Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18655-18663. doi: 10.1073/pnas.1907833116. Epub 2019 Aug 27.

A promising bioconjugate vaccine against hypervirulent Klebsiella pneumoniae.

Author information

1
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
2
VaxNewMo, St. Louis, MO 63108.
3
Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC 3010, Australia.
4
Human Health Therapeutics, National Research Council Canada, Ottawa, ON K1A 0R6, Canada.
5
Division of Pediatric Infectious Diseases, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110.
6
VaxNewMo, St. Louis, MO 63108; christian.harding@vaxnewmo.com.

Abstract

Hypervirulent Klebsiella pneumoniae (hvKp) is globally disseminating as a community-acquired pathogen causing life-threatening infections in healthy individuals. The fact that a dose as little as 50 bacteria is lethal to mice illustrates the dramatic increase of virulence associated with hvKp strains compared with classical K. pneumoniae (cKp) strains, which require lethal doses greater than 107 bacteria. Until recently, these virulent strains were mostly antibiotic-susceptible. However, multidrug-resistant (MDR) hvKp strains have been emerging, spawning a new generation of hypervirulent "superbugs." The mechanisms of hypervirulence are not fully defined, but overproduction of capsular polysaccharide significantly impedes host clearance, resulting in increased pathogenicity of hvKp strains. While there are more than 80 serotypes of K. pneumoniae, the K1 and K2 serotypes cause the vast majority of hypervirulent infections. Therefore, a glycoconjugate vaccine targeting these 2 serotypes could significantly reduce hvKp infection. Conventionally, glycoconjugate vaccines are manufactured using intricate chemical methodologies to covalently attach purified polysaccharides to carrier proteins, which is widely considered to be technically challenging. Here we report on the recombinant production and analytical characterization of bioconjugate vaccines, enzymatically produced in glycoengineered Escherichia coli cells, against the 2 predominant hypervirulent K. pneumoniae serotypes, K1 and K2. The K. pneumoniae bioconjugates are immunogenic and efficacious, protecting mice against lethal infection from 2 hvKp strains, NTUH K-2044 and ATCC 43816. This preclinical study constitutes a key step toward preventing further global dissemination of hypervirulent MDR hvKp strains.

KEYWORDS:

bioconjugation; glycoconjugate; hypervirulent Klebsiella pneumoniae; vaccine

PMID:
31455739
DOI:
10.1073/pnas.1907833116
Free full text

Conflict of interest statement

Conflict of interest statement: M.F.F. and C.M.H. have a financial stake in VaxNewMo, a for-profit entity developing bioconjugate vaccines against Streptococcus pneumoniae and Klebsiella pneumoniae using patented technology derived from the data presented in this and other published manuscripts.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center