Recombinant poxvirus and method for regulating the expression of toxic conditional gene products of said recombinant poxvirus in a producing cell

Abstract

The present invention is in the field of viral immunotherapy. The invention provides 1) an efficient recombinant poxvirus expressing a toxic conditional gene product that affects the viability of the recombinant poxvirus itself if left unregulated, or 2) a recombinant poxvirus expressing a conditional gene product with an improved safety profile, a method of producing them, a composition comprising them and therapeutic uses related thereto.

Description

[0001] RECOMBINANT POXVIRUS AND METHOD FOR REGULATING THE EXPRESSION OF TOXIC CONDITIONAL GENE PRODUCTS OF SAID RECOMBINANT POXVIRUS IN A PRODUCING CELL TECHNICAL FIELD OF THE INVENTIONThe present invention is related to 1) an efficient recombinant poxvirus expressing a toxicconditional gene product that affects the viability of the recombinant poxvirus itself ifleft unregulated or 2) a recombinant poxvirus expressing a conditional gene product withan improved safety profile, methods of producing one of them, compositions comprisingone of them and therapeutic uses related thereto.BACKGROUND ART Immunotherapy seeks to boost the host’s immune system to help the body to eradicatepathogens and abnormal cells. Widely used in traditional vaccination, immunotherapy isalso being actively investigated as a potential modality for treating severe, chronic orlife-threatening diseases in attempt to stimulate specific and innate immune responses.A vast number of immunotherapeutics have been described in the literature for decades. In particular, several viral and non-viral vectors have now emerged, all of them havingrelative advantages and limits making them more appropriate to certain indications (seefor example Cattaneo and Russell, 2017, PLOS Pathogens doi:10.1371 / journalppat.1006190; Kaufman et al., 2015, Nature Reviews Drug Discovery 14: 642-661; Gomez et al., 2013 expert Rev Vaccines 12(12): 1395-1416). A huge number of immunotherapy platforms are being evaluated in clinical trials and the number of current clinical studies based on poxvirus therapy, whether oncolytic or not, reflects theirinteresting therapeutic potential. For example, recombinant vaccinia virus (VV)-basedvectors are attractive candidates for their excellent safety profile and their capacity to combine robust cellular antigen-specific immune responses with a generalized stimulation of the innate immune system. Recombinant virus, including recombinant poxviruses represent an emerging therapeutic platform for the treatment of cancers because of their advantages over conventional therapeutic modalities, such as for example chemotherapy. For example, recombinant poxviruses can selectively replicate in cancer cells, while sparing normal cells and tissues,thus limiting off-target cell killing and toxicities and thereby offer levels of potency andspecificity that are potentially far higher than conventional cancer treatments. Modifications of the naturally occurring poxviruses have already been practiced in order to enhance the ability of poxviruses to infect and lyse 100% of the tumor cells, which isdifficult to achieve in in vivo context. For this purpose, many strategies are currentlyused to modify the viruses (e.g.: tropism modification to redirect virus to the cancer cell surface). Oncolytic poxviruses are often “armed” with enzyme-prodrug systems that enhance the oncolytic efficacy of the virus therapy by exerting a strong bystander effect and thus permit elimination of neighboring uninfected tumor cells. For example, armement with the so-called FCU1 suicide gene, encoding a bifunctional chimeric polypeptide that combines the enzymatic activities of FCY1 and FUR1, efficiently catalyzed the direct conversion of 5-fluorocytosine (5-FC), a nontoxic antifungal agent, into the toxic metabolites 5-fluorouracil (5-FU) and 5-fluorouridine-5'monophosphate (5- FUMP), thus bypassing the natural resistance of certain human tumor cells to 5- fluorouracil (Erbs et al., 2000, Cancer Res., 60(14): 3813-22). Foloppe et al. showed thata VACV expressing the FCU1 gene has potent anti-tumor effect both in vitro and in vivoin a murine model of a human colon tumor (Foloppe et al., 2008, Gene Ther., 15:1361– 1371). The vaccinia viruses expressing the FCU1 fusion suicide gene, combined with the administration of the 5-fluorocytosine (5-FC) prodrug, displayed a highly potent anti-tumor effect both in vitro and in vivo. The potential of FCU1 delivered by an oncolyticcowpox virus as therapeutic agent was also explored (Ricordel et al., 2017, MolecularTherapy – Oncolytics, 7: 1-11). The cowpox viruses expressing the FCU1 fusion suicidegene, combined with the administration of the prodrug, also displayed an anti-tumor effect in vitro. Recombinant poxvirus and method for regulating the expression of toxic conditional gene products of said recombinant poxvirus in a producing cellWhile recombinant poxviruses are a versatile platform well suited for transgenevectorization and with approved safety profile, the expression of certain heterologousgenes from the viruses can be deleterious to the virus itself or cytotoxic to the packagingcell (Jason et al., 2007, Molecular biotechnology, Vol. 35, 263). Concerning the virusitself, some heterologous genes render the recombinant poxviruses also geneticallyunstable and led to an accumulation of the recombinant poxviruses with impaired expression, challenging the upscale and manufacture of recombinant poxviruses(Neckermann et al. 2024, Immunology, 15:1338492). This instability induced by thetransgene expression of the recombinant poxviruses is also a common issue in the field(Wyatt et al. 2009, Journal of Virology, 83(7176); Wyatt et al., 2008, Virology 372:260-72; Wang et al. 2010, Vaccine, 28:1547-57). As also mentioned by Colloca et al., thereare also several evidences indicating that the high transgene expression in the cell ofproduction can interfere with the virus replication (Colloca et al., 1999, Proc Natl AcadSci U S A., 96(6):2615-20). Recently, a novel curative approach against tumors has gained a wide interest as it mayovercome some issues related to the use of chemotherapy such