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WO2008016984A2 - Vaccin polysaccharide et utilisations de celui-ci - Google Patents

Vaccin polysaccharide et utilisations de celui-ci Download PDF

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Publication number
WO2008016984A2
WO2008016984A2 PCT/US2007/074985 US2007074985W WO2008016984A2 WO 2008016984 A2 WO2008016984 A2 WO 2008016984A2 US 2007074985 W US2007074985 W US 2007074985W WO 2008016984 A2 WO2008016984 A2 WO 2008016984A2
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WIPO (PCT)
Prior art keywords
polysaccharide
polypeptide
gbs
composition
alp3
Prior art date
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Ceased
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PCT/US2007/074985
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English (en)
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WO2008016984A3 (fr
Inventor
Lawrence C. Madoff
Lawrence Paoletti
Dennis L. Kasper
Catherine Lachenauer
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Brigham and Womens Hospital Inc
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Brigham and Womens Hospital Inc
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Publication of WO2008016984A2 publication Critical patent/WO2008016984A2/fr
Publication of WO2008016984A3 publication Critical patent/WO2008016984A3/fr
Anticipated expiration legal-status Critical
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Classifications

    • 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
    • A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
    • A61K39/092—Streptococcus
    • 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
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins

Definitions

  • This invention relates to antigenic compositions that include a group B Streptococcus polypeptide and to methods of using the compositions to elicit an immune response.
  • Group B Streptococcus (GBS; Streptoccocus agalactiae) is a gram-positive coccus that frequently colonizes the human genital and gastrointestinal tracts. GBS is a common cause of invasive infection in neonates, pregnant women, and immunocompromised subjects. Prior to the 1990's, virtually all invasive GBS infections were caused by serotypes Ia, Ib, II, and III. Recently, serotype VIII group B streptococci have become increasingly prevalent in Japan and represent more than 20% of colonizing isolates.
  • the invention is based, in part, on the discovery of an alpha-like protein 3 (ALP3) in group B Streptococcus that induces an immune response to polysaccharide antigens.
  • ALP3 polypeptide can be used alone or in combination with a polysaccharide antigen, e.g., a group B streptococcal antigen.
  • the ALP3 polypeptide can also be used as a carrier for polysaccharides, e.g., GBS polysaccharides, which induce a reduced immune response as compared to the response induced when conjugated with an ALP3 polypeptide.
  • the invention features an antigenic composition that includes an ALP3 polypeptide in combination with, e.g., physically associated with, a polysaccharide, e.g., a GBS polysaccharide.
  • a polysaccharide e.g., a GBS polysaccharide.
  • the combination can enhance immunogenicity of the polysaccharide in a host organism and/or stimulate an immune response which is more effective for protecting a host organism than the polysaccharide in the absence of an ALP3 polypeptide.
  • the ALP3 polypeptide is covalently associated with the polysaccharide, e.g., the GBS polysaccharide.
  • the ALP3 polypeptide can be linked directly or via a linking agent to the polysaccharide, e.g., the GBS polysaccharide.
  • the ALP3 polypeptide is linked to the polysaccharide, e.g., the GBS polysaccharide, via an amine bond between an epsilon amino group and a reduced sialic acid residue.
  • the ALP3 polypeptide can be linked to the polysaccharide, e.g., the GBS polysaccharide, via reductive amination.
  • the polysaccharide is a polysaccharide described herein.
  • the polysaccharide is a GBS polysaccharide from a GBS type Ia, Ib, II, III, IV, V, VI, VII, or VlII strain or modified polysaccharides thereof.
  • the GBS polysaccharide is a GBS type V polysaccharide, a GBS type VIII polysaccharide, or modified polysaccharides thereof. Examples of GBS polysaccharides include, but are not limited to, those described in U.S. Publication No. 20060134142, the contents of which are incorporated herein by reference.
  • the composition includes a pharmaceutically acceptable carrier, and/or an adjuvant, such as alum, or complete or incomplete Freund's adjuvant.
  • an adjuvant such as alum, or complete or incomplete Freund's adjuvant.
  • the composition includes one or more additional polypeptides, one or more additional polysaccharides, or combinations thereof.
