Pneumococcal conjugate vaccine formulations

a conjugate vaccine and pneumococcal technology, applied in the field of pneumococcal conjugate vaccine formulations, can solve the problems of limited serotype coverage of prevnar® in certain regions of the world, and the complications of these diseases can be significan

Inactive Publication Date: 2020-02-20
MERCK SHARP & DOHME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]The present invention provides a formulation comprising (i) one or more polysaccharide-protein conjugates; (ii) a pH buffered saline solution having a pH in the range from 5.0 to 7.5; (iii) an aluminum salt; and (iv

Problems solved by technology

Furthermore, the complications of these diseases can be significant with some studies reporting up to 8% mortality and 25% neurologic sequelae with pneumococcal meningitis.
However, infants and young children respond poorly to unconj

Method used

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  • Pneumococcal conjugate vaccine formulations
  • Pneumococcal conjugate vaccine formulations
  • Pneumococcal conjugate vaccine formulations

Examples

Experimental program
Comparison scheme
Effect test

example 1

on of DTFB Carrier Protein

Use of Multimodal Anion Exchange Chromatography for DTFB Preparation

[0134]Purified CRM197, obtained through expression in Pseudomonas fluorescens as previously described (See International Patent Application Publication No. WO 2012 / 173876 A1), was digested with recombinant trypsin using a 1:500 molar ratio of trypsin to CRM197 for approximately 1 hour at approximately 22° C. in 50 mM Tris, pH 8.0. Dithiotheritol (DTT) in 50 mM Tris, pH 8 was then added to a final concentration of 5 mM for 30 minutes at approximately 22° C. to reduce the disulfide bond between the A and B fragments of the proteolytically-cleaved CRM197.

[0135]The digestion reaction was then loaded onto a multimodal anion exchange chromatography column (Capto™ Adhere, GE Healthcare) equilibrated with 50 mM Tris, pH 8. The column was washed with 50 mM Tris, pH 8, and the DTFB product was eluted with a gradient of 0.45 M to 0.65 M sodium chloride in 50 mM Tris, pH 8. The product was concentrated...

example 3

on of Polysaccharides to DTFB Carrier Protein Using Reductive Amination in Aqueous Solution

Preparation of Serotype 3-DTFB (ST3-DTFB) Conjugate for Mouse Immunogenicity Studies

[0151]Purified serotype 3 polysaccharide obtained as described in Example 2 was dissolved in water. Ps size reduction to an average molecular weight of approximately 200 kDa was performed using a probe sonicator with the sample cooled in ice. The sonicated sample was 0.2 micron-filtered and stored at 2-8° C. The polysaccharide solution was concentrated by diafiltration against a 30 kDa NMWCO tangential flow filtration membrane.

[0152]Polysaccharide was prepared for conjugation using sodium metaperiodate oxidation (See Anderson et al., 1986, J. Immunol. 137:1181-1186; and U.S. Patent Application Publication No. US20110195086). A 100 mM sodium metaperiodate solution was added to the polysaccharide solution in 50 mM sodium acetate. The sample was mixed for 14-18 hours at 19-25° C. protected from light. Ethylene gly...

example 6

unogenicity Study Using ST3-DTFB Monovalent Conjugate Formulation

[0182]The immungenicity of ST3-DTFB compared to ST3-CRM197 was evaluated in a mouse model. Adjuvanted formulations for administration to mice were prepared by mixing 24 μL of sterile-filtered conjugate (1:10 in saline—0.1258 mg DTFB or CRM197-conjugated polysaccharide per mL) with 62 μL of APA, and 3.664 ml of sterile saline for a dose of 0.08 μg of polysaccharide and 5 μg of aluminum per 100 μL. The formulated vaccines were stored in individual borosilicate stoppered vials at 2-8° C. to support individual immunizations.

[0183]ST3-DTFB was evaluated in 6-8 week old female Balb / C mice (n=10 / group). Mice were immunized with ST3-DTFB / APA and two ST3-CRM197 / APA lots made using unique ST3-DTFB and ST3-CRM197 conjugate preparations prepared as described in Examples 3 and 4. The ST3 PnPs concentration was 0.08 μg per dose in a 0.1 ml volume, with 5 μg of APA, given intraperitoneally on days 0, 14 and 28. Sera were collected pr...

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Abstract

The present invention provides pneumococcal conjugate vaccine formulations comprising surfactant systems incorporating polysorbate 20 or a combination of a poloxamer and a polyol.

Description

FIELD OF INVENTION[0001]The present invention provides pneumococcal conjugate vaccine formulations comprising surfactant systems incorporating polysorbate 20 or a combination of a poloxamer and a polyol.BACKGROUND OF THE INVENTION[0002]Streptococcus pneumoniae, one example of an encapsulated bacterium, is a significant cause of serious disease world-wide. In 1997, the Centers for Disease Control and Prevention (CDC) estimated there were 3,000 cases of pneumococcal meningitis, 50,000 cases of pneumococcal bacteremia, 7,000,000 cases of pneumococcal otitis media and 500,000 cases of pneumococcal pneumonia annually in the United States. See Centers for Disease Control and Prevention, MMWR Morb Mortal Wkly Rep 1997, 46(RR-8):1-13. Furthermore, the complications of these diseases can be significant with some studies reporting up to 8% mortality and 25% neurologic sequelae with pneumococcal meningitis. See Arditi et al., 1998, Pediatrics 102:1087-97.[0003]The multivalent pneumococcal poly...

Claims

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Application Information

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IPC IPC(8): A61K39/385A61K47/10A61K47/20A61K47/26A61K47/36C07K1/107C07K14/315
CPCA61K2039/70A61K47/20A61K47/36C07K1/1072A61K47/26A61K39/385A61K2039/6037A61K47/10A61K2039/55C07K14/3156A61K9/0019A61K47/34A61K9/10A61P31/04A61K47/6415A61K47/646A61K39/092A61K47/02A61K47/22A61K9/08A61K9/0095A61K2039/542
Inventor SMITH, WILLIAM J.GIOVARELLI, CECILIANAWROCKI, DENISE K.
Owner MERCK SHARP & DOHME CORP
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