ZA200204725B - Attenuated microorganisms for the treatment of infection. - Google Patents
Attenuated microorganisms for the treatment of infection. Download PDFInfo
- Publication number
- ZA200204725B ZA200204725B ZA200204725A ZA200204725A ZA200204725B ZA 200204725 B ZA200204725 B ZA 200204725B ZA 200204725 A ZA200204725 A ZA 200204725A ZA 200204725 A ZA200204725 A ZA 200204725A ZA 200204725 B ZA200204725 B ZA 200204725B
- Authority
- ZA
- South Africa
- Prior art keywords
- microorganism
- gene
- mutation
- disrupts
- salmonella
- Prior art date
Links
- 244000005700 microbiome Species 0.000 title claims description 38
- 208000015181 infectious disease Diseases 0.000 title claims description 9
- 230000002238 attenuated effect Effects 0.000 title description 13
- 230000035772 mutation Effects 0.000 claims description 36
- 108090000623 proteins and genes Proteins 0.000 claims description 32
- 229960005486 vaccine Drugs 0.000 claims description 25
- 241000607142 Salmonella Species 0.000 claims description 19
- 101100533947 Mus musculus Serpina3k gene Proteins 0.000 claims description 16
- 101100257418 Mus musculus Serpina3n gene Proteins 0.000 claims description 16
- 239000000427 antigen Substances 0.000 claims description 14
- 108091007433 antigens Proteins 0.000 claims description 14
- 102000036639 antigens Human genes 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- 101100533513 Salmonella typhimurium (strain LT2 / SGSC1412 / ATCC 700720) sifA gene Proteins 0.000 claims description 9
- 230000014509 gene expression Effects 0.000 claims description 9
- 102000004169 proteins and genes Human genes 0.000 claims description 9
- 101150074451 clpP gene Proteins 0.000 claims description 6
- 101150043719 clpP1 gene Proteins 0.000 claims description 5
- 101150102296 clpP2 gene Proteins 0.000 claims description 5
- 101150091444 ompR gene Proteins 0.000 claims description 5
- 101100311043 Salmonella typhimurium (strain LT2 / SGSC1412 / ATCC 700720) sseC gene Proteins 0.000 claims description 4
- 101100131762 Streptococcus sanguinis ssaB gene Proteins 0.000 claims description 4
- 230000007918 pathogenicity Effects 0.000 claims description 4
- 101150055060 spiC gene Proteins 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 101150075472 ycf27 gene Proteins 0.000 claims description 4
- 101100216993 Bacillus subtilis (strain 168) aroD gene Proteins 0.000 claims description 3
- 208000035143 Bacterial infection Diseases 0.000 claims description 3
- 101100311022 Salmonella typhimurium (strain LT2 / SGSC1412 / ATCC 700720) ssaT gene Proteins 0.000 claims description 3
- 208000037386 Typhoid Diseases 0.000 claims description 3
- 101150042732 aroC gene Proteins 0.000 claims description 3
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 201000008297 typhoid fever Diseases 0.000 claims description 3
- 208000005176 Hepatitis C Diseases 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 208000005252 hepatitis A Diseases 0.000 claims description 2
- 208000002672 hepatitis B Diseases 0.000 claims description 2
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 claims 1
- 230000009885 systemic effect Effects 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 238000012217 deletion Methods 0.000 description 5
- 230000037430 deletion Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 210000000349 chromosome Anatomy 0.000 description 4
- 230000005847 immunogenicity Effects 0.000 description 4
- 229940125575 vaccine candidate Drugs 0.000 description 4
- 208000036142 Viral infection Diseases 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- 230000001018 virulence Effects 0.000 description 3
- 241000282412 Homo Species 0.000 description 2
- 101000599573 Homo sapiens InaD-like protein Proteins 0.000 description 2
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 101150037081 aroA gene Proteins 0.000 description 2
- 101150040872 aroE gene Proteins 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000012224 gene deletion Methods 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 238000005215 recombination Methods 0.000 description 2
- 230000006798 recombination Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 208000026426 spleen abscess Diseases 0.000 description 2
- -1 ssal Proteins 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000013598 vector Substances 0.000 description 2
- 101150096316 5 gene Proteins 0.000 description 1
