title: Phase 1 testing of detoxified LPS/group B meningococcal outer membrane protein vaccine with and without synthetic CPG 7909 adjuvant for the prevention and treatment of sepsis.
abstract: BACKGROUND
  Gram-negative bacteria (GNB) are a leading cause of nosocomial infection and sepsis. Increasing multi-antibiotic resistance has left clinicians with fewer therapeutic options. Antibodies to GNB lipopolysaccharide (LPS, or endotoxin) have reduced morbidity and mortality as a result of infection and are not subject to the resistance mechanisms deployed by bacteria against antibiotics. In this phase 1 study, we administered a vaccine that elicits antibodies against a highly conserved portion of LPS with and without a CpG oligodeoxynucleotide (ODN) TLR9 agonist as adjuvant.
  
  
  METHODS
  A vaccine composed of the detoxified LPS (dLPS) from E. coli O111:B4 (J5 mutant) non-covalently complexed to group B meningococcal outer membrane protein (OMP). Twenty healthy adult subjects received three doses at 0, 29 and 59 days of antigen (10 μg dLPS) with or without CPG 7909 (250 or 500 μg). Subjects were evaluated for local and systemic adverse effects and laboratory findings. Anti-J5 LPS IgG and IgM antibody levels were measured by electrochemiluminesence. Due to premature study termination, not all subjects received all three doses.
  
  
  RESULTS
  All vaccine formulations were well-tolerated with no local or systemic events of greater than moderate severity. The vaccine alone group achieved a ≥ 4-fold "responder" response in IgG and IgM antibody in only one of 6 subjects. In contrast, the vaccine plus CPG 7909 groups appeared to have earlier and more sustained (to 180 days) responses, greater mean-fold increases, and a higher proportion of "responders" achieving ≥ 4-fold increases over baseline.
  
  
  CONCLUSIONS
  Although the study was halted before all enrolled subjects received all three doses, the J5dLPS/OMP vaccine, with or without CpG adjuvant, was safe and well-tolerated. The inclusion of CpG increased the number of subjects with a ≥ 4-fold antibody response, evident even after the second of three planned doses. A vaccine comprising J5dLPS/OMP antigen with CpG adjuvant merits further investigation.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier: NCT01164514.
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, 685 West Baltimore Street, HSF 1, Suite 480, Baltimore, MD 21201, United States. Electronic address: across@medicine.umaryland.edu.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Cross
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, 685 West Baltimore Street, HSF 1, Suite 480, Baltimore, MD 21201, United States. Electronic address: Ngreenbe@medicine.umaryland.edu.
authors.forename: Nancy
authors.initials: N
authors.lastname: Greenberg
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, 685 West Baltimore Street, HSF 1, Suite 480, Baltimore, MD 21201, United States. Electronic address: mbilling@medicine.umaryland.edu.
authors.forename: Melissa
authors.initials: M
authors.lastname: Billington
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, 685 West Baltimore Street, HSF 1, Suite 480, Baltimore, MD 21201, United States. Electronic address: lzhang@medicine.umaryland.edu.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201, United States. Electronic address: cdefilip@medicine.umaryland.edu.
authors.forename: Christopher
authors.initials: C
authors.lastname: DeFilippi
authors.affiliation: The Emmes Corporation, 401 N. Washington Street, Rockville, MD 20850, United States. Electronic address: rmay@emmes.com.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: May
authors.affiliation: The Emmes Corporation, 401 N. Washington Street, Rockville, MD 20850, United States. Electronic address: kbajwa@emmes.com.
authors.forename: Kanwaldeep K
authors.initials: KK
authors.lastname: Bajwa
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000293:Adolescent; D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood; D001425:Bacterial Outer Membrane Proteins / Q000008:administration & dosage / Q000276:immunology* / Q000633:toxicity; D015331:Cohort Studies; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology* / Q000633:toxicity; D008297:Male; D008589:Meningococcal Infections / Q000517:prevention & control*; D022401:Meningococcal Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D018805:Sepsis / Q000517:prevention & control*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D001425:Bacterial Outer Membrane Proteins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; D022401:Meningococcal Vaccines; D009838:Oligodeoxyribonucleotides; C483020:ProMune
keywords: Adjuvant; CpG ODN; Endotoxin; Lipopolysaccharide; Phase 1 study; Sepsis