EP3074418A2 - Composition vaccinale pour la prevention et/ou le traitement de leishmanioses, peptides immunogenes et procede d'obtention - Google Patents
Composition vaccinale pour la prevention et/ou le traitement de leishmanioses, peptides immunogenes et procede d'obtentionInfo
- Publication number
- EP3074418A2 EP3074418A2 EP14830587.3A EP14830587A EP3074418A2 EP 3074418 A2 EP3074418 A2 EP 3074418A2 EP 14830587 A EP14830587 A EP 14830587A EP 3074418 A2 EP3074418 A2 EP 3074418A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- psar
- psa
- leu
- ser
- ala
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
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Classifications
-
- 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
- A61K39/002—Protozoa antigens
- A61K39/008—Leishmania antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/44—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from protozoa
-
- 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 subject of the invention is a vaccine composition for the prevention and / or treatment of leishmaniases in mammals. It also relates to immunogenic peptides and their production process.
- Leishmaniases are among the most serious parasitic infections affecting humans in the world. Three hundred and fifty million people are exposed in eighty - eight countries spread over four of the five continents, and sixteen million of them carry the parasite. They are responsible for a broad spectrum of clinical manifestations: cutaneous, mucocutaneous and visceral.
- Visceral leishmaniasis is caused by parasites of the Leishmania donovani complex (L. infantum, L. chagasi and L. donovani) which are intracellular parasites of the macrophage.
- Leishmania donovani complex Unlike other Leishmania species causing the integumentary forms of the disease (L. major, L. brasiliensis, ...) that affect the dermis or mucous membranes, leishmanias of the donovani complex have an ability to spread to all deep organs (liver, spleen, ganglion and bone marrow) where they multiply.
- Visceral leishmaniasis also affects the canine population, which is a reservoir of parasites supplying the cycle of transmission continuously. It is due to L. infantum / chagasi, a species responsible for a zoonosis of domestic and wild canids widespread throughout the world. It affects millions of dogs in Europe, Asia, North Africa and South America. Symptomatic dogs, but also asymptomatic, constitute a source of parasites for the transmission of LV in humans.
- first-generation vaccines based on the use of whole attenuated or dead parasites (including autoclaved), combined or not with adjuvants, were intended primarily to protect against cutaneous leishmaniases by trying to reproduce the levels of protection obtained with live parasites.
- first-generation vaccines based on the use of whole attenuated or dead parasites (including autoclaved), combined or not with adjuvants, were intended primarily to protect against cutaneous leishmaniases by trying to reproduce the levels of protection obtained with live parasites.
- first-generation vaccine or recombinant (second-generation vaccine) native proteins have been tested. Some vaccine candidates have given a good level of protection against experimental infection. the mouse.
- third-generation DNA vaccines have been developed with the nucleotide sequences encoding the proteins used in second generation vaccines (References 1, 2 and 3).
- mice have been successfully explored in mice, such as the antigens based on antigens present in sandfly saliva (References 4 and 5), which have made it possible to obtain relative resistance to experimental infection. at Leishmania major.
- LEISH-Fl consisting of 3 recombinant fusion proteins (TSA-LmSTI1-LelF) formulated with a monophosphorylated lipid and squalene in a stable emulsion (MPL-SE).
- TSA-LmSTI1-LelF 3 recombinant fusion proteins
- MPL-SE monophosphorylated lipid and squalene in a stable emulsion
- CaniLeish® which is a product composed of secretion excretion antigens (AES) of L. infantum promastigotes (based on WO 9426899 and its extensions, on behalf of IRD). Canine leishmaniasis thus sees its preventive measures profoundly modified and completed.
- AES secretion excretion antigens
- Vaccination not only controls the development of the disease, but also significantly decreases the parasite load in the dog and thus contributes to the interruption of the transmission cycle of LV in sandflies, dogs and humans.
- the solution provided by the invention is based on the work carried out by some of the co-inventors on the major immunogen naturally secreted excreted antigens (AES).
