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WO1995018231A1 - Compositions pour vaccins comprenant des vecteurs bacteriens vivants pour la protection contre l'infection a yersinia pestis - Google Patents

Compositions pour vaccins comprenant des vecteurs bacteriens vivants pour la protection contre l'infection a yersinia pestis Download PDF

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Publication number
WO1995018231A1
WO1995018231A1 PCT/GB1994/002818 GB9402818W WO9518231A1 WO 1995018231 A1 WO1995018231 A1 WO 1995018231A1 GB 9402818 W GB9402818 W GB 9402818W WO 9518231 A1 WO9518231 A1 WO 9518231A1
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WO
WIPO (PCT)
Prior art keywords
microorganism
plasmid
thr
seq
recombinant dna
Prior art date
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Ceased
Application number
PCT/GB1994/002818
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English (en)
Inventor
Richard William Titball
Ethel Diane Williamson
Sophie Emma Clare Leary
Petra Claire Farquhar Oyston
Angela Howells
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UK Secretary of State for Defence
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UK Secretary of State for Defence
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Filing date
Publication date
Application filed by UK Secretary of State for Defence filed Critical UK Secretary of State for Defence
Priority to JP7517658A priority Critical patent/JPH09507028A/ja
Priority to EP95904620A priority patent/EP0741786A1/fr
Priority to AU13222/95A priority patent/AU1322295A/en
Publication of WO1995018231A1 publication Critical patent/WO1995018231A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/74—Vectors or expression systems specially adapted for prokaryotic hosts other than E. coli, e.g. Lactobacillus, Micromonospora
    • 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
    • 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