  • additional polypeptides and polysaccharides include, but are not limited to, an alpha C protein polypeptide, an Rib polypeptide, a GBS beta C protein polypeptide, an epsilon polypeptide, an R protein (e.g., an Rl or R4 protein), an alpha-like protein, a surface protein of group b streptococcus 1 (spbl), an spb2, a laminin binding protein (Lmb), a C5a peptidase, a matrix adhesion (Ema) polypeptide, a capsular polysaccharide, or an antigenic fragment of any of these polypeptides.
  • R protein e.g., an Rl or R4 protein
  • Lmb laminin binding protein
  • C5a peptidase a matrix adhesion (Ema) polypeptide
  • the additional polypeptide or polypeptides can be from a strain of GBS type Ia, Ib, II, III, IV, V, VI, VII, or VIII strain.
  • the composition includes two, three, four, five or more different polypeptides.
  • the capsular polysaccharide is a capsular polysaccharide from GBS type Ia, Ib, II, HI, IV, V, VI, VII, or VIII strain or modified versions of such polysaccharides.
  • the composition includes two, three, four, five or more different polysaccharides.
  • the composition can include an ALP3 polypeptide physically associated with more than one polysaccharide, e.g., more than one GBS polysaccharide.
  • the composition can include an ALP3 polypeptide physically associated with a GBS type III strain polysaccharide and an ALP3 polypeptide physically associated with a GBS type V strain polysaccharide.
  • the composition can include an ALP3 polypeptide physically associated with any combination of a first polysaccharide from a first GBS strain and a second polysaccharide from a second GBS strain.
  • the invention features a method of eliciting an immune response in a mammal by administering to the mammal a composition including an ALP3 polypeptide in combination with, e.g., physically associated with, a polysaccharide, e.g., a GBS polysaccharide.
  • a composition including an ALP3 polypeptide in combination with, e.g., physically associated with, a polysaccharide, e.g., a GBS polysaccharide.
  • the ALP3 polypeptide is covalently associated with the GBS polysaccharide.
  • the ALP3 polypeptide can be linked directly or via a linking agent to the GBS polysaccharide.
  • the ALP3 polypeptide is linked to the polysaccharide, e.g., a GBS polysaccharide, via an amine bond between an epsilon amino group and a reduced sialic acid residue.
  • the ALP3 polypeptide can be linked to the polysaccharide via reductive amination.
  • the composition is administered to the mammal two, three, four, or more times.
  • the polysaccharide is a polysaccharide described herein.
  • the polysaccharide is a GBS polysaccharide from a GBS type Ia, Ib, II, III, IV, V, VI, VII, or VIII strain or modified polysaccharides thereof.
  • the GBS polysaccharide is a GBS type V strain polysaccharide, a GBS type VIIl strain polysaccharide, or modified polysaccharides thereof. Examples of GBS polysaccharides include, but are not limited to, those described in U.S. Publication No. 20060134142, the contents of which are incorporated herein by reference.
  • the composition includes a pharmaceutically acceptable carrier, and/or an adjuvant, such as alum, or complete or incomplete Freund's adjuvant.
  • an adjuvant such as alum, or complete or incomplete Freund's adjuvant.
  • the composition includes one or more additional polypeptides, one or more additional polysaccharides, or combinations thereof.
  • additional polypeptides and polysaccharides include, but are not limited to, an alpha C protein polypeptide, an Rib polypeptide, a GBS beta C protein polypeptide, an epsilon polypeptide, an R protein (e.g., an Rl or R4 protein), an alpha-like protein, a surface protein of group b streptococcus 1 (spbl ), an spb2, a laminin binding protein (Lmb), a C5a peptidase, a matrix adhesion (Ema) polypeptide, a capsular polysaccharide, or an antigenic fragment of any of these polypeptides.
  • R protein e.g., an Rl or R4 protein
  • Lmb laminin binding protein
  • C5a peptidase a matrix adhesion (Ema) polypeptide
  • the additional polypeptide or polypeptides can be a polypeptide of GBS type Ia, Ib, II, III, IV, V, VI, VII, or VIIl strain.
  • the composition includes two, three, four, five or more different polypeptides.
  • the capsular polysaccharide is a capsular polysaccharide from GBS type Ia, Ib, II, III, IV, V, VI, VII, or VIII strain or modified versions of such polysaccharides.