- the invention therefore aims to use, as a vaccine molecule, a PSA, as obtained by implementing said strategy and / or the use of a part of this molecule, and their applications. prophylactic and / or immunotherapeutic agents in mammals.
- the invention also aims, as new molecules, major immunogens of AES, and a portion of these immunogens, as produced according to the method of the invention.
- the invention is further directed to a preventive and / or therapeutic vaccine composition comprising such an immunogenic molecule and / or a part of this molecule and the antibodies directed against this molecule.
- the invention thus relates to the use, as a vaccine molecule in a mammal, of a PSA such as leishmania, or a part of this PSA, hereinafter referred to as ES PSAR, having immunogenic properties, said PSA is presenting in soluble, native, recombinant form.
- a PSA such as leishmania
- ES PSAR a part of this PSA
- Soluble PSA refers to soluble PSA excreted / secreted into leishmania culture supernatant.
- “Native PSA” refers to a PSA as produced in a culture supernatant by a leishmania, comprising the co- and post-translational modifications of a PSA such as leishmania, or a part of this PSA having immunogenic properties, said PSA, hereinafter referred to as ES PSAr, being in soluble form, native in conformation, recombinant or a part of such PSA.
- Recombinant PSA refers to a PSA as expressed by genetic recombination, integrated into the genome of the host cells of the expression system.
- E PSAr generally means a PSA of leishmania, in soluble, native, recombinant form or a part of such PSA.
- the PSA sequence comprises a signal peptide involved in the secretory pathways located at the end of the amino-terminal part of the molecule, a variable number of repeat domains rich in leucine (LRR motifs, for "Leucine”). Rich Repeats ”) and a carboxy-terminal portion of the proline-rich molecule, threonine and cysteine (see Figure 1).
- the end of the carboxy terminal part comprises a hydrophobic anchoring signal GPI or anchor GPI (Glycosyl Phosphatidyl Inositol).
- PSA also has the particularity of being present in all species of leishmania (integumentary and visceral), which represents a real advantage in terms of cross-vaccination vis-à-vis the different clinical expressions of leishmaniasis.
- the invention relates to the use of the entire ES PSAr molecule.
- the term "whole PSAr PS” means that the protein possesses the co- and post-translational modifications of the native molecule, as produced by the parasite and is not truncated.
- the invention aims to use an ES PSAr that does not include all the co- and post-translational modifications.
- the invention relates to the use of a deglycosylated ES PSAr.
- the use according to the invention comprises a glycosylated PSAR PS.
- the invention relates to the use of an ES PSAr devoid of the GPI anchor of the hydrophobic part in the C-terminal end. In another variant embodiment, the invention relates to the use of a PS PS ES devoid of the carboxy terminal part.
- the invention relates to the use of the C-terminal part of a PSA or ES PSAr molecule (hereinafter referred to as C-ter PSA or Oter ES PSAr) as isolated of a leishmaniasis culture excretion / secretion supernatant.It is a non-native molecule, as encoded by a truncated DNA sequence of PSA or ES PSAr
- the invention relates to the use as a vacant molecule of an ES PSAr as obtained from the PSA of L. amazonensis or a leishmania donovani complex, especially L. infantum or L. donovani, or the complex braziliensis and tropica.
- the invention thus aims in particular at using an ES PSAr of sequence SEQ ID No. 1.
- This ES PSAr is obtained more particularly from the PSA produced by L. amazonensis deleted from its hydrophobic membrane anchoring peptide.
- the ES PSAr is more particularly obtained from the PSA of L. infantum of sequence SEQ ID No. 2 or L. donovani of sequence SEQ ID No. 3, these sequences also being deleted at the carboxy-terminal end of their hydrophobic membrane anchoring peptide.
- the vaccine molecule used may correspond to a part of the ES PSAr, in particular at the C-terminal end.
- Such a molecule has in particular the sequence SEQ ID No. 4.
