Methods for improving the adsorption of polysaccharide-protein conjugates and multivalent vaccine formulation obtained thereof
Inventors
DHERE, Rajeev Mhalasakant • Malviya, Hitesh Kumar • Jana, Swapan Kumar • Pisal, Sambhaji Shankar • MALLYA, Asha Dinesh • MAHOR, Sunil • GAUTAM, Manish Maheshkumar • JOSHI, Chetan Vilas • MALEPATI, Venkata Vamsi Krishna • JADHAV, Prashant Shivaji
Assignees
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Publication Number
US-10729780-B2
Publication Date
2020-08-04
Expiration Date
Abstract
The present invention provides methods for preparation of stable multivalent pneumococcal polysaccharide-protein conjugate vaccine formulations. Instant stable formulations show optimal percent adsorption for each conjugate wherein, aggregation can be prevented by employing i) Individual or separate adsorption for conjugates that otherwise show lower percent adsorption by combined adsorption ii) Histidine-Succinic acid buffer system along with shift in pH from neutral pH to acidic pH iii) a polysaccharide to protein ratio between 0.5 to about 1.4 iv) a six-bladed Rushton type turbine impeller in formulation vessels.
Core Innovation
The disclosed invention provides stable multivalent Streptococcus pneumoniae polysaccharide-protein conjugate vaccine formulations. The compositions include at least 10 distinct Streptococcus pneumoniae polysaccharide protein conjugates with polysaccharides selected from defined pneumococcal serotypes. At least one conjugate includes CRM197 as a carrier protein, at least one includes tetanus toxoid (TT) as a carrier protein, and at least one includes diphtheria toxoid (DT) as a carrier protein.
A central feature is the adsorption behavior of the conjugates onto an aluminium adjuvant, with adsorption in the range of 75-99%. Serotypes 6A, 9V and 23F are individually adsorbed on an aluminium adjuvant, while other selected serotypes are mixed and adsorbed to the aluminium adjuvant, as described for the multivalent panels. The formulation also contains histidine-succinic acid buffer in a concentration between 10 mM and 40 mM.
The document further describes improved stability characterized by reduced aggregation and precipitation and reduced aggregate-related vial rejection. Aggregation and low adsorption are addressed by combined adsorption and formulation conditions, including histidine-succinic acid buffer with a pH shift from neutral to acidic and selecting polysaccharide-to-protein ratios in the stated range.
Claims Coverage
The provided independent claims are clm-00001 and clm-00008. Each independent claim defines a stable multivalent Streptococcus pneumoniae polysaccharide-protein conjugate vaccine composition with specified serotype panels, defined carrier protein assignment (CRM197 and/or TT and DT), aluminium-adjuvant adsorption behavior, a defined adsorption range (75-99%), and histidine-succinic acid buffer at 10-40 mM. The inventive features below summarize the core constraints recited for each independent claim.
Stable multivalent Streptococcus pneumoniae polysaccharide-protein conjugate vaccine with defined serotype and carrier composition
A stable multivalent Streptococcus pneumoniae polysaccharide-protein conjugate vaccine composition comprising at least 10 distinct Streptococcus pneumoniae polysaccharide protein conjugates having polysaccharide selected from the listed serotypes, wherein at least one conjugate has CRM197 as a carrier protein, at least one conjugate has tetanus toxoid (TT) as a carrier protein, and at least one conjugate has diphtheria toxoid (DT) as a carrier protein.
Aluminium-adjuvant adsorption with individual and mixed serotype groupings and 75-99% adsorption
Serotypes 6A, 9V and 23F are individually adsorbed on an aluminium adjuvant, serotypes selected from 1, 2, 3, 4, 5, 6B, 7F, 12F, 14, 15B, 18C, 19A, 19F, and 22F are mixed and adsorbed to an aluminum adjuvant, and the adsorption is in the range of 75-99%.
Histidine-succinic acid buffer concentration 10 mM to 40 mM
The composition has histidine-succinic acid buffer in a concentration between 10 mM and 40 mM.
Stable multivalent composition of 10 CRM197-conjugated serotypes with aluminium-adjuvant adsorption split
A stable multivalent Streptococcus pneumoniae polysaccharide-protein conjugate vaccine composition comprising 10 distinct Streptococcus pneumoniae polysaccharide protein conjugates having polysaccharide from serotypes 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, and 23F wherein the polysaccharides are conjugated to CRM197 as the carrier protein, wherein serotype 6A, 9V and 23F are individually adsorbed on an aluminium adjuvant, and serotypes selected from 1, 5, 6B, 7F, 14, 19A, and 19F are mixed and adsorbed to an aluminum adjuvant.
Aluminium-adjuvant adsorption range 75-99% and histidine-succinic acid buffer 10 mM to 40 mM
The adsorption is in the range of 75-99%, and wherein said composition has histidine-succinic acid buffer in a concentration between 10 mM and 40 mM.
Across clm-00001 and clm-00008, claim coverage centers on stable multivalent Streptococcus pneumoniae polysaccharide-protein conjugate vaccine compositions defined by specific serotype sets, specified carrier protein assignments (CRM197 and/or TT and DT in clm-00001; CRM197 only in clm-00008), aluminium-adjuvant adsorption split into individually adsorbed and mixed-adsorbed serotype groupings, an aluminium-adjuvant adsorption range of 75-99%, and histidine-succinic acid buffer at 10-40 mM.
Stated Advantages
Improved alum adsorption (typically 75-99%).
Reduced aggregation/precipitation.
Reduced aggregate-related vial rejection.
Documented Applications
Stable multivalent Streptococcus pneumoniae polysaccharide-protein conjugate vaccine formulations (including exemplar PCV10 and PCV16/PCV16 and PCV10/PCV16 compositions) with aluminium adjuvant adsorption behavior and histidine-succinic acid buffer.
Formulations described for 16 valent or 17 valent compositions where the Streptococcus pneumoniae serotype 6A-CRM197 conjugate provides increased immunogenicity.
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