Phase 1 trial of a 24-valent Klebsiella capsular polysaccharide vaccine and an eight-valent Pseudomonas O-polysaccharide conjugate vaccine administered simultaneously

Edelman, Robert; Taylor, David N.; Wasserman, Steven S.; McClain, J. Bruce; Cross, Alan S.; Sadoff, Jerald C.; Que, John U.; Cryz, Stanley J.

doi:10.1016/s0264-410x(94)80054-4

Cited by 58 publications

(43 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[7][8][9][10] Among the different cell constituents, two surface components are mainly being discussed as candidates for an anti-Klebsiella vaccine: LPS and CPS. 11,12 While the utilization of LPS antigens in Klebsiella vaccines is favored by the existence of only 9 different O-types, the adverse toxic reactions present a great drawback of active immunization with LPS-containing vaccines, although they can be reduced by detoxification.…”

Section: Identification and Characterization Of Antigens As Vaccine Cmentioning

confidence: 99%

Identification and characterization of antigens as vaccine candidates againstKlebsiella pneumoniae

Lundberg

Senn

Schuler

et al. 2013

Human Vaccines & Immunotherapeutics

View full text Add to dashboard Cite

Section: Identification and Characterization Of Antigens As Vaccine Cmentioning

confidence: 99%

Identification and characterization of antigens as vaccine candidates againstKlebsiella pneumoniae

Lundberg

Senn

Schuler

et al. 2013

Human Vaccines & Immunotherapeutics

View full text Add to dashboard Cite

“…Early studies suggest that LPS-deficient strains failed to show significantly different pathogenesis from the wild-type (WT) strain (5). By contrast, CPS demonstrates the most distinguished characteristic of virulence factors for K. pneumoniae, and is implicated in the internalization of pathogens into epithelial cells (6). The capsule may protect the bacterium from phagocytosis by macrophages, through an escape from bactericidal serum factors (6).…”

mentioning

confidence: 99%

“…By contrast, CPS demonstrates the most distinguished characteristic of virulence factors for K. pneumoniae, and is implicated in the internalization of pathogens into epithelial cells (6). The capsule may protect the bacterium from phagocytosis by macrophages, through an escape from bactericidal serum factors (6). Other studies also demonstrated that isogenic CPS mutant strains of K. pneumoniae exhibited higher levels of adherence and internalization to lung cells and were more invasive, compared with WT counterparts (4).…”

mentioning

confidence: 99%

Lipid-Based Signaling Modulates DNA Repair Response and Survival against Klebsiella pneumoniae Infection in Host Cells and in Mice

Huang

Weaver

et al. 2013

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Klebsiella pneumoniae causes serious infections in the urinary tract, respiratory tract, and blood. Lipid rafts, also known as membrane microdomains, have been linked to the pathogenesis of bacterial infection. However, whether lipid rafts affect K. pneumoniae internalization into host cells remains unknown. Here, we show for the first time that K. pneumoniae was internalized into lung cells by activating lipid rafts. Disrupting lipid rafts by methyl-b-cyclodextrin inhibited pathogen internalization, impairing host defense. A deficient mutant of capsule polysaccharide (CPS) showed a higher internalization rate than a wild-type strain, indicating that CPS may inhibit bacterial entry to host cells. Furthermore, lipid rafts may affect the function of extracellular regulated kinase (ERK)-1/2, and knocking down ERK1/ 2 via short, interfering RNA increased apoptosis in both alveolar macrophages and epithelial cells after infection. To gain insights into bacterial pathogenesis, we evaluated the impact of lipid rafts on DNA integrity, and showed that raft aggregates also affect DNA damage and DNA repair responses (i.e., 8-oxoguanine DNA glycosylase [Ogg1]) through the regulation of reactive oxygen species. Importantly, cells overexpressing Ogg1 demonstrated reduced cytotoxicity during bacterial infection. Taken together, these results suggest that lipid rafts may modulate bacterial internalization, thereby affecting DNA damage and repair, which is critical to host defense against K. pneumoniae.Keywords: Klebsiella pneumoniae infection; internalization; alveolar epithelial cells; lipid rafts; capsule polysaccharide Klebsiella pneumoniae causes serious infections in multiorgan systems, and is the third most commonly isolated bacterium from the blood of patients with sepsis (1). Because K. pneumoniae rapidly develops multidrug-resistant strains, this "superbug" can also cause outbreaks in intensive care units, imposing significant financial burdens and dangerous health threats (2, 3). Despite intensive research during the past few decades, the pathogenesis of K. pneumoniae, including its internalization of alveolar cells, is incompletely understood. K. pneumoniae expresses two critical antigens on its cell surface, LPS (an O antigen) and capsule polysaccharide (CPS; a K antigen) (4). These two antigens contribute to pathogenicity through interactions with host cells in different manners (5). LPS is a major component of Gramnegative bacterial cell walls with high immunogenicity, but its role in pathogenesis remains elusive. Early studies suggest that LPS-deficient strains failed to show significantly different pathogenesis from the wild-type (WT) strain (5). By contrast, CPS demonstrates the most distinguished characteristic of virulence factors for K. pneumoniae, and is implicated in the internalization of pathogens into epithelial cells (6). The capsule may protect the bacterium from phagocytosis by macrophages, through an escape from bactericidal serum factors (6). Other studies also demonstrated that isogenic CPS mutant...

