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.

Increased vaccine tolerability and protection via NF-κB modulation

“…CpG has demonstrated great promise in increasing seroprotective antibody titers in human clinical trials (18,19). However, the excessive inflammatory response induced by some vaccine formulations incorporating CpG sequences has increased the cost of its development and reduced the number of vaccines where it has been implemented (13,(17)(18)(19). Despite the promise of CpG, only one vaccine, HEPLISAV-B created by Dynavax Technologies, has achieved approval for use in humans.…”

“…CpG DNA also enables vaccines to be produced with less antigen (14), induces protective responses faster (15), and produces effective antitumor activity (16,17). CpG has demonstrated great promise in increasing seroprotective antibody titers in human clinical trials (18,19). However, the excessive inflammatory response induced by some vaccine formulations incorporating CpG sequences has increased the cost of its development and reduced the number of vaccines where it has been implemented (13,(17)(18)(19).…”

Vaccines against extraintestinal pathogenic Escherichia coli (ExPEC): progress and challenges

“…Results trended toward sustained anti-LPS IgG and IgM responses after 180 but not 236 days. 49 However, the trial was underpowered due to recruitment ending prematurely.…”

A pilot study of an anti-endotoxin Ig-enriched bovine colostrum to prevent experimental sepsis

“…In two separate Phase I studies, it has been shown to be safe, well tolerated, and immunogenic. 36 , 37 …”