WO2014037445A1 - Preparation of live vaccines - Google Patents
Preparation of live vaccines Download PDFInfo
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- WO2014037445A1 WO2014037445A1 PCT/EP2013/068373 EP2013068373W WO2014037445A1 WO 2014037445 A1 WO2014037445 A1 WO 2014037445A1 EP 2013068373 W EP2013068373 W EP 2013068373W WO 2014037445 A1 WO2014037445 A1 WO 2014037445A1
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- WIPO (PCT)
- Prior art keywords
- antibiotic
- colonies
- mutants
- campylobacter
- strains
- Prior art date
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Classifications
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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
- A61K39/0275—Salmonella
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- 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
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
- C12N1/205—Bacterial isolates
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- 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
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/36—Adaptation or attenuation of cells
-
- 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
- A61K2039/106—Vibrio; Campylobacter; Not used, see subgroups
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
- C12R2001/42—Salmonella
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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 provides a method for the generation of a live vaccine containing stable bacteria carrying at least three attenuating mutations and a vaccine containing bacteria obtained by said method.
- mutants attenuated by metabolic drift are characterized by the following advantages:
- Costs for preparation are low and the degree of attenuation via the desired selection of an increased generation time and, thus, reduced colony size, respectively, is, in principle, almost arbitrary.
- MD mutants can be selected and isolated as:
- MD "res" spontaneous MD antibiotic resistence clones of, e.g., streptomycin, rifampicin, fosfomycin, fusidic acid, nalidixic acid. These clones can be isolated with a frequency of more than 1% in relation to the virulent resistant clones. MD "res” and virulent resistant clones result from different mutations. Accordingly, MD “res” and attenuation can be regarded as a functional entity.
- streptomycin independent (Sm-id) suppressor mutants derived from streptomycin dependent (Smd) clones consist of a broad spectrum of clones characterized by clone specifically graduated reduced colony sizes and increasing degrees of attenuation, respectively, from almost wild type virulence to over- attenuation (mini colonies).
- ribosomal mutations increase the normal misreading (mistranslation) more or less and the exclusive suppressor mutation also causes attenuation.
- chicks tolerate facultative pathogenic Salmonella (and generally even Campylobacter) without showing any clinical symptoms.
- the low virulence of these wild strains for chicks requires vaccine strains showing a moderate degree of attenuation ensuring on the one hand immunogenicity for chicks but excluding on the other hand a hazard for human beings.
- One criterion of the efficacy of vaccine strains is, e.g., the verifiable reduction of the degree of colonization after challenge.
- MD attenuated live vaccines expressing all components of the bacteria e.g., outer membrane proteins
- the technical problem underlying the present invention is to provide improved live vaccine strains characterized by increased stability.
- Sm-id/ MD “res” vaccine strains of Salmonella and Campylobacter have not been described in the prior art.
- vaccine strains having four, five or even six attenuating mutations generated by the graduated incorporation of two or three Sm-id mutations and an additional MD “res" (A a, A a) marker are novel as well, for streptomycin: Smd 1 ⁇ Sm-id I ⁇ Smd a ⁇ Sm-id II ⁇ Sm-a ⁇ Sm-id III (six attenuating mutations) and Sm-id 1/ Sm-id II/ MD "res" (five attenuating mutations), respectively.
- Campylobacter coli and Campylobacter jejuni Viable counts on Petri dishes with Caso-agar against the incubation period
- mutants having Sm resistance could only be obtained by plating of ⁇ 24h/39°C culture material.
- no Smd mutants could be found among the resistant colonies having normal size or slightly reduced size.
- Campylobacter applying with distinct delay
- the majority of the clones could be characterized as being Smd clones.
- Figure 1 Examples of Salmonella vaccine strains characterized by three attenuating mutations.
- Figure 2 Examples of Campylobacter vaccine strains characterized by three attenuating mutations Incubation of the plates was at 39°C for about 4 8 and 72 hours, respectively.