- 101100163490 Alkalihalobacillus halodurans (strain ATCC BAA-125 / DSM 18197 / FERM 7344 / JCM 9153 / C-125) aroA1 gene Proteins 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 241001167018 Aroa Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 101100491986 Emericella nidulans (strain FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139) aromA gene Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 241000589989 Helicobacter Species 0.000 description 1
- 241000701806 Human papillomavirus Species 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 102100037978 InaD-like protein Human genes 0.000 description 1
- 108091029795 Intergenic region Proteins 0.000 description 1
- 108010036940 Levansucrase Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 206010039438 Salmonella Infections Diseases 0.000 description 1
- 101100532775 Salmonella typhimurium (strain LT2 / SGSC1412 / ATCC 700720) sctL2 gene Proteins 0.000 description 1
- 101100422342 Salmonella typhimurium (strain LT2 / SGSC1412 / ATCC 700720) ssaM gene Proteins 0.000 description 1
- 101100422343 Salmonella typhimurium (strain LT2 / SGSC1412 / ATCC 700720) ssaO gene Proteins 0.000 description 1
- 101100311018 Salmonella typhimurium (strain LT2 / SGSC1412 / ATCC 700720) ssaQ gene Proteins 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 235000011941 Tilia x europaea Nutrition 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 101150102858 aroD gene Proteins 0.000 description 1
- 101150108612 aroQ gene Proteins 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- 239000013599 cloning vector Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007852 inverse PCR Methods 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 229960001443 live attenuated oral typhoid Drugs 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000009711 regulatory function Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000003938 response to stress Effects 0.000 description 1
- 101150025220 sacB gene Proteins 0.000 description 1
- 206010039447 salmonellosis Diseases 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 101150094761 ssaB gene Proteins 0.000 description 1
- 101150116294 ssaJ gene Proteins 0.000 description 1
- 101150012196 ssaP gene Proteins 0.000 description 1
- 101150020648 sseC gene Proteins 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 229940104152 vivotif Drugs 0.000 description 1
Classifications
-
- 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
Description
ATTENUATED MICROORGANISMS FOR THE TREATMENT OF INFECTION i Field of the Invention
This invention relates to attenuated microorganisms that can be used in vaccine & 5 compositions for the prevention or treatment of bacterial or viral infections.
It is well established that live attenuated micro-organisms are highly effective vaccines; immune responses elicited by such vaccines are often of greater magnitude and of longer duration than those produced by non-replicating immunogens. One explanation for this may be that live attenuated strains establish limited infections in the host and mimic the early stages of natural infection. In addition, unlike killed preparations, live vaccines are able to induce potent cell-mediated responses which may be connected with their ability to replicate in antigen-presenting cells, such as macrophages.
There has been a long history of the use of live attenuated Salmonella vaccines as safe and effective vaccines for the prevention of salmonellosis in animals and humans. Indeed, the live attenuated oral typhoid vaccine, Ty21a (Vivotif), manufactured by the Swiss Serum Vaccine Institute, has proved to be a very successful vaccine for the prevention of typhoid fever and has been licensed in many countries ‘ 20 including the US and Europe.
However, the attenuation of this strain was achieved using chemical mutagenesis techniques and the basis of attenuation of the strain is not fully understood. Because of this, the vaccine is not ideal in terms of the number of doses (currently four) and the number of live organisms that have to be given at each dose.
Modern molecular biology techniques, coupled with the increasing knowledge of Salmonella pathogenesis, has led to the identification of several genes that are essential for the in vivo growth and survival of the organisms. This has provided new gene targets for attenuation, leading to the concept that future vaccine strains can be ‘rationally’ attenuated by introducing defined non-reverting mutations into selected > 30 genes known to be involved in virulence. This will facilitate the development of improved vaccines, particularly in terms of the immunogenicity and therefore the
J number of doses that have to be given.
