Background Since protective efficacy of the current typhoid vaccines--oral whole-cell SalmonellaTyphi Ty21a and parenteral Vi-capsular polysaccharide preparation--is not optimal, and no vaccines are available against paratyphoid or non-typhoidalSalmonella(NTS) serotypes, new approaches deserve to be explored. The immunological mechanisms elicited by the two typhoid vaccines are mainly targeted against different structures. We studied whether these vaccines would enhanceS.Typhi-specific immune response and cross-reactivity against otherSalmonellae, if administered concomitantly. Materials and methods Volunteers were immunized simultaneously with Ty21a and Vi vaccines (Ty21a+Vi group) or with either of the two singly (Ty21a and Vi groups). All volunteers were investigated for circulating specific and cross-reactive plasmablasts, identified by ELISPOT as IgA, IgG or IgM antibody-secreting cells (ASC) reactive withS. Typhi,S. Paratyphi A/B/C, or selected NTS serotypes (S. Enteritidis,S. Typhimurium). Results In the Ty21a+Vi group, no specific or cross-reactive plasmablasts were detected before vaccination. After vaccination, the number ofS. Typhi-specific plasmablasts (878 ASC/106PBMC, 95%CI 554-1201) proved higher than in the Ty21a (339 ASC/106PBMC;p<0.001) and Vi (149 ASC/106PBMC;p<0.001) groups. Likewise, cross-reactive responses in the Ty21a+Vi group were higher than in the Ty21a and Vi groups (Ty21a+Vi vs Ty21a: ASC againstS. Paratyphi A/B,S. Enteritidis andS. Typhimuriump<0.05, againstS. Paratyphi Cp<0.01; Ty21a+Vi vs Vi: againstS. Paratyphi C not significant, othersp<0.0001). A gut-directed homing profile was seen among O antigen-specific and a systemic one among Vi antigen-specific plasmablasts. Conclusions Concomitant administration of Ty21a and Vi vaccines is well tolerated and induces an additive immune response to the two vaccines. Thus it enhances the magnitude of both typhoid-specific plasmablast responses and those cross-reacting with paratyphoid and most important NTS serotypes. The data encourage concomitant use of Ty21 and Vi vaccines for those at risk.