Antigenic conjugates of conserved lipopolysaccharides of gram negative bacteria

Abstract

Antigenic conjugates are provided which comprise a carrier protein covalently bonded to the conserved portion of a lipopolysaccharide of a gram negative bacteria, wherein said conserved portion of the lipopolysaccharide comprises the inner core and lipid A portions of said lipopolysaccharide, said conjugate eliciting a cross reactive immune response against heterologous strains of said gram negative bacteria.

What is claimed is:  
     
         1 . An antigenic conjugate comprising a carrier protein covalently bonded to the conserved portion of a lipopolysaccharide of a gram negative bacteria, wherein said conserved portion of the lipopolysaccaride comprises the inner core and lipid A portions of said lipopolysaccaride, said conjugate eliciting a cross reactive immune response against heterologous strains of said gram negative bacteria.  
     
     
         2 . An antigenic conjugate as in  claim 1 , wherein said conjugate elicits a cross reactive immune response against heterologous genera of gram negative bacteria.  
     
     
         3 . An antigenic conjugate as in  claim 1 , wherein said lipopolysaccharide is de-O-acylated.  
     
     
         4 . An antigenic conjugate as in  claim 1 , wherein said carrier protein is selected from the group consisting of tetanus toxin or toxoid, diptheria toxin or toxoid, mutant of diptheria toxin CRM 197 , pseudomonas exotoxin A, cholera toxin or toxoid, Group A streptococcal toxins, pneumolysin of  Streptococcus pneumoniae,  filamentous haemagglutinin (FHA), FHA fragments of  Bordetella pertussis;  pili or pilins of  Neisseria gonorrhoeae,  pili or pilins of  Neisseria meningitidis;  outer membrane proteins of  Neisseria meningitidis,  outer membrane proteins of  Neisseria gonorrhoeae;  C5A peptidase of Streptococcus and surface protein of  Moraxella catarrhalis.    
     
     
         5 . An antigenic conjugate as in  claim 1 , wherein said carrier protein is linked to said conserved portion of the lipopolysaccharide with a compound selected from the group consisting of Sulfosuccinimidyl-6-(3-[2-pyridyldithio]propionamido)-hexanoate (Sulfo-LC-SPDP); succinimidyl-6-(3-[2-pyridyldithio]propionamido)-hexanoate (LC-SPDP); Traut's reagent (2-iminothiolane); N-succinimyl-S-acetyl thioacetate (SATA); N-Succinimidyl-3-(2-pyridyl dithio)propionate (SPDP), succinimidyl acetyl thiopiopionate (SATP), succinimidyl-4-(N-maleimido methyl)cyclohexane-1-carboxylate (SMCC), maleimido benzoyl-N-hydroxy succinimide ester (MBS), N-succinimidyl (4-iodoacetyl)aminobenzoate (SIAB), succinimidyl 4-(p-maleimidophenyl)butyrate (SMPB), bromoacetic acid-N-hydroxy succinimide (BANS) ester, 1-ethyl-3-(3-dimethylamino propyl) carbodiimide (EDAC), adipic acid dihydrazide (ADH), cystamine and dithiobis(succinimidyl propionate) (DTSSP).  
     
     
         6 . An antigenic conjugate as in  claim 1  wherein said gram negative bacteria is selected from the group consisting of  Neisseria meningitidis, Neisseria gonorrhoeae, Haemophilus influenzae,  non-typeable  Haemophilus influenzae, Haemophilus ducreyi, Helicobacter pylori, Escherichia coli,  Chlamydia, Salmonella,  Salmonella typhimurium, Salmonella minnesota, Proteus mirabilis, Pseudomonas aeruginosa, Moraxella catarrhalis, Bordetella pertussis,  Shigella, Klebsiella, and  Vibrio cholerae.    
     
     
         7 . An antigenic conjugate as in  claim 6 , wherein said gram negative bacterium is  Neisseria meningitidis.    
     
     
         8 . An antigenic conjugate comprising the carrier protein diptheria toxin CRM 197  covalently bonded to the conserved portion of a lipopolysaccharide of  Neisseria meningitidis  with long chain N-succinimidyl-3-(2-pyridyldithio)-propionate, and bromoacetic acid-N-hydroxysuccinimide ester, wherein said conserved portion of the lipopolysaccharide comprises the inner core and lipid A portions of said lipopolysaccharide, said conjugate eliciting a cross reactive immune response against heterologous strains within the genus  Neisseria meningitidis.    
     
     
         9 . An antigenic conjugate as in  claim 8 , wherein said conjugate elicits a cross reactive immune response against heterologous genera of gram negative bacteria.  
     
     
         10 . A vaccine formulation comprising an effective amount of the antigenic conjugate of  claim 1 .  
     
     
         11 . A vaccine formulation comprising an effective amount of the antigenic conjugate of  claim 2 .  
     
     
         12 . A vaccine formulation comprising an effective amount of the antigenic conjugate of  claim 8 .  
     
     
         13 . A vaccine formulation comprising an effective amount of the antigenic conjugate of  claim 9 .  
     
     
         14 . A method of immunizing an individual to prevent disease caused by a gram negative pathogen, comprising vaccinating the individual with a prophylactically effective amount of vaccine formulation comprising an antigenic conjugate comprising a carrier protein covalently bonded to the conserved portion of a lipopolysaccharide of a gram negative bacteria, wherein said conserved portion of the lipopolysaccharide comprises the inner core and lipid A portions of said lipopolysaccharide, said conjugate eliciting a cross reactive immune response against heterologous strains of said gram negative bacteria.  
     
     
         15 . A method as in  claim 14 , wherein the vaccine formulation is administered to said individual by a route of administration selected from the group consisting of intradermal, intramuscular, intraperitioneal, intravenous, vaginal, subcutaneous, ocular, intranasal, and oral administration.  
     
     
         16 . A method as in  claim 14 , wherein said vaccine formulation further comprises a physiological carrier and an adjuvant.  
     
     
         17 . A method for preventing bacterial sepsis in a mammal in need thereof, comprising administering an effective amount of a formulation comprising an antigenic conjugate comprising a carrier protein covalently bonded to the conserved portion of a lipopolysaccharide of a gram negative bacteria, wherein said conserved portion of the lipopolysaccharide comprises the inner core and lipid A portions of said lipopolysaccharide, said conjugate eliciting a cross reactive immune response against heterologous strains of said gram negative bacterial organisms.  
     
     
         18 . A method for preventing bacterial sepsis in a mammal in need thereof, comprising administering an effective amount of a formulation comprising an antigenic conjugate comprising a carrier protein covalently bonded to the conserved portion of a lipopolysaccharide of a gram negative bacteria, wherein said conserved portion of the lipopolysaccharide comprises the inner core and lipid A portions of said lipopolysaccharide, said conjugate eliciting a cross reactive immune response against heterologous genera of gram negative bacterial organisms.