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WO2004054611A1 - Vaccin meningococcique a base de proteines de membrane externe porb2 et pora - Google Patents

Vaccin meningococcique a base de proteines de membrane externe porb2 et pora Download PDF

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Publication number
WO2004054611A1
WO2004054611A1 PCT/GB2003/005479 GB0305479W WO2004054611A1 WO 2004054611 A1 WO2004054611 A1 WO 2004054611A1 GB 0305479 W GB0305479 W GB 0305479W WO 2004054611 A1 WO2004054611 A1 WO 2004054611A1
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Prior art keywords
vaccine
protein
serogroup
pora
outer membrane
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PCT/GB2003/005479
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English (en)
Inventor
Einar Rosenqvist
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NASJONALT FOLKEHELSEINSTITUTT
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NASJONALT FOLKEHELSEINSTITUTT
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Priority to AU2003288558A priority Critical patent/AU2003288558A1/en
Publication of WO2004054611A1 publication Critical patent/WO2004054611A1/fr
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    • 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
    • A61K39/095—Neisseria
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55516—Proteins; Peptides
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers

Definitions

  • the present invention concerns a protein-based vaccine against Neisseria meningi tidis, an important causative agent for bacterial meningitis and sepsis.
  • the invention concerns protein-based vaccines being protective against diseases caused by meningococcal serogroups such as one or more of serogroups W-135 C, Y or X, or preferably against all of these serogroups using a single vaccine, which comprises PorB and PorA outer membrane proteins.
  • the present invention provides a vaccine that is specific for a particular serotype and serosubtype of N. meningi tidis, being serotype 2a; 2b or 2c, serosubtype PI.5, 2 or PI.5, 10.
  • meningi tidis is one of the most common causes of • purulent meningitis all over the world, with large epidemics spread during the last decade throughout vast areas of Africa, the so-called "Meningitis Belt”.
  • Meningococci are commonly classified into serogroups, serotypes, serosubtypes and immunotypes ; the classification is based on differences between the strains related to their antigenic c.apsular polysaccharides , outer membrane proteins, and lipopolysaccharides . Based on antigenic properties of capsular serogroup polysaccharides, meningococci have been divided into 12 "serogroups": A, B, C, 29E, H, I, K, L, W-135, X, Y and Z. Of these, the serogroups A, B, C, W-135 and Y are most common.
  • the polysaccharides generally consist of one or more types of sugars linked together in a certain way, for example, serogroup C polysaccharide is composed of units of the sugar N-acetyl neuraminic acid linked via a 2-9 linkage .
  • the meningococci are subclassified according to the antigenic (protein) components of their outer membrane, and there exist large antigenic differences among strains.
  • the meningococci are accordingly assigned to more than 20 "serotypes" based on specific conformational epitopes on one of the major outer membrane proteins, the PorB protein molecule.
  • Meningococcal strains are further divided into a high number of "serosubtypes" based on differences in the PorA protein molecule (i.e. PorA PI.5, 2) .
  • the "immunotype" of meningococci relates to the type of lipopolysaccharide (LPS) .
  • meningococci are generally classified into serogroups, serotypes and serosubtypes on the basis of antigenic differences in their capsular polysaccharides, class 2/3 (PorB2 and PorB3 proteins) outer membrane proteins and class 1 (PorA proteins) outer membrane proteins, respectively.
  • class 2/3 PorB2 and PorB3 proteins
  • class 1 PorA proteins
  • Serogroup A has so far been the cause of the majority of the cases both in endemic and epidemic situations, including the explosive epidemic outbreaks in the "Meningitis Belt” in Africa. Meningitis epidemics caused by serogroup C meningococci have recently caused several outbreaks in Europe, North America and Australasia where especially newborns and young adults are infected. Only very recently the serogroup W-135 meningococci have appeared as a cause of outbreaks of disease .
  • N. meningi tidis bacteria have the ability to change the genetic material responsible for capsule production and thus switch serogroups, i.e. B to C or vice versa.