- Campylobacter coli I wild strain/ Sm-id 5.5/ Pho 1 and Pho 2;
- Figure 3 Examples of Salmonella vaccine constructs characterized by (two), four, five or six attenuating 10 mutations. Incubation of the plates was at 37°C for about 20 hours.
- FIG. 4 Examples of Campylobacter vaccine constructs characterized by (two), four, five or six attenuating mutations. Incubation of the plates was at 39°C for about 48 hours.
- the present invention provides a method for the generation of a bacterial live vaccine containing stable bacteria carrying at least three (and up to six or seven) attenuating mutations, wherein said method comprises the following steps:
- step (d) growing a clone obtained in step (c) in a medium supplemented with a second antibiotic that may differ from the first antibiotic (e.g., an aminoglycoside such as streptomycin, neomycin, kanamycin, spectinomycin, gentamicin, amikacin, and tobramycin; rifampicin, fusidic acid, nalidixic acid, fosfomycin, ) having a suitable concentration, preferably an about tenfold MIC;
- a second antibiotic e.g., an aminoglycoside such as streptomycin, neomycin, kanamycin, spectinomycin, gentamicin, amikacin, and tobramycin; rifampicin, fusidic acid, nalidixic acid, fosfomycin, ) having a suitable concentration, preferably an about tenfold MIC;
- the bacterial strain of step (a) is, preferably, obtained from "wild" virulent strains. These strains can be taken from diseased animals (e.g., chicken). The starting natural strains which are used should have a certain degree of virulence.
- step (a) The choice of the antibiotic for selecting the mutants of step (a) is guided by reasons of a practical nature. For example, streptomycin is known to lead rapidly to the development of resistant and dependent strains among the microorganisms.
- the antibiotic of step (a) is streptomycin.
- other aminoglycoside antibiotics such as neomycin, kanamycin, spectinomycin, gentamicin, amikacin, and tobramycin, and rifampicin, fusidic acid and nalidixic acid may also be suitable as the antibiotic of step (a).
- resistance to the antibiotic can result from different modification mechanisms.
- the genetic modification may affect a chromosome of the bacterium.
- the chromosomal modification is a rare event which, once carried out, ensures the stability of the acquired properties.
- mini colonies as used herein relates to bacterial colonies
- characterized by a reduction of size Preferably, they are characterized by a size of ⁇ 10% of the corresponding wild strain colonies.
- the selection of attenuated bacterial strains as a function of growth criteria on media containing an antibiotic is an operation which has been used for various species with the object, notably, of causing the appearance of strains having reduced virulence.
- the bacterial strains according to the invention characterized by at least three (and up to six or seven) attenuating mutations are in the first place non-virulent strains selected, from natural virulent strains, for their growth capacity on a medium with a high content of an antibiotic such as streptomycin, and in addition, which can only be developed satisfactorily in the presence of the antibiotic (step (b). For this reason, these strains are said to be dependent on, e.g., streptomycin (Smd mutant).
- the strains of step (c) are mutants selected from the antibiotic dependent strains and which have the particularity of being able to develop in the absence of streptomycin due to the introduction of a second attenuating mutation or marker. These strains are called Sm-id strains.
- a washing step is carried out between steps (b) and (c) .
- the preferred medium for step (c) is a Salmonella Caso (SC) medium (e.g., for Salmonella) or a Caso medium (e.g., for Campylobacter).
- SC Salmonella Caso
- Caso medium e.g., for Campylobacter
- Step (d) allows introducing an additional MD antibiotic resistance (“res”) mutation (as a third attenuating marker).
- the antibiotic is
- step (d) The concentration of the antibiotic in step (d) can be determined by the person skilled in the art according to routine procedures.
- concentration of the antibiotic in step (d) can be determined by the person skilled in the art according to routine procedures.
