EP0894005A1 - Vaccin a base de salmonella typhimurium - Google Patents

Vaccin a base de salmonella typhimurium

Info

Publication number
EP0894005A1
EP0894005A1 EP97906536A EP97906536A EP0894005A1 EP 0894005 A1 EP0894005 A1 EP 0894005A1 EP 97906536 A EP97906536 A EP 97906536A EP 97906536 A EP97906536 A EP 97906536A EP 0894005 A1 EP0894005 A1 EP 0894005A1
Authority
EP
European Patent Office
Prior art keywords
typhimurium
strain
avirulent
fad
pathogenic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97906536A
Other languages
German (de)
English (en)
Inventor
Paul S. Cohen
David C. Laux
David P. Franklin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rhode Island Board of Education
Original Assignee
Rhode Island Board of Education
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rhode Island Board of Education filed Critical Rhode Island Board of Education
Publication of EP0894005A1 publication Critical patent/EP0894005A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
    • C07K14/255—Salmonella (G)
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
    • A61K2039/522—Bacterial cells; Fungal cells; Protozoal cells avirulent or attenuated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to vaccines useful for the prevention or modification of microbial pathogenesis.
  • One aspect of this invention relates to the identification and isolation of avirulent mutants of microbial bacteria suitable for such vaccines.
  • Another aspect of the invention relates to the use of such avirulent mutant bacteria as carriers of antigens derived from the disease causing pathogens, such that the resulting recombinant bacteria may be used as a vaccine against the disease, or diseases, from which the antigens were derived.
  • the means by which a warm blooded animal overcomes microbial pathogenesis is a complex process. Immunity to microbial pathogenesis is one means by which a warm blooded animal avoids pathogenesis, or suffers a less intense pathogenic state. Incomplete immunity to a given pathogen results in morbidity and mortality in a population exposed to a pathogen.
  • vaccines based on live but attenuated micro ⁇ organisms induce a highly effective type of immune response.
  • live vaccines have the advantage that, once the animal host has been vaccinated, entry of the microbial pathogen into the host induces an accelerated recall of earlier, cell-mediated or humoral immunity which is able to control the further growth of the organism before the infection can assume clinically significant proportions.
  • Vaccines based on a killed pathogen are generally conceded to be unable to achieve this type of response.
  • vaccines that contain a live pathogen present the danger that the vaccinated host upon vaccination may contract the disease against which protection is being sought.
  • a vaccine that possesses the immunizing attributes of a live vaccine but that is not capable of causing an undesirable infection upon vaccination.
  • a vaccine based on an avirulent, auxotrophic strain of Salmonella typhimurium has been utilized as an experimental immunogen, Hoiseth et al., Nature 291:238-239 (1981).
  • Curtiss in United States Patent 5,294,441, teaches an immunogenic composition based on an avirulent derivative of S. typhimurium .
  • the avirulent derivative is derived from a virulent wild strain.
  • the derivatives carry the mutations
  • This invention provides a live vaccine against a microbial pathogen. Because the immune response of the vertebrate host to antigens, in particular surface antigens, of the pathogenic microorganism is the basic mechanism of protection by vaccination, a live vaccine should retain the antigenic complement of the wild-type strain.
  • the live vaccine should be avirulent, substantially incapable of multiplication in the host, and should have substantially no probability for reverting to a virulent wild strain.
  • This vaccine contains, as its immunogenic agent, a live avirulent mutant strain of the microbial pathogen to which an immune reaction is to be induced.
  • the vaccine contains the avirulent mutant strain in an effective amount together with a physiologically tolerable carrier and is free from an infective amount of any virulent strain of the pathogen.