as aspecificity, highdosages with accompanying side effects and chemoresistance induction. Cancer therapymay be thus approached using immunotoxins as suicide genes that can induce at a verylow level of expression cell death, damaging in most cases the translation machinery ofquiescent or proliferating cells (Ardini et al., 2022, Toxins, 14(9): 579). As mentioned byArdini et al. 2022, many immunotoxins have been studied as components of suicide geneand could be interested therapeutic molecules. However, due to their important toxicprofile, a targeted delivery also needs to be considered to allow the immunotoxins to beexpressed solely in cancer cells and to exert its toxic / enzymatic activity. In most cases,delivery using viral vector is particularly attractive due to the ability to encode the genewithin the viral genome, as well as for its ability to limit off-target effects. However, thehighly toxicity of these immunotoxins also remains their main barrier to their use, as theyare also deleterious for the delivery system and / or because they kill any cells used forvector production, such as viral vector production with a reduced vector yields or acomplete inhibition of the virus growth. Some strategies have already been explored to overcome the deleterious effects of atoxic heterologous gene on the viral vector as delivery system or on the producer cell ofthe viral vector. WO2007 / 073513 discloses a method of propagating and producing anadenoviral vector encoding a heterologous gene whose expression inhibits viral growth inthe packaging cells. To resolve the technical problem, it is proposed a cell expressing aTetracycline repressor protein (TetR) and an adenoviral vector comprising theheterologous gene sequence placed under the control of a promoter / tetracycline operonoperator (TetO) combination. Consequently, the system is based solely on a constitutiverepression, as it entirely depends on the packaging cell line itself. While viral vectorswere produced with higher yield, it cannot be quantitatively regulated (Jason et al. 2007).Similarly, WO2019 / 081673 discloses a specific cell line for supporting high levels ofadenoviral vectors production. With a tetracycline repressor expressed under the controlof a cellular promoter, the production of viral particles is conditionally linked to thepresence or absence of tetracycline, rendering the expression inducible or repressible.To be adapted to recombinant MVA (Modified Vaccinia Virus Ankara), Neckermann et al.2024 developed a continuous avian cell line modified to suppress transgene expressionduring recombinant MVA (rMVA) generation, selection and amplification, achieved byconstitutively expressing a tetracycline repressor in combination with a chimeric viralpromoter sustained by the rMVA.Finally, Strizker et al. discloses a doxycycline-inducible promoter system into oncolyticrecombinant Vaccinia viruses (VACVs) based on the tet operon of transposon (Tn10) fusedto poxviral promoter and operably linked to a gene product. Experiments with reportergene product have shown that the system enables the production of a non-deleteriousgene product only in the presence of TetR when doxycycline is present (Stritzker et al.,2014, Journal of Virology, 88(19):11556-67). While different strategies have been explored, there still remains a need for an efficient modified recombinant poxvirus that encoding a detrimental heterologous gene productfor the poxvirus itself or for the producer cell and the method of producing thereof.Recombinant poxvirus and method for regulating the expression of conditional gene products of said recombinant poxvirus with an improved safety profile While recombinant poxviruses are a versatile platform well suited for transgenes vectorization and with an approved safety profile, it cannot be totally excluded that some patients may develop serious adverse reactions. It is especially true for cancer patients, which typically have some level of immunosuppression profiles. If serious complication events do arise, some solutions exist such as vaccinia immunoglobulin (VIG) and cidofovir administrations to the patient. However, VIG treatment can cause severe side effects, for example hypotension or renal dysfunction. On the other side, the cidofovir is solely recommended if VIG treatment fails or the patient is close to the death and presents also serious side effects. Other strategies have been explored by modifying the recombinant poxvirus itself to reduce the potential adverse effects. In particular, US2013 / 0171189 discloses a recombinant vaccinia virus with a “built-in safety mechanism” to control the virus replication, system based on genetic elements of the tetracycline operon and a modified Tet repressor gene. In such cases, if serious complications from uncontrolled viral replication occur, the replication can be downregulated through the addition or removal of tetracycline antibiotics. Similarly, Grigg et al., 2013 have developed a safety mechanism for Vaccinia virus basedon the conditional expression of IFN-γ under a controlled tetracycline-inducible Vacciniavirus promoter for use in vaccines and oncolytic cancer therapies (Grigg et al., 2013,PNAS, 110:38, 15407-15412). These safety mechanism viral vectors use elements from thetet operon to regulate a gene that can stop viral replication in vivo. When tetracycline antibiotics such as Doxycycline are present, IFN-γ is expressed and leads to virus clearance in vivo. However, even though systems allow to repress the virus itself, it is also reasonable thatsome of exogeneous heterologous genes’ products could have detrimental effects eitheron the patient’s cancer treatment if they are expressed at the wrong time or if the expression levels are too high and a strategy to decorrelate the replication of the virus itself from the expression of an exogeneous heterologous gene encoded is of medical interest. To facilitate safe and efficient heterologous gene delivery, Azad et al., 2023 proposed to adapt the available drug-controlled gene systems to enable control of virally encoded transgene expression by designing fusions of an operator element of different drug- inducible systems with Vaccinia virus promoters to produce synthetic promoters (Azad et al., 