  • the composition includes two, three, four, five or more different polysaccharides.
  • the composition can include an ALP3 polypeptide physically associated with more than one polysaccharide, e.g., more than one GBS polysaccharide.
  • the composition can include an ALP3 polypeptide physically associated with a GBS type III strain polysaccharide and an ALP3 polypeptide physically associated with a GBS type V strain polysaccharide.
  • the composition can include an ALP3 polypeptide physically associated with any combination of a first polysaccharide from a first GBS strain and a second polysaccharide from a second GBS strain.
  • the method elicits the production of antibodies, e.g., IgG or IgM antibodies, in the mammal that recognize the ALP3 polypeptide and/or thepolysaccharide, e.g., the GBS polysaccharide.
  • the method elicits a protective response in the mammal, where the mammal is less likely to develop an infection, e.g., a group B streptococcal infection.
  • the method can further include evaluating an immune response to bacteria, e.g., GBS bacteria in the mammal (e.g., evaluating humoral immune response and/or a cell-mediated immune response).
  • the mammal (e.g., human or nonhuman primate) receiving the composition is at risk for infection with a bacteria, e.g., a GBS bacteria.
  • a bacteria e.g., a GBS bacteria.
  • the mammal can be immunocompromised or at risk of becoming immunocompromised or is elderly.
  • the mammal is pregnant.
  • the individual is a neonate, a woman in a peripartum period, or a nonpregnant adult.
  • the individual has diabetes mellitus or a malignancy.
  • the invention features a method of preparing an immunogenic composition, including linking a polysaccharide with an ALP3 polypeptide.
  • the ALP3 polypeptide is covalently associated with the polysaccharide, e.g., a GBS polysaccharide.
  • the ALP3 polypeptide can be linked directly or via a linking agent to the polysaccharide, e.g., a GBS polysaccharide.
  • the invention features a method of preventing or treating an infection caused by a group B Streptococcus including administering to an individual an effective amount of an antigenic composition including an ALP3 polypeptide in combination with a GBS polysaccharide, e.g., a composition described herein.
  • administering the effective amount of the composition prevents one or more of sepsis, pneumonia, meningitis, chorioamnionitis, or postpartum endometritis.
  • the individual is a neonate, a woman in a peripartum period, or a nonpregnant adult.
  • the individual is immunocompromised, or has diabetes mellitus or a malignancy.
  • Another aspect of the invention features a method of preventing or treating a disorder associated with a GBS infection that includes administering to an individual an effective amount of an antigenic composition including an ALP3 polypeptide in combination with a GBS polysaccharide, e.g., a composition described herein,
  • the disorder is sepsis, pneumonia, meningitis, chorioamnionitis, or postpartum endometritis.
  • the individual is a neonate, a woman in a peripartum period, or a nonpregnant adult.
  • the individual is immunocompromised, or has diabetes mellitus or a malignancy.
  • FlG. 1 is a schematic diagram illustrating the amino acid domains of a full-length ALP3 polypeptide.
  • the ALP3 polypeptide of group B Streptococcus can be useful to induce an immune response to an infection caused by a pathogen that can be viral, bacterial, or eukaryotic.
  • An ALP3 polypeptide was originally isolated from a type VIII GBS strain (JM9-130013, a neonatal sepsis isolate), and has subsequently been identified in a type V strain.
  • the full-length ALP3 polypeptide includes a 56 amino acid signal sequence, a 172 amino acid N-terminal sequence, followed by an "A" region containing 51 amino acids, and then a "U" region of 137 amino acids.
  • B a "B” repeat region containing five tandem repeals, each 79 amino acids long, and one partial repeat of 13 amino acids.
  • B repeat region is a C-terminal region of 45 amino acids, including a cell wall-associating motif (LPXTGX) (SEQ ID N0:3).
  • an "ALP3 polypeptide” can include a full-length ALP3 polypeptide that is a polypeptide having an N-terminal sequence, an A region, a U region, a B region and a C- terminal region, such as a polypeptide having the sequence of SEQ ID NO:1, and fragments thereof.
  • An ALP3 polypeptide can also include more than one, e.g., two, three, four, five, six, seven, eight, nine, ten but not more than fifty, thirty, twenty, fifteen, of the regions discussed above.
