WO2008133984A1 - Combinations of gene deletions for live attenuated shigella vaccine strains - Google Patents
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- WO2008133984A1 WO2008133984A1 PCT/US2008/005342 US2008005342W WO2008133984A1 WO 2008133984 A1 WO2008133984 A1 WO 2008133984A1 US 2008005342 W US2008005342 W US 2008005342W WO 2008133984 A1 WO2008133984 A1 WO 2008133984A1
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- shigella
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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
- A61K39/025—Enterobacteriales, e.g. Enterobacter
- A61K39/0283—Shigella
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
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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
- 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
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- 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 generally to Shigella vaccine, strains, their use in vaccines, and the methods for treatment of dysentery.
- Shigella spp. is the causative agent of bacillary dysentery.
- the distal end of the colon and the rectum, which show intense and acute mucosal inflation, are the areas of the gastrointestinal (GIT) moat most affected during shigellosis.
- GIT gastrointestinal
- a very low inoculum of 10-100 bacteria is sufficient to cause the disease, which then spreads easily, often directly, by the fecal-oral route or by flies contaminating food and water.
- Appropriate antibiotics such as those effective against gram-negative bacteria, are used to combat Shigella infection; however, as with most bacterial pathogens, an increase in antibiotic resistance has dramatically emphasized the need for a safe and effective vaccine.
- Recent Shigella vaccine candidates include subcellular complexes purified from virulent cultures (e.g., Invaplex vaccine) that encompass detoxified lipopoly saccharide (LPS) conjugated to carrier proteins and live attenuated vaccine strains. Attempts to utilize whole-cell inactivated organisms that are given in high and multiple doses have met with poor immunogenicity and protective efficacy. Live vaccines appear to offer a better approach since they mimic natural infection while subverting the clinical outcome.
- virulent cultures e.g., Invaplex vaccine
- LPS lipopoly saccharide
- US 5762941 illustrates one live vaccine approach and involves the loss of virG(icsA) gene in S. flexneri 2a, S. sonnei, and S. dysenteriae 1.
- Vaccine strains SC602, WRSSl, and WRSdI resulted, of which SC602 and WRSSl were tested in Phase 1 trials on human volunteers and found to be safe at oral doses ranging from 10 3 to 10 4 CFU. However, 15-25% of the volunteers administered SC602 or WRSSl showed symptoms of mild diarrhea and fever.
- U. S. patents US5589380 and US5468639 illustrate another approach, whereby two candidate genes, setAB(shETl) and senA(shET2), are utilized since they have previously been shown to encode enterotoxic activity. While setAB(shETl) is present predominantly on the chromosome of S. flexneri 2a strains, the senA(shET2) gene is located on the large virulence plasmid of all Shigella strains.
- CVD 1204 An article in the Journal of Infectious Disease 2004, 190: 1745-54 illustrates a still further approach to achieve a live Shigella vaccine.
- senB(shET2-2) constitutes a putative enterotoxin gene that shares >60% homology at the amino acid level with senA(shET2-l) and could be a functional analog of senA(shET2).
- CVD 1208 is given at very high doses (10 9 ) which can induce fever in 10% of subjects.
- US patent US6759241 is directed towards an approach involving the msbB2 gene in live vaccine development.
- the msbB2 gene encodes a fatty acyl transferase enzyme that adds fatty acid residues to the lipid A portion of the bacterial LPS molecule.
- the lipid A portion constitutes an endotoxin that is responsible for the potent inflammatory activity and pyrogenic properties of bacterial LPS.
- a mutation in the msbB gene results in a less toxic LPS but, unlike E. coli, Shigella has two msbB genes, the first (msbBl) on the chromosome and the second (msbB2) on the virulence plasmid.
- a review article in Expert Review Vaccines 2006, 5:5 discusses several live- attenuated Shigella vaccines with well-defined mutations in specific genes.
- the immune responses obtained with each vaccine strain were compared with data obtained from challenge trials using wild-type Shigella strains.
- the data from these trials indicated that live attenuated vaccine strains elicited immune reposnes comparable to individuals challenged with wild-type Shigella strains.
- the combination of gene deletions is expected to eliminate reactogenicity while inducing protective immune responses.
- the invention relates to Shigella vaccine candidates of all 4 major serotypes whose primary attenuating feature is deletion of the virG(icsA) gene and additional deletions in two or more of setAB(shETl), senA(shET2), senB(shET2-2), stxAB, and msbB2 genes.