2023, Nature communications, 14:3035). As Doxycycline (DOX) is an approved antibiotic with well-established pharmacokinetic and pharmacodynamic, development of DOX-controlled promoter based on a TetO-controlled Vaccinia virus promoter andcombined to a tetracycline repressor protein has been investigated. As previously stated,Strizker et al., 2014 also discloses a doxycycline-inducible promoter system into oncolytic recombinant Vaccinia viruses (VACVs) based on the tet operon of transposon (Tn10) fused to poxviral promoter and operably linked to a gene product. Experiments with reporter gene product have shown that the system enables the production of a non-deleteriousgene product only in the presence of TetR when doxycycline is present (Stritzker et al.,2014, Journal of Virology, 88(19):11556-67). While different strategies have been explored, there still remains a need for a more efficient and more tightly regulable gene expression poxviral vector, therapeutic vaccineand oncolytic viruses, with improved safety profile for administering safely to a subject,without affecting its efficacy and to provide the clinician with opportunities to tune both the timing and the level of therapeutic transgenes’ expression if medical complications or undesired events are observed.These technical problems are solved by the provision of the embodiments as defined inthe claims. Other and further aspects, features and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention. These embodiments are given for the purpose of disclosure. SUMMARY OF THE INVENTION Recombinant poxvirus and method for regulating the expression of toxic conditional gene products of said recombinant poxvirus in a producing cell In the context of a first aspect of the invention, the inventors have designed a novel recombinant poxvirus, methods of generating said recombinant poxvirus and using such recombinant poxvirus.Unexpectedly, the recombinant poxvirus according to the first aspect of of the inventiondisplays a better regulation of the expressed conditional gene product, therefore suchregulated conditional gene product expression does not interfere negatively (directly orindirectly) with the said recombinant poxvirus’ production and without modifying itsreplication’s ability. Repressing the conditional gene product during poxvirusamplification strongly increased the genomic stability of poxvirus. In a first aspect, the present invention thus relates to a recombinant poxvirus comprising in its genome at least one nucleic acid sequence encoding a conditional gene product, wherein the nucleic acid sequence encoding a conditional gene product is operably linked to at least one poxviral promoter and at least one Tetracycline operator (TetO) sequence; wherein expression of the nucleic acid sequence encoding a conditional gene product is inducible or repressible by the conditional binding of a transcriptional regulator protein; wherein said TetO sequence is located upstream (5’ end), downstream (3’ end) and / or within of the poxviral promoter operably linked to said nucleic acid sequence encoding a conditional gene product; wherein the conditional gene product affects the viability ofthe recombinant poxvirus. The TetO sequence is preferably located upstream (5’ end) ofthe poxviral promoter operably linked to said nucleic acid sequence encoding a conditional gene product. In one embodiment, said recombinant poxvirus is a poxvirus of the Chordopoxvirinae family, preferably selected from the group consisting of Avipoxvirus genus, Capripoxvirus genus, Leporipoxvirus genus, Molluscipoxvirus genus, Orthopoxvirus genus, Parapoxvirusgenus, Suipoxvirus genus, Cervidpoxvirus genus, Yatapoxvirus genus and chimeric poxvirusthereof. In one embodiment, the conditional gene product is a toxic conditional gene product.In another embodiment, the poxviral promoter is selected from late, intermediate, orearly / late poxviral promoters. In a further embodiment, the recombinant poxvirus comprises in its genome at least two nucleic acid sequences encoding respectively two conditional gene products, wherein the nucleic acid sequences encoding the two conditional gene products are operably linked respectively to two poxviral promoters and one TetO sequence. In still a further embodiment, the recombinant poxvirus further comprises a nucleic acid sequence inserted in its genome encoding at least a transcriptional regulator operably linked to a constitutive poxviral promoter. In a further embodiment, the present invention relates to a producer cell comprising therecombinant poxvirus according to the first aspect of the invention, wherein atranscriptional regulator is expressed. In still a further embodiment, the present invention relates to a recombinant nucleic acid molecule comprising at least one nucleic acid sequence encoding a conditional gene product, wherein the nucleic acid sequence encoding a conditional gene product is operably linked to at least one poxviral promoter and at least one Tetracycline operator (TetO) sequence; wherein expression of the nucleic acid sequence encoding a conditional gene product is inducible or repressible by the conditional binding of a transcriptional regulator protein; wherein said TetO sequence is inserted located upstream (5’ end), downstream (3’ end) and / or within of the poxviral promoter operably linked to said nucleic acid sequence encoding a conditional gene product, wherein the conditional geneproduct affects the viability of the recombinant poxvirus. The TetO sequence is preferablylocated upstream (5’ end) of the poxviral promoter operably linked to said nucleic acid sequence encoding a conditional gene product. In still a further embodiment, the present invention relates to a poxviral transfer plasmid comprising the recombinant nucleic acid molecule according to the first aspect of the present invention. In still a further embodiment, the present invention relates to a method for producing arecombinant poxvirus according to the first aspect of the present invention, said methodcomprising the steps of: a) infecting a producer cell with a parental poxvirus, so as to obtain an infected producer cell, b) transfecting the infected producer cell with a poxviral transfer plasmidaccording to