  • an ALP3 polypeptide can include an N-terminal or C-terminal fragment of ALP3 but can have more than one of the "B" repeat regions or portions of the "B" region.
  • an ALP3 polypeptide can include two, three, four, five, six, seven, eight, nine, ten but not more than fifty, thirty, twenty, fifteen "B" regions or portion or portions of "B” regions.
  • An ALP3 polypeptide can be a functional fragment or derivative of a full length ALP3 polypeptide that does not essentially affect the immunogenicity or protective antibody-producing function of the polypeptide as compared to the activity of an ALP3 polypeptide having the amino acid sequence of SEQ ID NO: 1 , or a mature form of the ALP3 polypeptide of SEQ ID NO: 1.
  • a functional derivative will have a sequence similar to a full length ALP3 polypeptide such as the polypeptide having the amino acid sequence of SEQ ID NO: 1 or mature form of the ALP3 polypeptide of SEQ ID NO:1, but will include at least some amino acid changes (deletion, insertions, inversions, substitutions, etc.).
  • Amino acid substitutions can be conservative substitutions, which include exchanges of one amino acid for another with similar polarity, steric arrangement, or of the same class (e.g., hydrophobic, acidic or basic).
  • An ALP3 polypeptide can be 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to a full length ALP3 polypeptide such as the ALP3 polypeptide of SEQ ID NO: 1.
  • Percent identity between two amino acid sequences is determined by standard alignment algorithms such as, for example, Basic Local Alignment Tool (BLAST) described in Altschul et al, J. MoI. Biol. 215:403-410, 1990; the algorithm of Needleman et ai, J. MoI. Biol. 48:444-453, 1970; or the algorithm of Meyers et al., Comput. Appl. Biosci. 4:11-17, 1988.
  • BLAST Basic Local Alignment Tool
  • a derivative of an ALP3 polypeptide can, e.g., differ from a full length ALP3 polypeptide by at least 1, 2, 3, 5, 10, 15 amino acids but not more than 100, 75, 50, 30, 20 amino acids, e.g., it can differ by at least 1 , 2, 3, 5, 10, 15 amino acids but not more than 100, 75, 50, 30, 20 amino acids from SEQ ID NO: 1.
  • Methods of assaying immune response include, for example, measuring antibody titers in a subject (e.g., by ELlSA, including quantitative ELISA), or providing a challenge, such as a skin test, and assaying for a reaction.
  • An immune response can also be assayed by opsonophagocytic assay where the serum from immunized individuals is mixed with human polymorphonuclear leukocytes, complement (e.g., from human serum or rabbit serum), and GBS expressing one or more of the relevant antigens. The ability of the serum to kill the GBS over a fixed time period is tested (Baltimore et al., J. Immunol, 118: 673-678, 1977).
  • passive mouse protection can be assayed, where the ability of serum from individuals immunized by the vaccine is administered to mice and the mice subsequently challenged with GBS. Survival of the mice is a measure of the protective capacity of the vaccine.
  • polysaccharide refers to a polysaccharide from a pathogen that is not naturally associated with an ALP3 polypeptide sequence or fragment of an ALP3 polypeptide, and modified versions of such polysaccharides.
  • Polysaccharides include monosacharides, disaccharides, and longer chains.
  • a "GBS polysaccharide” is a GBS polysaccharide from GBS that is not naturally associated with an ALP3 polypeptide sequence or fragment of an ALP3 polypeptide, and modified versions of such polysaccharides.
  • the GBS polysaccharide can be, e.g., a capsular polysaccharide from a type I (e.g., type Ia, or type Ib), type II, type III, type IV, type V, type VI, type VII or type VlII GBS strain.
  • modified GBS polysaccharides include those described in U.S. Publication No. 20060134142.
  • the GBS polysaccharide is typically a polysaccharide that, when introduced into a mammal, elicits antibodies that are capable of reacting with group B Streptococcus.
  • an "antigenic composition” is a composition including at least one antigenic polysaccharide, antigenic polypeptide, or a DNA encoding an antigenic polypeptide, that will elicit an immune response when the composition is administered to a subject.
  • An antigenic composition is also called a vaccine.