  • the avirulent strain is placed in the carrier for delivery to a warm blooded animal in a dosage amount sufficient to confer protection against a virulent strain of the same pathogen.
  • the invention in another aspect comprises a method for preparing a live non-virulent vaccine from a virulent pathogenic microorganism, which vaccine is substantially incapable of reverting to virulence in a vertabrae host subject susceptible to said microorganism which comprises subjecting a virulent strain of said microorganisms to mutating conditions resulting in a mutated microorganism resulting in a block in at least one biosynthetic pathway which renders said organism auxotrophic with a requirement for a metabolite normally unavailable in host susceptible to said microorganism.
  • the desired mutagenesis can be achieved by one of several methods.
  • the method of mutagenesis applied depends on the organism subjected to the procedure. Generally it is preferred that the mutation be as localized as much as possible and further that the reversion to the original genotype of the pathogen be as limited as possible.
  • Mutagenesis by DNA insertion is preferred and can be accomplished by transposon mutagenesis. This is a relatively non-reverting mutation accomplished at a localized site in the chromosome.
  • a general transducing phage such as phage P22, able to adsorb to bacteria of a wide range of genera (if necessary after appropriate genetic modification of their lipopolysaccharide character, to provide the necessary ability to adsorb this phage) can be used to transduce a non ⁇ functional biosynthetic gene, inactivated by insertion of a transposon or otherwise, from its original host to a pathogenic bacterial strain of a different species of genus, wherein it will have some probability of incorporation into the chromosome, therefore replacing the homologous wild-type gene, to produce an auxotrophic transductant.
  • the vaccines are produced by introducing a non-reverting mutation in at least one gene, where each mutation is of a sufficient number of bases in tandem to insure a substantially zero probability of reversion and assurance of the non-expression of each mutated gene, in the sense of its total inability to determine production of an enzymatically active protein.
  • the type and number of genes transduced will result in the likelihood that a host for the vaccine will provide the necessary nutrients for proliferation and will have a probability of reversion approximating zero.
  • the resulting auxotrophic strain will be an avirulent live vaccine having the desired immunogenicity in that the mutation will not affect the production of the antigens which trigger the natural immune response of the host. At the same time, the mutation results in an avirulent live vaccine incapable of growing in the host.
  • mutants that are determined to be avirulent as compared to the parental strain on the basis of the in vivo assays can then be further tested for their ability to confer protection against challenge with the parental strain by immunizing the host with the mutant strain prior to exposure of the host to the virulent parent strain. Protection is defined as the ability of the host animal to survive the challenge of a lethal dose of the virulent parent strain after immunization with the mutant.
  • mutant isolation, screening in vivo, and immunization with the selected mutants provide means by which avirulent strains of pathogenic microorganisms are obtained that are suitable for use in vaccines.
  • one or more genes coding for the desired antigens, or for enzymes for synthesis of the desired antigen(s), may be introduced into the host as expression cassettes.
  • Expression cassettes includes transcriptional and translational initiation and termination regions bordering the structural genes of interest with the structural genes under the regulatory control of such regions.
  • the expression cassette may be a construct or may be or from part of a naturally-occurring plasmid such as the plasmid encoding the enzymes for production of the O-specific part of the LPS of Shigella sonnei .
  • the expression cassette is a construct, it may be joined to a replication system for episomal maintenance or may be introduced into the bacterium under conditions for recombination and integration.
