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• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0045—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Galacturonans, e.g. methyl ester of (alpha-1,4)-linked D-galacturonic acid units, i.e. pectin, or hydrolysis product of methyl ester of alpha-1,4-linked D-galacturonic acid units, i.e. pectinic acid; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/02—Bacterial antigens
  • A61K39/025—Enterobacteriales, e.g. Enterobacter
  • A61K39/0275—Salmonella
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants

Definitions

• the present disclosure relates generally to the field of medicine, and specifically to microbiology, immunology, and vaccines, and more specifically, typhoid vaccines,
• Typhoid fever is an acute and life-threatening febrile illness, If is caused by Saimoneiia typhi (8, typhi). It is estimated that 16-33 million new typhoid fever cases and 500,000 - 600,000 deaths occur annually. Contaminated food and wafer are the main sources of infection. The risk of infection is the highest in developing countries with poor sanitation, e.g., Asia, Africa, and Latin America.
• Vi polysaccharide vaccine administered parenterally in a single dose
• oral live attenuated Ty21 a vaccine an oral live attenuated vaccine.
• the Vi polysaccharide vaccine is licensed for use in persons ⁇ 2 years old and provides about 70% protection that lasts for three years.
• the oral liquid live vaccine is licensed for use in persons over 2 years old and confers about 53-78% protection after three or four doses.
• Another oral live vaccine in capsule form is approved for persons over 5 years old and provides a similar level of protection after four doses,
• Vi polysaccharide vaccines are available in the US and Europe, one (Typhim Vi ® ) made by Sanofi-Pasteur and the other (Typherix ® ) made by GSK.
• Each vaccine dose is formulated with 25 pg Vi polysaccharide and phenol as the preservative and is administered by intramuscular or subcutaneous injection. Revaccination is recommended every two years in the US.
• the Vi polysaccharide vaccine is also being made in other countries, including India and China. [0008] These vaccines are produced by large-scale fermentation of the wild-type S.
• the Vi vaccine similar to most polysaccharide-based vaccines, is a T ⁇ independent antigen and does not elicit a boosting or memory response upon revaccination (WHO/!VB/12,02). It is not effective in infants or toddlers under 2 years old.
• a Vi polysaccharide-protein conjugate vaccine is being developed by covalent linking of Vi polysaccharide to a protein carrier.
• the conjugate vaccine is a T-dependent antigen and has a boosting effect upon revaccination.
• O-acetyiation and molecular weight are the critical determinants of the immunogenicify of Vi polysaccharides. Studies have shown that removal of the O-acetyl group at C3 reduces its immunogenicity, Jarvis et al., J. Bacterial. 94:1408-1410 (1967); Szewczyk and Taylor, Infect immun. 29:539-544 (1980); Szu et al., infect immun, 59:4555-4581 (1991); Rijpkema et al., Bioiogicais. 32:1 1-6 (2004).
• the amount of O-acetylation is expressed as the degree of O-acetylation (DOAc, ratio of O-acetyl group/Gal UA [moie/moie]) or as the acetyl group content ( ⁇ ) per mg polysaccharide.
• DOAc degree of O-acetylation
• ⁇ acetyl group content
• the O-acety! group content and molecular weight are the potency indicators for the current Vi vaccines (Product insert, Typhim Vi ® ). Production of potent Vi polysaccharide vaccines is dependent on the preservation of the Vi poiysaccharide structure. Many early attempts to produce potent Vi polysaccharides failed because the polysaccharide was degraded during the purification process.
• the PGA is often produced in the sodium salt form or sodium pofygalacturonate,
• polygalacturonic acid is used herein interchangeably with “polygafacturonate.”
• LM pectins and PGAs are commonly obtained by demeihylation of HM pectins under alkaline pH conditions. While these conditions remove the methyl groups, they invariably break the polymer backbone, which results in a decreased molecular weight.
• the instant disclosure provides O-acetyiated high moiecular weight poiygalacturonic acids (GAc-HPGA) or pharmaceuiscally acceptable salts thereof, having at least one of: (a) a molecular weight greater than 1 x 10 6 Da; (ta) a degree of methylation iess than about 10% per mole; and (c) an intervening rhamnose content ranging from about 2% to about 15% per mole, useful as a synthetic immunogenic Vi antigen.
• the instant disclosure further provides methods of preparing an O-acetylated poiygalacturonic acid or pharmaceutically acceptable salt thereof of, pharmaceutical compositions and/or vaccine compositions comprising the same, and methods of immunization using any of the foregoing.