  • treatment refers to administering a composition in an amount, manner, and/or mode effective to improve a condition, symptom, or parameter associated with a disorder (e.g., a disorder associated with a GBS infection) or to reduce onset, progression, or exacerbation of the disorder (including secondary damage caused by the disorder), to either a statistically significant degree or to a degree detectable to one skilled in the art. Accordingly, treating can achieve therapeutic and/or prophylactic benefits.
  • An effective amount, manner, or mode can vary depending on the subject and may be tailored to the subject.
  • treatment also encompasses the prophylactic treatment of subjects with an elevated risk for infection, e.g., a GBS infection, such as a neonate, a pregnant woman or a woman in the peripartum period, or a nonpregnant adult.
  • a GBS infection such as a neonate, a pregnant woman or a woman in the peripartum period, or a nonpregnant adult.
  • Other subjects having an elevated risk of infection, e.g., a GBS infection include adults with diabetes mellitus, malignancy, or immunocompromised adults.
  • an amount effective to treat refers to an amount of an antigenic composition that is effective, upon single or multiple dose administrations to a subject, to improve or prophylactically treat a condition, symptom, or parameter associated with a disorder or to reduce onset, progression, or exacerbation of the disorder, to either a statistically significant degree or to a degree detectable to one skilled in the art.
  • the terms “prevent”, “preventing”, and “prevention” mean that the treated subject either does not develop a clinically observable level of the condition at all, or develops it more slowly and/or to a lesser degree than he/she would have absent the treatment.
  • infection by GBS may not occur at all in an individual who receives the antigenic composition described herein, or symptoms of infection may develop, or manifest themselves more slowly and/or to a lesser degree than the individual would have absent administration of the composition.
  • a treatment will be said to have "prevented” the condition (e.g., a GBS infection, or a symptom associated with a GBS infection) if it is given during exposure of a subject to a stimulus that would have been expected to produce a given manifestation of the condition, and results in the subject's experiencing fewer and/or milder symptoms of the condition than otherwise expected.
  • a treatment can "prevent” infection by resulting in the subject's displaying only mild overt symptoms of the infection; it does not imply that there must have been no penetration of any cell by the infecting microorganism.
  • An antigenic composition can be said to prevent a disease if its administration to an individual results either in the total or partial attenuation (i.e., suppression) of a symptom or condition of the disease, or in the total or partial immunity of the individual to the disease.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion).
  • the antigenic composition may be provided in a substance that protects it from the action of acids and other natural compounds that may inactivate it.
  • An antigenic composition described herein can be, for example, a polysaccharide-based vaccine, a protein-based vaccine, or a DNA-based vaccine.
  • a polysaccharide-based antigenic composition includes an ALP3 polypeptide unassociated with, or associated with, e.g., physically associated with a polysaccharide.
  • the ALP3 polypeptide may be covalently associated with a GBS polysaccharide.
  • the ALP3 polypeptide can be linked directly to the GBS polysaccharide or via a linking agent.
  • a protein linker region e.g., of 1, 2, 3, 4, 5, 6, or more amino acids
  • the ALP3 polypeptide and the polysaccharide are chemically linked, such as by reductive amination.
  • An ALP3 polypeptide can be used as a carrier for a polysaccharide (e.g., a capsular polysaccharide).
  • Polysaccharides by themselves are incompletely immunogenic.
  • Carrier polypeptides or polypeptide fragments that are coupled to other antigenic polypeptides can enhance immunogenicity of an antigen, e.g., a polypeptide or a polysaccharide and result in antibody levels that are less variable (see, e.g., Kasper et al, J. Clin. Investig. 98:2308-2314, 1996, and Gravekamp et al., Infec. and Immun. 67:2491-2496, 1999).
  • Suitable polysaccharides for use in embodiments of this invention include, but are not limited to, polysaccharides from encapsulated bacteria.
  • the polysaccharides can be from any source. For example, they can be derived from naturally-occurring bacteria, genetically engineered bacteria, or can be produced synthetically.
  • the polysaccharides can be subjected to one or more processing steps. For example, the polysaccharides can be processed by purification, functionalization, depolymerization using mild oxidative conditions, deacelylation, and the like. Post processing steps can also be employed, if desired. Methods for synthesizing, preparing, and/or purifying suitable polysaccharides are known in the art and can be employed.