  • the "capsular switch" may be caused by environmental selection pressure, such as an altered immune response in a population after vaccination with a polysaccharide-based vaccine.
  • Such phenomena are of particular concern, since epidemics may result as a consequence of the bacteria "avoiding" the antibodies raised by vaccination.
  • serogroup W-135 bacteria have caused epidemics in Africa, possibly as a result of mass vaccination campaigns using serogroup A and C polysaccharides .
  • vaccines directed to particular serogroups may have the unfortunate consequence of provoking capsular switch, thus improved vaccines that target alternative antigens are required.
  • OM outer membrane
  • the serogroup-specific capsular polysaccharides may form an external loosely bound layer.
  • protein may be an essential component to confer the wanted long-term immunological effects, and this has led to protein-polysaccharide conjugate vaccines currently under investigation.
  • Such proteins can induce both T-cell immunological memory and B-cell immunological memory towards the vaccine antigen, whereas the commonly used conjugate proteins, such as tetanus or diphtheria toxoids, induce only T-cell memory against the carrier protein. Further, as the toxoid proteins mentioned herein are used in other vaccines, there may be a risk of carrier-specific suppression.
  • the polysaccharide vaccines generally are efficient, they have weaknesses related to inherent properties of the human immunological system as discussed previously.
  • the polysaccharides are T-cell independent antigens and as such do not induce immunological memory, and the duration of protection in adult may be limited to about 3 years as mentioned above. Further, the polysaccharide-based vaccines do not induce protective antibodies in infants, due to an immature immunological system, especially in children below 2 years of age. T-cells, particularly T-helper cells, are thought to regulate antigen-specific B cell • memory. Immunologic memory underpins long-term immunity. Thus, if an antigen is T-cell independent, long term immunological -memory is compromised.
  • serogroup C and serogroup Y polysaccharides can be used as efficient vaccines against disease caused by strains of the same serogroups .
  • the serogroup C and Y polysaccharide vaccines have inherent weaknesses : they are T-cell independent antigens, not inducing immunological memory; and they do not give protection in infants less than 2-4 years of age. Further, repeated vaccination with a C polysaccharide vaccine may induce hyporesponsiveness, which is undesirable.
  • conjugation with a protein may be a way to improve the vaccine, but as preparation of conjugate vaccines is expensive, vaccine costs may be a serious problem for universal distribution in poor areas.
  • Proteins of the outer membrane are important for stabilising the outer membrane (OM) structure.
  • OM outer membrane
  • major outer membrane proteins such as PorA (class 1 protein) , PorB (class 2 and 3 proteins) , Rmp, and Opa and Ope (class 5 proteins) .
  • These proteins may be of significant importance for the efficiency of a protein-based vaccine, which may give protection to children below 4 years of age, preferably below 2 years of age and most preferably below 1 year of age .
  • Strains of N. meningi tidis may be serotype or serosubtyped using routine methods. Generally, to determine which PorB (serotype) and PorA (serosubtype) proteins are present, antibodies to the particular proteins may be used, and detected via dotblotting, or ELISA. Such methods are routine. If the serotyping/ serosubtyping is performed by dotblotting, the bacteria in solution are dropped onto nitrocellulose, blocked with an inert solution (such as Bovine Serum Albumin) and a monoclonal antibody added, which can be labelled or conjugated, and the signal from the label is detected, or a substrate is added (e.g. for a conjugated enzyme such as horseradish peroxidase, the substrate added is chromogenic such as trimethylbenzene) which develops a signal/detectable colour change.
  • an inert solution such as Bovine Serum Albumin
  • non-serotypable since serotyping fails, and are thus designated as NT (non- typable) .
  • serosubtype A recent example is an outbreak in Niger where some of the strains were designated X:NT:P1.5.
  • Such nontypable (but serosubtypable) strains may also be a target for the vaccine of the present invention.
  • the vaccine according to the present invention is protein based, and thus -is a vaccine containing substantial amounts of proteins, especially outer membrane proteins, that can elicit immunological response in humans to one or more of said proteins .