Although many attenuated strains of Salmonella are now known, few have qualified as potential vaccine candidates for use in humans. This may be due in part
’ to the need to balance the immunogenicity of the vaccine with the possibility of the
Salmonella microorganism becoming reactive. a It is clear that the selection of appropriate targets for attenuation which will result in a suitable vaccine candidate, is not straightforward and cannot easily be predicted. bi 5 Many factors may influence the suitability of the attenuated strain as an appropriate vaccine, and there is much research being carried out to identify suitable strains. For example, many attenuated strains tested as vaccine candidates lead to vaccinemia or abscesses in the patient.
It is therefore desirable to develop a vaccine having a high degree of immunogenicity with reduced possibility of the microorganism strain reverting to an reactive form.
The present invention is based on the finding that several combinations of attenuating mutations introduced into a Salmonella microorganism can produce a vaccine having a high degree of immunogenicity and a low risk of the microorganism reverting to a reactive form. The resulting vaccine strains exhibit good side-effect profiles.
According to a first aspect of the invention, a Salmonella microorganism has an attenuating mutation which disrupts the expression of a gene located within the Spi2 pathogenicity island, and a further mutation which disrupts the expression of any of the genes cIpP, ompR, sifA, sseC or ssaB.
According to a second aspect of the invention, a Salmonella microorganism has an attenuating mutation which disrupts the expression of an aro gene, and a further mutation which disrupts the expression of any of the genes clpP or sifA.
The Salmonella microorganisms may be used in the manufacture of a medicament for intravenous or oral delivery for the treatment of a bacterial or viral infection, e.g. for the treatment of typhoid.
The microorganisms and vaccine compositions of the present invention may be & 30 prepared by known techniques.
The choice of particular Salmonella microorganism and the selection of the
J appropriate mutation, can be made by the skilled person without undue experimentation. A preferred microorganism is Salmonella typhimurium. \
’ A first set of mutants comprises a first mutation in a gene located within the region of the Salmonella pathogenicity island two (Spi2); this region is disclosed in 0 WO-A-9617951.
Spi2 is one of two classical pathogenicity islands located on the Salmonella ¥ 5 chromosome. Spi2 comprises several genes that encode a type lll secretion system involved in transporting Spi2-encoded virulence-associated proteins (so-called effector proteins) outside of the Salmonella bacteria and potentially directly into target host cells such as macrophages. Part of Spi2 (the apparatus genes) encodes the secretion apparatus of the type lil system. Spi2 is absolutely essential for the pathogenesis and virulence of Salmonella in the mouse, an observation now documented by several different groups around the world. S. typhimurium Spi2 mutants are highly attenuated in mice challenged by the oral, intravenous and intraperitoneal routes of administration.
In a preferred embodiment, the gene in the Spi2 region is an apparatus gene.
Apparatus genes located within Spi2 are now well characterised; see for example
Hensel et al., Molecular Microbiology, (1997); 24(1): 155-167. Genes suitable for use in the present invention include ssaV, ssaJ, ssaK, ssal, ssaM, ssaO, ssaP, ssaQ, ssaR, ssaS, ssaT, ssal and ssaH genes.
The mutation in the Spi2 region does not necessarily have to be within a gene to disrupt the function. For example, a mutation in an upstream regulatory region may also disrupt gene expression, leading to attenuation. Mutations in an intergenic region may also be sufficient to disrupt gene function.
In a preferred embodiment of the invention, the Spi2 gene is ssaV and the further mutation disrupts any of cipP, ompR, sifA or sseC. In a separate preferred embodiment, the mutation disrupts ssaT and the further mutation disrupts ssaB.
The clpP gene is described in Gifford et al., Gen. Microbiol., 1993; 139:913-920.
The encoded protein is a stress-response protease. :
The ompR gene is described in Chatfield et al., Infection and Immunity, 1991: 59(1): 449-452. The encoded protein is a component of a two-component system (OmpR-EnvZ) with a global regulatory function, and is also a regulator for the two- a 30 component system ssrA-ssrB in Spi2 (Lee et al., J. Bacteriol., 2000; 182(3): 771-781).
