Salmonella Typhi Vi capsule prime-boost vaccination induces convergent and functional antibody responses

Abstract

Vaccine development to prevent Salmonella Typhi infections has accelerated over the past decade, resulting in licensure of new vaccines, which use the Vi polysaccharide (Vi PS) of the bacterium conjugated to an unrelated carrier protein, as the active component. Antibodies elicited by these vaccines are important for mediating protection against typhoid fever. However, the characteristics of protective and functional Vi antibodies are unknown. In this study, we investigated the human antibody repertoire, avidity maturation, epitope specificity, and function after immunizations with a single dose of Vi-tetanus toxoid conjugate vaccine (Vi-TT), and after a booster with plain Vi PS (Vi-PS). The Vi-TT prime induced an IgG1-dominant response, while the Vi-TT prime followed by the Vi-PS boost induced IgG1 and IgG2 antibody production. B-cells from recipients who received both prime and boost showed evidence of convergence with shared V gene usage and CDR3 characteristics. The detected Vi antibodies showed heterogeneous avidity ranging from 10µM-500pM, with no evidence of affinity maturation after the boost. Vi-specific antibodies mediated Fc effector functions, which correlated with antibody dissociation kinetics but not with association kinetics. We identified antibodies induced by prime and boost vaccines that recognized subdominant epitopes, indicated by binding to the de-O-acetylated Vi backbone. These antibodies also mediated Fc-dependent functions, such as complement deposition and monocyte phagocytosis. Defining strategies on how to broaden epitope targeting for Salmonella Typhi Vi and enriching for antibody Fc functions that protect against typhoid fever will advance the design of high efficacy Vi vaccines for protection across diverse populations.

Functional Activities of O-Polysaccharide and Hemolysin Coregulated Protein 1 Specific Antibodies Isolated from Melioidosis Patients

“…However, our study indicates an important role for IgG-OPS in C3b deposition on B. pseudomallei and suggests that high levels of antibodies may play a role in controlling B. pseudomallei infections. The role of specific antibodies for complement activation against other bacterial and viral infections have been demonstrated previously, for example, in Neisseria meningitidis serogroup B ( 29 ), Escherichia coli 0111B4 ( 30 ), Salmonella Typhi ( 31 ), immunodeficiency virus (HIV) antibodies ( 32 ). These studies show human monoclonal antibodies to specific antigens are most efficient in cell lysis and C3 deposition on infected cells ( 32 ).…”

A tool for evaluating heterogeneity in avidity of polyclonal antibodies

“…The slower k d (2×10 -5 to 1×10 -3 s -1 ) were associated with higher responses (60 to 95% of the total response) than the >1×10 -2 s -1 k d (5 to 50% of the responses) as shown in Figure 6A . The Vi-PS being a polymeric antigen likely presents different epitopes that can be targeted by the vaccine elicited antibodies and hence the heterogeneity in avidity observed here could arise not only due to competition but also due to difference in fine specificities ( 33 ). Overall, PAART analysis dissected the avidity of polyclonal IgG antibodies of most of the VAST study vaccinees into at least two bins differing in dissociation rates ( k d ranging from 2×10 -5 to 1×10 -3 s -1 and k d ≥1×10 -2 s -1 ) and further revealed the inter-group difference in proportion of avidity diverseness.…”

Vi polysaccharide and conjugated vaccines afford similar early, IgM or IgG-independent control of infection but boosting with conjugated Vi vaccines sustains the efficacy of immune responses

“…In the context of using TCV in humans it can be hypothesised that TCV are superior to Vi-PS vaccines due to the longer lasting antibody responses induced and not the antibody isotypes induced. A single immunization with TCV offers excellent protection (57) but additional immunizations may enhance this protection through extending its longevity rather than its magnitude. In this regard it is noteworthy that in our studies, two immunizations of 2 µg Vi-TT induced higher IgG titres than one immunization with 4 µg Vi-TT.…”