impact protective outcomes. To interrogate the relationship between antibody properties and protection against typhoid fever, we analyzed humoral responses from participants in a vaccine efficacy (VE) trial using a controlled human infection model (CHIM) who received either a purified Vi polysaccharide (Vi-PS) or Vi tetanus toxoid conjugate (Vi-TT) vaccine followed by oral challenge with live S. Typhi. We determined the avidity, overall magnitude, and vaccine-induced fold-change in magnitude from before immunization to day of challenge of Vi IgA and IgG subclass antibodies. Amongst those who received the Vi-PS vaccine, Vi IgA magnitude (FDR p = 0.01) and fold-change (FDR p = 0.02) were significantly higher in protected individuals compared with those individuals who developed disease (“diagnosed”). In the Vi-TT vaccine group, the responses of protected individuals had higher fold-change in Vi IgA (FDR p = 0.06) and higher Vi IgG1 avidity (FDR p = 0.058) than the diagnosed Vi-TT vaccinees, though these findings were not significant at p < 0.05. Overall, protective antibody signatures differed between the Vi-PS and Vi-TT vaccines, thus, we conclude that although the Vi …