A Semi‐Synthetic Glycoconjugate Vaccine Candidate for Carbapenem‐Resistant <i>Klebsiella pneumoniae</i>

Seeberger, Peter H.; Pereira, Claney L.; Khan, Naeem; Xiao, Guozhi; Diago-Navarro, Elizabeth; Reppe, Katrin; Opitz, Bastian; Fries, Bettina C.; Witzenrath, Martin

doi:10.1002/ange.201700964

Cited by 16 publications

(13 citation statements)

References 75 publications

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“…Though humoral responses to a CR-Kp hexasaccharide vaccine were predominantly mIgG (38), mIgG 3 antibodies, like hIgG 2 , are the primary humoral response to Tindependent antigens such as polysaccharide capsules, and the predominant monoclonal antibody subclass identified after vaccination with full length capsule (14,39,40). This suggests that mIgG 3 has some evolutionary importance in protecting against encapsulated organisms.…”

Section: Discussionmentioning

confidence: 99%

The Role of IgG Subclass in Antibody-Mediated Protection against Carbapenem-ResistantKlebsiella pneumoniae

Motley

Diago-Navarro

Banerjee

et al. 2020

Preprint

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Monoclonal antibodies (Abs) have the potential to assist in the battle against multidrug-resistant bacteria such as Carbapenem-Resistant Klebsiella pneumoniae (CR-Kp). However, the characteristics by which these Abs function, such as the role of antibody subclass, must be determined before such modalities can be carried from the bench to the bedside. We performed a subclass switch on anti-capsular monoclonal murine IgG3 (mIgG3) hybridomas and identified and purified a murine IgG1 (mIgG1) hybridoma line through sib selection. We then compared the ability of the mIgG1 and mIgG3 antibodies to control CR-Kp ST258 infection both in vitro and in vivo. We found by ELISA and flow cytometry that mIgG3 has superior binding to CR-Kp CPS and superior agglutinating ability compared to mIgG1. The mIgG3 also predictably had better complement-mediated serum bactericidal activity than the mIgG1 and also promoted neutrophil-mediated killing at concentrations lower than the mIgG1. In contrast, the mIgG1 had marginally better activity in improving macrophage-mediated phagocytosis. Comparing their activities in a pulmonary infection model with wild type as well as neutropenic mice, both antibodies reduced organ burden in a non-lethal challenge, regardless of neutrophil status, with mIgG1 having the highest overall burden reduction in both scenarios. However, at a lethal inoculum, both antibodies showed reduced efficacy in neutropenic mice, with mIgG3 retaining the most activity. These findings suggest the viability of monoclonal Ab adjunctive therapy in neutropenic patients that cannot mount their own immune response, while also providing some insight into the relative contributions of immune mediators in CR-Kp protection.ImportanceCarbapenem-resistant Klebsiella pneumoniae is an urgent public health threat that causes life-threatening infections in immunocompromised hosts. Its resistance to nearly all antibiotics necessitates novel strategies to treat it, including the use of monoclonal antibodies. Monoclonal antibodies are emerging as important adjuncts to traditional pharmaceuticals, and studying how they protect against specific bacteria such as Klebsiella pneumoniae is crucial to their development as effective therapies. Antibody subclass is often overlooked but is a major factor in how an antibody interacts with other mediators of immunity. This paper is the first to examine how the subclass of anti-capsular monoclonal antibodies can affect efficacy against CR-Kp. Additionally, this work sheds light on the viability of monoclonal antibody therapy in neutropenic patients, who are most vulnerable to CR-Kp infection.

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Section: Discussionmentioning

confidence: 99%

The Role of IgG Subclass in Antibody-Mediated Protection against Carbapenem-ResistantKlebsiella pneumoniae

Motley

Diago-Navarro

Banerjee

et al. 2020

Preprint

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“…Antibodies against rhamnose have been described as highly abundant in humans (52). Trirhamnoside 252, based on the capsular polysaccharide (CPS) of a broadly drug-resistant Klebsiella pneumoniae strain (53,54), displayed the highest fluorescence intensities. The rhamnosides were followed by a lessdefined group with several representatives within the top 20 according to median intensity comprising glycans that contain the nonmammalian monosaccharides N-acetyl-D-mannosamine (ManNAc) and FucNAc/D-FucNAc.…”

Section: Precursorsmentioning

confidence: 99%

Microbe-focused glycan array screening platform

Geissner

Reinhardt

Rademacher

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Interactions between glycans and glycan binding proteins are essential for numerous processes in all kingdoms of life. Glycan microarrays are an excellent tool to examine protein–glycan interactions. Here, we present a microbe-focused glycan microarray platform based on oligosaccharides obtained by chemical synthesis. Glycans were generated by combining different carbohydrate synthesis approaches including automated glycan assembly, solution-phase synthesis, and chemoenzymatic methods. The current library of more than 300 glycans is as diverse as the mammalian glycan array from the Consortium for Functional Glycomics and, due to its microbial focus, highly complementary. This glycan platform is essential for the characterization of various classes of glycan binding proteins. Applications of this glycan array platform are highlighted by the characterization of innate immune receptors and bacterial virulence factors as well as the analysis of human humoral immunity to pathogenic glycans.

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“… 2014 ), has recently been demonstrated to bind a specific mAb and to promote, after conjugation, the production of phagocytic antibodies (Seeberger et al. 2017 ).…”

Section: Approaches For Production Of Glycoconjugate Vaccinesmentioning

confidence: 99%

Potential targets for next generation antimicrobial glycoconjugate vaccines

Micoli¹,

Costantino

Adamo

2018

FEMS Microbiology Reviews

141

109

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Cell surface carbohydrates have been proven optimal targets for vaccine development. Conjugation of polysaccharides to a carrier protein triggers a T-cell-dependent immune response to the glycan moiety. Licensed glycoconjugate vaccines are produced by chemical conjugation of capsular polysaccharides to prevent meningitis caused by meningococcus, pneumococcus and Haemophilus influenzae type b. However, other classes of carbohydrates (O-antigens, exopolysaccharides, wall/teichoic acids) represent attractive targets for developing vaccines. Recent analysis from WHO/CHO underpins alarming concern toward antibiotic-resistant bacteria, such as the so called ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) and additional pathogens such as Clostridium difficile and Group A Streptococcus. Fungal infections are also becoming increasingly invasive for immunocompromised patients or hospitalized individuals. Other emergencies could derive from bacteria which spread during environmental calamities (Vibrio cholerae) or with potential as bioterrorism weapons (Burkholderia pseudomallei and mallei, Francisella tularensis). Vaccination could aid reducing the use of broad-spectrum antibiotics and provide protection by herd immunity also to individuals who are not vaccinated.This review analyzes structural and functional differences of the polysaccharides exposed on the surface of emerging pathogenic bacteria, combined with medical need and technological feasibility of corresponding glycoconjugate vaccines.

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A Semi‐Synthetic Glycoconjugate Vaccine Candidate for Carbapenem‐Resistant Klebsiella pneumoniae

Cited by 16 publications

References 75 publications

The Role of IgG Subclass in Antibody-Mediated Protection against Carbapenem-ResistantKlebsiella pneumoniae

The Role of IgG Subclass in Antibody-Mediated Protection against Carbapenem-ResistantKlebsiella pneumoniae

Microbe-focused glycan array screening platform

Potential targets for next generation antimicrobial glycoconjugate vaccines

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