  • the present invention relates to novel vaccines for provision of protection against infection with the organism Yersinia pestis (Y-_ pestis) and to compositions containing them.
  • Y-_ pestis Yersinia pestis
  • compositions containing them are particularly provided.
  • parentally and orally active vaccines capable of offering protection against bubonic and pneumonic plague, particularly by induction of mucosal immunity in both humans and other animals.
  • Y. pestis is the highly virulent causative organism of plague in a wide range of animals, including man. Infection with this organism results in a high rate of mortality. Studies have shown that the high virulence is due to a complex array of factors encoded by both the chromosome and three plasmids, including the Lcr genes (see Straley, (1991) Microb. Pathogen 10: pp ⁇ 7-91), a fibrinolysin (Sodeinde & Goguen, (1988) Infec. Immun 56: pp2743-2748) , and a capsule.
  • the capsule surrounding Y. pestis cells is composed of a protein -polysaccharide complex, the protein component of which is known as Fraction 1 (Fl) (see Baker et al (1952) J. Immunol 68: ppl31-l45) which is only fully expressed at 37°C.
  • Fraction 1 Fraction 1
  • This complex confers resistance to phagocytosis, possibly by forming aqueous pores in the membranes of phagocytic cells (Rodrigues et al (1992) J. Med. Biol. Res.
  • the cafl gene encoding Fl antigen has been cloned and sequenced (Galyov et al (1990) FEBS Letters 277: pp230-232) and recombinant Fl expressed and purified from E.coli induced a protective response in BALB/c mice sufficient to protect against challenge with 10 5 virulent plague bacilli (Simpson et al (1990) Am. J. Trop. Med. Hyg. 43(4): PP389-396) . Such resistance to infection by Y. pestis is correlated with high titres of Fl antibody.
  • the current vaccine for plague is the Cutter vaccine which comprises formaldehyde killed plague bacilli and is administered to the body by intramuscular injection.
  • parenteral immunisation although effective in inducing systemic immunity, does not effectively induce mucosal immunity (McGhee et al, (1992) Vaccine 10., 75-88). So far no Y. pestis vaccine capable of producing a protective immune response at mucosal surfaces has been developed.
  • the present inventors have now provided recombinant DNA constructs that when incorporated into DNA of a microorganism, particularly of a human or animal gut colonising microorganism, are capable of transforming it such that it is able to express a protein which produces a protective immune response against Yersinia pestis in the human or animal body when the gut colonising microorganism is administered by oral routes.
  • Preferred forms of the present invention provide such DNA constructs that transform such a microorganism while allowing it to maintain its ability to colonise the human or animal gut and thus provide sustained administration, ie. by exposure of antigen to the human or animal body immune system, preferably with systemic invasion of the human or animal body.
  • vectors eg.plasmids containing the DNA constructs of the invention, that are capable of transforming a human or animal gut colonising microorganism such that it is capable of expressing a protein which produces a protective immune response against Yersinia pestis in a human or animal body when the microorganism is administered by oral or parenteral routes, preferably allowing the microorganism to maintain ability to colonise the human or animal gut, and preferably subsequently systemically to invade the body.
  • microorganisms preferably human or animal gut colonising microorganisms, transformed with a vector containing recombinant DNA, eg. a plasmid containing recombinant DNA, according to the invention such that it is enabled to express a protein which produces a protective immune response against Yersinia pestis in a human or animal body when the microorganism is administered by oral or parenteral routes, and preferably allows the microorganism to maintain its ability to colonise the human or animal gut, and preferably invade systemically.