the first aspect of the present invention, so as to obtain a transfected producer cell, c) culturing the transfected producer cell under conditions which are appropriate for enabling the recombinant poxvirus to be produced, so as to obtain an infected producer cell culture comprising the recombinant poxvirus, d) recovering the recombinant poxvirus from said infected producer cell culture; and optionally; e) purifying said recovered recombinant poxvirus.Unexpectedly, said method for producing a recombinant poxvirus efficiently repressesthe expression of the toxic conditional gene product encoded into the poxvirus genome,allowing the poxvirus’ production and without modifying its replication’s ability. Indeed, as the expression of the toxic gene product into a producer cell impers the production of the poxvirus, the method according to the invention solves this production problem. Recombinant poxvirus and method for regulating the expression of conditional gene products of said recombinant poxvirus with an improved safety profileIn the context of a second aspect of the invention, the inventors also designed a novelrecombinant poxvirus expressing a conditional gene product with an improved safety profile, the method of producing thereof, the composition thereof and the therapeutic use related thereto. Unexpectedly, the recombinant poxvirus according to the second aspect of the invention displays an improved safety profile by a fine expression’s regulation of a gene product, without affecting virus’ replication or expression of other gene product that could be encoded into the said recombinant poxvirus’ genome. As a consequence, the said recombinant poxvirus according to the second aspect of the invention preserves the virus itself and the host to a potential toxicity’s profile of the conditional gene product expression. These regulatory features allow also the gene product expression to be quickly shut down whether adverse effects are detected for a patient. Furthermore, these fine expression’s regulation systems according to the second aspect of the invention will prove critical to the delivery of potent toxic payloads that can be locally therapeutically effective but have significant toxicity when delivered systemically.In a second aspect, the present invention thus relates to a recombinant poxviruscomprising in its genome at least one nucleic acid sequence encoding a conditional gene product; wherein the nucleic acid sequence encoding a conditional gene product is operably linked to at least one poxviral promoter and at least one TetO sequence; and at least one nucleic acid sequence encoding a transcriptional regulator protein that conditionally binds to the TetO sequence; wherein said TetO sequence is located upstream (5’ end), downstream (3’ end) and / or within of the poxviral promoter operably linked to said nucleic acid sequence encoding a conditional gene product; wherein expression of the conditional gene product is inducible or repressible by a tetracycline antibiotic or a derivative thereof. The TetO sequence is preferably located upstream (5’ end) of the poxviral promoter operably linked to said nucleic acid sequence encoding a conditional gene product. In one embodiment, said recombinant poxvirus is a poxvirus of the Chordopoxvirinae family, preferably selected from the group consisting of Avipoxvirus genus, Capripoxvirus genus, Leporipoxvirus genus, Molluscipoxvirus genus, Orthopoxvirus genus, Parapoxvirus genus, Suipoxvirus genus, Cervidpoxvirus genus, Yatapoxvirus genus and chimeric poxvirus thereof. In another embodiment, the conditional gene product is a therapeutic molecule. According to an embodiment, said therapeutic molecule is selected from the list consisting of immune checkpoint inhibitors, cytokines, agents that affect the regulation of cell surface receptors, agents that affect angiogenesis, agents that stimulates stem cells to produce granulocytes and / or macrophages and a combination thereof. In an embodiment, the conditional gene product is toxic for a host cell or a mammalian host. In one embodiment, the conditional gene product is selected from the group consisting of bacterial toxins, plant toxins, enzymes, cytokines, self-antigens, virus genes. Examples of conditional gene product as defined as toxic according to the invention include without limitation gene products selected from the groups consisting of: -bacterial toxins, such as diphtheria toxin (DT-A), Pseudomonas exotoxin,Clostridium perfringens enterotoxin, Streptolysin O, Enterotoxin H; -plant toxins such as ricin, abrin, pokeweed antiviral protein, Gypsophilin-S,saporin or gelonin; -enzymes such as SAMHD1, nitric oxide synthetases eNOS or iNOS;- cytokines such as IL-12, TGF beta or TGF gamma;- self-antigens such as HER2 / neu, CEA, Hepcam, PSA, PSMA, Telomerase, gplOO,Melan- A / MART- 1, Muc-1, NY-ESO-1, Survivin, Stromelysin 3, Tyrosinase, MAGE3,CML6S, CML66, OY-TES-1, SSX- 2, SART-1, SART-2, SART-3, NYC0-5S, NY-BR-62,hKLP2 and VEGF;- virus genes such as HBV Core-Envelope protein, human immunodeficiency virus(HIV) envelope glycoprotein, HCV E1-E2 protein, rabies glycoprotein, HIV-1 gp160, HIV-1 gp140, vesicular stomatitis virus G glycoprotein; and -any polypeptides that are toxic for the host cell or interfere with the replicationof the recombinant poxvirus. In a further embodiment, the present invention relates to a recombinant nucleic acid molecule comprising at least one nucleic acid sequence encoding a conditional gene product, wherein the nucleic acid sequence encoding a conditional gene product is operably linked to at least one poxviral promoter and at least one Tetracycline operator (TetO) sequence; wherein expression of the nucleic acid sequence encoding a conditional gene product is inducible or repressible by the conditional binding of a transcriptional regulator protein; wherein said TetO sequence is inserted located upstream (5’ end), downstream (3’ end) and / or within of the poxviral promoter operably linked to said nucleic acid sequence encoding a conditional gene product. The recombinant nucleic acid molecule according to the second aspect of the present invention may further comprise at least one nucleic acid sequence encoding a transcriptional regulator