- the invention relates to the use, as a vaccine molecule, of an ES PSAr in soluble form, as produced by insertion of a vector comprising the gene encoding ES PSAr into a eukaryotic recombinant leishmanian expression system.
- the recombinant expression system used is that of a nonpathogenic leishmania in mammals.
- the invention is particularly directed to the use, as a vaccine molecule, of ES PSAr in soluble form, as produced by insertion of the gene encoding ES PSAr, into a eukaryotic recombinant expression system consisting of Leishmania tarentolae or alternatively of the gene coding for a part of ES PSAr, in particular a part devoid of its hydrophobic part as indicated above.
- this system allows the integration of the expression vector containing the gene coding for ES PSAr in the 18S rRNA locus of the chromosome of Leishmania tarentolae which has a very high transcription rate and thus the obtaining of an abundant amount of the ⁇ recombinant.
- the protein can be produced with all or part of the co- and post-translational modifications of Leishmania proteins.
- the invention also relates to a method for producing ES PSAr in soluble form, comprising the characteristics defined above.
- this method comprises the integration of an expression vector comprising the gene encoding ES PSAr in a non-pathogenic eukaryotic recombinant system for humans or animals.
- the transfection by the vector is carried out in the locus of a chromosome of a non-pathogenic leishmania having a high level of transcription.
- a particularly suitable leishmania is L. tarentolae, at the promastigote stage.
- the insertion in the 18 s rRNA locus of the chromosome whose transcription rate is high makes it possible to obtain high production yields.
- the expression vector used is advantageously a plasmid.
- pF4X1.4 is particularly suitable for the implementation of the invention. Sequences necessary for post-translational modifications in L. tarentolae are introduced on both sides of the cloning cassette.
- the ES PSAr protein thus produced is a soluble protein in leishmania culture supernatants, possessing the properties of the native protein, in particular one or more of the co- and posttranslational modifications of Leishmania proteins, such as acetylation, hydroxylation, disulfide bridges, glycylation, glycosylation, phosphorylation, lipid anchoring and the like.
- deglycosylated ES PSAr in one variant of the invention, is produced from the culture of the promastigote forms of L. tarentolae in the presence of tunicamicyne.
- Tunicamycin is an antibiotic that inhibits the GlcNAc phosphotransferase (GPT) enzyme. It thus inhibits the N-glycosylation necessary for fixing the precursors of N-glycosides on the dolichol diphosphate (see FIG. 3).
- the culture of L. tarentolae promastigote transgenes is advantageously carried out in the fully defined culture medium as described in the aforementioned international application in the name of IRD and its extensions, which makes it possible to recover PSA produced without serum contaminants. and cell provided by conventionally used culture media,.
- a purification step can be carried out for example by chromatography of gel affinity.
- the production of the C-ter portion of PSA is advantageously carried out in a recombinant bacterial system, followed preferably by a purification step.
- the expression vector used which comprises the cDNA of the gene coding for the carboxy-terminal part of PSA, is in particular a plasmid.
- a plasmid construct suitable for carrying out the invention comprises the elements for producing a recombinant protein with a 6-Histidine tag in position
- the colonies producing the desired recombinant proteins are selected and after amplification in culture are advantageously purified.
- the invention is directed in particular to a glycosylated PSAR PS or alternatively a deglycosylated PSAr ES.
- ES PSAr a deleted ES PSAr, in particular devoid of the GPI anchor and therefore the hydrophobic peptide in the C-terminal position, which makes it possible to avoid aggregation phenomena and the formation of inclusion bodies during production. from ES PSAr.
- the invention aims as a new product, the molecule consisting of the C-ter PSA portion of the protein as defined above.
- ES PSAR protein as well as its carboxy-terminal part (C-ter PSA), in combination with an adjuvant, confer in the dog a very high level of protection against an experimental infection. to L. infantum.
- the examples also show a protective and induced immuno-reaction on human cells, which confirms the results obtained in dogs and allows to consider the development of a human vaccine.