  • the protective response provided preferably includes protection at mucosal surfaces.
  • One preferred recombinant DNA, and plasmids comprising it are characterised in that they comprise a lacZ promoter in frame with a sequence encoding for all or part of the cafl antigen. Still further preferred recombinant DNA utilises a caflR positive regulator derived from the Fl operon itself. It is further preferred that the caflM fragment is included for the purposes of assisting export of mature protein through the cell wall of the host organism, ie. the transformed cell and/or the caflA fragment that encodes proteins thought to be important in anchoring the Fl subunit to the cell wall.
  • the recombinant DNA includes the lacZ promoter it is preferably incorporated into a vector such as pUCl ⁇ that has the all or part of the cafl encoding sequence inserted in frame with the lacZ promoter
  • microorganisms of the invention are preferably attenuated microorganisms not capable of causing disease in humans or animals, eg. such as the Salmonella aro A or aro C mutants, preferably of species Salmonella fyphimurium or a Salmonella tvphi.
  • Preferred vaccine compositions are provided as such microorganisms together with a pharmaceutically acceptable carrier, eg. saline or buffer.
  • Attenuated microorganisms such as S. tvphimurium have been well characterised as carriers for various heterologous antigens (Curtiss, (1990 ); New Generation Vaccines, Woodrow & Levine (eds) Marcel Dekker Inc. New York; Cardenas and Clements, (1992) ibid). Attenuation may be effected in a number of ways, such as by use of the aro A and/or aro C mutation approach (see Hosieth et al (1981) Nature 291, 238-239; Dougan et al (1986) Parasite Immunol 9, I51-I6O; Chatfield et al (1989) Vaccine 7, 495-498).
  • a particularly preferred recombinant DNA comprises a DNA sequence as described in SEQ ID No 4.
  • the inventors have determined the sequence of a still further preferred recombinant DNA which when included within suitable vectors within, or integrated directly into the chromosomal DNA of, gut dwelling microorganisms results in still stronger expression of protective Fl, Fl fusion or Fl truncate proteins.
  • This recombinant DNA is particularly characterised in that it it comprises the complete Fl operon including caflR, a positive regulator of Fl expression; caflM, encoding for the proposed chaperone sequence which assists in export of the Fl sub-units across the cell wall; caflA, thought to encode a protein which anchors the Fl into the cell wall; all in addition to the cafl gene encoding the Fl subunit or a truncate or fusion product thereof.
  • SEQ ID No 1 is the sequence of a PCR primer oligonucleotide corresponding to the first 21 bases encoding for mature cafl with an additional 5' region encoding for a Sacl site.
  • SEQ ID No 2 is the sequence of a PCR primer oligonucleotide corresponding to the sequence of cafl which encodes a 'stem loop' downstream of the termination codon with an added 5' region encoding Sacl and Accl sites.
  • SEQ ID No 3 is that of a PCR primer oligonucleotide corresponding to an internal end region of the cafl gene starting 107 bases downstream from the end of the first oligonucleotide.
  • SEQ ID No 4 is that of the pFGAL2a construct showing the fusion of the first few bases of the ⁇ -galactosidase sequence in the vector with cafl minus its signal sequence and having a 5' tail including a Sac I restriction site; the sequence is shown up to the cafl AACC 3' end with some vector bases.
  • SEQ ID No 5 is that of the protein encoded by pFGAL2a.
  • SEQ ID No 6 is that of pFSIG3a: including cafl sequence encoding mature Fl expressed as a fusion with the E. coli LTB signal sequence encoded by the vector and having 5' tail including a Sacl restriction site; the sequence shown to AACC at 3' end of cafl and its adjoining vector bases.
  • SEQ ID No 7 is that of the protein encoded by pFSIG3a.