  • Such an immune response is T-cell dependent.
  • the vaccine may further comprise other types of molecules, e.g. lipopolysaccharides (LPS) and phospholipids, which may elicit an immunological response, or strengthen the immunological response towards the proteins .
  • the vaccine may contain outer membrane proteins from alternative N. meningi tidis strains, thus forming hybrid polyvalent vaccines.
  • the vaccine may optionally contain serogroup polysaccharides . It has now surprisingly been found that protection, including long-term and low-age protection (e.g.
  • protein-based vaccines comprising specific outer membrane proteins (PorB2 and PorA) to combat the epidemics of Africa and elsewhere, which involve infection by bacterial strains which express a particular combination of PorB2 (i.e. class 2) outer membrane protein and PorA (class 1) protein.
  • Such strains may include, but are not limited to, bacteria of serogroups W-135, C, Y and X. Additionally, bacteria that are classified as NT may also be protected against by the vaccine of the invention.
  • the present invention provides a vaccine comprising one or more outer membrane protein of type PorB2 and one or more outer membrane protein of type PorA.
  • the vaccine is serogroup independent. It will be understood by those skilled in the art that such a vaccine will be effective against all JV. meningi tidis bacteria that have the particular outer membrane (OM) proteins PorB2 and PorA in their outer membrane.
  • OM outer membrane
  • one advantage of such a vaccine is that it is impervious to "capsular switch" as described previously.
  • using a combination of PorB2 and PorA proteins may provide a vaccine that is protective against disease caused by any one of serogroup W-135, C, Y or X meningococci.
  • the protein based vaccine may thus be prepared from any one of serotype W-135, C, Y or X bacterial strains that possesses the required combination of PorB2 and PorA proteins, preferably one of PorB2 2a, 2b or 2c; and PorA PI.5, 2, or PI.5, 10, or a combination thereof.
  • PorB and PorA proteins are envisaged i.e. 2a: PI.5, 2, 2a: PI.5, 10, 2b: PI.5, 2, 2b: PI.5, 10, 2c: PI.5, 2 and/or 2c : PI.5, 10.
  • Protein-based vaccines according to the invention may comprise proteins of the outer membrane presented in several ways to the vaccinated individual, and in a preferred embodiment the proteins are provided in outer membrane vesicles (OMVs) or fragments thereof.
  • OMVs outer membrane vesicles
  • Such vesicles or fragments may be prepared by known detergent extraction techniques, whereby the outer membrane of N. meningi tidis is disintegrated to further reform as OMV at the order of 1/10 the size of the bacterium.
  • a suitable method is described in WOOl/91788, which is incorporated herein by reference.
  • a serogroup W-135 OMV vaccine preparation raised antibodies in mice being bactericidal towards strains of the W-135 strain, as well as towards heterologous strains of serogroups C and Y. All of said strains were classified as serotype 2a: serosubtype PI.5, 2.
  • PorB proteins are outer membrane proteins placed in class 2 or 3. Class 2 proteins are of particular interest herein.
  • N. meningi tidis bacteria may be classified upon the basis of the PorB protein present in the outer membrane into particular serotypes.
  • PorB is an outer membrane porin which has the ability to translocate from the bacterial outer membrane to other membranes such as the plasma membrane of host cells, where it forms a regulated pore that modulates cellular signalling.
  • Several types of PorB proteins exist, and N. meningi tidis can accordingly be divided into serotypes according to the PorB protein type .
  • Common serotypes include protein 2a, protein 2b, and protein 2c.
  • PorB2 protein is PorB2 protein 2a.
  • PorA proteins (class 1 proteins) are the antigens used as the basis for allocating meningococcal serosubtypes.
  • PorA is a pore-forming protein and its principal function is to make small channels in the bacterial outer membrane .
  • Examples of PorA protein serosubtypes are PI .5 , PI.5,1, PI.5, 2 and PI.5, 10; PI.7, 2, PI.7, 4, PI.7, 12 and PI.7, 16.