- This immunoreactivity is accompanied by the production TH1-type cytokines and a T-cytotoxic response evidenced by the production of granzyme B.
- the invention therefore also relates to a vaccine composition for the prevention and / or treatment of leishmaniases in humans or animals, characterized in that it comprises:
- an ES PSAr protein in soluble form, of leishmania and / or a truncated ES PSAr, in particular depicted from the GPI anchor, and / or the C-ter peptide portion of PSA such as leishmania, or ES PSAr and
- one or more adjuvants and / or one or more immunomodulators are provided.
- the adjuvant is advantageously chosen from those capable of inducing a cell-mediated response leading to the elimination of the parasite.
- Suitable adjuvants include those of the TLR3, TLR4, TLR5, TLR7, TLR8, TLR9 classes, saponins and their derivatives, oil-in-water or water-in-oil emulsions, polysaccharides, cationic liposomes, virosomes or polyelectrolytes.
- Suitable immunomodulators include phlebotomy saliva proteins, cytokines and heat shock protein (HSP).
- the vaccine composition of the invention is particularly in a form allowing administration by different routes, such as the subcutaneous, intradermal, intramuscular, parenteral, oral, endonasal or mucosal route.
- the vaccine composition defined above is especially suitable for the manufacture of a drug or a vaccine, an in vivo or in vitro diagnostic reagent for the induction or diagnosis in mammals of cell-mediated immunity dependent on Th1-type lymphocytes and / or humoral effector immunity.
- composition is suitable for induction or diagnosis in the mammal of the passage from a Th2 type immune state to a Th1 type immune state, or for the induction or diagnosis in the mammal of isotype specific antibodies.
- Such antibodies and the antisera containing them also form part of the invention.
- FIGS. 1 to 18, which represent, respectively,
- FIG. 1 a schematic representation of the Leishmania PSA protein
- FIG. 2 the polypeptide analysis of purified ES PSAr in SDS-PAGE gel (reducing and non-reducing conditions
- FIG. 4 the polypeptide analysis of C-ter PSA (SEQ ID NO: 4) purified in SDS-PAGE gel (reducing and non-reducing conditions,
- FIG. 5 Electrophoretic analysis of ES PSAr soluble glycoproteins (SEQ ID NO: 1 deglycosylated (1 and 3), native ES PSAR (2 and 4)),
- FIG. 6 IgG2 versus AES ELISA expressed in optical density (OD)
- FIG. 7 IgG2 versus ES PSAR ELISA expressed in optical density (OD)
- FIG. 8 IgG2 versus C-ter PSA ELISA expressed in optical density (OD),
- FIG. 9 Effect of the sera of vaccinated dogs (CaniLeish®, ES PSAr and C-ter PSA) on the viability and proliferation of the promastigotes of
- T0 pre-immune sera
- T5 sera taken two months after the administration of three doses of the vaccine
- Figure 10 Neutralizing effect of anti-ES PSAr and anti-C-ter PSA monospecific polyclonal rabbit sera (used at different dilutions (1/10, 1/50 and 1/100), - Figure 11: Effect of a serum monospecific polyclonal rabbit directed against the C-ter PSA portion (carboxy-terminal portion of PSA) used at different dilutions (1/25 and 1/50) on the growth of promastigote forms of.
- FIG. 12 Evaluation, compared to a control, of the number of promastigotes / mL with concentrations of PS PS 17.8 ⁇ and 0.22 ⁇ , at different addition times,
- FIG. 13 Leishmanicidal activities of the canine macrophages of the placebo group versus the group vaccinated before (T0), one month after the administration of two doses of vaccine (T3) and two months after the injection of three doses (T5),
- Figure 14 Determination of interferon (IFN) - ⁇ levels present in the co-culture supernatants of cells from placebos and vaccinated dogs (ES PSAr or C-ter PSA).