- streptomycin note: most Sm-id mutants are streptomycin sensitive and therefore suited for an additional MD Sm "res" marker
- fosfomycin corresponds to an MIC value of about tenfold, and for fusidic acid to an MIC value of about fourfold.
- Campylobacter at least 200 ⁇ g fosfomycin/ml and at least 100 ⁇ g streptomycin/ml, respectively, are used.
- step (e) the Sm-id/ MD antibiotic "res" strains of the previous step
- step (f) the clones isolated from step (e) having the graduated reduction of the colony size as stable property are provided.
- steps (a) to (c) are at least repeated once for the generation of bacteria carrying at least four
- This method allows to generate new attenuating mutants, e.g., according to the following schemes (shown for Sm) :
- any antibiotic capable of inducing metabolic drift (MD) mutations can be used for the purposes of the present invention, e.g., streptomycin (note: most Sm-id mutants are streptomycin sensitive and therefore suited for an additional MD Sm “res” marker), rifampicin, fosfomycin, fusidic acid or nalidixic acid.
- MD metabolic drift
- the method of the present invention is not restricted to particular bacteria.
- Salmonella sp. and Campylobacter sp. other bacteria such as Salmonella sp. and Campylobacter sp., other bacteria such as Salmonella sp. and Campylobacter sp., other bacteria such as Salmonella sp. and Campylobacter sp., other bacteria such as Salmonella sp. and Campylobacter sp., other bacteria such as Salmonella sp. and Campylobacter sp., other bacteria such as
- Staphylococcus aureus Escherichia coli, Bacillus cereus (Pseudoanthrax),
- Yersinia sp. such as Y. pestis, Klebsiella sp., Listeria sp., Aeromonas sp., Shigella sp., Pasteurellal Avibacterium sp., Riemerella sp., Ornithobacterium
- rhinotracheale Boroletella sp., and Pseudomonas sp. can also be used for generating bacterial live vaccine containing stable bacteria according to the methods of the present invention.
- S. enterica subspecies enterica such as the following Serovars: Dublin, Gallinarum (biovars Gallinarum and Pullorum), Choleraesuis, Typhisuis, Typhi, Paratyphi A,B,C, Abortusequi, Abortusovis,
- Salmonella mutants are isolated from log phase cultures and as mini-colonies that start appearing after at least or more than 48 h at 37 °C incubation.
- Campylobacter mutants are isolated as mini-colonies that start appearing after at least or more than 72 h at 39°C incubation.
- the present invention also provides alive bacterial strains obtainable by the method of the invention as well as a vaccine comprising alive bacterial strains of the invention and a biologically acceptable carrier.
- the vaccinating compositions may of course be constituted by means of freshly cultivated bacteria.
- the vaccine composition of the present invention is freeze-dried.
- the medium in which they are suspended is not critical. Of course, this medium must not interfere with the good viability of the bacteria that they contain.
- the vaccine of the present invention is administered in an amount suitable for immunization of an individual and may additionally contain one or more common auxiliary agents.
- the employed term "amount suitable for immunization of an individual” comprises any amount of bacteria with which an individual can be immunized.
- An “"amount suitable for immunization of an individual” may be determined using methods known to one skilled in the art.
- the term "individual” as used herein comprises an individual of any kind. Examples of such individuals are animals (and humans).
- the administration of the vaccine preferable is the oral route but also injection may be made at various sites of the individual intramuscularly, subcutaneously, intradermally or in any other form of application. It may also be favourable to carry out one or more "booster injections" having about equal amounts.