  • Non-limiting examples of polysaccharides for use in this invention include, but are not limited to, pneumococcal polysaccharides, for example, of serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 1OA, HA, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F; meningococcal polysaccharides, for example, of serotypes A, B, C, W 135, and Y, Haemophilus influenzae type b polysaccharide polyribosylribitol phosphate, and Salmonella typhi Vi polysaccharide.
  • pneumococcal polysaccharides for example, of serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 1OA, HA, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F
  • Polysaccharides of pneumococcal and group B streptococcal serotypes, and meningococcal serogroups are also suitable for use herein, as T-independent polysaccharide antigens, for example, polysaccharides derived from group A streptococcus, Staphylococci, Enterococci, Klebsiella pneumoniae, E. coli, Pseudomonas aeruginosa, and Bacillus anthracis. While bacterial polysaccharides are particularly preferred, gram (-) bacterial lipopolysaccharides and their polysaccharide derivatives, and viral polysaccharides can also be employed.
  • a polysaccharide e.g., a GBS polysaccharide
  • polysaccharides can be oxidized by treatment with periodate (or a related reagent, e.g., paraperiodic acid or potassium metaperiodate) to leave aldehydic termini at sites with vicinal dihydroxy groups.
  • a polysaccharide can be reacted with the ALP3 polypeptide under conditions that conjugate the components, e.g., using a linking reagent or via direct coupling to the moiety.
  • Conjugation to the ALP3 polypeptide may be carried out, e.g., by reductive amination (see, e.g., Schwartz and Gray, Arch. Biochem. Biophys. 181: 542-549, 1977).
  • reductive amination see, e.g., Schwartz and Gray, Arch. Biochem. Biophys. 181: 542-549, 1977.
  • cyanoborohydride ions or another reducing agent which will not reduce the reducing ends of interest nor adversely affect the polypeptide or polysaccharide.
  • An antigenic composition can have other components, including other antigens, such as other GBS antigens for an enhanced immune response.
  • the antigenic compositions described herein can be formulated with salts, buffers or adjuvants or other substances which are desirable for improving the efficacy of the composition.
  • adjuvants may enhance a mammal's immune response to an ALP3 polypeptide, or an ALP3- polysaccharide combination, e.g., to enhance antibody production and/or to induce an immune response with lower doses of polysaccharide.
  • the adjuvant and the composition are mixed prior to presentation to the immune system, or are presented separately, but into the same site of the animal being immunized.
  • Adjuvants include water emulsions (e.g., complete and incomplete Freund's adjuvant); oil; iron oxide; sodium alginate; aluminum hydroxide, aluminum and calcium salts (i.e., alum); unmethylated CpG motifs; glucan; dextran sulfate; bacterial extracts (e.g., mycobacterial extracts); QS-21 (Aquila Biopharmaceuticals, Inc., Framingham, Mass.); MPLTM (3-0-deacylated monophosphoryl lipid A; Corixa, Hamilton, Mont.); 529 (an amino alkyl glucosamine phosphate compound, Corixa, Hamilton, Mont.), N-acetyl-muramyl-L-theronyl-D-isoglutamine (thr-MDP); N-acetyl- normuramyl-L-alanyl-D-isoglutamine (CGP 11637, referred to as nor-MDP); and N- acetyl
  • compositions described herein can be formulated in a suitable carrier media for administration to a subject (e.g., a media including sodium phosphate-buffered saline at a neutral pH, and/or an aluminum phosphate solution, or another conventional media).
  • suitable carrier media for administration to a subject (e.g., a media including sodium phosphate-buffered saline at a neutral pH, and/or an aluminum phosphate solution, or another conventional media).
  • suitable carrier media e.g., a media including sodium phosphate-buffered saline at a neutral pH, and/or an aluminum phosphate solution, or another conventional media.
  • compositions for administration to a subject can contain from about 0.01 to 1000 ⁇ g/mLper dose of an antigenic composition described herein, e.g., about 0.1 to about 500 ⁇ g/mL per dose, about 5 to about 300 ⁇ g/mL per dose, or about 10 to about 50 ⁇ g/mLper dose.