- T0 pre-immune sera
- T5 sera taken two months after the administration of three doses of the vaccine
- Figure 15 Evaluation of the levels of nitric oxide (NO) produced in the supernatants of co-culture of the cells from placebos and vaccinated dogs (ES PSAr or C-ter PSA).
- T0 pre-immune sera
- T5 sera taken two months after the administration of three doses of the vaccine
- Figure 17 Determination of Percentages of Parasitologically Positive Dogs in Placebos and Groups of Dogs Vaccinated with C-ter PSA,
- Figure 18 Determination of parasite loads by RT-PCR in dogs of placebo and vaccinated groups.
- Example 1 Obtaining, producing and purifying recombinant proteins
- a hyperimmersum generated in the rabbit and directed against the exosproting secretion antigens (AES) of L. amazonensis promastigote and a monoclonal antibody (E2) specifically directed against the major immunogen of parasitic AES were used to screen a bank cDNA of promastigote and amastigote forms (produced in 1ZAPII) of L. amazonensis.
- sequence SEQ ID No. 1 is derived from the LaPSA38 gene coding for the entire 45 kDa (372 aa) protein which corresponds to WO 2005/051989 in the name of IRD and the sequence SEQ ID No. 4 is derived from the truncated gene.
- PSA19 which codes for the carboxy- terminal of LaPSA38. This is the C-ter PSA part, 19kDa (119 aa).
- the sequence SEQ ID No. 2 is derived from the LiJll gene.
- the LiJll gene was obtained by using the C-ter PSA sequence (radiolabeled probe) to screen a cosmid library of genomic DNA of L. infantum promastigotes, which made it possible to characterize a homologous PSA in Leishmania infantum (PSA IJll). 463 aa (50 kDa).
- PSAIJll of L. infantum exhibits strong sequence homology with that of LAPSA38s of L. amazonensis in its amino- (73.8%) and carboxy- (77.5%) terminal parts with a number of motifs. higher leucine-rich repeat (9 against 6) (in the aforementioned international application WO 2005/051989, said gene coding for the non-recombinant protein corresponds to SEQ ID No. 11 and the protein encoded in SEQ ID No. 12).
- This step is carried out with a gene expression system in L. tarentolae marketed by Jena Bioscience: “Leishmania tarentolae Gene Expression Starter Kit”.
- This expression system uses the parasite itself to produce its own protein. The latter has many advantages for the production of therapeutic proteins:
- Leishmania tarantolae is a non-pathogenic lizard parasite for humans. Its manipulation does not require any restrictive security measures;
- L. tarentolae is easily grown in cell suspension in completely defined culture media (no contamination with other foreign proteins), at 26 ° C, with a good yield (of the order of 10 cells per ml, population doubling time of 4 h.);
- This expression system makes it possible to produce proteins native to Leishmania.
- the parasite contains the machinery necessary for the expression of native eukaryotic proteins;
- the protein produced possesses all post-translational modifications of Leishmania proteins such as glycosylation and disulfide bond formation;
- the vector used in this system makes it possible to clone the gene of interest in a bacterial system and then to express the protein in Leishmania tarentolae;
- the LaPSA38s gene was amplified and then modified by site-directed mutagenesis to allow the production of a protein with a poly-histidine tag (5 histidines) partially carboxy-terminal, and delete the site of anchoring to the membrane.
- plasmids were specifically constructed to allow the production of the recombinant protein in the culture medium supernatant from which it can be easily isolated.
- This construct was transfected into Leishmania tarentolae where it was integrated into the genome of the parasite at the promastigote stage, by homologous recombination, conferring at the same time a resistance to nseothorin (NTC), to select the recombinant individuals.
- NTC nseothorin
- Overexpression is done thanks integration of the gene within the 18S rRNA locus, taking advantage of the high level of transcription of host RNA polymerase I.
- This plasmid also contains around the cloning cassette the sequences necessary for the co- and post-translational modifications in elshmania tarentolae, making it possible to obtain a protein in its native form.