  • the construct will normally be joined to a marker, e.g., a structural gene, and regulatory regions providing for antibiotic resistance or complementation in an auxotrophic host, so that the expression vector will usually include a replication system, e.g., plasmid or viral, one or more markers and the expression cassette of the structural gene of interest.
  • Structural genes of interest come from diverse sources, such as bacteria, viruses, fungi, protozoa, metazoan parasites or the like.
  • the structural genes may encode envelope proteins, capsid proteins, surface proteins, toxins, such as exotoxins or enterotoxins, or the genes of interest may specify proteins, enzymes or other proteins needed for synthesis of a polysaccharide or oligosaccharide antigen or for modification of a saccharide-containing antigen, such as LPS, of the host bacterial strain, or for synthesis of a polypeptide antigen, such as the capsular antigen of Bacillus anthracis .
  • genes may be isolated in conventional ways employing probes where at least a partial amino acid or nucleic acid sequence is known, using Western blots for detection of expression, using ⁇ gtll for expression of fused proteins for obtaining probes, identification of the antigen by the reaction of transconjugant bacterial colonies with antibody and detecting complex formation, e.g. , agglutination, etc.
  • genes of interest include those specifying the heat-labile and heat-stable enterotoxins of enterotoxigenic E. coli or Vibrio chlorea strains, surface, envelope or capsid proteins of T. cruzi, B. pertussis, Streptococci, e.g. S. pneumoniae, Haemophilus, e.g., H. infiuenzae, Neisseria, e.g., N. meningitidis, Pseudomonas, e.g., P.
  • aeruginosa Pasteurella, Yersinia, Chlamydia, Rickettsia, adenovirus, astrovirus, arenavirus, coronavirus, herpes virus, myxovirus, paramyxovirus, papovavirus, parvovirus, picoranvirus, pxovirus, reovirus, retrovirus, rhabdovirus, rotavirus, togavirus, etc. or the genes specifying the enzymes needed for synthesis of polysaccharide, or for modification of the oligo- or polysaccharide antigen of the bacterial host strain.
  • the construct or vector may be introduced into the host strain by any convenient means such as conjugation, e.g., F + or Hfr strain, transformation, e.g., Ca precipitated DNA, transfection, transduction, etc; by fusion into fimbriae of flagella or intracellularly.
  • conjugation e.g., F + or Hfr strain
  • transformation e.g., Ca precipitated DNA, transfection, transduction, etc
  • fusion into fimbriae of flagella or intracellularly e.g., Bactas, Bactas, or D, which includes most species which are specific pathogens of particular vertabrae hosts.
  • Illustrative of the salmonella causing disease for which live vaccines can be produced are S. typhimurium ⁇ S. typhi; S. abortusovi ⁇ S. abortus-equi ; S. dublin; S. gallinarum ⁇ S. pullorum ⁇ as well as other which are known or may be discovered to cause infections in mammals
  • Other organisms for which the subject invention may also be employed include Shigella, particularly S. flexneri and S. sonnei ⁇ Haemophilus, particularly N. meningitidis and N. gonorrohoeae; Pasteurella, particularly P. multocida and Yersinia, particularly Y. pestis .
  • the subject vaccines may be used in a wide variety of vertebrates.
  • the subject vaccines will find particular use with mammals such as man and domestic animals.
  • Domestic animals include bovine, ovine, porcine, equine, caprine, domestic fowl.
  • Leporidate e.g., rabbits, or other animal which may be held in captivity or may be a vector for a disease affecting a domestic vertebrate.
  • an attenuated strain of S. typhimurium is mutated with a selected bacteriophage.
  • a mutant embodying the invention designated S. typhimurium SR-11 Fad " , is characterized by the inability to utilize fatty acids and citrate for growth. The mutant is avirulent and immunogenic. DESCRIPTION OF THE PREFERRED EMBODIMENT(S)
  • S. typhimurium SR-11 was selected as the pathogen. Mutagenesis was performed in S. typhimurium
  • Selected mutant alleles were bacteriophage P22 HT105 inf transduced from S. typhimurium TT10427 into S. typhimurium SR-11.
  • BALB/C mice (Charles River Laboratories, Wilmington, MA) were selected as the experimental animals because of their sensitivity to S. typhimuriumSR-11.