- the strain will have three or more deletions in the identified genes and will be safer, resulting in the absence of or reduced fever and diarrhea when tested in human volunteers.
- the following vaccine strains have been constructed: WRSS3 ( ⁇ senA, ⁇ senB, ⁇ virG, ⁇ msbB2), WRSf2G15 ( ⁇ virG, ⁇ setAB, ⁇ senA, ⁇ senB, ⁇ msbB2), and WRSd5 ( ⁇ virG, ⁇ stxAB, ⁇ senA, ⁇ senB, ⁇ msbB2).
- the strains of the invention are designed to protect against dysentery and diarrhea caused by Shigella flexneri, Shigella sonnei, Shigella dysenteriae, and Shigella boydii.
- the strains of the invention can be used in mixtures of live attenuated polyvalent vaccines that contain two or more serotypes of Shigella (e.g., Shigella flexneri and Shigella sonnei).
- the strains of the invention can also be used in combination with live attenuated vaccines against enterotoxigenic E. coli (ETEC) to provide protection against dysentery and diarrhea caused by these bacteria.
- ETEC enterotoxigenic E. coli
- multivalent vaccines employing these strains can protect against the common serogroups of Shigella and ETEC.
- Prime-boost whereby initial immunization with a live vaccines is followed by immunization with a subunit vaccine, will provide protection against dysentery and diarrhea caused by Shigella.
- the Shigella vaccine strains of the invention can be used as carriers of antigens from other diarrheal pathogens such as Campylobacter, mucosal delivery vectors for other prokaryotic antigens, vectors for eukaryotic antigens, and carriers of immune modulators such as cytokines.
- the Shigella vaccine strains of the invention can be used at doses as low as 10 4 to 10 6 CFU. While virG(icsA)-based vaccines have been tested in humans and shown to be reasonably safe, 15-25% of the volunteers have shown reactogenic symptoms that are unacceptable. The deletion of the virG(icsA) gene combined with deletions of genes associated with enterotoxic activity, putative enterotoxins, and/or genes associated with LPS toxicity will create a safer oral Shigella vaccine.
- the Shigella vaccine strains are characterized as having the virG(icsA) gene deletion/inactivation in combination with two or more of setAB(shETl), senA(shET2), senB(shET2-2), stxAB, and msbB2 genes.
- the Shigella vaccine is a nonvirulent strain of 4 serogroups, namely S. flexneri, S. sonnei, S. dysenteriae, and S. boydii. .
- the Shigella vaccine strains are characterized by one or more of the following traits: invasiveness in epithelial cells, absence of plaques in epithelial cell monolayers, absence of keratoconjunctivitis induction in guinea pig eyes, induction of immune responses that are protective from challenge in guinea pigs, and efficient excretion from monkeys after a intragastric inoculation of 10 10 CFU.
- the Shigella vaccine strains can be formulated as an immunogenic composition wherein the strains are mixed with a pharmaceutically acceptable carrier and are present in an amount that induces a protective immune response after one or more administrations.
- the multistrain vaccine composition can be formulated as a single dose that achieves a protective immune response. The exact amount may be empirically determined and would be variable depending on animal type, weight, condition, and age.
- compositions and strains of the invention can be packaged as a kit to facilitate handling and provide optimal protection.
- the kit may comprise one or more containers, each of which contains a specific Shigella vaccine strain or mixture of strains.
- the amount or type of stains may be selected as part of a regimen or application.
- the Shigella vaccine strains of the invention can be packaged with written instructions and in a manner to preserve viability of the strains.
- the Shigella vaccine strains of the invention When administered to a subject in a single dose or series of doses, the Shigella vaccine strains of the invention induce a mucosal (oral or intranasal) immune response.
- One advantage of the vaccine formulation is that a protective response can be achieved in a single oral dose containing relatively few colony forming units (10 4 to 10 6 CFU) compared to the alternatives of multiple doses of a live, noninvasive vaccine or inactivated whole cell vaccine strains.
- FIG. 1 shows the construction of specified Shigella vaccine strains, namely WRSSl, WRSS2, and WRSS3.
- FIG. 2 shows characterization of the WRSS 1 , WRSS2, and WRSS3 vaccine strains via HeLa cell immunoassay (2A), colony immunoblotting (2B), and plaque assay (2C).
- FIG. 3 shows the guinea pig immunization protocol for WRSS 1 , WRSS2, and WRSS3.
- FIG. 4 shows serum antibody titers (4A) and mucosal antibody titers (4B) in occularly immunized guinea pigs.