- the promastigote transgenes of L. tarentolae were adapted in the completely defined medium developed by the IRD (WO application cited above and its extensions) so as to easily purify the parasite protein from the culture supernatants and to produce it in the absence of any foreign protein (molecules of serum and cellular origin).
- the purification from the culture medium supernatants of the ES PSAr thus produced was carried out by Agarose-Nickel gel affinity chromatography.
- LAPSA38snr of L. amazonensis was produced with a production yield of 0.2 to 0.3 mg of purified protein per liter of culture, sufficient to allow its use in the development of new analytical methods and its evaluation as a vaccine candidate. It corresponds to an apparent molecular weight of 45 kDa and a theoretical molecular weight of 37 kDa. It has the sequence SEQ ID No. 1 referred to above. This protein has 349 amino acids; his ft is 5.07.
- the cDNAs of the LaPSA19s gene were inserted into plasmid pQE-31.
- the plasmids were specifically constructed to allow the production of a recombinant protein having a 6-His-tag in the amino-terminal position and a tag cleavage site.
- the transformation with pQE-31-6 (His) -C00H LaPSAl9s was carried out in chemically competent E. coli M15 bacterial cells.
- the recombinant colonies were selected to produce the recombinant proteins.
- the most productive clone was amplified in culture.
- the corresponding C-ter PSA protein was purified on Agarose-Nickel gel.
- a yield of about 1 g of recombinant protein per liter of culture was obtained. It comprises 119 amino acids and has a molecular weight of 18 kDa under reducing conditions and in dimer form, under non-reducing conditions, a molecular weight of 36 kDa (see FIG. 4).
- This clinical trial reported hereinafter aims to compare in the same vaccination trial in dogs "Beagle" the protective effects of the two recombinant proteins ES PSAr and C-ter PSA on groups of 9 dogs and 5 dogs respectively.
- a placebo group of 5 dogs constitutes the control group not vaccinated.
- An experimental challenge infection is performed 2 months after the immunization protocol.
- Clinical and parasitological follow-up are carried out every 2 months until 8 months after the experimental infection.
- QA21 is used at 60 ⁇ s per vaccine dose, the equivalent amount of adjuvant used in the CaniLeish vaccine. Used alone and at this concentration, it has no significant effect on the immune system of the dog and mouse.
- the immunization protocol includes 3 injections by the subcutaneous route performed at one month intervals. Three groups of dogs were selected as follows:
- Group 1 Placebo (Physiological Injection for Injection);
- Group 2 Injection of 25 ⁇ g of LaES PSAr adjuvanted with 60 ⁇ g of QA-21;
- Group 3 Injection of 25 ⁇ g of C-ter PSA (protein of sequence SEQ ID No. 4) adjuvated with 60 of QA-21.
- T3 one month after administration of two T5 vaccine doses: two months after three doses of the vaccine.
- 3 - CLINICAL FOLLOW-UP
- An experimental challenge infection injection of 10 9 metacyclic promastigotes of L. infantum intravenously was performed 2 months after the immunization protocol. Clinical and parasitological follow-ups conducted every 2 months for 8 months after experimental infection.
- PCR and culture of bone marrow samples at T0, 2 months post-challenge (T6), 4 months post-challenge (T7), and 6 months post-challenge (T8) were performed to highlight the presence of the parasite or its DNA.
- ELISA techniques were used to analyze the antibody responses in the dogs in the study.
- the mean titers of IgG2 anti-AES, anti-ES PSAr and anti-Cter PSA antibodies were compared by ELISA between placebo dogs and vaccinated dogs before immunization (T0) and at different post-immunization times:
- the determined anti-Leishmania IgG antibody responses were negative in all dogs in the pre-immunization study and in all dogs in the T5 placebo group.
- IgG2 isotype antibodies specifically against AES (FIG. 6), ES PSAr (FIG. 7) and C-ter PSA (FIG. 8) are demonstrated in all vaccinated dogs from the first month after administration of two vaccine doses (T3) and two months after three doses of the vaccine (T5).