- the vaccine of the present invention may be prophylactic, that is, the compounds are administered to prevent or delay the development of an infection or colonisation, e.g. an infection/colonisation caused by Salmonella or
- Salmonella enterica ssp. enterica Serovar Infantis Smid4-22/Rif2 DSM 26682
- Campylobacter coli K2848/11 Smidl8/Sm2 DSM 26683
- Salmonella enterica subsp. enterica serovar Virchow Salmonella enterica subsp. enterica serovar Virchow
- Salmonella paratyphi B (var. L-Tartrat+, formerly Java),
- Campylobacter coli Campylobacter jejuni (provided by Lohmann Animal Health,
- Campylobacter medium 1000 ml Campylobacter medium (Caso-medium) contain: 35 g Caso Agar (Sifin), 3 g yeast extract, 3 g casein hydrolysate, 4 g activated carbon, 0.25 g FeSC , 0.25 g sodium pyruvate, 5 g agar Kobe (Roth).
- Salmonella medium 1000 ml Salmonella medium (SC-medium) contain: 35 g Caso Agar (Sifin), 3 g yeast extract, 1 g glucose, 5 g agar Kobe (Roth).
- Streptomycin (Sm) (Roth No. 0236.2), fosfomycin (Pho) (Sigma No. P5396), rifampicin (Rif) (Riemser Arzneistoff AG, Fatol Eremfat 600 mg)
- the calculated frequency of the Smd clones in relation to resistant mutants was > 1%.
- Bacterial material obtained from a Caso agar Petri dish culture (24h/39°C; about 10 10 cfu) that had been inoculated in such a way that the entire surface of the disc was covered was plated on 1 or 2 Caso agar Petri dishes supplemented with 100 ⁇ g streptomycin/ml and incubated for 72h at 39°C.
- colonies having a clearly reduced size (diameter is ⁇ 25% of the normal size) with a frequency of about 20% - compared to the colonies having normal sizes and colonies having slightly reduced sizes - could be detected.
- About one-third of these colonies were Smd clones.
- the calculated frequency of the Smd clones in relation to resistant mutants was > 5% .
- Bacterial material obtained from a Caso agar (supplemented with 100 ⁇ streptomycin/ml) Petri dish culture (24h/39°C) that had been inoculated in such a way that the entire surface of the disc was covered was subjected to one washing step, plated on Caso medium in a ratio of 1:1 (about 3xl0 9 cfu) to 1:4 and then incubated for 72h at 39°C. Under these culturing conditions the majority of Smd clones showed the development of ⁇ 10 attenuated revertants (on average). Most of these attenuated revertants were Sm sensitive.
- Sm-id clones showing a reduced colony size of about > 50% compared to the wild type strain colonies were further processed.
- Campylobacter strains and the Smd mutants derived thereof allow isolation of Sm-id revertants without any problems. However, it is possible to isolate Sm-id revertants also from the problematic strains using, for example, several independent Smd mutants.
- Salmonella 10 9 " 10 cfu of the selected Sm-id clones were incubated on SC medium supplemented with an about tenfold MIC value concentration of rifampicin or streptomycin (as regards fusidine acid the about fourfold MIC value concentration) , respectively, and incubated for 48 hours at 37°C.
- Campylobacter The material of a Petri dish culture (Caso medium) that was inoculated with the Sm-id mutant in such a way that it covered the whole surface and incubated for 24h at 39°C was plated at a ratio of 1:4 to 1:8 on Caso medium supplemented with 200 ⁇ g fosomycin/ml or 100 ⁇ g strep to mycin/ml and incubated for >72h at 39°C.
- the colonies showing (more or less) reduced sizes were isolated and subjected to serial passages. About 20% of these clones maintained the clone specifically graded reduction of colony size as a stabile feature.
- the generation of vaccine strains having 4 or 6 attenuated mutations was achieved by sequentially incorporating a second and, optionally, a third Sm-id suppressor mutation into a basic Sm-id I clone: Sm-id II Sm-id II/ Sm-id III.
- Salmonella About 10 10 cfu of the basic Sm-id I mutant (or the Sm-id II starting strain) were plated on SC medium supplemented with 500 ⁇ g
- Sm-resistant colonies are Smd mutants (now growing primarily as colonies having "normal sizes") .