protein that conditionally binds to the TetO sequence and expression of the conditional gene productis then inducible or repressible by a tetracycline antibiotic or a derivative thereof. TheTetO sequence is preferably located upstream (5’ end) of the poxviral promoter operably linked to said nucleic acid sequence encoding a conditional gene product. In still a further embodiment, the present invention relates to a poxviral transfer plasmid comprising the recombinant nucleic acid molecule according to the second aspect of the present invention. In a further embodiment, the present invention relates to a method for producing the recombinant poxvirus according to the second aspect of the invention comprising the steps of:a) infecting a producer cell with a parental poxvirus, so as to obtain an infectedproducer cell,b) transfecting the infected producer cell with a poxviral transfer plasmid accordingto the second aspect of the invention, so as to obtain a transfected producer cell,c) culturing the transfected producer cell under conditions which are appropriate forenabling the recombinant poxvirus to be produced, so as to obtain an infected producer cell culture comprising the recombinant poxvirus,d) recovering the produced recombinant poxvirus from the infected producer cellculture and optionally;e) purifying said recovered recombinant poxvirus.In a further embodiment, the present invention relates to a composition comprising the recombinant poxvirus according to the second aspect of the invention, or the recombinantpoxvirus obtained according to the above-mentioned method according to the secondaspect of the invention, and a pharmaceutically acceptable vehicle.In another embodiment, the present invention relates to the recombinant poxvirusaccording to the second aspect of the invention, or the composition according to the second aspect of the invention, for use for treating or preventing a proliferative disease, preferably a cancer. In a further embodiment, the present invention relates to a method of treating or preventing a proliferative disease comprising administering to a subject the recombinant poxvirus or the composition according to the second aspect of the invention. In an embodiment, such method of treating or preventing a proliferative disease further comprises administering a tetracycline antibiotic in an amount sufficient to induce or repress expression of the conditional gene product.Other and further embodiments, features and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention. These embodiments are given for the purpose of disclosure. DESCRIPTION OF THE FIGURESFigure 1 shows a schematic map of pTG19520, reporter transfer plasmid used to generatefurther transfer plasmids varying in their upstream sequences of the Firefly luciferasecoding sequence. The Firefly luciferase and the Renilla luciferase are under expressioncontrol of a pH5R promoter and a pATI promoter respectively. The sequence referenced asJ2R R arm and J2R L arm are respectively the right and left arms of recombinationsurrounding the J2R locus. AmpR is the ampicillin resistance gene, AvrII and ApaI arerestriction enzymes sites.Figure 2 shows ratio of Firefly luciferase luminescence / Renilla luciferase luminescenceF / R for each poxviral pA14L promoter / TetO combinations by infected / transfected HeLacells. As a decrease of firefly luciferase can be caused by the repressor or by a side effect such as cell death, ratio of Fluc luminescence with the control Rluc luminescence werecalculated. The ratios F / R (Firefly luciferase / Renilla luciferase) are reported for eachpoxviral promoter / TetO combination, in presence or in absence of the TetR. Resultsreferenced as pA14L show the expression ratio without TetO; results referenced as pA14L-O2 show expression ratio with promoter pA14L with TetO in 3’ position of the promoter;results referenced as O2-pA14L show expression ratio with promoter pA14L with TetO in5’ position of the promoter. The ratio obtained for the poxviral promoter devoid of theTetO2 in absence of TetR was arbitrarily set at 1 as a reference. The percentage ofrepression was obtained by adapting the method described by Campos-Melo, D., et al.(2014) for miRNAs (see M&M). The fold reduction was obtained by dividing the F / R ratiomeasured in absence of TetR by the ratio measured in presence of TetR. RLU means Relative Light Units (Luminescence). Figure 3 shows level of expression of IL-12 under the control of different promoters (pF17R, pF17R-O2 and pSEL-O2) by infected HeLa cells and T-REx™-HeLa cells at a MOI of 10-2by recombinant VACVs and control VACVs deprived of the TetO2 and incubated for 48hours. The infection of T-REx™-HeLa cells was performed in absence or in presence of 0.1µg / mL of doxycycline. The culture supernatants were harvested and the expression of IL-12 was analyzed by ELISA using the DuoSet®ELISA development system Human IL-12 (R&D Systems).Figure 4 shows the experimental approach used to generate recombinant vaccinia virusCOPTG19745.Figure 5 shows the expression of a Core-Env fusion protein. Western blot was performedin reducing SDS-PAGE with HeLa, T-REx™-HeLa cells or T-REx™-HeLa cells in presence of doxycycline either uninfected (Mock) or infected with COPTG19745 or VVTG18058. Detection was performed by using the mouse monoclonal antibody Hep B cAg 10E11 (Santa Cruz, sc-23947) specific for the Core-Env fusion and by using a rabbit polyclonal raisedagainst the MVA p14 protein. The presence of Core-Env fusion protein is indicated by anarrow.Figure 6 shows the repression of the Luciferase activities induced by plasmids expressingthe revTetR proteins. Luciferase activities were measured after transient transfection / infection experiments with the plasmids expressing the revTetR variants andwith the plasmid expressing the Firefly luciferase under the control of pF17R-O2 poxviralpromoter in HeLa cells cultured in presence or absence of doxycycline during 24h.A GFP-expressing plasmid pTG15839 was used as control plasmid (CTRL). Various revTetRproteins were evaluated. They originated from either derivates from the TetR protein(class B) or derivates from the repressor TetR (BD) resulting from the fusion of aminoacids 1 to 50 of TetR (class B) and amino