Novel semi-synthetic meningococcal conjugate vaccine

Abstract

The present invention relates to novel semi-synthetic meningococcal conjugate vaccine comprising novel synthetic oligosaccharide conjugated to a carrier protein. The present invention also relates to novel synthetic meningococcal oligosaccharide and a process for its preparation.

1 . A novel synthetic meningococcal C oligosaccharide of formula (I) 
       
         
           
           
               
               
           
         
         Wherein m is an integer from 2-10 and n is an integer from 6-10; 
         R1 and R2 are same or different and independently represent H, C1-6alkyl, acetyl; 
         R3 represents azide, NR5R6, wherein R5 and R6 are same or different and independently represent H, C1-6 alkyl, aryl; 
         R4 represents H, C1-6 alkyl, alkali metal cation selected from Li, Na, K and Cs. 
       
     
     
         2 . A novel semisynthetic meningococcal C vaccine of the formula (II)
 wherein m is an integer from 2-10 and n is an integer from 6-10;   R1 and R2 are same or different and independently represent H, C1-6alkyl, acetyl;   R5 represent H, C1-6 alkyl, aryl;   R4 represents H or C1-6 alkyl;   CP represents a carrier protein;   L1 is a bond, —O—, —S—, —NR8-, —C(═O)—, —NR8C(═O)—, —NR8C(═O)O—, —C(═O)NR8-, —OC(═O)NR8-, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR8C(═S)—, —C(═S)NR8-, trans-CR9=CR9, cis-CR9=CR9, —C≡C—, —OC(R9)2-, —C(R9)20-, —NR8C(R9)2-, —C(R9)2NR8- —SC(R9)2-, —C(R9)2S—, —S(═O)2O—, —OS(═O)2-, —S(═O)2NR8-, —NR8S(═O)2-, or an optionally substituted C1-20 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —S—, —NR8-, —C(═O)—, NR8C(═O)—, —NR8C(═O)O—, —C(═O)NR8-, —OC(═O)NR8- —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR8C(═S)—, —C(═S)NR8-, trans-CR9=CR9-, cis-CR9=CR9-, —C═C—S(═O)2O—, —OS(═O)2-, —S(═O)2NR8-, or —NR8S(═O)2, wherein R8 is hydrogen, optionally substituted C1-6 alkyl, or a nitrogen protecting group, or R8 is joined with the adjacent carbon atom to form an optionally substituted heterocyclic ring, and wherein each occurrence of R9 is independently selected from the group consisting of hydrogen, halogen, optionally substituted C1-10 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R9 is joined with the adjacent carbon or nitrogen or oxygen atom to form an optionally substituted carbocyclic or heterocyclic ring, or two R9 groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;   L2 is a moiety derived from a crosslinking reagent capable of crosslinking the carrier and L1 and is selected from   
       
         
           
           
               
               
           
         
         R7 is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted acyl, or a nitrogen protecting group. 
       
     
     
         3 . A process for the preparation of novel semisynthetic meningococcal conjugate vaccine as claimed in  claim 2 , which comprises the steps of:
 a) synthesizing the meningococcal oligosaccharide of formula (I) of  claim 1 ,   b) activating the oligosaccharide,   c) derivatizing a carrier protein,   d) conjugating the meningococcal oligosaccharide obtained in step (b) with the carrier protein to form a conjugate vaccine and   e) purifying the conjugate vaccine obtained in step (d).   
     
     
         4 . The process as claimed in  claim 3 , wherein the step of activating oligosaccharide is carried out using bromoacetic N-hydroxysuccinimide (NHS) ester, 6-Maleimidohexanoic acid NHS ester, 6-(iodoacetamido)caproic acid NHS ester, maleimidopropionoic acid NHS ester, maleimidoacetic acid NHS ester, maleimidobenzoic acid NHS ester. 
     
     
         5 . The process as claimed in  claim 3 , wherein the step of derivatizing the carrier protein is carried out using 6-3-(acetyl thio) propionic acid N-hydroxysuccinimide ester, acetylthio-hexadecanoic acid NHS ester. 
     
     
         6 . The semisynthetic meningococcal C conjugate vaccine of  claim 2 , wherein the carrier protein is selected from Tetanus toxoid, diphtheria toxoid or CRM197. 
     
     
         7 . The synthetic meningococcal oligosaccharides of  claim 1 , selected from: 
       
         
           
           
               
               
           
         
       
     
     
         8 . An immunogenic composition comprising novel semisynthetic meningococcal C conjugate of  claim 6  is selected from: 
       
         
           
           
               
               
           
         
         wherein CRM197 is cross reacting moiety 197, DT is diphtheria toxoid and TT is tetanus toxoid. 
       
     
     
         9 . A pharmaceutical composition comprising (a) a novel semisynthetic meningococcal C conjugate vaccine as claimed in  claim 2  and (b) a pharmaceutically acceptable carrier. 
     
     
         10 . The composition of  claim 9 , further comprising a saccharide antigen from one or more of serogroups A, W135 and Y of  N. meningitidis , the saccharide being an oligosaccharide and being conjugated to the carrier protein. 
     
     
         11 . The composition of  claim 10 , further comprising a vaccine adjuvant. 
     
     
         12 . The composition of  claim 11 , which is a vaccine against a disease caused by  Neisseria meningitidis.    
     
     
         13 . (canceled) 
     
     
         14 . The composition of  claim 9  further comprising 1 μg to 10 μg of each polysaccharide selected from Meningococcal serogroups A, Y and W-135, conjugated individually to 5 to 20 μg of carrier protein.