• HPGA high moiecular weight poiygalacturonic acid
• HPGA DM" ⁇ 10%), a very high molecular weight (>1 x 10 6 Da), and a high Gal UA (sodium salt) content (>90%).
• HPGA's chemical and physical properties are summarized in Table 1.
• HPGA is soluble in water, but poorly soluble directly in saline or buffered saline (150 mM NaCi). Like a L pectin, it can form a gel with calcium ions. The gelation occurs immediately when mixed with calcium.
• HPGA typically has a purity of >99% and contains a minimal amount of neutral sugars and proteins ( ⁇ 0.5%).
• HPGA is a high molecular weight polyga!acturonic acid having at least one of the following characteristics: (1) a molecular weight greater than 1 x 10 6 Da, (2) a degree of methylation less than about 10% per mole, and (3) an intervening rhamnose content ranging from about 2% to about 15% per mole.
• OAc-HPGA is an O-acylated high molecular weight polyga!acturonic acid having at least one of the following characteristics: (1) a molecular weight greater than 1 x 10 6 Da, (2) a degree of methylation less than about 10% per mole, and (3) an intervening rhamnose content ranging from about 2% to about 15% per mole.
• the present disclosure provides a synthetic and immunogenic Vi antigen which can be used as a new typhoid vaccine with significant advantages over the current Vi vaccines with respect to safety, effectiveness, and cost.
• the synthetic Vi antigen an O-acetylated high molecular weight polygalacturonic acid (OAc-HPGA, e.g., GelSife-OAcTM) or pharmaceutically acceptable salt thereof is generated by O-acetylation of a novel high molecular weight polygalacturonic acid (HPGA, e.g., GelSite ® ).
• HPGA novel properties discussed above make it an ideal substrate for a synthetic Vi polysaccharide analog by O-acetylation.
• OAc-HPGA for example, GelSite-OAcTM
• GelSite-OAcTM is produced by a chemical process at a very high yield (weight yield >100%). It has a high degree of O-acetylation (DOAc) as the ratio of O-acetyl group/Gal UA [mole/mole] (>100% or >50% (mole/mole) at either the C2 or C3 position) or as the acetyl group content (pmole) per mg polysaccharide (>4.8 pmole/mg), and a high molecular weight (>1 x 10 6 Da), thus exceeding the potency specifications of the current Vi vaccines.
• DOAc O-acetylation
• the OAc-HPGA or pharmaceutically acceptable salt thereof has a molecular weight greater than 1 x 10 a Da.
• the OAc-HPGA has a molecular weight greater than 1 x 10 6 Da, a degree of methylation less than about 10% per mole, and a degree of O-acefylation greater than 100%, or a degree of O-acetyiation greater than 50% at either the C2 or C3 position.
• the OAc-HPGA is a synthetic immunogenic Vi antigen.
• the OAc-HPGA or pharmaceutically acceptable salt thereof has substantially the same antigenicity as Vi polysaccharide vaccine and is immunogenic.
• the OAc-HPGA or pharmaceutically acceptable salt thereof induces a 2-fold or greater rise in antibody titers upon second immunization.
• the OAc-HPGA or pharmaceutically acceptable salt thereof is effective as a synthetic immunogenic Vi antigen in people under 2 years of age without conjugation to a protein carrier.
• the OAc-HPGA or pharmaceutically acceptable salt thereof is effective as a vaccine against typhoid fever.
• the present disclosure further provides a method of producing OAc-HPGA, which incorporates the unique properties of HPGAs of the disclosure to simplify the process and ensure a high recovery or yield.
• OAc- HPGAs e.g., GelSsfe-OAcTM
• GelSite ⁇ the plant-based starting material
• the process further comprises forming an acid gel with HPGA or a salt thereof prior to reacting with the mixture of acetic acid and acetic anhydride,
• the process further comprises reacting the HPGA or a salt thereof with perchloric acid.
• the HPGA used in the process is derived from Aloe vera.
• An additional objective of the disclosure is to provide pharmaceutical compositions comprising the OAc-HPGA or pharmaceutically acceptable salts thereof of the disclosure, optionally comprising at least one pharmaceutically acceptable excipient.
• the present disclosure also provides a method of inducing a protective immune response against Salmonella typhi by administering O ⁇ acetylated polygalacturonic acid (OAc-HPGA) to an animal or human.
• O ⁇ acetylated polygalacturonic acid OAc-HPGA
• the disclosure provides methods of immunizing a subject against Salmonella typhi and/or typhoid fever, comprising administering to the subject in need thereof an effective amount of an OAc-HPGA or pharmaceutically acceptable salt thereof or pharmaceutical compositions of any of the foregoing according to the disclosure.