  • the protein based vaccine comprises the serosubtype PI .5 , most preferably PI .5 , 2.
  • the invention provides a vaccine derived from the outer membrane of serogroup W-135, serogroup C, serogroup Y or serogroup X N. meningi tidis, characterised in that said outer membrane contains PorB2 protein 2a, 2b or 2c, preferably 2a and PorA PI.5, 2 or PI . ' 5, 10, preferably PI.5, 2.
  • Said vaccine thus contains PorB2 protein 2a, 2b or 2c and PorA PI.5, 2 or PI.5, 10. It is thus effective as a vaccine for protecting individuals from infection with meningococcal bacteria with serotype 2a, 2b or 2c and serosubtype PI.5, 2 or PI.5, 10 irrespective of serogroup.
  • the present invention provides a vaccine for serotype 2a, 2b or 2c : serosubtype PI.5, 2 or PI.5, 10 meningococcal bacteria which comprises PorB2 protein 2a or 2b or 2c and PorA PI.5, 2 or PI.5, 10.
  • the vaccine comprises PorB2 protein 2a and PorA PI.5, 2.
  • the vaccine of the invention is derived from the outer membrane of a serotype 2a, serosubtype PI.5, 2 meningococcal bacteria, such as those of serogroup
  • the vaccine comprises outer membrane vesicles (OMVS) derived from the outer membrane of a meningococcal bacteria of serotype 2a, 2b or 2c ;
  • OMVS outer membrane vesicles
  • the OMV is derived from a strain that is serotype 2a; serosubtype PI.5, 2.
  • Said vaccine may thus be prepared according to the method set out in WO 01/91788, from suitable bacteria, e.g. a serotype 2a; serosubtype PI.5, 2 bacteria.
  • Said bacteria is preferably selected from serogroup W-135, X, Y or C which are serotype 2a; serosubtype PI.5, 2.
  • a major advantage of providing the vaccine of the invention is to provide a vaccination which is not serogroup (i.e. polysaccharide specific) and thus use of the vaccine will not be affected by "capsule switching" .
  • the key aspect to this invention was to find the right combination of antigens which were suitably immunogenic to develop a vaccine which was cross-reactive for several serogroups of meningococcal bacteria.
  • the present inventors have developed an effective vaccine which is protein-based, thus inducing long-term immunological memory, is suitable for use in children under the age of 2 years and is cross-reactive for the majority of serogroups W-135, C and Y, particularly those which are serotype 2a, serosubtype PI.5, 2. It thus overcomes the inherent problems with providing a solely polysaccharide serogroup-based vaccine.
  • the invention further extends to a method of vaccination comprising the administration of the vaccine of the invention to a patient.
  • Said patient is a human in need of vaccination against meningococcal infection.
  • Said vaccine may be administered in any suitable fashion, but is preferably administered via injection in a suitable sterile suspension with appropriate pharmaceutical excipients .
  • the invention provides a vaccine comprising one or more PorB2 protein and one or more PorA from meningococcal bacteria for use in protecting against meningococcal disease .
  • Said PorB protein is selected from protein 2a, 2b or 2c.
  • PorA protein is selected from PI.5, 2 and PI.5, 10. Any combination of PorB and PorA is envisaged.
  • OMV comprising PorB2 and PorA as a vaccine
  • Said vaccine may be used to protect against serotype 2a, serosubtype PI.5, 2 infection in a preferred embodiment.
  • the vaccine of the present invention may be supplied together with any pharmaceutically acceptable excipients, for any suitable mode of administration.
  • the vaccine is formulated as a sterile solution for injection.
  • the vaccine according to the invention may according to a preferred embodiment be prepared by a process comprising the steps of
  • steps a-c are performed in a closed apparatus as an integrated process as described in WO 01/91788.
  • the vaccine according to the invention may further comprise one or more antigens such as further outer membrane proteins, LPS or polysaccharides of the same or another meningococcal serogroup, preferably of serogroups A, C, W-135 or Y, most preferably of serogroup A.