The sseC gene is described in Medina et al., Infection and Immunity, 1999:
J 67(3): 1093-1099. The function of the encoded product is unknown.
o ’ ’ The ssaB gene is described in Hensel, Molecular Microbiology, 2000; 36(5):1015-1023. The encoded product is a known substrate protein for Spi2, and . interacts with normal endosomal trafficking in macrophages.
A second separate set of mutants comprise a first mutation that disrupts an aro ¥ 5 gene. This mutation may be termed an "auxotrophic mutation" as the aro gene is essential in a biosynthetic pathway present in Salmonella, but not present in mammals.
Therefore, the mutants cannot depend on metabolites found in the treated patient to circumvent the effect of the mutation. Suitable genes for the auxotrophic mutation, include aroA, aroC, aroD and aroE. In the preferred embodiment, aroC is disrupted.
The second mutation disrupts any of the clpP or sifA genes. ClpP is described above. The sifA gene is described in Stein et al., Mol. Microbiol., 1996; 20(1):151-164 and Beuzon ef al, EMBO J., 2000; 19(13): 3235-3249. The sifA gene product is involved in the production in epithelial cells of lysosomal glycoprotein-containing structures.
The mutations may be introduced into the microorganism using any known technique. Preferably, the mutation is a deletion mutation, where disruption of the gene is caused by the excision of nucleic acids. Alternatively, mutations may be introduced by the insertion of nucleic acids or by point mutations. Methods for introducing the mutations into the specific regions will be apparent to the skilled person.
For example, gene deletions may be created by first amplifying the target gene plus flanking DNA using PCR and a high fidelity polymerase. The amplified product may then be cloned into a suitable cloning vector. PCR primers can be designed to delete the gene when used in inverse PCR, to generate an initial construct. The PCR primers may contain an Xbal site to introduce a new restriction site and thus provide a marker for the gene deletion. The deletion construct can then be transferred to a suicide vector for transfer to the Salmonella chromosome. This construct can be electroporated or conjugated into the desired strain, and recombinants containing the plasmid integrated into the chromosome at the homologous site (merodiploids), selected using an antibiotic resistance marker carried on the plasmid. The suicide - 30 vector may also contain the sacB gene that encodes the enzyme levan sucrase, which is toxic to most Gram-negative bacteria in the presence of sucrose. Sucrose selection
J may therefore be employed to isolate colonies where a second recombination event has occurred, resulting in loss of the plasmid from the chromosome. This second recombination event can result in two outcomes, re-generation of the wild-type allele
’ | or generation of a deletion mutant. Colonies containing the deletion mutation may then be identified by colony-PCR and the deletion confirmed by Southern blot analysis. @ In addition to the two mutations, the Salmonella microorganism may also comprise heterologous antigens. The attenuated microorganism can therefore act as é 5 a delivery vehicle for administering antigens against other bacterial or viral infections.
Antigens which are suitable for use in this way will be apparent to the skilled person and include:
Pathogenic E. coli antigens, i.e. ETEC
Hepatitis A, B and C antigens
Lime disease antigens
Vibrio cholera antigens
Helicobacter antigens
Herpes Simplex virus antigens
Human papilloma virus antigens
This system also has the potential to deliver therapeutic proteins, peptides or nucleic acids for the treatment of patients, e.g. patients infected with hepatitis.
Cytokines are an example of suitable therapeutic proteins which may be delivered by the mutant microorganisms. Methods for the delivery of heterologous antigens or therapeutic proteins using the vaccine compositions will be apparent to the skilled person.
Vaccines made using the microorganisms of the invention have application to the treatment of infections in human patients and in the treatment of veterinary infections.
The double mutation provides an effective means to attenuate the microorganism to provide a safe vaccine candidate.
The vaccine compositions provide effective protection even in immuno- compromised patients, and importantly offer a low risk in developing spleen abscesses.
