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

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.

Persistence of Antibody After a Vi-Tetanus Toxoid Conjugate Vaccine and Effect of Boosting With a Plain Polysaccharide Vaccine on Vi Antibody and Antigen-Specific B Cells

“…Previous studies have shown that polysaccharide-conjugate vaccines induce long lived antigen specific memory B cells (34). We have previously shown that Vi-TT vaccination induces Vi specific memory B cells which are significantly elevated above baseline 28 days after vaccination, while Vi-PS showed no significant change in memory B cell formation (25). Our data add to this and suggest that Vi specific memory B cells are not detectable in peripheral blood 19-23 months after Vi-TT vaccination.…”

“…Vi-PS booster vaccination induced a significant increase in the frequency of Vi IgA ASCs between pre-boost (median = 3.0 ASCs/10 6 PBMCs) and 7 days post-boost (median = 7.7 ASCs/ 10 6 PBMCs), while no significant change was observed for ASCs producing anti-Vi IgG or IgM (Figure 6). In contrast, the initial Vi-TT vaccination induced significant increases in both Vi specific IgG and IgM ASCs (25). No data were collected on the anti-Vi IgA ASC response to primary conjugate vaccination.…”

Association of Antibody-Dependent Neutrophil Phagocytosis With Distinct Antibody Glycosylation Profiles Following Typhoid Vaccination

“…Conversely, during infection with S. Typhi, the Vi capsule enables the bacterium to evade antibody-mediated neutrophil responses (30,31), and in vitro models of S. Typhi have shown its ability to evade the oxidative burst and phagosome maturation within monocytes and neutrophils after phagocytosis (32,33), ultimately resulting in bacterial dissemination. Vaccination with Vi-TCV however induces gut homing plasma cells that produce Vi-specific antibodies (34). Given the increase in ADNP following vaccination, these antibodies may have a role in activating Fc receptors on neutrophils to bring about phagocytosis, thus overcoming the natural ability of S. Typhi to evade neutrophilmediated responses.…”

The Route of Vaccine Administration Determines Whether Blood Neutrophils Undergo Long-Term Phenotypic Modifications

“…High-dimensional cytometry, including mass cytometry and spectral flow cytometry, is a powerful technique to monitor immunity, identify cell subsets associated with diseases or potent responses to vaccines, and decipher the complex mechanisms of the immune response to vaccines (20)(21)(22)(23)(24)(25)(26)(27). However, the comparison and integration of different datasets generated at multiple sites and on different days is challenging, even when using the same technology.…”