  • the additional polysaccharides, outer membrane proteins or LPS may be mixed into the vaccine at any of the steps (for example, any one of steps a to g if the vaccine is prepared as an OMV) of its preparation.
  • the vaccine of the invention is preferably derived from one strain of N. meningi tidis and thereby obtain a multivalant vaccine (with regard to serogroup) .
  • Figure 1 is a photograph of a Comassie Blue-stained SDS- PAGE gel, on which OMV preparations from serogroups B (44176) , A (MK 686/02) and two serogroup W-135 strains (Bufa 196/02 and Bufa 222/02) have been run. Relevant protein antigens, such as PorA and PorB2 are shown;
  • Figure 2 shows the ELISA lgG responses against OMV derived from strain Bufa 222/02 after vaccination of mice with Bufa 196/02 and Bufa 222/02 OMV vaccines.
  • the plot shows ELISA IgG response versus strain type.
  • the experimental method is described in Example 2c;
  • Figure 3 is a plot of Log 2 titre versus strain type. It shows the observed bactericidal properties of sera obtained from mice vaccinated with OMV vaccines from strains Bufa 196/02 and Bufa 222/02, against the W-135 strain Bufa 196/02, as described in Example 3a;
  • OMV outer membrane vesicles
  • the two W-135 strains were grown on Tryptic Soy Agar (TSA) plates with VITOX and used as inoculum for cultivation in a shake culture, as disclosed in WOOl/91788.
  • TSA Tryptic Soy Agar
  • VITOX Zinc Soy Agar
  • a synthetic modified Catlin medium (MC6) was used, having a low iron content (1/10 of original recipe for MC6) .
  • WO 01/91788 was followed.
  • bacterial pellets were collected by centrifuging, and a buffer (0.1 M Tris-HCl with 10 mM EDTA, pH 8.6) was added.
  • a second buffer (10% sodium deoxychelate (DOC) in the first buffer, pH 8.9) was added to give a final DOC concentration of 0.5% for extraction.
  • the extracted suspensions were centrifuged, the supernatants were centrifuged in the cold, and supernatants were centrifuged at higher speed. OMV-containing supernatants were stored cold.
  • OMVs were characterised by election microscopy, SDS-PAGE and immunoblot techniques .
  • Electron microscopy (negative straining) showed vesicles with diameters of about 50 to 200 micrometers, as previously found for serogroup A and B OMV preparations.
  • LPS pattern of the OMV preparations were analysed using SDS-PAGE with silver staining for carbohydrate.
  • mice used in the immunisation procedure were groups of outbred NMRI female mice (weight 12-14 g) , receiving two subcutaneous doses of vaccine (prepared as in Example 1) with an interval of 3 weeks . Sera were obtained 2 weeks after the second immunisation. For each vaccine to ' be tested, two groups (12 mice) received either 1 or 10 mg of OMV vaccine. A fifth control group (6 mice) was left un-immunised.
  • OMV vaccines Two OMV vaccines were prepared from W-135 strains BuFal96/02 and BuFa222/02, respectively, and 1 or 10 ug doses were injected into mice (five groups in total) as described in Example 2a.
  • Sera were obtained after vaccination (Examples 2a-b) , and immunogenicity of the vaccines was analysed by detecting the binding of IgG antibodies in the sera to OMV prepared as in Examples la-b from the W135 strain BuFa 222/02.
  • Example 2a Experiments using the method of Example 2a were performed, using OMV vaccines from further strains of serogroup W135 and from serogroups C and Y, all strains being selected to possessing similar protein patterns as found for BuFal96/02 and BuFa 222/02. Similar results are obtained, demonstrating that OMV vaccines also of serogroups C and Y, having the same protein pattern as W-135 strains, induce antibodies against W-135 OMV.
  • the immunogenicity of the vaccines to specific outer membrane proteins in OMVs was analysed by detecting the binding of IgG antibodies of sera from immunized mice.
