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

Lindsay C Dahora,Rachel L Spreng,Andrew J Pollard,Celina Jin,S Moses Dennison,Georgia D Tomaras,Kelly E Seaton,S Munir Alam,Frederick Feely,Elizabeth Jones,Lu Zhang,Jennifer Hill,Ryan Mathura

doi:10.3389/fimmu.2019.02582

Abstract

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.

Highlights

The bacterial pathogen Salmonella enterica serovar Typhi
To determine the relationship between the immune responses elicited by Vi polysaccharide (Vi-PS) and Vi-tetanus toxoid (Vi-TT) vaccines, a principle components analysis (PCA) was conducted (Figure 1D)
Vi-TT vaccinees clustered away from Vi-PS vaccinees on the basis of higher tetanus and higher Vi antibody responses (Figure 1D), indicating that response to tetanus was a substantial driver of the differences observed between vaccine groups

Summary

Introduction

The bacterial pathogen Salmonella enterica serovar Typhi Typhi) is the leading cause of enteric fever world-wide and is responsible for nearly 20 million infections and ∼200,000 deaths annually. Antibiotics have been the standard treatment for infection. Typhi clones has dramatically increased in endemic regions including the emergence and spread of an extensively drug resistant (XDR) clone throughout Pakistan in 2018 [3, 4]. This has sparked concern for continued spread of XDR S. Vaccination efforts against typhoid fever have become the primary focus for prevention [5]

Objectives

Methods

Results

Conclusion