acids 51 to 208 of TetR (class D). The fold reduction was obtained by dividing the F / R ratio measured in absence of TetR by the ratio measured in presence of TetR.Figure 7 shows a schematic map of pTG20229, a “dual” reporter transfer plasmid.Firefly luciferase and Renilla luciferase are placed downstream two poxviral promotersoriented in the opposite direction with a unique TetO sequence inserted between both promoters. The NanoLuc® luciferase coding sequence is placed under the control the poxviral promoter pA26L. NanoLuc® luciferase was used as an internal standard tonormalize expression of Firefly luciferase and of Renilla luciferase.Figure 8 shows a schematic representation of doxycycline daily treatment.Figure 9 shows a schematic representation of doxycycline unique treatment.Figure 10 shows the Firefly luciferase activity after daily administration of doxycycline.Swiss nude mice bearing intraperitoneal HCT-116 tumor cell xenografts were injected IV with 105or 106PFU of VACV revTetR pF17R-O2 or VACV pF17R-O2 and treated daily with 10 µg / g of doxycycline. Luciferases expressions were measured at D3 post-injection. The ratio obtained with VACV pF17R-O2 in absence of doxycycline at 105PFU or 106PFU was arbitrarily set at 1.Figure 11 shows the Firefly luciferase activity after a unique administration of doxycycline.Swiss nude mice bearing intraperitoneal HCT-116 tumor cell xenografts were injected IV with 105or 106PFU of VACV pF17R-O2 TetR or VACV pF17R-O2 and treated once by i.p. administration with 10 µg / g of doxycycline at day 2. Luciferases expressions were measured at D3 post-injection. The ratio obtained with VACV pF17R-O2 in absence of doxycycline at 105PFU or 106PFU was arbitrarily set at 1.Figure 12 shows the Firefly luciferase activity after a unique administration of two dosesof doxycycline. Control of the repression of Firefly luciferase expressed by VACV TetR pF17R-O2 injected intravenously using a unique doxycycline i.p. administration (10 µg / g or 100 µg / g) in Swiss nude mice bearing intraperitoneal HCT-116 tumor cell xenografts. The ratio obtained with VACV pF17R-O2 using doxycycline at 10 µ / g or 100 µg / g was arbitrarily set at 1.Figure 13 shows the Firefly luciferase activity after daily administration of two dosesdoxycycline. Control of the repression of Firefly luciferase expressed by VACV pF17R-O2TetR or VACV pF17R-O2 revTetR injected intravenously in Swiss nude mice bearing intraperitoneal HCT-116 tumor cell xenografts receiving doxycycline i.p. administration (10 µg / g and 100 µg / g) from day -1 to day 2 post-injection. The ratio obtained with VACV pF17R-O2 using doxycycline at 10 µ / g or 100 µg / g was arbitrarily set at 1. DETAILED DESCRIPTION OF THE INVENTIONIt is well known in the art that a gene product inserted into a recombinant poxvirus canbe deleterious for the viability of the recombinant poxvirus, by being toxic for the hostcell, as a cell of production for producing said recombinant poxvirus, or by interferingwith the replication of the recombinant poxvirus. As a consequence, the present invention may provide in a first aspect of the invention a recombinant poxvirus that resolves these technical issues. The inventors also surprisingly found that a recombinant poxvirus comprising in its genome at least one nucleic acid sequence encoding a conditional gene product; wherein the nucleic acid sequence encoding a conditional gene product is operably linked to at least one poxviral promoter and at least one TetO sequence; and at least one nucleic acid sequence encoding a transcriptional regulator protein that conditionally binds to the TetO sequence; wherein said TetO sequence is located upstream (5’ end), downstream (3’ end) and / or within of the poxviral promoter operably linked to said nucleic acid sequence encoding a conditional gene product; wherein expression of the conditional gene product is inducible or repressible by a tetracycline antibiotic or a derivative thereof is suited to overcome the above mentioned technical issues. As a consequence, a fine tuning of temporal expression’s regulation of a gene product would be strengthened, without affecting virus’ replication or expression of other gene product that could be inserted into the said recombinant poxvirus. Advantageously, the invention may thus provide in asecond aspect of the invention a recombinant poxvirus that preserves the virus or thesubject from the toxicity's profile of the conditional gene product.General definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.As used herein throughout the entire application, the terms “a” and “an” are used in thesense that they mean “at least one”, “at least a first”, “one or more” or “one or aplurality” of the referenced compounds or steps, unless the context dictates otherwise.For example, the term "a cell" includes a plurality of cells, including mixtures thereof. The term “at least” refers to either the number preceded by the expression “at least”,considered as the minimum, or a number above said minimum. The terms “at least one”or “one or more” refer to either one or a number above one (e.g. 2, 3, 4, 5, etc.).The term “and / or” wherever used herein includes the meaning of “and”, “or” and “all orany other combination of the elements connected by said term”. By way of example, theterm “and / or” used in a sentence such as “A and / or B” is intended to include “A and B”, “A or B”, “A” (alone) and “B” (alone). Likewise, the term “and / or” used in a sentence such as “A, B, and / or C” is intended to include each of the following: “A, B and C”; “A, B or C”; “A or C”; “A or B”; “B or C”; “A and C”; “A and B”; “B and C”; “A” (alone); “B” (alone); and “C” (alone).The term “about”, “approximately”, “roughly, or “around” as used herein means within10% up or down (higher or lower), preferably within 8% up or down (higher or lower), andmore preferably within 5% up or down (higher or lower) of a given value or range.As used herein, when used to define products, compositions and methods, the term“comprising” (and any form of comprising, such as “comprise” and “comprises”),“having” (and any form of having, such as “have” and “has”), “including” (and any formof including, such as “includes” and “include”), or “containing” (and any form ofcontaining, such as “contains” and “contain”) are open-ended and do not excludeadditional, unrecited elements or method steps. Thus, a polypeptide “comprises” anamino acid sequence when the amino acid sequence might be part of the final amino acid sequence of the polypeptide. Such a polypeptide can have up to several hundredadditional amino acids residues. “Consisting essentially of” or “consisting essentially in”means excluding other components or steps of any essential significance. Thus, acomposition consisting essentially of the recited components would not exclude trace contaminants and pharmaceutically acceptable carriers. Thus, a polypeptide “consists essentially of” an amino acid sequence when such an amino acid sequence is present withoptionally only a few additional amino acid residues. “Consisting of” or “consisting in”means excluding more than trace elements of other components or steps. For example, a polypeptide "consists of” an amino acid sequence when the polypeptide does not contain any amino acids but the recited amino acid sequence. The use of the term “for example” and its corresponding abbreviation “e.g.” (whether italicized or not) means that the specific terms recited are representative examples of the disclosure that are not intended to be limited to the specific examples referenced or cited unless explicitly stated otherwise. The terms “amino acids”, “residues” and “amino acid residues” are used interchangeably and encompass natural amino acids as well as amino acid analogues (e.g., non-natural, synthetic, and modified amino acids, including D or L optical isomers).The terms “protein”, “polypeptide” and “peptide” are used interchangeably and referto polymers of amino acid residues which comprise at least nine or more amino acidscovalently linked by peptide bonds. The polymer can be linear, branched or cyclic andmay comprise naturally occurring and / or amino acid analogs and it may be interruptedby non-amino acids. No limitation is placed on the maximum number of amino acidscomprised in a polypeptide. As a general indication, if the amino acid polymer is morethan 50 amino acid residues, it is preferably referred to as a “polypeptide” or a “protein” whereas if it is 50 amino acids long or less, it is referred to as a “peptide”. Unless otherwise indicated, amino acid sequences are written left to right in amino to carboxy orientation. The term “polypeptide” encompasses native polypeptides, modified polypeptides (including derivatives, variants, mutants, or analogs), polypeptide fragments, polypeptide multimers (e.g., dimers), recombinant polypeptides, fusion polypeptides among others. Within the context of the present invention, the terms “nucleic acid”, “nucleic acid molecule”, “polynucleotide”, "nucleic acid sequence" and “nucleotide sequence” areused interchangeably and define a polymer of any length of either deoxyribonucleotides(DNA) or polyribonucleotides (RNA) or mixed polyribopolydeoxyribonucleotides. Theseterms encompass single or double-stranded, linear, or circular, natural or synthetic, unmodified or modified versions thereof (e.g., genetically modified polynucleotides;optimized polynucleotides), sense or antisense polynucleotides, chimeric mixtures (e.g.,RNA-DNA hybrids). Exemplary DNA nucleic acids include without limitation, complementary DNA (cDNA), genomic DNA, plasmid DNA, vectors, viral DNA (e.g., viral genomes, viral vectors), oligonucleotides, probes, primers, coding DNA, non-coding DNA, or any fragment thereof. Exemplary RNA nucleic acids include, without limitation, messenger RNA (mRNA), precursor messenger RNA (pre-mRNA), coding RNA, non-coding RNA, etc. Nucleic acid sequences described herein may be synthesized by standard methods known in the art, e.g., by use of an automated DNA synthesizer (such as those that are commercially available from Biosearch, Applied Biosystems, etc.) or obtainedfrom a naturally occurring source (e.g., a genome, cDNA, etc.) or an artificial source(such as a commercially available library, a plasmid, etc.) using molecular biologytechniques well known in the art (e.g., cloning, PCR, etc).The term “nucleotide” refers to any of various compounds consisting of a sugar, usually ribose or deoxyribose, a purine or pyrimidine base, and one or more phosphates. The expression “nucleotide” designates both ribonucleotides and deoxyribonucleotides.As used herein, a “functional gene” (including a “functional transgene”) refers to a genethat is capable of expressing an RNA or protein product, wherein the RNA or protein product retains at least one functional activity. As used herein, a “non-functional gene” (including a “nonfunctional transgene”) refers to a gene that is not capable of expressing an RNA or protein product that retains any functional activity. A nonfunctional gene canrefer to a gene that has been fully removed or replaced. A nonfunctional gene can alsorefer to a gene that has been partially removed or replaced, wherein the partial removalor replacement renders the remaining portion of the gene incapable of expressing an active RNA or protein product. A “coding sequence” or “encoding sequence” is a nucleic acid sequence that can betranscribed and translated into a polypeptide in a cell in vitro or in vivo when placedunder the control of appropriate regulatory sequences. “Regulatory sequences”, or“Regulatory element”, include nucleotide sequences located upstream (5’ non-codingsequence), within, or downstream (3’ non-coding sequence) of a coding sequence, and which influence the transcription, RNA processing or stability, or translation of the associated coding sequence. Regulatory sequences include promoters, translation leader sequences, introns, polyadenylation recognition sequences, RNA processing sites, effector binding sites and stem-loop structures. The boundaries of a coding sequence are determined by a start codon at the 5’ end, and a translation stop codon at the 3’ end. Coding sequences include, but are not limited to, prokaryotic sequences, cDNA from mRNA, genomic DNA sequences, and synthetic DNA sequences. If a coding sequence is intended for expression in a eukaryotic cell, a polyadenylation signal and transcription termination sequence can be located 3’ of the coding sequence. “Operably linked” means that a polynucleotide of interest is linked to a regulatory element in a manner that allows for expression of the polynucleotide sequence. In someaspects provided herein, the regulatory element comprises or consists of a promoter suchas a poxviral promoter, a regulable promoter (inducible or repressible promoter), aconstitutive promoter or an endogenous promoter. “Promoter” refers to a nucleic acid sequence that regulates, either directly or indirectly,transcription of a nucleic acid coding sequence to which it is operably linked. As usedherein, it also means a minimal sequence sufficient to ensure the regulation of thetranscription, as a fragment of or a sequence comprising the said promoter, that stillretains the ability to promote the transcription of the operably linked nucleic acid codingsequence.