  • the blots showed strong antibody binding to PorA for most sera. In addition, a very strong binding was observed to the NadA and Opa proteins with OMVs from BuFal96/02 as antigen.
  • Example 1 The efficiency of the vaccines of Example 1 to provide protection against N. meningi tidis strains was tested with a serum bactericidal assay (SBA) with human complement, an assay believed to correlate with protection against meningococcal disease.
  • Sera from immunised and non-immunised mice (Example 2a) were tested for their ability to kill selected bacteria, three different meningococcal strains, in the presence of complement.
  • SBA serum bactericidal assay
  • Sera were obtained after vaccination with OMV vaccines obtained using strains BUFal96/02 and BuFa222/02 as described in Example 2 a-b.
  • mice With 10 ⁇ g doses, all mice demonstrated strong bactericidal activity. There was no significant difference between vaccines from the two strains. With 1 ug dose of OMV vaccine from strain BuFa222/02, only five of the 12 mice showed SBA activity. Sera from non-immunised mice did not show SBA activities. Results are illustrated in Figure 3.
  • Example 4 Monoclonal antibody against PorB2 (P2.2a) are bactericidal against serogroup W and C strains
  • a murine monoclonal antibody (l-lP2a) , directed against the PorB2 molecule P2.2a was tested in the serum bactericidal assay (SBA) .
  • SBA serum bactericidal assay

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Abstract

La présente invention concerne des vaccins à base de protéines comprenant des protéines de membrane externe spécifiques (PorB2 et PorA) destinés à combattre les éléments épidémiques qui entraînent une infection par des souches bactériennes qui expriment une combinaison particulière de la protéine de membrane externe PorB2 et de la protéine de membrane externe PorA. Ces souches peuvent comprendre, notamment, une bactérie de n'importe lequel des sérogroupes W-135, C, Y et X. La présente invention concerne un vaccin comprenant une ou plusieurs protéines de membrane externe du type PorB2 et une ou plusieurs protéines de membrane externe du type PorA.
PCT/GB2003/005479 2002-12-16 2003-12-16 Vaccin meningococcique a base de proteines de membrane externe porb2 et pora Ceased WO2004054611A1 (fr)

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NO20026049 2002-12-16
NO20026049A NO20026049D0 (no) 2002-12-16 2002-12-16 Protein-basert vaksine mot meningokokk serogruppe W-135 sykdom
NO20034372 2003-09-23
NO20034372 2003-09-23

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Cited By (8)

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GB2414667A (en) * 2004-06-03 2005-12-07 Isis Innovation Vaccine compositions of N. meningitidis PorA and FetA antigens
WO2006024946A3 (fr) * 2004-09-03 2006-11-30 Chiron Srl Ameliorations en rapport avec les vesicules de la membrane exterieure de meningocoque
US9206399B2 (en) 2004-10-29 2015-12-08 Glaxosmithkline Biologicals Sa Immunogenic bacterial vesicles with outer membrane proteins
US9259462B2 (en) 2010-09-10 2016-02-16 Glaxosmithkline Biologicals Sa Developments in meningococcal outer membrane vesicles
US9610342B2 (en) 1999-05-19 2017-04-04 Glaxosmithkline Biologicals Sa Combination neisserial compositions
US9636393B2 (en) 1999-11-29 2017-05-02 Glaxosmithkline Biologicals Sa Compositions comprising Neisseria meningitidis antigens from serogroups B and C
US9687789B2 (en) 2003-07-15 2017-06-27 Glaxosmithkline Biologicals Sa Ultrafiltration for preparing outer membrane vesicles
US9764027B2 (en) 2012-09-18 2017-09-19 Glaxosmithkline Biologicals Sa Outer membrane vesicles

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WO2001091788A1 (fr) * 2000-06-02 2001-12-06 Statens Institutt For Folkehelse Vaccin comprenant des vesicules de membrane externe utilise contre les maladies causees par le serogroupe a de neisseria meningitidis et methode de preparation
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