  • the LD 50 for BALB/C mice was found to be 8.2 x IO 4 Colony Forming Units (CFU) with a mean death time of 8 days following peroral infection.
  • the S. typhimurium strains were routinely grown aerobically in Luria broth (LB) and plated on Luria agar (LA). hen platings were done from animal tissues, MacConkey agar was utilized, which is selective for the particular group of organisms of interest. Mutants were isolated on Minimal Broth Davis agar plates containing oleate and citrate as carbon sources. Media utilized was formulated in accordance with the following recipes.
  • S. typhimurium LT7 TT10605 contains an F lac plasmid which carries TnlOd Cam, a defective TnlO which lacks a transposase gene and has chloramphenicol resistance substituted for tetracycline resistance (Elliot and Roth, Mol. Gen. Genet. 213:332-338).
  • TnlOd Cam was introduced into S. typhimurium TT10427 from a bacteriophage P22 HT lysate of 5.
  • TnlOd Cam-induced chloramphenicol resistant mutants were selected on LA containing 30 ⁇ g/ml of chloramphenicol as described by Elliot and Roth (Mol. Gen. Genet. 213:332-338). Colonies were toothpicked to Minimal Broth Davis agar plates containing either glucose or both oleate and citrate as carbon sources. Mutants that grew utilizing glucose as the carbon source but not oleate and citrate were bacteriophage P22 HT105 inf transduced into S. typhimuriumSR-11 using chloramphenicol for selection. All transductants tested grew utilizing glucose as the sole carbon source but did not grow with oleate as the carbon source . One mutant , designated S. typhimurium SR-11 Fad " was shown to be free of P22 HT105 int by growth on the Green
  • SR-11 Fad shuts down part of the tricarboxylic acid cycle as well as the glyoxylate shunt in an as yet unknown way.
  • Preparation of Vaccine against Salmonella S. typhimurium SR-11 Fad " is avirulent.
  • S. typhimurium SR- 11 and S. typhimurium SR-11 Fad " were grown aerobically overnight at 37°C. The cultures were centrifuged, washed twice in HEPES-Hanks buffer, pH 7.4 (Cohen et al.. Infect. Immun. 40; 62-
  • mice BALB/C mice, S. typhimurium SR-11 Fad " is completely avirulent.
  • S . typhimurium SR-11 Fad protects BALB/C mice against S . typhimurium SR-11 .
  • mice Three weeks after peroral inoculation, two mice each originally inoculated with IO 9 , I O 8 , and I O 7 CFU of S. typhimurium SR-11 Fad " were challenged with I O 9 CFU of S. typhimurium . None of the mice died and all appeared completely healthy throughout the course of the experiment . In contrast , an age- matched set of six mice which were not inoculated all died by nine days after peroral challenge with IO 9 CFU of S. typhimurium SR-11 .
  • CFU Liver Weight CFU/Liver Spleen Weight CFU/Spleen SR-11 Fad "
  • mice orally infected with SR-11 at single doses of between 10 7 and IO 9 CFU contained much larger numbers in liver (about 3 x IO 7 CFU per organ) and spleen (about 2 x
  • CFU Liver Weight
  • Liver Spleen Weight CFU/Spleen
  • SR-11 Fad is also attenuated relative to SR-11 when administered intraperitoneally.
  • Four out of four BALB/c mice were killed by injection of 50 CFU SR-11 intraperitoneally whereas at the same doses, four out of four mice survived intraperitoneal injection of SR-11 Fad " .
  • only two out of five mice survived intraperitoneal injection of 150 CFU of SR-11 Fad" and only one out of five mice survived intraperitoneal doses of 1.5 x IO 3 and 1.5 x IO 4 CFU (see Table 5).
  • mice orally dosed with SR-11 Fad " challenged with IO 9 CFU of SR-11 21 days later, and bled 60 days later was assayed.
  • the second mouse originally dosed orally with IO 8 CFU of SR-11 Fad' had a serum agglutination tier of 1:4 against both strains, and the third mouse had a serum agglutination titer of 1:16 against both strains (see Table 6).
  • Normal BALB/c mouse serum did not agglutinate either strain.
  • the serum titer against Widal antigens (O-side chain) was determined on the serum taken from one mouse originally dosed with IO 8 CFU of SR-11 Fad " , challenged with IO 9 CFU of SR-11 21 days later, and bled 30 days later.
  • the serum titer against Widal antigens was 1:320. Normal mouse serum did not show any reactivity.

