A Synthetic Carbohydrate–Protein Conjugate Vaccine Candidate against <i>Klebsiella pneumoniae</i> Serotype K2

Ravinder, M.; Liao, Kuo-Shiang; Cheng, Yang‐Yu; Pawar, Sujeet; Lin, Tzu‐Lung; Wang, Jann-Tay; Wu, Chung‐Yi

doi:10.1021/acs.joc.0c01404

Cited by 22 publications

(14 citation statements)

References 48 publications

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“…The KpSC polysaccharide capsule and lipopolysaccharide (LPS) antigens are pathogenicity factors [10][11][12][13] and among the key targets for novel control strategies [7,[14][15][16][17][18]. Of particular interest, there is mounting evidence that capsule and/or LPS immunisation can elicit a protective immune response, and several anti-KpSC capsule and/or LPS vaccines have entered clinical trials [19][20][21][22][23]. However, considerable antigenic diversity exists within the KpSC population (>77 serologically defined capsule types [24][25][26], >8 LPS O antigen serotypes [16,27], and many more predicted on the basis of genomic data [28,29]), and there is a paucity of sero-epidemiological knowledge, which hampers efficient vaccine design.…”

Section: Introductionmentioning

confidence: 99%

Kaptive 2.0: updated capsule and LPS locus typing for the Klebsiella pneumoniae species complex

Wick

Judd

Holt

2021

Preprint

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The outer polysaccharide capsule and lipopolysaccharide antigens are key targets for novel control strategies targeting Klebsiella pneumoniae and related taxa from the K. pneumoniae species complex (KpSC), including vaccines, phage and monoclonal antibody therapies. Given the importance and growing interest in these highly diverse surface antigens, we had previously developed Kaptive, a tool for rapidly identifying and typing capsule (K) and outer lipopolysaccharide (O) loci from whole genome sequence data. Here, we report two significant updates, now freely available in Kaptive 2.0 (github.com/katholt/kaptive); i) the addition of 16 novel K locus sequences to the K locus reference database following an extensive search of >17,000 KpSC genomes; and ii) enhanced O locus typing to enable prediction of the clinically relevant O2 antigen (sub)types, for which the genetic determinants have been recently described. We applied Kaptive 2.0 to a curated dataset of >12,000 public KpSC genomes to explore for the first time the distribution of predicted O (sub)types across species, sampling niches and clones, which highlighted key differences in the distributions that warrant further investigation. As the uptake of genomic surveillance approaches continues to expand globally, the application of Kaptive 2.0 will generate novel insights essential for the design of effective KpSC control strategies.Significance as a BioResource to the communityKlebsiella pneumoniae is a major cause of bacterial healthcare associated infections globally, with increasing rates of antimicrobial resistance, including strains with resistance to the drugs of last resort. The latter have therefore been flagged as priority pathogens for the development of novel control strategies.K. pneumoniae produce two key surface antigen sugars (capsular polysaccharide and lipopolysaccharide (LPS)) that are immunogenic and targets for novel controls such as a vaccines and phage therapy. However, there is substantial antigenic diversity in the population and relatively little is understood about the distribution of antigen types geographically and among strains causing different types of infections. Whereas laboratory-based antigen typing is difficult and rarely performed, information about the relevant synthesis loci can be readily extracted from whole genome sequence data. We have previously developed Kaptive, a freely available tool for rapid typing of Klebsiella capsule and LPS loci from genome sequences.Kaptive is now used widely in the global research community and has facilitated new insights into Klebsiella capsule and LPS diversity. Here we present an update to Kaptive facilitating i) the identification of 16 additional novel capsule loci, and ii) the prediction of immunologically relevant LPS O2 antigen subtypes. These updates will enable enhanced sero-epidemiological surveillance for K. pneumoniae, to inform the design of vaccines and other novel Klebsiella control strategies.Data summaryThe updated code and reference databases for Kaptive are available at https://github.com/katholt/KaptiveGenome accessions from which reference sequences of novel K loci were defined are listed in Supplementary Table 1, and genomes from which these loci were detected (along with the corresponding Kaptive output) are listed in Supplementary Table 2.Accessions for the genomes screened for O types/subtypes (along with the corresponding Kaptive output) are listed in Supplementary Table 3.The authors confirm all supporting data, code and protocols have been provided within the article or through supplementary data files.Repositories1.1RepositoriesGenome sequence from which the novel K locus KL182 was defined has been deposited under the accession JAJHNT000000000.

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Section: Introductionmentioning

confidence: 99%

Kaptive 2.0: updated capsule and LPS locus typing for the Klebsiella pneumoniae species complex

Wick

Judd

Holt

2021

Preprint

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“…A recent study investigating synthetic K2 capsular polysaccharides conjugated with diphtheria toxin (DT) demonstrated production of specific anti-capsular antibodies in mice which displayed in vitro bactericidal activity through complement system activation [59]. However, in vivo protection was not evaluated in that study.…”

Section: Capsular Polysaccharidesmentioning

confidence: 99%

Current Stage in the Development of Klebsiella pneumoniae Vaccines

et al. 2021

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Klebsiella pneumoniae is a bacterium capable of colonizing mucous membranes, causing serious infections. Widespread antibiotic resistance in K. pneumoniae-either through intrinsic mechanisms or via acquisition from different species, especially in hospital environments-limits the therapeutic options against this pathogen, further aggravating the disease burden. To date, there are no vaccines available against K. pneumoniae infection. Although formulations based on capsular polysaccharides have been proposed, the high variability in capsular serotypes limits vaccine coverage. Recombinant vaccines based on surface exposed bacterial antigens are a promising alternative owing to their conservation among different serotypes and accessibility to the immune system. Many vaccine candidates have been proposed, some of which have reached clinical trials. The present review summarizes the current status of K. pneumoniae vaccine development. Different strategies including whole cell vaccines, outer membrane vesicles (OMVs), ribosome, polysaccharide, lipopolysaccharide (LPS), and protein-based formulations are discussed. The contribution of antibody and cell-mediated responses is also presented. In summary, K. pneumoniae vaccines are feasible and a promising strategy to prevent infections and to reduce the antimicrobial resistance burden worldwide.

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“…Despite the fact that to date, the expression of biosynthetic pathways and glycoengineering to produce bacterial glycans provides cheaper and versatile method to develop carbohydrates vaccines [94], recent advances in carbohydrate synthesis allowed access to many complex oligosaccharides on a large scale and with precise control of the structure [44]. Synthetic strategies aimed at the development of conjugate vaccines containing protein/peptide carriers are mainly based on the incorporation of either a synthetic bacterial carbohydrate antigen [95][96][97][98][99][100][101][102][103][104][105], their synthetic structural mimics, or chimeric oligosaccharides [11]. Relevant examples of the latter approach were reported during the last decade.…”

Section: Protein-based Glycoconjugatesmentioning

confidence: 99%