- Sm-id mutants By use of these Smd clones derived from Sm-id I strains and Sm-id II strains, respectively, Sm-id mutants were again isolated according to the approach described in Example 3a. Clones having the desired reduction of colony size were treated further.
- Campylobacter The material obtained from a Caso medium Petri dish culture that was inoculated with an Sm-id mutant in such a way that the entire surface was covered and incubated for 24h at 39°C was plated at a ratio of 1:4 on Caso medium supplemented with 100 ⁇ streptomycin/ml and incubated for 72h at 39°C. Besides the about 15 Sm resistant colonies having a "normal size" 2 to 3 small colonies could be detected. 50% of these colonies are Smd clones.
- Smd clones (derived from Sm-id I strains and Sm-id II strains, respectively) were used as starting clones - according to Example 3 ⁇ b) - for again isolating Sm-id mutants. Clones showing the desired reduction of colony size were treated further.
- Salmonella The incorporation of an advantageous MD antibiotic "res" mutation into selected Sm-id II Sm-id II mutants as an additional 5 th attenuation- and recognition marker was carried out analogously according to the approach described in Example 4(a).
- Campylobacter The incorporation of an advantageous MD antibiotic "res" mutation into selected Sm-id 1/ Sm-id II mutants as an additional 5 th
- Suspensions of the corresponding wild type strains and the MD mutants derived from these strains are diluted logarithmically and then plated on culture medium in such a way that per Petri dish 10 to 50 well definable single colonies can be obtained. At least 5 Petri dishes per grade of dilution are prepared in order to compensate for differences in growth due to the medium. Single colonies grown under standardized conditions (e.g., identical times of incubation, identical layer thicknesses of the medium) are photographed. Digital photographs are processed with the CellProfiler program (Broad Institute): The diameters of the individual colonies were determined and saved. After averaging of the values the data are plotted as bar graphs in relation to the sizes of the wild type strain colonies (given as 100%).
- vaccine strains harbouring three (four, five and six, respectively) attenuating mutations were grown in common liquid media up to logarithmic phase.
- vaccine suspensions and vaccine sediments were grown in common liquid media up to logarithmic phase.
- the vaccines obtained were administrated (according to the kind of indication one, two or three doses) by oral or parenteral administration.
Abstract
Description
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Priority Applications (19)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020157014763A KR101835946B1 (en) | 2012-12-07 | 2013-09-05 | Preparation of live vaccines |
EP18181260.3A EP3415643B1 (en) | 2012-09-05 | 2013-09-05 | Preparation of live vaccines |
EP13765974.4A EP2929058B1 (en) | 2012-12-07 | 2013-09-05 | Preparation of live vaccines |
EP20157537.0A EP3714899A1 (en) | 2012-09-05 | 2013-09-05 | Preparation of live vaccines |
PL13765974T PL2929058T3 (en) | 2012-12-07 | 2013-09-05 | Preparation of live vaccines |
CN201380063591.0A CN104995292A (en) | 2012-12-07 | 2013-09-05 | Preparation of live vaccines |
BR112015011944A BR112015011944A8 (en) | 2012-12-07 | 2013-09-05 | stable attenuated bacterial strain, its uses and method for its generation, vaccine composition |
AU2013311675A AU2013311675A1 (en) | 2012-12-07 | 2013-09-05 | Preparation of live vaccines |
NZ70915413A NZ709154A (en) | 2012-12-07 | 2013-09-05 | Preparation of live vaccines |
MX2015007195A MX368393B (en) | 2012-12-07 | 2013-09-05 | Preparation of live vaccines. |
