Immunogenicity and Induction of Functional Antibodies in Rabbits Immunized with a Trivalent Typhoid-Invasive Nontyphoidal Salmonella Glycoconjugate Formulation.

Scott Baliban,Mohammed Amin,Raphael Simon,Brittany Curtis,Vadrevu Mohan,Andrew Lees,Krishna Ella,Gangadhara Naidu,R Rao,Jessica Allen,Ramasamy Venkatesan,Myron Levine,D Rao

doi:10.3390/molecules23071749

Abstract

Typhoid fever due to Salmonella Typhi and invasive nontyphoidal Salmonella (iNTS) infections caused by serovars Enteritidis (SE) and Typhimurium (STm) are major pediatric health problems in sub-Saharan Africa. Typhoid has high complication rates, and iNTS infections have high case fatality rates; moreover, emerging antimicrobial resistance is diminishing treatment options. Vi capsule-based typhoid conjugate vaccine (Typbar-TCV™), licensed in India and pre-qualified by the World Health Organization, elicits durable immunity when administered to infants, but no iNTS vaccines are licensed or imminent. We have developed monovalent SE and STm glycoconjugate vaccines based on coupling lipopolysaccharide-derived core-O polysaccharide (COPS) to phase 1 flagellin protein (FliC) from the homologous serovar. Herein, we report the immunogenicity of multivalent formulations of iNTS COPS:FliC conjugates with Typbar-TCV™. Rabbits immunized with the trivalent typhoid-iNTS glycoconjugate vaccine generated high titers of serum IgG antibody to all three polysaccharide antigens for which anti-COPS IgG antibodies were directed primarily against serogroup-specific OPS epitopes. Responses to SE and STm FliC were lower relative to anti-COPS titers. Post-vaccination rabbit sera mediated bactericidal activity in-vitro, and protected mice after passive transfer against challenge with virulent SE or STm Malian blood isolates. These results support accelerated progression to clinical trials.

Highlights

The bacterial species Salmonella enterica encompasses more than 2500 serovariants, of which a subset are associated with human clinical infections [1]
We previously reported the development of invasive nontyphoidal Salmonella (iNTS) glycoconjugate vaccines for S
Typhimurium OPS conjugates have previously been seen between mice and rabbits [22,23]

Summary

Introduction

The bacterial species Salmonella enterica encompasses more than 2500 serovariants, of which a subset are associated with human clinical infections [1]. A human-restricted pathogen, causes typhoid fever, that is characterized by fever, abdominal discomfort and frontal headaches. Molecules 2018, 23, x FOR PEER REVIEW. Molecules 2018, 23, 1749 pathogen, causes typhoid fever, that is characterized by fever, abdominal discomfort and frontal headaches. In the pre-antibiotic era, the case fatality rate of typhoid fever was 10–20%. Non-typhoidal (NTS) serovars generally a broad hosta range, and when illness in humans is Salmonella (NTS)

Methods

Results

Conclusion