Active immunization with a detoxified endotoxin vaccine protects against lethal polymicrobial sepsis: its use with CpG adjuvant and potential mechanisms.
BACKGROUND
An experimental vaccine for sepsis, composed of detoxified Escherichia coli J5 lipopolysaccharide (LPS) complexed with the outer membrane protein (OMP) of Neisseria meningitidis group B, induces anti-core glycolipid antibody and has been tested in pilot studies in human volunteers.


METHODS
Mice were immunized with the LPS-J5/OMP vaccine with or without synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs as a vaccine adjuvant (CpG ODN). The efficacy of the vaccine-induced antibody response was tested in a cecal ligation and puncture model.


RESULTS
Immunization resulted in a >20-fold increase in anti-core glycolipid antibody levels, which were further increased 5-fold by the addition of CpG ODN, compared with the levels in mice in the control group. The vaccine provided a survival advantage after a cecal ligation and puncture was performed (P < .01) and significantly decreased the levels of bacteria in organs. Immunoglobulin G (IgG) anti-core glycolipid antibodies were decreased in mice to a significantly greater extent than were levels of total circulating IgG or IgG to the OMP part of the vaccine complex, suggesting specific epitope binding and clearance.


CONCLUSIONS
These results indicate that the detoxified LPS-J5/OMP vaccine induces high levels of antibody against the core glycolipid of LPS and functions in vivo to promote clearance of gram-negative bacteria and improve the outcome of experimental polymicrobial intra-abdominal sepsis.
Opal
Steven M
SM
Infectious Disease Division, Brown Medical School, Providence, RI 02860, USA. Steven_Opal@brown.edu
Palardy
John E
JE
Chen
Wilbur H
WH
Parejo
Nicolas A
NA
Bhattacharjee
Apurba K
AK
Cross
Alan S
AS
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001425:Bacterial Outer Membrane Proteins / Q000008:administration & dosage / Q000276:immunology*; D004195:Disease Models, Animal; D004731:Endotoxins / Q000008:administration & dosage / Q000276:immunology*; D004926:Escherichia coli / Q000276:immunology; D006017:Glycolipids / Q000276:immunology; D016905:Gram-Negative Bacterial Infections / Q000517:prevention & control*; D007074:Immunoglobulin G / Q000097:blood; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology; D008099:Liver / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009345:Neisseria meningitidis / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology*; D018805:Sepsis / Q000517:prevention & control*; D013154:Spleen / Q000382:microbiology; D016019:Survival Analysis; D014611:Vaccination / Q000379:methods*; D014612:Vaccines
D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D001425:Bacterial Outer Membrane Proteins; C408982:CPG-oligonucleotide; D004731:Endotoxins; D006017:Glycolipids; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D014612:Vaccines; C485022:lipopolysaccharide, E coli J5; C044101:endotoxin, Escherichia coli