EA201590856A EA030355B1 (en) | 2012-12-07 | 2013-09-05 | Preparation of live vaccines |
US14/440,942 US10828362B2 (en) | 2012-12-07 | 2013-09-05 | Preparation of live vaccines |
JP2015541042A JP6336461B2 (en) | 2012-12-07 | 2013-09-05 | Preparation of live vaccine |
PL18181260T PL3415643T3 (en) | 2012-09-05 | 2013-09-05 | Preparation of live vaccines |
CA2901322A CA2901322C (en) | 2012-12-07 | 2013-09-05 | Preparation of live vaccines |
ES13765974.4T ES2686325T3 (en) | 2012-12-07 | 2013-09-05 | Preparation of live vaccines |
HK16101864.3A HK1213949A1 (en) | 2012-12-07 | 2016-02-19 | Preparation of live vaccines |
AU2017219152A AU2017219152B2 (en) | 2012-12-07 | 2017-08-29 | Preparation of live vaccines |
US16/985,458 US11904008B2 (en) | 2012-12-07 | 2020-08-05 | Preparation of live vaccines |
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EP12008206 | 2012-12-07 |
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US14/440,942 A-371-Of-International US10828362B2 (en) | 2012-12-07 | 2013-09-05 | Preparation of live vaccines |
US16/985,458 Division US11904008B2 (en) | 2012-12-07 | 2020-08-05 | Preparation of live vaccines |
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Citations (6)
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DD294420A5 (en) * | 1990-05-18 | 1991-10-02 | Karl-Marx-Universitaet Leipzig,De | METHOD FOR THE PRODUCTION OF LIVESTOCK VACCINES AGAINST LISTERIOSIS |
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2013
- 2013-09-05 WO PCT/EP2013/068373 patent/WO2014037445A1/en active Application Filing
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DD294420A5 (en) * | 1990-05-18 | 1991-10-02 | Karl-Marx-Universitaet Leipzig,De | METHOD FOR THE PRODUCTION OF LIVESTOCK VACCINES AGAINST LISTERIOSIS |
WO1995007101A2 (en) * | 1993-09-04 | 1995-03-16 | Tad Pharmazeutisches Werk Gmbh | Living salmonella vaccine |
WO1999049026A1 (en) * | 1998-03-25 | 1999-09-30 | Peptide Therapeutics Limited | Bacteria attenuated by a non-reverting mutation in each of the aroc, ompf and ompc genes, useful as vaccines |
WO2004089408A2 (en) * | 2003-04-07 | 2004-10-21 | Xenova Research Limited | Vaccine preparations comprising live or killed attenuated mutant neisseria bacteria |
WO2005078068A1 (en) * | 2004-02-12 | 2005-08-25 | The University Of Queensland | Live attenuated salmonella for use as vaccine |
DE102008062941A1 (en) * | 2008-12-23 | 2010-07-01 | Universität Leipzig | New vaccine strains having two or three different attenuation active metabolic drift mutations, which result in smaller colonies with corresponding longer generation time and correlated attenuation degree |
Non-Patent Citations (3)
Title |
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LINDE K ET AL: "Stable Salmonella live vaccine strains with two or more attenuating mutations and any desired level of attenuation", VACCINE, ELSEVIER LTD, GB, vol. 8, no. 3, 1 June 1990 (1990-06-01), pages 278 - 282, XP023709951, ISSN: 0264-410X, [retrieved on 19900601], DOI: 10.1016/0264-410X(90)90058-T * |
RAFAEL ANTONIO CASARIN PENHA FILHO ET AL: "Control of Salmonella Enteritidis and Salmonella Gallinarum in birds by using live vaccine candidate containing attenuated Salmonella Gallinarum mutant strain", VACCINE, vol. 28, no. 16, 1 April 2010 (2010-04-01), pages 2853 - 2859, XP055051084, ISSN: 0264-410X, DOI: 10.1016/j.vaccine.2010.01.058 * |
SHEHATA AWAD ALI ET AL: "Safety and efficacy of a metabolic drift live attenuated Salmonella Gallinarum vaccine against fowl typhoid.", AVIAN DISEASES MAR 2013, vol. 57, no. 1, March 2013 (2013-03-01), pages 29 - 35, XP008165192, ISSN: 0005-2086 * |
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