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

• Published in: Vaccine Vol. 33; no. 48; pp. 6719 - 6726
• Main Authors: Cross, Alan S., Greenberg, Nancy, Billington, Melissa, Zhang, Lei, DeFilippi, Christopher, May, Ryan C., Bajwa, Kanwaldeep K.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 27.11.2015; Elsevier Limited
• Subjects: Adjuvant; adjuvants; Adjuvants, Immunologic - administration & dosage; Adolescent; Adult; adults; adverse effects; agonists; Allergy and Immunology; Antibiotic resistance; Antibiotics; antibodies; Antibodies, Bacterial - blood; Antigens; Bacteria; Bacterial Outer Membrane Proteins - administration & dosage; Bacterial Outer Membrane Proteins - immunology; Bacterial Outer Membrane Proteins - toxicity; Cohort Studies; Confidence intervals; CpG ODN; cross infection; Drug-Related Side Effects and Adverse Reactions - epidemiology; Drug-Related Side Effects and Adverse Reactions - pathology; E coli; Endotoxin; Endotoxins; Escherichia coli; Female; Gram-negative bacteria; Human subjects; Humans; Immunization; immunoglobulin G; Immunoglobulin G - blood; immunoglobulin M; Immunoglobulin M - blood; Immunoglobulins; Laboratories; Lipopolysaccharide; lipopolysaccharides; Lipopolysaccharides - administration & dosage; Lipopolysaccharides - immunology; Lipopolysaccharides - toxicity; Male; Meningococcal Infections - prevention & control; Meningococcal Vaccines - administration & dosage; Meningococcal Vaccines - adverse effects; Meningococcal Vaccines - immunology; Middle Aged; morbidity; mortality; multiple drug resistance; mutants; Neisseria meningitidis; Nosocomial infection; Nosocomial infections; oligodeoxyribonucleotides; Oligodeoxyribonucleotides - administration & dosage; outer membrane proteins; Patient safety; Phase 1 study; resistance mechanisms; Sepsis; sepsis (infection); Sepsis - prevention & control; Toll-like receptor 9; Treatment Outcome; Vaccines; Young Adult; dLPS; gMFI; TSH; Phase 1 study; CpG ODN; Endotoxin; ECL; OMP; Lipopolysaccharide; Sepsis; GNB; MDR; Adjuvant; CpG; cytosine and guanosine triphosphate oligodeoxynucleotides joined by phosphorothioate; geometric mean fold increase; thyroid stimulating hormone; outer membrane protein; detoxified LPS; electrochemiluminescence; Gram-negative bacteria; multidrug resistant
• ISSN: 0264-410X; 1873-2518; 1873-2518
• DOI: 10.1016/j.vaccine.2015.10.072

•A vaccine elicits antibodies against a highly conserved core region of GNB endotoxin.•This detoxified endotoxin vaccine with and without two different doses of CPG 7909 adjuvant was given to healthy subjects.•The adverse effects of those given vaccine+CPG 7909, vaccine alone or placebo were similar.•Addition of CPG 7909 appeared to increase and accelerate the IgG and IgM antibody responses to the core glycolipid.•This vaccine merits further investigation as an adjunct to therapy against GNB infections. 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. 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 (10μg dLPS) with or without CPG 7909 (250 or 500μg). 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. 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. 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. ClinicalTrials.gov Identifier: NCT01164514.