  • the compositions can elicit effective levels of antibody against the ALP3 polypeptide and GBS polysaccharide in a mammal. The exact dosage can be determined by routine dose/response experimentation.
  • Polysaccharide conjugate compositions can be administered as a single immunization or in a series, e.g., two, three or four doses at 1 month, 2 month, 3 month, or longer intervals.
  • a booster may be given one year, two years, or more after the initial immunization or primary series of immunizations.
  • An exemplary immunization schedule for pregnant women is a single dose given in the second or early third trimester.
  • a single dose can be used for immunization of non-pregnant adults.
  • the requirement for subsequent booster doses in adults can be based on the immunogenicity of the polysaccharide composition and ongoing surveillance of efficacy of the vaccine in eliciting an immune response.
  • the "effective amount" of the antigenic composition is one which is sufficient to achieve the desired biological effect.
  • the desired biological effect is the production of antibodies in the recipient in response to the antigenic composition, which subsequently protects the recipient from infection, e.g., infection by GBS. Infection can be prevented or treated, as described above.
  • the dosage needed to provide an effective amount of the composition will vary depending upon such factors as the subject's age, condition, sex, and extent of disease, if any, and other variables which can be adjusted by one of ordinary skill in the art.
  • compositions described herein can be administered parenterally by injection, rapid infusion, nasopharyngeal absorption (intranasopharangeally), dermoabsorption, or orally.
  • the compositions may alternatively be administered intramuscularly, or intravenously.
  • Compositions for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Carriers or occlusive dressings can be used to increase skin permeability and enhance antigen absorption.
  • Liquid dosage forms for oral administration may generally comprise a liposome solution containing the liquid dosage form.
  • Suitable forms for suspending liposomes include emulsions, suspensions, solutions, syrups, and elixirs containing inert diluents commonly used in the art, such as purified water.
  • inert diluents such as purified water.
  • such compositions can also include adjuvants, wetting agents, emulsifying and suspending agents, or sweetening, flavoring, or perfuming agents.
  • the antigenic compositions can be administered to a mammal, such as a human.
  • the compositions are also suitable for administration to a nonhuman mammal such as a nonhuman primate (such as a monkey or ape), a rabbit, mouse, rat, goat, cow, bull, pig, horse, sheep, wild boar, sea otter, cat, or dog.
  • a nonhuman primate such as a monkey or ape
  • an antigenic composition described herein may be for either a "prophylactic" or “therapeutic” purpose.
  • the composition is provided in advance of any symptom of infection, e.g., group B Streptococcus infection.
  • the prophylactic administration of the composition serves to prevent or attenuate any subsequent infection.
  • the composition is provided upon the detection of a symptom of actual infection, including signs or symptoms of sepsis or meningitis.
  • the therapeutic administration of the composition serves to attenuate any actual infection.
  • the antigenic composition may therefore be provided either prior to the onset of infection (so as to prevent or attenuate an anticipated infection) or after the initiation of an actual infection.
  • the antigenic compositions described herein can be administered to pregnant women to prevent infection during the peripartum period.
  • Such treatment can prevent, for example, GBS- related infections related to, for example, chorioamnionitis, postpartum endometritis, and sepsis.
  • the antigenic compositions can also be administered to prevent infection in a neonate.
  • GBS infections in neonates often occur in utero or during passage through the vagina and can subsequently cause sepsis, pneumonia, and/or meningitis. Heavy colonization with GBS may also lead to premature birth.
  • Administration of the antigenic compositions described herein to a pregnant woman can treat or prevent, for example, a GBS infection in the woman, and also prevent infection of the neonate while in utero or during delivery.
  • Administration of the antigenic composition can thereby be used to prevent GBS-associated symptoms in a neonate, including the prevention of sepsis, pneumonia, and/or meningitis.
  • the antigenic compositions described herein can also be used to treat or prevent infection by a pathogen, e.g., GBS infection, and associated symptoms, in nonpregnant adults.
  • the antigenic compositions can be administered to nonpregnant adults to treat or prevent sepsis, soft tissue infections, and other focal infections.
  • Nonpregnant adults that are particularly susceptible to infection, e.g., by GBS include adults with diabetes mellitus, malignancy, or immunocompromised adults.
  • an immunocompromised adult may be undergoing or have undergone chemotherapy, or stem cell, bone marrow, or organ transplantation.
