When applied to the present study, the protective efficacy of Ty21a would increase in the order Salmonella Paratyphi A → Salmonella Paratyphi B → Salmonella Typhi. A lower efficacy against Salmonella

Paratyphi than Salmonella Typhi appears consistent see more with previous reports from field trials and from travelers [17] and [18]. Along with the increasing efficacy against typhoid fever, an increasing number of vaccine doses is expected to be associated with an increase in the cross-protective efficacy: even though a significant protection against typhoid fever is achieved already with three vaccine doses, the levels of cross-protection against paratyphoid fever appear somewhat lower in field trials [17], consistent with the lower numbers of plasmablasts in this study. Administration of four doses, as recommended in the US, could result in a further increase in the cross-protective efficacy. Even with three doses, if the response in an individual would be too weak to confer full cross-protection, the question remains whether the level of antibodies achieved would be enough to contribute to a milder outcome of the PD0332991 mouse disease than in unvaccinated persons. The homing

profiles of Salmonella Typhi- and Salmonella Paratyphi B-specific cross-reactive plasmablasts in the vaccinees were similar to one another and also similar to the pathogen-specific plasmablasts in enteric fever. In both groups, a pronounced targeting to the intestine was observed, as interpreted by the very high expression of intestinal HR, α4β7 and lower expression of l-selectin. Such a profile appears beneficial with respect to the

intestinal transmission route both of the vaccine and of the enteric fever. The similarities between natural infection and Ty21a in eliciting a gut-directed cross-reactive immune response against Salmonella Paratyphi add to the view that Ty21a closely imitates a natural typhoid infection. In conclusion, this study is the first to show that the Ty21a vaccine and enteric fever both elicit cross-reactive humoral immune responses to both Salmonella Paratyphi A and B. The potential cross-protection only against paratyphoid fever conferred by these immune mechanisms encourage further efficacy studies. As there are no vaccines against paratyphoid fever in clinical use, even a partial protection with a currently available vaccine would be valuable. The study was partly supported by the specific Finnish governmental subsidy for health science research (SP) and partly by Crucell Switzerland AG (formerly Berna Biotech). The funding sources had no involvement in study design, data collection, analysis, interpretation of data, writing of the report or in the decision to submit the article for publication. We thank Dr.