Development of an anti-endotoxin vaccine for sepsis

Abstract

Gram-negative bacterial lipopolysaccharide (LPS, endotoxin) is an important initiator of sepsis, a clinical syndrome that is a leading cause of death in intensive care units. Vaccines directed against core LPS structures that are widely conserved among Gram-negative bacteria (GNB) have been developed for the treatment and/or prevention of sepsis. Killed whole bacterial vaccines (E. coli O111:B4, J5 [Rc chemotype] mutant and S. minnesota, Re chemotype) protected mice against experimental sepsis. Human J5 immune antisera reduced the mortality from GNB sepsis in a large controlled clinical trial; however, subsequent clinical studies with antiendotoxin antibodies did not demonstrate protective efficacy in sepsis. Multiple clinical studies have since demonstrated a correlation between the level of circulating antibodies to LPS core and morbidity and mortality in different clinical settings. We therefore developed a subunit vaccine by combining detoxified J5 LPS (J5 dLPS) with the outer membrane protein (OMP) from group B N. meningitidis. This vaccine was highly efficacious in experimental models of sepsis and progressed to phase 1 clinical trial. While well-tolerated, this vaccine induced only 3-4-fold increases in anti-J5 dLPS antibody. Addition of the TLR9 agonist, oligodeoxynucleotide with a CpG motif, as adjuvant to the vaccine increased antibody levels in mice and the vaccine/CpG combination will progress to phase 1 human study. Additional vaccines in which the core glycolipid was either conjugated to carrier protein or incorporated into liposomes have been developed, but have not progressed to clinical trial. Should an antiendotoxin vaccine become available, a new immunization strategy directed towards distinct populations at risk will be required.