Detoxified endotoxin immunogenic compositions and uses thereof
Inventors
Cross, Alan S. • Bhattacharjee, Apurba K. • Zollinger, Wendell D. • Opal, Steven M.
Assignees
MEMORIAL HOSPITAL OF RHODE ISLAND • University of Maryland Baltimore • United States Department of the Army
Publication Number
US-9616116-B2
Publication Date
2017-04-11
Expiration Date
2026-10-24
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Abstract
The present invention provides an immunogenic composition of a lipopolysaccharide vaccine and a non-alum adjuvant. The immunogenic composition may be detoxified J5 core lipopolysaccharide of Escherichia coli non-covalently complexed with group B meningococcal outermembrane protein. Also provided are methods for preventing an infection caused by a Gram-negative bacteria in an individual via administering the immunogenic compositions to the individual.
Core Innovation
The invention provides an immunogenic composition comprising a lipopolysaccharide vaccine and a non-alum adjuvant, specifically a detoxified J5 core lipopolysaccharide of Escherichia coli non-covalently complexed with group B meningococcal outer membrane protein combined with a Toll-like receptor 9 (TLR9) agonist such as a CpG 7909 oligodeoxynucleotide. This combination elicits a strong antibody response to conserved core glycolipid epitopes present on many Gram-negative bacteria, offering heterologous protection against a wide spectrum of clinically relevant Gram-negative bacterial pathogens.
The problem addressed is that Gram-negative bacteria cause many life-threatening infections such as pneumonia, sepsis, and infections by biodefense agents, with limited effective vaccines that provide broad heterologous protection. Prior vaccines elicited antibodies mainly against serotype-specific outer sugars of lipopolysaccharide, offering limited protection. Furthermore, prior attempts including monoclonal antibodies to lipid A were unsuccessful, and the human antibody response to detoxified LPS J5 vaccines was modest. There was a need for a vaccine that induces high antibody titers to conserved core glycolipid epitopes and effective immunoadjuvants to enhance human responses.
The invention solves this by combining the detoxified J5 core lipopolysaccharide vaccine non-covalently complexed with group B meningococcal outer membrane protein with a non-alum adjuvant consisting of a TLR9 agonist such as CpG oligodeoxynucleotides, which markedly enhances anti-core lipopolysaccharide antibody responses. The immunogenic composition effectively protects against heterologous Gram-negative bacterial infections and sepsis, including infections caused by select agents, by inducing antibodies that facilitate bacterial clearance and reduce inflammatory cytokines and endotoxin levels. The immunogenic composition can be administered by various routes including subcutaneous, intramuscular, and intranasal.
Claims Coverage
The patent includes one independent composition claim and one independent method claim encompassing immunization against heterologous Gram-negative bacterial infections. The independent claims focus on the specific composition and methods of use with defined components and administration parameters.
Immunogenic composition consisting of detoxified E. coli J5 core lipopolysaccharide complexed with group B meningococcal outer membrane protein and CpG 7909
An immunogenic composition comprising a detoxified E. coli J5 core lipopolysaccharide of the Rc chemotype non-covalently complexed with group B meningococcal outer membrane protein combined with CpG 7909 oligodeoxynucleotide as a non-alum adjuvant.
Method of active immunization against heterologous Gram-negative bacteria
A method comprising administering an immunologically effective amount of the immunogenic composition (detoxified E. coli J5 core LPS complexed with group B meningococcal OMP plus CpG 7909) to an individual to actively immunize against infection by heterologous Gram-negative bacteria.
Routes of administration for the immunogenic composition
The immunogenic composition can be administered subcutaneously, intramuscularly, or intranasally for effective active immunization.
Concentrations of vaccine components in the immunogenic composition
The immunogenic composition comprises the detoxified E. coli J5 core lipopolysaccharide complexed with meningococcal outer membrane protein at a concentration of about 5 to 50 micrograms and CpG 7909 at about 250 to 500 micrograms.
Elicitation of functional anti-J5 core lipopolysaccharide antibodies
The immunogenic composition induces anti-J5 core lipopolysaccharide antibodies in the individual that bind to heterologous Gram-negative bacteria, enabling heterologous protection.
The claims cover a vaccine composition consisting of detoxified E. coli J5 core lipopolysaccharide complexed with group B meningococcal outer membrane protein and CpG 7909, methods of active immunization using this composition, specified administration routes, defined concentrations, and the elicitation of protective antibodies against heterologous Gram-negative bacteria.
Stated Advantages
The combination of detoxified LPS J5 vaccine with CpG oligodeoxynucleotides leads to marked enhancement of anti-core glycolipid antibody responses compared to vaccine alone.
The immunogenic composition provides heterologous protection against a broad spectrum of Gram-negative bacteria, including select agents and biowarfare pathogens.
The vaccine with CpG adjuvant reduces inflammatory cytokine levels, endotoxin levels, and bacterial load in experimental models of sepsis and infection.
Intranasal administration induces both systemic and mucosal antibody responses, including IgA, and provides protection against lethal Gram-negative bacterial pneumonia.
The detoxified LPS J5/OMP vaccine has been safely administered in human Phase I trials; addition of CpG increases immunogenicity without compromising safety.
Other non-alum adjuvants such as ADVAX and HILTONOL enhance the antibody response, suggesting flexibility in adjuvant choice.
Documented Applications
Preventing and treating infections caused by Gram-negative bacteria inducing sepsis and polymicrobial sepsis.
Prevention of infections caused by select agents including Burkholderia pseudomallei, Francisella tularensis (tularemia), and Yersinia pestis (plague).
Active immunization to prevent lethal Gram-negative bacterial pneumonia caused by pathogens like Klebsiella pneumoniae and Pseudomonas aeruginosa.
Use for individuals at risk of sepsis including trauma victims, surgical patients, and individuals exposed to biodefense agents.
Administration in healthy human subjects for immunization against Gram-negative bacterial infections as demonstrated in Phase I clinical trials.
Potential use in prevention or amelioration of complications caused by endotoxin leakage such as heat-related injury and graft-versus-host disease in stem cell transplantation.
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