- FIG. 5 shows the protective efficacy of WRSS 1 , WRSS2, and WRSS3 following a wild-type strain challenge.
- FIG. 6 shows the monkey intragastric immunization protocol.
- FIG. 7 shows the vaccine excretion results for WRSS 1 , WRSS2, and WRSS3 in the monkey immunization protocol.
- FIG. 8 shows the Construction of Shigella vaccine strains WRSf2G12 and WRSf2G15 via S. flexneri strain 2457T.
- FIG. 9 shows the Characterization of the WRSf2G12 and WRSf2Gl 5 vaccine strains via colony immunoblotting (A) and HeLa cell invasion assay (B).
- FIG. 10 shows the Guinea pig ocular (OC) immunization protocol.
- FIG. 11 shows the Serum antibody titer (A) and mucosal (B) antibody titer in ocularly immunized guinea pigs.
- FIG. 12 shows the Protective efficacy of SC602, WRSf2G12, and WRSf2G15 following challenge with wild-type S. flexneri strain 2457T.
- WRSS 1 , SC602, and WRSdI which are the three Shigella vaccine candidates based on deletions of the virG(icsA) gene, have been recently tested in Phase 1 clinical trials on healthy adults, indicating that all three vaccines are safe when given orally in doses ranging from 10 3 to 10 4 CFU.
- volunteers vaccinated with SC602 were protected from severe dysentery following challenge with a homologous wild-type S. flexneri 2a strain.
- expanded phase 1 clinical trials revealed that an unacceptable number of the volunteers given SC602 or WRSSl had symptoms of mild diarrhea and fever.
- New, second-generation virG(icsA)-based S. sonnei vaccine candidates (WRSS2 and WRSS3) with additional deletions in two plasmid-borne enterotoxins and a lipid A modifying gene, which should reduce the reactogenic symptoms associated with WRSSl, have been constructed.
- WRSS2 Consisting of deletions in virG(icsA), ShET2-l (senA), and ShET2-2 (senB)
- WRSS3 Consisting of deletions such as in WRSS2 with an additional deletion in the plasmid-borne msbB2 gene
- WRSS2 consististing of deletions in WRSS2 with an additional deletion in the plasmid-borne msbB2 gene
- WRSS3 consististing of deletions such as in WRSS2 with an additional deletion in the plasmid-borne msbB2 gene
- deletion of the senA, senB, and the plasmid-borne msbB2 genes do not alter the protective immune responses induced with vaccine strains carrying a single virG(icsA) mutation.
- the first generation vaccine strain (WRSSl) was constructed using a suicide vector as described in Hartman AB et al. 1998.
- WRSS2 and WRSS3 were constructed via a series of deletion mutations using ⁇ -red recombineering as described in Ranallo et al 2007. Additional modifications to complete construction of WRSS2 include the loss of tetracycline resistance using fusaric acid.
- the msbB2 gene was deleted from WRSS2 and genomic PCR analysis was used to confirm all gene deletions.
- the strains were then characterized by HeLa cell invasion assay, colony immunoblotting, and the plaque assay as shown in Figure 2.
- Blood and mucosal secretions were collected as serum antibody responses (Figure 4A) and mucosal antibody responses (Figure 4B) from guinea pigs immunized with WRSSl, WRSS2, and WRSS3.
- Serum IgG-specific, serum IgA-specific, and mucosal IgA-specific immune responses against S. sonnei LPS and S. sonnei invasin-LPS complex (Invaplex) were measured by the ELISA assay.
- the IgG and IgA antibody responses were determined for day 0 (DO), day 14 (D 14), and day 28 (D28) as well as two weeks after challenge (CLG).
- the geometric mean titer (GMT) of each group was calculated with 95% confidence intervals as indicated by error bars. No significant differences between WRSSl, WRSS2, and WRSS3 immune responses were detected by the one-way ANOVA test.
- the S. flexneri 2a strain 2457T was used to construct the attenuated Shigella strains indicated in figure 8.
- the first generation vaccine strain SC602 (not shown) is similar to WRSf2G but is too reactogenic when given to human volunteers at doses greater than 10 4 colony forming units.
- More attenuated strains (WRSf2G10-15) were constructed through a series of deletion mutations using ⁇ red recombineering. Genomic PCR analysis was used to confirm all gene deletions. The strains were then characterized by HeLa cell invasion assay and colony immunoblotting (see Figure 9).
