Infections caused by gram negative bacteria may be complicated by sepsis, multi-organ failure, and death. Since the mortality has not changed during the last decade, new strategies to supplement conventional antibiotic therapy and supportive care are required. We developed a vaccine composed of detoxified lipopolysaccharide (LPS) from E. cell Ol11:B4, Rc (JS) chemotype complexed to the outer membrane protein of group B meningococcus 05 dLPS/OMP vaccine). This vaccine induces antibodies to a highly conserved region of bacteria LPS that are protective both actively and passively in animal models of sepsis. In the last grant period we administered this vaccine to 24 human subjects. The vaccine was safe and well-tolerated, but the antibody response was lower than that measured in rabbits and rodents. Consequently, in this proposal we wish to evaluate the safety, immuno-genicity and functional activity of this vaccine when given with the adjuvants, MF-59 and oligonucleotide (CpG), each of which has been safely administered to humans. Earlier, we found that vaccine-induced antibody bound heterologous LPS, enhanced the clearance of bacteria and endotoxin from the circulation of rats and neutralized the ability of LPS to induce cytokines ex vivo and to prime superoxide formation by human neutrophils. We now will correlate antibody levels following vaccine/adjuvant immunization with functional activity in vivo (clearance studies and protective activity) and in vitro (LPS binding and LPS neutralization studies). These activities may serve as surrogate markers for vaccine efficacy (Specific Aim I). We then will do a phase I study of vaccine and adjuvants in human subjects (Specific Aim II). J5 LPS inhibits the binding of vaccine-induced antibody to heterologous LPS. We therefore will determine if there is a specific J5 LPS epitope by comparing the inhibitory activity of complete and subunit structures of 35 LPS with other core LPS species, and will develop monoclonal antibodies to this epitope with the vaccine (Specific Aim III). The role of complement, macrophages and neutrophils in the functional activity of anti-J5 dLPS antibodies will be defined as well as the effect of immunization on LPS surface receptors (toll-like receptor 4 and CD14) of cells from both animals and humans (Specific Aim IV). If successful, these studies will lead to phase II and Ill studies for the prevention and treatment of sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042181-07
Application #
7061703
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Korpela, Jukka K
Project Start
1999-04-15
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2009-04-30
Support Year
7
Fiscal Year
2006
Total Cost
$395,083
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Cross, Alan (2016) Endotoxin: Back to the Future. Crit Care Med 44:450-1
Cross, Alan S (2014) Anti-endotoxin vaccines: back to the future. Virulence 5:219-25
Chen, Wilbur H; Basu, Subhendu; Bhattacharjee, Apurba K et al. (2010) Enhanced antibody responses to a detoxified lipopolysaccharide-group B meningococcal outer membrane protein vaccine are due to synergistic engagement of Toll-like receptors. Innate Immun 16:322-32
Cross, Alan S (2010) Development of an anti-endotoxin vaccine for sepsis. Subcell Biochem 53:285-302
Chen, Wilbur H; Kang, Tae Jin; Bhattacharjee, Apurba K et al. (2008) Intranasal administration of a detoxified endotoxin vaccine protects mice against heterologous Gram-negative bacterial pneumonia. Innate Immun 14:269-78
Cross, Alan S; Chen, Wilbur H; Levine, Myron M (2008) A case for immunization against nosocomial infections. J Leukoc Biol 83:483-8
Cross, Alan S; Opal, Steven M; Palardy, John E et al. (2003) Phase I study of detoxified Escherichia coli J5 lipopolysaccharide (J5dLPS)/group B meningococcal outer membrane protein (OMP) complex vaccine in human subjects. Vaccine 21:4576-87
Opal, S M; Palardy, J E; Parejo, N et al. (2001) Lipopolyamines as a therapeutic strategy in experimental Gram-negative bacterial sepsis. J Endotoxin Res 7:35-8
Cross, A S; Opal, S M; Warren, H S et al. (2001) Active immunization with a detoxified Escherichia coli J5 lipopolysaccharide group B meningococcal outer membrane protein complex vaccine protects animals from experimental sepsis. J Infect Dis 183:1079-86