• administration of the pharmaceutical composition induces an antibody response
• administration of the pharmaceutical composition induces a 2-fold or greater rise in antibody titers upon second immunization.
• OAc-HPGA or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as a synthetic immunogenic Vi antigen that has substantially the same antigenicity as Vi polysaccharide vaccine and is immunogenic.
• !t is a further objective of this disclosure to provide use of an OAc- HPGA or pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for the manufacture of a medicament for vaccination against typhoid fever.
• the present disclosure further provides a typhoid vaccine formulated with OAc-HPGA optionally comprising at least one pharmaceutically acceptable excipient.
• OAc-HPGA may optionally be conjugated to a protein carrier to potentially further enhance its immunogenicity.
• OAc-HPGA can potentially make 20-40 million doses of the vaccine at 25-50 ⁇ xg/dose. It is plant-based and therefore does not contain endotoxin (lipopolysacchande, LPS) which is the most dangerous contaminant in vaccines purified from gram negative bacteria such as S. typhi. Compared to the existing Vi polysaccharide vaccine, OAc-HPGA could be a much safer, less expensive and more effective vaccine. The economic advantage also makes it easier and more affordable to expand production and use of the typhoid vaccine worldwide, especially in endemic areas of developing countries.
• endotoxin lipopolysacchande, LPS
• Fig. 1 illustrates structures of Vi polysaccharide, HPGA (e.g., GelSite ® ), and OAc-HPGA (GelSite-OAcTM).
• HPGA e.g., GelSite ®
• OAc-HPGA GelSite-OAcTM
• the basic galacfuronic acid (Gal UA) residue is shown for Vi polysaccharide, HPGA and OAc-HPGA.
• FIG. 2 illustrates the O-acetylation process for production of OAc- HPGA (GelSite-OAcTM).
• the asterisk indicates the optional use of a small amount of perchloric acid as the catalyst.
• Fig, 3 illustrates size exclusion chromatograms of GeiSite® and GelSite-OAcTM, together with Dextran Standards.
• the Dextran Standards used were 1.597, 214.8, and 39.9 kDa.
• Fig. 4 illustrates the antigenicity of O-acetylated poiygalacturonic acid (Ge!Site-OAcTM), as tested in immunodiffusion assay.
• Each well received 20 ⁇ ! polysaccharide (200 Mg/ml) or reference serum (center well).
• the agarose plate was kept in a wet chamber overnight.
• the wells were charged as follows: 1 ) GelSite ® ; 2) O-acetylated poiygalacturonic acid 1x; 3) O-acetylated polygalacturonic acid 2x; 4) 0-acetylated polygalacturonic acid 3x; and C) Vi polysaccharide.
• Fig. S illustrates any effect of DOAc on immune responses to GeiSite-OAcTM.
• Balb/c mice were immunized twice with Vi vaccine or GelSite- OAcTM having different DOAc at 2.5 pg/mouse , 4 weeks apart.
• Specific IgG was measured using the Vi polysaccharide (A) or GelSite-OAcTM (B) as the antigen.
• Fig. S illustrates any dose-dependent effect of GeiSite-OAcTM.
• Baib/c mice were immunized twice with GeiSite-OAcTM (DOAc, 1.75) at the different indicated doses, 6 weeks apart.
• Specific IgG was measured by ELISA using the Vi polysaccharide (A) or GeiSite-OAc (B) as the antigen.
• Fig, 7 illustrates any cross reactivity. Pooled serum samples from different study groups were reacted with GelSite ® (A), GeiSite-OAcTM (B) or Vi polysaccharide (C).
• Fig. 8 illustrates the cross-boosting effect. Specific IgG antibodies were measured with Vi polysaccharide (A) or GelSite ⁇ OAcTM(B).
• Fsg. 9 shows IgG subclass distribution. Specific IgG antibodies of different subclasses were measured by ELISA. Titers were determined by the end point (2-fold higher than the background, > 0.2 OD). Antibodies were measured with Vi polysaccharide (A) or GelSite ⁇ OAcTM(B) as the antigen.
• Fig. 10 illustrates protection against lethal challenge with live S. Typhi.
• Balb/c mice immunized twice with Vi vaccine or GelSite-OAcTM having different DOAc at 2.5 pg/mouse , 4 weeks apart. Animals were challenged with 100 LD50 of S, Typhi at week 2 following the second immunization.
• A % survival
• B Mean body weight.
• Fig. 11 illustrates the correlation of DOAc with immunogenicity of GelSite-OAcTM.