- Each guinea pig was challenged with 1x10 CFU/eye of wild type S. flexneri strain 2457T 27 days after the final immunization (see Figure 12). Guinea pigs were inoculated in the conjunctival sac and evaluated for keratoconjunctivitis for 4 days. The reactions were scored as follows: 0, no inflammation or mild disease; 1, mild keratoconjunctivitis; 2, keratoconjunctivitis without purulence; and 3, severe keratoconjunctivitis with purulence. All guinea pigs immunized with the different vaccine strains (SC602, WRSf2G12, and WRSf2G15) were protected against keratoconj uncti vitis .
- flexneri 2a vaccine having the combination of gene deletions did not affect the colonization of either strain. Since colonization of the gut is key to the generation of a protective immune response, these results indicate that a multivalent mixture of vaccine candidates of different serotypes, attenuated by a combination of gene deletions described in this patent application, can be administered to volunteers and be expected to be safe and elicit a protective immune response to each serotype. The possibility of combining these strains into a multivalent mix that can be given at one time and that would still be given at fairly low doses (in the range of 10 4 to 10 6 cfu) adds value to this patent application.
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Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
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CA2685132A CA2685132C (en) | 2007-04-25 | 2008-04-25 | Combinations of gene deletions for live attenuated shigella vaccine strains |
EP08743288.6A EP2150274B1 (en) | 2007-04-25 | 2008-04-25 | Combinations of gene deletions for live attenuated shigella vaccine strains |
BRPI0816842A BRPI0816842A2 (en) | 2007-04-25 | 2008-04-25 | shigella vaccine strain, immunogenic composition, vaccine, individual treatment kit and method. |
RU2009143526/10A RU2467763C2 (en) | 2007-04-25 | 2008-04-25 | Combinations of gene deletions for live attenuated vaccine strains of shigella |
CN200880019647A CN101720229A (en) | 2007-04-25 | 2008-04-25 | The gene deletions for live attenuated shigella vaccine strains combination |
MX2009011467A MX2009011467A (en) | 2007-04-25 | 2008-04-25 | Combinations of gene deletions for live attenuated shigella vaccine strains. |
AU2008246150A AU2008246150B2 (en) | 2007-04-25 | 2008-04-25 | Combinations of gene deletions for live attenuated shigella vaccine strains |
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US90797407P | 2007-04-25 | 2007-04-25 | |
US60/907,974 | 2007-04-25 |
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WO2008133984A4 WO2008133984A4 (en) | 2009-03-05 |
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US (2) | US8986708B2 (en) |
EP (1) | EP2150274B1 (en) |
CN (1) | CN101720229A (en) |
AU (1) | AU2008246150B2 (en) |
BR (1) | BRPI0816842A2 (en) |
CA (1) | CA2685132C (en) |
MX (1) | MX2009011467A (en) |
RU (1) | RU2467763C2 (en) |
WO (1) | WO2008133984A1 (en) |
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EP2758530A4 (en) | 2011-09-22 | 2015-04-29 | Jackson H M Found Military Med | Shigella-derived vector and methods of using the same |
CN108410790B (en) * | 2018-05-24 | 2019-05-14 | 中国人民解放军军事科学院军事医学研究院 | The preparation and application of ebgR gene knockout recombination Shigella |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US6759241B1 (en) * | 1999-10-04 | 2004-07-06 | University Of Maryland Biotechnology Institute | Adjuvant comprising a lipopolysaccharide antagonist |
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US5762941A (en) * | 1988-07-15 | 1998-06-09 | Institut Pasteur | Modified shigella having reduced pathogenicity |
AR242989A1 (en) * | 1988-07-15 | 1993-06-30 | Inst Pasteur I Nat De La Sante | A method for modifying a wild strain of a "shigella", in order to produce a modified strain suitable for preparing a vaccine against the wild strain, and a "shigella" strain thus modified. |
