Data_Sheet_1_IgA and IgG1 Specific to Vi Polysaccharide of Salmonella Typhi Correlate With Protection Status in a Typhoid Fever Controlled Human Infection Model.docx

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-PS and Vi-TT vaccines were observed to have similar efficacies, these vaccines may protect through different mechanisms. These data will inform studies on mechanisms of protection against typhoid fever, including identification of antibody effector functions, as well as informing future vaccination strategies.

采用伤寒沙门氏菌Vi荚膜多糖进行疫苗接种，该多糖为T细胞非依赖性抗原，可预防伤寒热的发生。此现象表明，仅Vi抗体即可在缺乏T细胞介导的免疫反应的情况下提供保护；然而，具有保护作用的Vi抗体尚未得到充分表征。我们假设疫苗诱导体内抗体的生物物理性质的变化，包括亚类分布和亲和力，可能影响保护效果。为了探究抗体特性与预防伤寒热之间的关系，我们利用受控人体感染模型（CHIM），分析了疫苗效力（VE）试验中接受纯化Vi多糖（Vi-PS）或Vi破伤风毒素结合物（Vi-TT）疫苗接种并在口服活S. Typhi挑战后参与者的体液反应。我们测定了Vi IgA和IgG亚类抗体在免疫前至挑战日的亲和力、总体强度和疫苗诱导的强度变化。在Vi-PS疫苗接种组中，与患病个体相比，受保护个体的Vi IgA强度（FDR p = 0.01）和强度变化（FDR p = 0.02）显著更高。在Vi-TT疫苗接种组中，受保护个体的Vi IgA强度变化（FDR p = 0.06）和Vi IgG1亲和力（FDR p = 0.058）高于患病个体，尽管这些发现未达到p < 0.05的显著性水平。总体而言，Vi-PS和Vi-TT疫苗的保护性抗体特征存在差异，因此，我们得出结论，尽管Vi-PS和Vi-TT疫苗观察到具有相似的效力，但这些疫苗可能通过不同的机制提供保护。这些数据将有助于研究预防伤寒热的机制，包括识别抗体效应功能，并为未来的疫苗接种策略提供指导。