  • SEQ ID No 8 is that of pFORFlb: including the entire cafl gene and having a 5' tail including a Sacl restriction site; the sequence shown to TATAG downstream of the cafl open reading frame. The two series encoded at the 5' end of the sequence are produced separately to the Fl fusion.
  • SEQ ID No 9 is that of the end of the first protein encoded by pFORFlb.
  • SEQ ID No 10: is that of the Fl fusion encoded by pFORFlb.
  • SEQ ID No 11 is that of primer FI0U2 used to amplify the Fl operon.
  • SEQ ID No 12 is that of primer M4D used to amplify the Fl operon.
  • SEQ ID No 13: is that of primer M3U used to amplify the Fl operon.
  • SEQ ID No 14 is that of primer FI0D2 used to amplify the Fl operon.
  • SEQ ID No 15 is that of a primer used with the primer of SEQ ID No 1 for preparation of pFSIG3a.
  • SEQ ID No 16 is that of a primer used with the primer of SEQ ID No 17 to produce pFORFlb.
  • SEQ ID No 17 is that of a primer used with the primer of SEQ ID No 16 to produce pFORFlb.
  • FIGURE
  • Figure 1 shows schematic representations of the positions of Fl sequences in the constructs pFGAL2a, pFSIG3a and pFORFlb.
  • Figure 2 shows to relative positions of the primers SEQ ID No 11 to 14, the retriction enzyme sites and the caflR, caflM, caflA and cafl subunits.
  • Y. pestis was grown aerobically at 28°C in Blood Agar Base broth, pH6.8, containing 15g/l proteose peptone, 2.5g/l liver digest, 5g/l yeast extract, 5g/l NaCl supplemented with 8 ⁇ ml 0.25# haemin in 1/lOON NaOH.
  • Strains of S. tvphimurium used were SL3261 and LB5010 as described by Hosieth & Stocker (1981) Nature (London) 291: p238-239 and Maskell et al (1987) Microb. Pathog. 2 pp211-221 respectively and these and E.coli JM109 were cultured and stored as described by Sambrook et al (1989) Molecular Cloning Manual.
  • Oligonucleotides were prepared with a Beckman 200A DNA synthesiser for use in the PCR.
  • Oligonucleotide GATCGAGCTCGGCAGATTTAACTGCAAGCACC (SEQ ID No 1) was synthesised corresponding to the first 21 bases of cafl immediately following the nucleotides encoding the signal sequence with an additional 5' region encoding a Sacl site and the complimentary oligonucleotide CAGGTCGAGCTCGTCGACGGTTAGGCTCAAAGTAG (SEQ ID No 2) corresponding to the sequence which encodes a putative 'stem loop' structure downstream of the cafl termination codon with an added 5' region encoding Sacl and Accl sites.
  • a DNA fragment was obtained after 35 cycles of amplification (95°C, 15 sees; 50°C, 15 sees; 72°C, 30 sees using a Perkin Elmer 96OO GeneAmp PCR system).
  • the fragment was purified, digested with Sacl and Accl, ligated into a similarly digested pUCl ⁇ plasmid and transformed into E. coli JM109 by electroporation. Electroporation was carried out using a Biorad Gene Pulser with 0.2 cm cuvettes at 1.25kV, 25 ⁇ F, ⁇ OOOhms with a time constant of 20.
  • a pFGAL2a colony containing the cloned cafl gene was identified by PCR using an oligonucleotide TGGTACGCTTACTCTTGGCGGCTAT (SEQ ID No 3) corresponding to an internal region of the gene 128 to 153 nucleotides from the site identified as the signal sequence cleavage site (see Galyov et al (1990)) and the SEQ ID No 2.
  • a culture of the E.coli - containing the pFGAL2a was grown at 37° c with shaking in Luria Broth containing lmM isopropyl- ⁇ -D-thiogalactopyranoside (IPTG) for 18 hours.
  • Whole cell lysates and periplasmic and cytoplasmic fractions of the bacteria were prepared as described by Sambrook et al (1989).
  • SDS-PAGE and Western blotting SDS-polyacrylamide gel electrophoresis (PAGE) and Western blotting were performed as described by Hunter et al (1993) Infec. Immun. 61. 3958-3965- Blots were probed with polyclonal antisera raised in sheep (B283) against killed Y. pestis (EV76 strain grown at 37°C) and bound antibody was detected with a horseradish peroxidase-labelled donkey anti-sheep IgG (Sigma) .
  • the pFGAL2a plasmid was isolated using general techniques described in Sambrook et al (1989) Molecular Cloning; a Laboratory Manual. 2nd Edition. Cold Spring Harbour Laboratory, New York. Purified plasmid was electroporated into S. typhimurium LB5010 (restriction " , modification * ) and methylated pFGAL2a was subsequently isolated from the LB5010 for electroporation into S. typhimurium SL3261 (aro A " ). Periplasmic and cytoplasmic fractions were prepared for SDS-PAGE and Western blotting as described above.