• HPGA e.g., GelSite ®
• ⁇ pH2.0 low pH
• the QAc- HPGA beads were solubsHzed by increasing the acidic pH to neutral pH. The acetylation process is highly efficient with >100% yield due to the simplicit of the process and addition of acetyl groups.
• the resulting OAoHPGA (e.g., GelSite ⁇ OAcTM) has a degree of O-acetylation (DOAc) of at least 130% or 100%, or at least 85%, or 50% at either the C2 or C3 position, and a high moiecular weight (>1.0 x 10 6 Da), thus closely resembling the native Vi polysaccharide (60-90% O-acetylation at C3 and 1-2 x 10 6 Da).
• DOAc can be readily increased to ⁇ 175% by extending the reaction time. Due to the addition of the acetyl groups, OAc-HPGA also has an increased molecular weight.
• the potency indicators for the current licensed Vi vaccines are the O-acetyl group content ( ⁇ 2 pmole O-acetyl group [at C3]/mg) and molecular weight of the Vi polysaccharide (50% of the polysaccharide ⁇ 2.5 x 10 4 Da) (WHO Expert Committee on Bioiogical Standardization, 1993).
• OAc- HPGA readily meets and exceeds both potency indicators for current Vi vaccines (>2.5 pmol O-acetyl group at either C2 or C3/mg and 70% of the polysaccharide ⁇ 1 x 10 6 Da, Table 2 and Fig. 3).
• OAc-HPGA e.g., GeiSite-OAcTM
• HPGA GelSite®
• OAc-HPGA e.g., GeiSite-OAcTM
• OAc-HPGA can directly dissolve in saline or buffered saline (150 mM NaCI).
• OAc-HPGA is antigenic as shown with the reference anti-Vi polysaccharide serum (Fig. 4). ⁇ t shared the same antigenicity as the Vi polysaccharide. Importantly, no reaction with HPGA was obtained, indicating that the OAc ⁇ HPGA does not cross-react with its unacetyiated parental molecule.
• OAc-HPGA such as GelSite-OAcTM
• mice Fsg. 5
• Specific antibodies can be detected by ELISA with Vi polysaccharide or OAc-HPGA as the antigen.
• acetylated LM pectin was not immunogenic in mice, which was attributed to its low molecular weight (4 x 10 5 Da) in comparison to the native Vi polysaccharide. Szu et al. Infect, Immun. 82:5545-5549 (1994).
• OAc-HPGA has a much higher molecular weight (>1 x 10 6 Da), which may be in part responsible for its immunogenicity. Again, no cross reactivity with its parent molecule (HPGA) was observed, which indicates the specific antibodies induced by the OAc-HPGA is directed toward the O-acetyl group, the most critical immunogenicity determinant of Vi polysaccharide.
• OAc-HPGA possesses the boosting effect or memory immune response, exhibiting more than a 2-fold rise in antibody titers upon the second immunization, No such boosting effect was observed with the Vi vaccine (Typhim Vi ® ) tested in parallel.
• the polysaccharide antigens are known to be T-independent and lack the immune memory or boosting effect.
• the memory or boosting immune response is only achieved with polysaccharide antigens by conjugating them with a protein carrier.
• OAc- HPGA is highly unique in possessing the boosting effect on its own without any conjugation, which is likely due to its novel chemical properties.
• the boosting effect can be induced not only with the GelSite-OAcTM, but also Vi vaccine as the second dose. This further confirms the structural similarity between the OAc-HPGA and Vi polysaccharide. This boosting effect potentially makes si effective in peopie under 2 years of age without conjugation to a protein carrier,
• boosting effect is used interchangeably with “memory immune response” and refers to an increase in immune response by about 2 ⁇ fold following the second immunization or revaccination.
• OAc-HPGA was fully protective in animals challenged with a lethal dose of live S. typhi, indicating the immune response induced by it is protective against S typhi. Together, these findings indicate that OAc-HPGA can potentially be developed as a new typhoid Vi vaccine which has distinct advantages over the current Vi vaccines with respect to manufacturing, cost, memory response and potential effectiveness in people under 2 years without conjugation to a protein carrier. OAc-HPGA can be produced in large quantities by a simple chemical process using the abundant, high quality HPGA from a plant source. Each kg of OAc-HPGA can potentially make 20-40 million doses of the vaccine at 25-50 pg polysaccharide per dose.
• OAc- HPGA does not contain endotoxin or LPS, which is a cell wall component of gram-negative bacteria such as S. typhi and the most dangerous contaminant in vaccines purified from these bacteria.
• LPS endotoxin
• This synthetic vaccine could be safer and less expensive than current licensed Vi vaccines.
