Vi-specific serological correlates of protection for typhoid fever

Abstract

Typhoid Vi vaccines have been shown to be efficacious in children living in endemic regions; however, a widely accepted correlate of protection remains to be established. We applied a systems serology approach to identify Vi-specific serological correlates of protection using samples obtained from participants enrolled in an experimental controlled human infection study. Participants were vaccinated with Vi-tetanus toxoid conjugate (Vi-TT) or unconjugated Vi-polysaccharide (Vi-PS) vaccines and were subsequently challenged with Salmonella Typhi bacteria. Multivariate analyses identified distinct protective signatures for Vi-TT and Vi-PS vaccines in addition to shared features that predicted protection across both groups. Vi IgA quantity and avidity correlated with protection from S. Typhi infection, whereas higher fold increases in Vi IgG responses were associated with reduced disease severity. Targeted antibody-mediated functional responses, particularly neutrophil phagocytosis, were also identified as important components of the protective signature. These humoral markers could be used to evaluate and develop efficacious Vi-conjugate vaccines and assist with accelerating vaccine availability to typhoid-endemic regions.

A Salmonella Typhi Controlled Human Infection Study for Assessing Correlation between Bactericidal Antibodies and Protection against Infection Induced by Typhoid Vaccination

“…Previous analysis of biophysical and functional antibody properties in our study cohort show that anti-Vi IgA quantity and avidity are strongly associated with protection after Vi vaccination [ 14 , 15 ]. However, IgA is not known to mediate complement dependent killing via that classical pathway as it is a poor activator of C1q that lacks a binding site in the FC region [ 32 ], nor does it correlate with SBA in our analyses.…”

“…Thus, the lack of correlation between SBA and ADCD could be due to inherent differences in complement, or effectors downstream of the C3b stage, or variable Vi expression of the bacteria. Neither bactericidal activity or complement deposition correlate highly with protection within our challenge model [ 15 ].…”

“…Multiple clinical observations were measured and described by Jin et al [ 10 ]. Quantification of anti-Vi antibodies and effector functions have also been measured previously, as detailed Jin et al [ 15 ]. Here we use the previously collected data to investigate the relationship between SBA and various antibody properties, or clinical presentation of acute typhoid fever.…”

“…The capacity of Vi-specific antibodies to induce certain effector functions may more strongly associate with protection. We have previously observed that distinct protective signatures are induced by Vi-PS and Vi-TT vaccines [ 15 ]. These protective signatures comprise both quantitative antibody (IgG and IgA) as well as functional responses mediated by innate cells, however, these analyses did not include evaluation of serum bactericidal activity (SBA).…”

Building a better antibody through the Fc: advances and challenges in harnessing antibody Fc effector functions for antiviral protection

“…The induction of a polyclonal antibody response against a given pathogen via vaccination can target multiple protective epitopes that can limit viruses at multiple steps of infection and dissemination. Correlates analysis of vaccines against both bacterial and viral pathogens indicate that the ability to recruit innate immune effector function may be a critical component of vaccine-mediated protection, [151][152][153] and the functional humoral response can be shaped by vaccine vectors, adjuvants, and vaccine regimens. 154 In the context of HIV vaccines, the induction of broadly neutralizing antibodies via vaccination has long been elusive.…”