  • mice Five female Balb/c mice were inoculated intravenously with either 5xl0 5 or 5xl0 7 cfu S. tvphimurium containing pFGAL2a in 200 ⁇ l phosphate buffered saline. Control mice were inoculated similarly with S. tvphimurium containing pUCl ⁇ with no insert. After 7 days the mice were killed by cervical dislocation and their livers and spleens removed.
  • mice Male Balb/c mice were inoculated with three doses of S.tvphimurium containing pFGAL2a, intravenously (i.v.) with 5xl0 7 cfu bacteria at 7 day intervals, or intragastrically (i.g.) by intubation with 1 x IO 10 cfu on days 1, 7 and 21.
  • mice from both the i.g. and intravenously inoculated groups were bled then killed by cervical dislocation and their livers and spleens taken. Livers were homogenised and plated onto L-agar to confirm that all Salmonella had been cleared.
  • mice were challenged subcutaneously with 50LD- 0 of Y. pestis strain GB.
  • Control mice were immunised i.v. and i.g. with S. tvphimurium containing pUCl ⁇ , intramuscularly with formaldehyde-killed plague vaccine (Cutter USP) or intraperitoneally with lO ⁇ g of purified Fl and survival rates assessed (see Table 1).
  • Construct plasmids and S. tvphimurium transformed by them were obtained using the method of Example 1 altered in so far as the PCR product was designed to be of SEQ ID No 2 after digestion with Sacl.
  • the digested product was ligated into Sacl digested pFS2.2 giving the sequence SEQ ID No 5 located as shown in Figure I.
  • This construct encodes for Fl which is expressed as a fusion with the E.coli LTB signal sequence.
  • the primer used instead of SEQ ID No 1 was that of SEQ ID Nd 15.
  • Construct plasmids and S. tvphimurium transformed by them were obtained using the method of Example 1 altered in so far as the PCR primers were selected to produce an amplification product which after digestion with Sacl/Accl consisted of SEQ ID No 6.
  • Primers used were of sequences SEQ ID NO 16 and SEQ ID No 17. This construct incorporates the cafl signal sequence in addition the mature protein sequence as shown in SEQ ID No 6 and Fig 1 which shows all bases downstream of the Sac I site used for digest.
  • S. typhimurium transformed as described above with either pFGAL2a, pFSIG3a, pFORFlb or unmodified pUCl ⁇ were administered to mice by intravenous or intragastric routes and compared in effect to intraperitoneal Fl and intramuscular Cutter vaccine as described above in Example 1.
  • MOLECULE TYPE DNA (genomic)
  • HYPOTHETICAL NO
  • ANTI-SENSE NO
  • ORIGINAL SOURCE
  • ORGANISM Yersinia pestis
  • xi SEQUENCE DESCRIPTION: SEQ ID NO: 1:
  • MOLECULE TYPE DNA (genomic)
  • HYPOTHETICAL NO
  • ANTI-SENSE NO
  • ORIGINAL SOURCE
  • ORGANISM Yersinia pestis
  • xi SEQUENCE DESCRIPTION: SEQ ID NO: 2:
  • MOLECULE TYPE DNA (genomic)
  • HYPOTHETICAL NO
  • ANTI-SENSE NO
  • ORIGINAL SOURCE
  • ORGANISM Yersinia pe
  • MOLECULE TYPE DNA (genomic)
  • HYPOTHETICAL NO
  • ANTI-SENSE NO
  • ORIGINAL SOURCE
  • GCA GCA GGT AAA TAC ACT GAT GCT GTA ACC GTA ACC GTA TCT AAC CAA 530 Ala Ala Gly Lys Tyr Thr Asp Ala Val Thr Val Thr Val Ser Asn Gin 155 1 0 165 170 TAATCCATAT AG 542
  • MOLECULE TYPE DNA (genomic)
  • HYPOTHETICAL NO
  • ANTI-SENSE NO
  • ORIGINAL SOURCE
  • ORGANISM Yersinia pestis
  • xi SEQUENCE DESCRIPTION: SEQ ID NO: 11:
  • MOLECULE TYPE DNA (genomic)
  • HYPOTHETICAL NO
  • ANTI-SENSE NO
  • ORIGINAL SOURCE
  • ORGANISM Yersinia pestis
  • xi SEQUENCE DESCRIPTION: SEQ ID NO: 12:
  • MOLECULE TYPE DNA (genomic)
  • HYPOTHETICAL NO
  • ANTI-SENSE NO
  • ORIGINAL SOURCE
  • ORGANISM Yersinia pestis
  • xi SEQUENCE DESCRIPTION: SEQ ID NO: 13:
  • MOLECULE TYPE DNA (genomic)
  • HYPOTHETICAL NO
  • ANTI-SENSE NO
  • ORIGINAL SOURCE
  • MOLECULE TYPE DNA (genomic)
  • MOLECULE TYPE DNA (genomic).
  • MOLECULE TYPE DNA (genomic)