• the economic advantage makes it easier and more affordable to expand production and use of typhoid vaccine worldwide, especially in endemic areas of developing countries.
• OAc-HPGA can be used for the development of a conjugate vaccine that may be even more immunogenic and protective for children under 2 years of age.
• Example 1 O-Acetyfation of GelSite Polymer
• the gel beads or strands are washed in deionized water to remove the acetylation reagents without any loss as acetyiated GelSite ® in acid form is insoluble in wafer.
• the acetyiated GelSite ® is then solubilized by neutralization with NaOH, which converts it from an acid to sodium salt, The whole process can be completed in one day except for the last drying step.
• DOAc Degree of O-Acetylation
• the DOAc is a key parameter for the GelSite-OAcTM.
• the acetylation process was highly efficient, yielding a DOAc >130% after just one round of reaction.
• the DOAc could be controlled by the duration of the acetylation reaction as well as the concentration of the acetic anhydride used, It could be further increased, along with an increase in the reaction time, while maintaining the same 30 min interval for addition of perchloric acid.
• a DOAc as high as 175% or 7.5 pmole/mg has been obtained.
• the maximum DOAc is 200% when both the C2 and C3 sites are fully acetylated.
• Perchloric acid The acetylation is initiated by addition of a small amount of perchloric acid as the catalyst. St was found that 20% perchioric acid was just as effective as 70% perchloric acid. Furthermore, a high DOAc (>100%) could be readily obtained with use of only 0.125 ml of 20% perchloric acid in the reaction mixture with 1 gram of GelSite ® described above, In addition, the 1 % perchloric acid in acetic acid was also found to be equally effective when used at the same amount of perchloric acid. The 70% perchloric acid is a strong acid. Thus, use of 1 % or 20% perchloric acid minimizes the use of hazardous reagents, increasing process safety.
• HPLC SEC size exclusion chromatography
• Dextran Dextran standards
• the molecuiar weight of polymers such as poiysaccharides is now generally determined using the more advanced HPLC - MALLS (multiple-angle laser-light scattering) method.
• HPLC SEC with dextran standard was adopted because it has been most widely used in studying the Vi polysaccharides in the published literature and for Vi vaccine potency measurement, thus allowing the results to be directly comparable to those reported previously.
• GelSite-OAcTM could be directly dissolved in saline or buffered saline (150 mM NaCI). These results indicate that the O- acetylation has altered the basic chemical and functional properties of the GelSite ® and that the resulting product, GelSite-OAcTM, is a new chemical entity.
• the immunodiffusion assay was performed in 1 % agarose as described by Szu et al. Infect, Immun. 82:5545-5549 (1994).
• the reference Vi polysaccharide antigen from Citrobacter freundii and reference burro serum against S. typhi were obtained from the National Institute of Child Health and Human Development (NICHD).
• the GelSite-OAcTM formed positive precipitation lines with the reference serum (Fig. 4). The strength of precipitating lines increased along with the increase in the DOAc, as shown with samples obtained after 1 , 2, and 3 rounds of acetylation with the Carson and aclay method (Fig, 4).
• Ge!Site ⁇ OAcTM shared the same or substantially the same antigenicity as the VI polysaccharide as evidenced by the merging of the precipitation lines from GelSite-QAcTM and Vi polysaccharide; no reaction was observed with the un-acetylated GelSite® (Fsg, 4).
• the terms "the same or substantially the same antigenicity as the Vi polysaccharide” means that the GelSite ⁇ OAcTM is reactive with the anti-Vi polysaccharide serum or antibodies.
• GelSite- OAcTM formed positive precipitation lines with the reference serum in the immunodiffusion assay of Szu et a!. which merged with the immunodiffusion assay precipitation lines of the Vi polysaccharide.
• the potency indicators for the current licensed Vi vaccines are the O-acetylafion content (>2 pmole /mg [at C3]) and molecular weight (50% of the polysaccharide > 2.5 x 10 4 Da) of the Vi polysaccharide (WHO Expert Committee on Biological Standardization, 1993; Keitel et al., 1994), With a DOAc of readily >2.5 pmoi /mg ⁇ > 85%) at either the C2 or C3 position and a molecular weight of >1 x 10 6 Da for >70% of the polysaccharide (Table 2 and Fig.3), GelSite-OAcTM exceeds both potency specifications.
• the Vi vaccine exhibited the same or decreased titers for all IgG subclasses following the second immunization, with the exception of gG2a, which showed a 2-fold increase. No apparent change in IgM levels were observed with either vaccine.

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