Vi-Vaccinations Induce Heterogeneous Plasma Cell Responses That Associate With Protection From Typhoid Fever.

Deborah L Cross,Joshua S Starr,Andrew J Pollard,Gerlinde Obermoser,Celina Jin,Holden T Maecker,Irina Mohorianu,Jennifer Hill,Marije K Verheul,Giorgio Napolitani,Elizabeth Jones,Christoph J Blohmke,Michael D Leipold

doi:10.3389/fimmu.2020.574057

Abstract

Vi-polysaccharide conjugate vaccines are efficacious against cases of typhoid fever; however, an absolute correlate of protection is not established. In this study, we investigated the leukocyte response to a Vi-tetanus toxoid conjugate vaccine (Vi-TT) in comparison with a plain polysaccharide vaccine (Vi-PS) in healthy adults subsequently challenged with Salmonella Typhi. Immunological responses and their association with challenge outcome was assessed by mass cytometry and Vi-ELISpot assay. Immunization induced significant expansion of plasma cells in both vaccines with modest T follicular helper cell responses detectable after Vi-TT only. The Vi-specific IgG and IgM B cell response was considerably greater in magnitude in Vi-TT recipients. Intriguingly, a significant increase in a subset of IgA+ plasma cells expressing mucosal migratory markers α4β7 and CCR10 was observed in both vaccine groups, suggesting a gut-tropic, mucosal response is induced by Vi-vaccination. The total plasma cell response was significantly associated with protection against typhoid fever in Vi-TT vaccinees but not Vi-PS. IgA+ plasma cells were not significantly associated with protection for either vaccine, although a trend is seen for Vi-PS. Conversely, the IgA- fraction of the plasma cell response was only associated with protection in Vi-TT. In summary, these data indicate that a phenotypically heterogeneous response including both gut-homing and systemic antibody secreting cells may be critical for protection induced by Vi-TT vaccination.

Highlights

Vi polysaccharide (Vi-PS) vaccines targeting Salmonella enterica serovar Typhi
Vispecific IgG antibody secreting cells (ASC) were detected in peripheral blood 7 days postvaccination in Vi-PS and Vi-tetanus toxoid (Vi-tetanus toxoid (TT)) vaccinees (Figure 1A, Vi-PS: n = 35, Vi-TT: n = 39, Supplementary Figure 1 for individual participant ASC kinetics)
Higher frequencies of Vi-specific IgG ASCs were detected in Vi-TT vaccinees in comparison with Vi-PS; median 82.5 per 106 peripheral blood mononuclear cell (PBMC) (IQR: 10141) versus 3 per 106 PBMCs (IQR 3-33.5) for Vi-TT and Vi-PS, respectively

Summary

Introduction

Vi polysaccharide (Vi-PS) vaccines targeting Salmonella enterica serovar Typhi (S. Typhi) are moderately protective against typhoid fever but are not widely used in endemic countries. Conjugate vaccines do not induce hypo-responsiveness to subsequent doses in the way that plain polysaccharide vaccines do, allowing for boosting regimens to be implemented [5]. These mechanisms have been exploited with great success in vaccines targeting encapsulated bacteria, including those against Streptococcus pneumoniae and Neisseria meningitidis, which has resulted in the inclusion of these glycoconjugate vaccines in routine infant immunization schedules [6, 7]. A recently developed Vi-tetanus toxoid (Vi-TT) conjugate vaccine was shown to be protective in a controlled human challenge model of typhoid fever [8] and demonstrated an efficacy of 81.6% in a Phase III, randomized, controlled trial in Nepal [9]. Immunogenicity of Vi-TT has been found to be significantly higher in comparison with Vi-PS [10]

Methods

Results

Conclusion