Spleen abscesses have been identified using vaccines based on a single mutation, and therefore the present compositions may offer a substantial benefit to patients. « 30 To formulate the vaccine compositions, the mutant microorganisms may be present in a composition together with any suitable pharmaceutically acceptable
W adjuvant, diluent or excipient. Suitable formulations will be apparent to the skilled person. The formulations may be developed for any suitable means of administration.
Preferred administration is via the oral or intravenous routes and the vaccines are live attenuated Salmonella microorganisms. The number of microorganisms that are
’ ’ required to be present in the formulations can be determined and optimised by the skilled person. However, in general, a patient may be administered approximately 107- . 10° CFUs of the microorganism, preferably approximately 108-10° CFUs per single dosage unit.
X 5
Sd
JF
Claims (14)
1. A Salmonella microorganism having an attenuating mutation which disrupts the " expression of a gene located within the Spi2 pathogenicity island, and a further
S. mutation which disrupts the expression of any of the genes clpP, ompR, sifA, sseC and pb 5 ssaB.
2. A Salmonella microorganism having an attenuating mutation which disrupts the expression of an aro gene, and a further mutation which disrupts the expression of any of the genes clpP and sifA.
3. A microorganism according to claim 2, wherein the aro gene is aroC.
4. A microorganism according to claim 1, wherein the Spi2 gene is ssaV, and the further mutation disrupts clpP, ompR, sifA or sseC.
5. A microorganism according to claim 1, wherein the Spi2 gene is ssaT, and the further mutation disrupts ssaB.
6. A microorganism according to any preceding claim, which further comprises a heterologous antigen or a therapeutic protein.
7. A microorganism according to claim 6, wherein the antigen is a hepatitis A, B or C antigen.
8. A microorganism according to any preceding claim, wherein the microorganism is Salmonella typhi Ty2.
9. A microorganism according to any preceding claim, for use in therapy.
10. A vaccine composition comprising a microorganism according to any of claims 1 to 8, an adjuvant and a physiologically acceptable diluent.
11. A composition according to claim 10, comprising from 107-10'° CFUs of the microorganism per dosage unit.
12 A composition according to claim 11, comprising 10%-10° CFUs of the microorganism per dosage unit.
13. Use of a microorganism as defined in any of claims 1 to 8, in the manufacture of a medicament for the treatment of systemic bacterial infection.
14. Use according to claim 13, wherein the infection is typhoid. op 30 i
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9930455.2A GB9930455D0 (en) | 1999-12-23 | 1999-12-23 | Vaccine compositions |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200204725B true ZA200204725B (en) | 2003-07-30 |
Family
ID=10866909
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200204725A ZA200204725B (en) | 1999-12-23 | 2002-06-12 | Attenuated microorganisms for the treatment of infection. |
Country Status (2)
Country | Link |
---|---|
GB (1) | GB9930455D0 (en) |
ZA (1) | ZA200204725B (en) |
-
1999
- 1999-12-23 GB GBGB9930455.2A patent/GB9930455D0/en not_active Ceased
-
2002
- 2002-06-12 ZA ZA200204725A patent/ZA200204725B/en unknown
Also Published As
Publication number | Publication date |
---|---|
GB9930455D0 (en) | 2000-02-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7887816B2 (en) | Attenuated microorganisms for the treatment of infection | |
KR100202771B1 (en) | Live vaccine | |
JP3024982B2 (en) | Live bacterial vaccine | |
Paterson et al. | Recent advances in the field of Salmonella Typhi vaccines | |
EP1129196B1 (en) | Virulence genes and proteins, and their use | |
US20030059442A1 (en) | Attenuated microorganisms for the treatment of infection | |
KR20040101258A (en) | Bacterial spores | |
ZA200204725B (en) | Attenuated microorganisms for the treatment of infection. | |
WO1999059630A9 (en) | Type iii bordetella secretion system | |
KR101797276B1 (en) | Multiple mutated Salmonella Typhimurium and vaccine composition for prevention of food poisoning | |
PL203551B1 (en) | Salmonella microorganism, vaccine composition containing the Salmonella microorganism and use of the Salmonella microorganism |