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Gastroenterology & Hepatology (AREA)
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Abstract

On décrit un vaccin vivant contre un pathogène mocrobien avirulent pratiquement incapable de se multiplier chez l'hôte et, en toute probabilité, dans l'impossibilité de redonner une souche sauvage virulente.
EP97906536A 1996-02-15 1997-02-13 Vaccin a base de salmonella typhimurium Withdrawn EP0894005A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US60179096A 1996-02-15 1996-02-15
US601790 1996-02-15
PCT/US1997/002074 WO1997029768A1 (fr) 1996-02-15 1997-02-13 Vaccin a base de salmonella typhimurium

Publications (1)

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EP0894005A1 true EP0894005A1 (fr) 1999-02-03

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EP97906536A Withdrawn EP0894005A1 (fr) 1996-02-15 1997-02-13 Vaccin a base de salmonella typhimurium

Country Status (5)

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EP (1) EP0894005A1 (fr)
JP (1) JP2000504726A (fr)
AU (1) AU2120197A (fr)
CA (1) CA2244807A1 (fr)
WO (1) WO1997029768A1 (fr)

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US7193017B2 (en) 2004-08-13 2007-03-20 Univation Technologies, Llc High strength biomodal polyethylene compositions
US7312279B2 (en) 2005-02-07 2007-12-25 Univation Technologies, Llc Polyethylene blend compositions
EP2103633A1 (fr) 2005-09-14 2009-09-23 Univation Technologies, LLC Procédé permettant de mettre en oeuvre un reacteur en phase gazeuse et de commander en même temps l'adhésivité de polymères
EP2112175A1 (fr) 2008-04-16 2009-10-28 ExxonMobil Chemical Patents Inc. Activateur de métallocènes comprenant au moins un ligand hétérocyclique substitué par halogène, coordonné à un alumoxane
WO2011103280A1 (fr) 2010-02-18 2011-08-25 Univation Technologies, Llc Procédés d'exploitation d'un réacteur de polymérisation
WO2011103402A1 (fr) 2010-02-22 2011-08-25 Univation Technologies, Llc Systèmes catalyseurs et procédés d'utilisation de ces derniers pour produire des produits de polyoléfine
WO2011129956A1 (fr) 2010-04-13 2011-10-20 Univation Technologies, Llc Mélanges de polymères et films obtenus à partir de ceux-ci
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US7193017B2 (en) 2004-08-13 2007-03-20 Univation Technologies, Llc High strength biomodal polyethylene compositions
US7312279B2 (en) 2005-02-07 2007-12-25 Univation Technologies, Llc Polyethylene blend compositions
EP2103633A1 (fr) 2005-09-14 2009-09-23 Univation Technologies, LLC Procédé permettant de mettre en oeuvre un reacteur en phase gazeuse et de commander en même temps l'adhésivité de polymères
EP3309182A2 (fr) 2007-11-15 2018-04-18 Univation Technologies, LLC Catalyseurs de polymérisation, leurs procédés de fabrication, leurs procédés d'utilisation et produits polyoléfiniques fabriqués à partir de ceux-ci
EP2112175A1 (fr) 2008-04-16 2009-10-28 ExxonMobil Chemical Patents Inc. Activateur de métallocènes comprenant au moins un ligand hétérocyclique substitué par halogène, coordonné à un alumoxane
WO2011103280A1 (fr) 2010-02-18 2011-08-25 Univation Technologies, Llc Procédés d'exploitation d'un réacteur de polymérisation
WO2011103402A1 (fr) 2010-02-22 2011-08-25 Univation Technologies, Llc Systèmes catalyseurs et procédés d'utilisation de ces derniers pour produire des produits de polyoléfine
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