show abstract

“…pneumoniae is considered an extracellular pathogen whose virulence is linked with the production of a polysaccharide capsule that provides protection against host defense mechanisms, particularly phagocytosis (8). Immunity against the encapsulated bacterium is largely mediated by antibodies specific for the capsular polysaccharide, an observation that has been exploited to develop prototypic vaccines against the bacterium (13). As with other capsule-based vaccines, e.g., 23-valent pneumococcus vaccine, the efficacy of similar K. pneumoniae vaccines will depend on the distribution of capsule or "K" serotypes (5,6).…”

mentioning

confidence: 99%

Seroepidemiology ofKlebsiella pneumoniaein an Australian Tertiary Hospital and Its Implications for Vaccine Development

et al. 2006

View full text Add to dashboard Cite

The aim of this study was to determine the diversity of Klebsiella pneumoniae capsular serotypes in an Australian setting. Consecutive (n ‫؍‬ 293) nonrepetitive isolates of K. pneumoniae from a large teaching hospital laboratory were analyzed. The majority of isolates were from urinary specimens (60.8%); the next most common source was sputum (14.3%), followed by blood (14%). Serotyping revealed a wide range of capsule types. K54 (17.1%), K28 (4.1%), and K17 (3.1%) were the most common, and K54 isolates displayed a high degree of clonality, suggesting a common, nosocomial source. In vitro, one K54 isolate was more adherent to urinary catheters and HEp-2 cells than four other tested isolates; it was slightly more resistant to chlorhexidine but was more susceptible to drying than heavily encapsulated strains. This is the first seroprevalence survey of K. pneumoniae to be performed on Australian isolates, and the high level of diversity of serotypes suggests that capsule-based immunoprophylaxis might not be useful for Australia. In addition there are significant differences in the predominance of specific serotypes compared to the results of surveys performed overseas, which has important implications for capsule-based immunoprophylaxis aimed at a global market.

show abstract

Phase 1 trial of a 24-valent Klebsiella capsular polysaccharide vaccine and an eight-valent Pseudomonas O-polysaccharide conjugate vaccine administered simultaneously

Cited by 58 publications

References 20 publications

Identification and characterization of antigens as vaccine candidates againstKlebsiella pneumoniae

Identification and characterization of antigens as vaccine candidates againstKlebsiella pneumoniae

Lipid-Based Signaling Modulates DNA Repair Response and Survival against Klebsiella pneumoniae Infection in Host Cells and in Mice

Seroepidemiology ofKlebsiella pneumoniaein an Australian Tertiary Hospital and Its Implications for Vaccine Development

Contact Info

Product

Resources

About