- Vaccine candidates do not induce anti-Leishmania IgG antibodies (antigen shown) in the dog by the indirect immunofluorescence technique (IFI, standard technique for serological diagnosis) in all vaccinated dogs (T3-negative IFI titre). and T5).
- IFI indirect immunofluorescence technique
- IgG2 isotype antibodies strongly demonstrates the induction of Th1 (protective immunity) type cellular immunity.
- Th1 protective immunity
- b - Functional biological role of antibodies produced bl- Effect of sera from vaccinated dogs (CaniLeish®, ES PSAr and C-ter PSA) on the viability and proliferation of Leishmania
- Transgenes promastigotes of L. infantum MONL ⁇ c! NEO 2 r / Luke) transfected with luciferase gene are incubated for 5 days in the absence or presence of serum (decomplementized) of placebos and vaccinated dogs. The number of parasites is determined by luminometry (RLU). The results are expressed as percentage inhibition of the proliferation of promastigotes.
- Promatigative forms were incubated in the presence of different dilutions (1/10, 1/50 and 1/100) of rabbit sera healthy or previously immunized with PSAR ES (or C-ter PSA and then washed three times by centrifugation for eliminate excess serum
- PSAR ES or C-ter PSA
- PI Parasite Index
- the leishmanicidal activities revealed by the Placébo group versus the Vaccinated group cells were evaluated before (T0) and one month after two doses of vaccine (T3) and two months after the injection of three doses ( T5).
- PCR gene amplification technique
- IgG2 isotype which seems to play a significant role in the protection (leishmanicidal and neutralizing effects); the polarization of the cell-mediated response towards a Th1-type pathway revealed by an increase in the production by IFN-gamma T lymphocytes leading to the activation by the classical macrophage pathway characterized by the increased synthesis of NO and therefore the elimination of intracellular leishmanias (leishmanicidal activity of canine macrophages).
- the immunogenicity of native recombinant PSA was evaluated on human cells by analyzing the profile of the cellular immune response generated ex vivo in humans.
- ES PSAr ability of ES PSAr to induce, ex-vivo, on human cells, a specific cell-mediated immune response by activating Thl-producing cytokine-producing T lymphocytes and / or Granzyme B from healthy donors as compared to individuals immune or healed exposed to visceral leishmaniasis L. infantum in the south of France, was evaluated. To this end, a set of immunological and parasitological methods, associated with clinical monitoring, has been set up.
- IFN-gamma ( ⁇ g / ml) in supernatants co-culturing human cells from healthy individuals (B, IND 8 to 15) and asymptomatic or cured immune individuals (A, IND there 7) exposed in southern France to visceral leishmaniasis L. infantum.
- TSLA Ldd8 total parasite extract of L. donovani promastigotes
- TSLA Ldi total parasite extract of L. infantum promastigotes.
- TSLA Ldd8 total parasite extract of L. donovani promastigotes
- TSLA Ldi total parasite extract of L. infantum promastigotes
- the analysis of the cell test results shows that the ES PSAr constituting the vaccine candidate is capable of inducing a specific Th1 type immune response, generating significant levels of IFN- gamma (Table 1), and / or a T-cytotoxic response determined by a significant production of Granzyme B (Tabeau 2) in asymptomatic or cured individuals with respect to individuals healthy.
- the results of the immunogenicity tests of the vaccine candidate ES PSAr confirm the interest of this recombinant protein to be selected to enter the composition of a vaccine against human leishmaniases.
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FR1361823A FR3014103B1 (fr) | 2013-11-29 | 2013-11-29 | Composition vaccinale pour la prevention et/ou le traitement de leishmanioses, peptides immunogenes et procede d'obtention |
PCT/IB2014/066425 WO2015079420A2 (fr) | 2013-11-29 | 2014-11-28 | Composition vaccinale pour la prevention et/ou le traitement de leishmanioses, peptides immunogenes et procede d'obtention |
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