Development of a broad spectrum glycoconjugate vaccine to prevent wound and disseminated infections with Klebsiella pneumoniae and Pseudomonas aeruginosa.

Marcela F Pasetti,Nicolas Hegerle,Sharon M Tennant,Ian Alan Holder,Paulo Lee Ho,Raphael Simon,James Sinclair,Myeongjin Choi,Jerod Brammer,Alan S Cross,Mohammed N Amin,Morgane Ollivault-Shiflett,Rachel S Laufer,Brittany Curtis,Andrew Lees,Franklin R Toapanta,Surekha Shridhar

doi:10.1371/journal.pone.0203143

Abstract

Klebsiella pneumoniae (KP) and Pseudomonas aeruginosa (PA) are important human pathogens that are associated with a range of infection types, including wound and disseminated infections. Treatment has been complicated by rising rates of antimicrobial resistance. Immunoprophylactic strategies are not constrained by antimicrobial resistance mechanisms. Vaccines against these organisms would be important public health tools, yet they are not available. KP surface O polysaccharides (OPS) are protective antigens in animal models of infection. Similarly, PA flagellin (Fla), the major subunit of the flagellar filament, is required for virulence and is a target of protective antibodies in animal models. We report herein the development of a combined KP and PA glycoconjugate vaccine comprised of the four most common KP OPS types associated with human infections (O1, O2, O3, O5), chemically linked to the two Fla types of PA (FlaA, FlaB). Conjugation of KP OPS to PA Fla enhanced anti-polysaccharide immune responses and produced a formulation that generated antibody titers to the four KP OPS types and both PA Fla antigens in rabbits. Passive transfer of vaccine-induced rabbit antisera reduced the bacterial burden and protected mice against fatal intravenous KP infection. Mice passively transferred with conjugate-induced antisera were also protected against PA infection after thermal injury with a FlaB-expressing isolate, but not a FlaA isolate. Taken together, these promising preclinical results provide important proof-of-concept for a broad spectrum human vaccine to prevent KP and PA infections.

Highlights

Nosocomial infections are a major risk factor upon hospitalization and are associated with a range of infections including those at surgical sites and wounds, pneumonias, intravenous catheter-based infections, urinary tract infections, and septicemia
The preclinical development of a broad-spectrum four component conjugate vaccine for Klebsiella pneumoniae (KP) and Pseudomonas aeruginosa (PA) based on chemical conjugation of the four prevalent KP O polysaccharides (OPS) types with the two PA flagellin types
The mutant was compared to wild-type phenotypically by measuring guanine auxotrophy, lack of capsule expression and attenuation

Summary

Introduction

Nosocomial infections are a major risk factor upon hospitalization and are associated with a range of infections including those at surgical sites and wounds, pneumonias, intravenous catheter-based infections, urinary tract infections, and septicemia. The recent emergence of antimicrobial resistance (AMR) among nosocomially-associated bacteria, including to antibiotics of last resort such as colistin, engenders significant clinical risk and threatens a return to the pre-antibiotic era. Two Gram-negative bacterial pathogens, Klebsiella pneumoniae (KP) and Pseudomonas aeruginosa (PA), account for a significant proportion of nosocomial infections and have been identified by the US Centers for Disease Control and Prevention (CDC) and the World Health Organization as being of highest concern due to the accelerating acquisition and spread of antibiotic resistance [1, 2]. As the clinico-epidemiological patterns for nosocomial infections with these pathogens are similar, a broad spectrum vaccine is warranted and would offer a potentially straightforward way to reduce their combined incidence [1]

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Conclusion