  • the antigenic compositions can be administered to these adults to prevent infection, e.g.. GBS infection.
  • the antigenic compositions may confer resistance to a pathogen, e.g., viral, bacterial, or fungal, by either passive immunization or active immunization.
  • a pathogen e.g., viral, bacterial, or fungal
  • passive immunization the composition is provided to a host (e.g., to a human or mammal) volunteer, and the elicited antisera is recovered and directly provided to a recipient suspected of having an infection caused by a group B Streptococcus.
  • the antigenic composition comprising an ALP3 polypeptide and a GBS polysaccharide is provided to a female at or prior to pregnancy or parturition, under condition of time and amount sufficient to cause the production of antisera which serve to protect both the female and the fetus or newborn, such as by passive incorporation of the antibodies across the placenta.
  • An antigenic composition can include an ALP3 polypeptide covalently linked to a GBS polysaccharide.
  • the ALP3 polypeptide can include the sequence of SEQ ID NO: 1 , below, or a fragment of SEQ ID NO: 1.
  • ALP3 polypeptide sequence ( SEO ID NO: 1) (GenPept ID No. AAGOl 394)
  • ALP3 DNA sequence (SEO ID NO:2) (GenBank Accession No. AF245663).
  • TheALP3 cDNA sequence is at nucleotide positions 365-2962.
  • rAlp3 The immunogenicity and protective efficacy of purified recombinant Alp3 (rAlp3) was evaluated in outbred mice. Specific IgG was elicited in mice following vaccination with rAlp3 or rAlp3 covalently coupled to purified GBS type III capsular polysaccharide (Tables 1 and 2). Purified rAlp3 also induced a strong immune response in rabbits.
  • rAlp3 can serve as an effective carrier protein for group B streptococcal polysaccharides.
  • mice were vaccinated on days 0, 21, and 42. All vaccines contained alum adjuvant.
  • mice were vaccinated on days 0, 21, and 42. All vaccines contained alum adjuvant.

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Abstract

La présente invention concerne des compositions antigènes comprenant un polypeptide ALP3 en association avec un polysaccharide tel qu'un polysaccharide des streptocoques du groupe B, et des procédés d'utilisation des compositions pour obtenir une réponse immunitaire.
PCT/US2007/074985 2006-08-01 2007-08-01 Vaccin polysaccharide et utilisations de celui-ci Ceased WO2008016984A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017114655A1 (fr) * 2015-12-30 2017-07-06 Minervax Aps Complexe immunogène provoquant une immunité protectrice contre un streptocoque du groupe b
US12173033B2 (en) 2015-10-21 2024-12-24 Minervax Aps Immunogenic fusion protein

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
LACHENAUER ET AL.: 'A Protective Surface Protein from Type V Group B Streptococci Shares N-Terminal Sequence Homology with the Alpha C Protein' INFECTION AND IMMUNITY vol. 64, no. 10, October 1996, pages 4255 - 4260 *
LACHENAUER ET AL.: 'Mosaicism in the Alpha-Like Protein Genes of Group B Streptococci' PNAS vol. 97, no. 17, 15 August 2000, pages 9630 - 9635 *
MAELAND ET AL.: 'Antigenic Determinants of Alpha-Like Proteins of the Streptococcus agalactiae' CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY vol. 11, no. 6, November 2004, pages 1035 - 1039 *
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WESSELS ET AL.: 'Immunogenicity in Animals of a Polysaccharide-Protein Conjugate Vaccine against Ype III Group B Streptococcus' J. CLIN. INVEST. vol. 86, November 1990, pages 1428 - 1433 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12173033B2 (en) 2015-10-21 2024-12-24 Minervax Aps Immunogenic fusion protein
WO2017114655A1 (fr) * 2015-12-30 2017-07-06 Minervax Aps Complexe immunogène provoquant une immunité protectrice contre un streptocoque du groupe b
US10888610B2 (en) 2015-12-30 2021-01-12 Minerv Ax Aps Immunogenic complex for eliciting protective immunity against group b streptococcus
US11484584B2 (en) 2015-12-30 2022-11-01 Minervax Aps Immunogenic complex for eliciting protective immunity against group B Streptococcus

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