SU1708351A1 (en) * | 1990-02-05 | 1992-01-30 | Научно-исследовательский институт эпидемиологии и микробиологии им.Н.Ф.Гамалеи | Shigella sonnei bacterial strain useable for preparing vital vaccine against sonne dysentery |
DE69012784D1 (en) * | 1990-02-06 | 1994-10-27 | Pasteur Institut | Transformed Shigella. |
US5589380A (en) * | 1992-06-05 | 1996-12-31 | University Of Maryland At Baltimore | Isolated DNA molecule encoding SHET1 of Shigella flexneri 2a and mutant Shigella flexneri 2a |
US5468639A (en) * | 1992-06-05 | 1995-11-21 | University Of Maryland At Baltimore | Isolated DNA molecule encoding ShET2 of Shigella flexneri 2a |
-
2008
- 2008-04-25 AU AU2008246150A patent/AU2008246150B2/en not_active Ceased
- 2008-04-25 EP EP08743288.6A patent/EP2150274B1/en not_active Not-in-force
- 2008-04-25 MX MX2009011467A patent/MX2009011467A/en not_active Application Discontinuation
- 2008-04-25 BR BRPI0816842A patent/BRPI0816842A2/en not_active IP Right Cessation
- 2008-04-25 RU RU2009143526/10A patent/RU2467763C2/en not_active IP Right Cessation
- 2008-04-25 CN CN200880019647A patent/CN101720229A/en active Pending
- 2008-04-25 CA CA2685132A patent/CA2685132C/en not_active Expired - Fee Related
- 2008-04-25 US US12/149,076 patent/US8986708B2/en active Active
- 2008-04-25 WO PCT/US2008/005342 patent/WO2008133984A1/en active Application Filing
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2015
- 2015-02-23 US US14/628,842 patent/US9320789B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US6759241B1 (en) * | 1999-10-04 | 2004-07-06 | University Of Maryland Biotechnology Institute | Adjuvant comprising a lipopolysaccharide antagonist |
Non-Patent Citations (9)
Title |
---|
COLLINS TODD A ET AL: "Safety and colonization of two novel virG(icsA)-based live Shigella sonnei vaccine strains in rhesus macaques (Macaca mulatta)", COMPARATIVE MEDICINE (MEMPHIS), vol. 58, no. 1, February 2008 (2008-02-01), pages 88 - 94, XP002495488, ISSN: 1532-0820 * |
EXPERT REVIEW VACCINES, vol. 5, 2006, pages 5 |
KOTLOFF ET AL., INFECTION AND IMMUNITY, AMERICAN SOCIETY FOR MICROBIOLOGY, vol. 68, no. 3, March 2000 (2000-03-01), pages 1034 - 1039 |
KOTLOFF K L ET AL: "Shigella flexneri 2a strain CVD 1207, with specific deletions in virG, sen, set, and guaBA, is highly attenuated in humans", INFECTION AND IMMUNITY, AMERICAN SOCIETY FOR MICROBIOLOGY. WASHINGTON, vol. 68, no. 3, 1 March 2000 (2000-03-01), pages 1034 - 1039, XP002454965, ISSN: 0019-9567 * |
RANALLO ET AL: "Immunogenicity and characterization of WRSF2G11: A second generation live attenuated Shigella flexneri 2a vaccine strain", VACCINE, BUTTERWORTH SCIENTIFIC. GUILDFORD, GB, vol. 25, no. 12, 13 February 2007 (2007-02-13), pages 2269 - 2278, XP005886446, ISSN: 0264-410X * |
VACCINE, vol. 25, 2007, pages 2269 - 2278 |
VENKATESAN MALABI M ET AL: "Construction, characterization, and animal testing of WRSd1, a Shigella dysenteriae 1 vaccine.", INFECTION AND IMMUNITY JUN 2002, vol. 70, no. 6, June 2002 (2002-06-01), pages 2950 - 2958, XP002495684, ISSN: 0019-9567 * |
VENKATESAN MALABI M ET AL: "Live-attenuated Shigella vaccines.", EXPERT REVIEW OF VACCINES OCT 2006, vol. 5, no. 5, October 2006 (2006-10-01), pages 669 - 686, XP009105559, ISSN: 1744-8395 * |
VENKATESAN, INFECTION AND IMMUNITY, vol. 70, no. 6, June 2002 (2002-06-01), pages 2950 - 2958 |
Also Published As
Publication number | Publication date |
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AU2008246150B2 (en) | 2013-07-25 |
EP2150274A1 (en) | 2010-02-10 |
RU2467763C2 (en) | 2012-11-27 |
AU2008246150A1 (en) | 2008-11-06 |
CN101720229A (en) | 2010-06-02 |
US20080267998A1 (en) | 2008-10-30 |
EP2150274B1 (en) | 2013-08-21 |
CA2685132C (en) | 2016-11-08 |
CA2685132A1 (en) | 2008-11-06 |
BRPI0816842A2 (en) | 2019-09-24 |
US9320789B2 (en) | 2016-04-26 |
US8986708B2 (en) | 2015-03-24 |
RU2009143526A (en) | 2011-05-27 |
MX2009011467A (en) | 2010-04-27 |
US20150165012A1 (en) | 2015-06-18 |
WO2008133984A4 (en) | 2009-03-05 |
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