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Abstract

Nouveaux produits de recombinaison d'ADN qui sont capables de transformer des micro-organismes de telle manière que ces derniers peuvent être utilisés comme vaccins vivants ou atténués induisant une réponse immunitaire au niveau des muqueuses. Des micro-organismes ainsi transformés et des compositions pour vaccins sont également décrits. Des produits de recombinaison préférés de la présente invention sont capables de transformer des micro-organismes de telle manière que ces derniers expriment la protéine à base de F1 tout en conservant la capacité de se loger dans un environnement intestinal humain ou animal. On a identifié plusieurs produits de recombinaison capables de transformer des micro-organismes séjournant dans les intestins tels que S. typhimurium ou S. typhi pour permettre la production d'antigène F1, mais la plupart de ces produits affectent le micro-organisme de telle manière qu'il ne peut plus fonctionner efficacement dans l'intestin, tout au moins dans la mesure où il ne peut plus exprimer l'antigène, par exemple parce qu'il est instable et perd le plasmide.
PCT/GB1994/002818 1993-12-24 1994-12-23 Compositions pour vaccins comprenant des vecteurs bacteriens vivants pour la protection contre l'infection a yersinia pestis Ceased WO1995018231A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP7517658A JPH09507028A (ja) 1993-12-24 1994-12-23 イエルシニア ペスチス （Ｙｅｒｓｉｎｉａ ｐｅｓｔｉｓ）感染から防御するための生細菌ベクターを含むワクチン組成物
EP95904620A EP0741786A1 (fr) 1993-12-24 1994-12-23 Compositions pour vaccins comprenant des vecteurs bacteriens vivants pour la protection contre l'infection a yersinia pestis
AU13222/95A AU1322295A (en) 1993-12-24 1994-12-23 Vaccine compositions comprising live bacterial vectors for protection against yersinia pestis injection

Applications Claiming Priority (2)

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GB9326425.7 1993-12-24
GB939326425A GB9326425D0 (en) 1993-12-24 1993-12-24 Vaccine compositions

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WO1995018231A1 true WO1995018231A1 (fr) 1995-07-06

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EP (1) EP0741786A1 (fr)
JP (1) JPH09507028A (fr)
AU (1) AU1322295A (fr)
CA (1) CA2179639A1 (fr)
GB (1) GB9326425D0 (fr)
WO (1) WO1995018231A1 (fr)

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WO1998024912A3 (fr) * 1996-12-04 1998-09-11 Heska Corp Vaccin contre la peste obtenu par recombinaison
WO2000061151A3 (fr) * 1999-04-12 2001-04-26 Us Health Un oligodesoxynucleotide et son emploi pour induire une reponse immunitaire
RU2197988C2 (ru) * 1995-03-13 2003-02-10 Дзе Секретэри Оф Стейт Фор Дефенс Противочумная вакцина
US6977245B2 (en) 1999-04-12 2005-12-20 The United States Of America As Represented By The Department Of Health And Human Services Oligodeoxynucleotide and its use to induce an immune response
US7344718B2 (en) 2003-01-31 2008-03-18 University Of North Dakota Yersinia species compositions
US7354909B2 (en) 2001-08-14 2008-04-08 The United States Of America As Represented By Secretary Of The Department Of Health And Human Services Method for rapid generation of mature dendritic cells
US7521063B2 (en) 2000-01-14 2009-04-21 The United States Of America As Represented By The Department Of Health And Human Services Multiple CPG oligodeoxynucleotides and their use to induce an immune response
US7524507B1 (en) * 1999-09-10 2009-04-28 The Secretary Of State For Defense In Her Brittanic Majesty's Government Of The United Kingdom Of Great Britain And Northern Ireland Recombinant microorganisms
US7572449B2 (en) 2002-08-31 2009-08-11 The Secretary Of State For Defense In Her Britannic Majesty's Government Of The United Kingdom Of Great Britain And Northern Ireland Vaccine against Yersinia comprising one or two antibodies, one specific for Yersinia pestis F1-antigen and the other one for Yersinia pestis V-antigen
US7615227B2 (en) 2001-12-20 2009-11-10 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Use of CpG oligodeoxynucleotides to induce angiogenesis
US8647633B2 (en) * 1996-08-27 2014-02-11 The United States Of America As Represented By The Secretary Of The Army Recombinant F1-V plague vaccine
US9211327B2 (en) 2011-06-22 2015-12-15 University Of North Dakota Use of YSCF, truncated YSCF and YSCF homologs as adjuvants
US9409956B2 (en) 2012-05-23 2016-08-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Salmonella typhi Ty21a expressing Yersinia pestis F1-V fusion protein and uses thereof

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