“Regulable promoter” refers to a promoter that regulates the expression of a nucleicacid sequence, indirectly either in presence or in absence of an exogeneous signal suchas a transcriptional regulator protein. A regulable promoter can be an inducible or arepressible promoter. In the context of the invention, the regulable promoter comprisesor consists of at least a TetO sequence and a poxviral promoter.“Constitutive promoter” refers to a promoter that allows for continuous transcription ofits associated gene product and is not subject to regulation by an exogeneous signal. An “endogenous promoter” is a promoter that is naturally associated with a gene or nucleic acid sequence. An endogenous promoter can be obtained, for example by isolating the 5' non-coding sequence located upstream of the coding segment and / or an exon. A “recombinant promoter” or “heterologous promoter” is a promoter that is not normally associated with a nucleic acid sequence in its natural environment. “Homologous recombination” refers to the insertion of a foreign DNA sequence (the “inserted DNA sequence”) into another DNA molecule (the “target DNA sequence”). In some cases, the inserted DNA sequences is targeted to a specific site within the target DNA sequence for homologous recombination. For targeted homologous recombination, the inserted DNA sequence typically contains sufficiently long regions of homology to a sequence of the target DNA sequence to allow complementary binding and incorporation of the inserted DNA sequence into the target DNA sequence. Longer regions of homology and greater degrees of sequence similarity generally increase the efficiency of homologous recombination. “Heterologous” describes the relationship of one nucleic acid or amino acid sequence to one or more different nucleic acid or amino acid sequences and indicates that the sequences are not found joined together in the same position, structure, and orientation in nature. The joining of heterologous sequences creates a non-naturally occurring juxtaposition of sequences. Such joining is the product of engineering performed in the laboratory. The products of such joining can be referred to as “recombinant.”The terms "analog", “derivative” or “variant” and the like can be used interchangeablyto refer to a component (polypeptide, nucleic acid, virus, etc) exhibiting one or more modification(s) with respect to the native counterpart. Any modification(s) can be envisaged, including substitution, insertion and / or deletion of one or morenucleotide / amino acid residue(s) or addition of other chemical groups. Thesemodifications can enhance stability, bioavailability, specificity, or activity compared tothe native counterpart. Preferred are variants that retain a degree of sequence identityof at least 75%, advantageously at least 80%, desirably at least 85%, preferably at least 90%, more preferably at least 95%, and even more preferably at least 98% identity after optimal global alignment with the sequence of the native counterpart, i.e. after alignment of the sequences to be compared taken in their entirety over their entire length. For illustrative purposes, “at least 75% identity” means 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.In a general manner, the term “identity”, “sequence identity”, or “identical” in thecontext of amino acid or nucleotide sequences refers to the correspondence between anamino acid sequence and another amino acid sequence of reference, or between a nucleicacid sequence and another nucleic acid sequence of reference. The “percentage ofidentity” or “percent identity” between two sequences is a function of the number ofidentical positions shared by the sequences after optimal global alignment (i.e., over thewhole lengths of the two aligned sequences), considering the number of gaps which needto be introduced for optimal alignment of the two entire sequences and the length ofeach gap. Various computer programs and mathematical algorithms are available in the art to determine the percentage of identity between amino acid sequences after optimal global alignment, such as the Stretcher, Mafft, ClustalW or ALIGN in Atlas of ProteinSequence and Structure (Dayhoff, M. O. 1981; vol.5, suppl., 3), and the algorithm ofNeedleman and Wunsh (Needleman, S. B. and Wunsch, C. D. J Mol. Biol. 1970;48(3): 443-53). Such computer programs and mathematical algorithms of global alignment areselected according to the common general knowledge of a person skilled in the art to perform the more bioinformatically or biologically relevant and optimal global alignment. Programs for determining identity between nucleotide sequences optimal globalalignment are also available in specialized data bases (e.g.: Genbank, the WisconsinSequence Analysis Package, BESTFIT, FASTA and GAP programs). The term “isolated” refers to a protein, a polypeptide, a peptide, a polynucleotide, a vector, etc., that is removed from its natural environment (i.e., separated from at least one other component(s) with which it is naturally associated or found in nature). For example, a nucleotide sequence is isolated when it is separated of sequences normally associated with it in nature (e.g., dissociated from a genome) but it can be associated with heterologous sequences. The term “obtained from”, “originating” or “originate” is used to identify the originalsource of a component (e.g., polypeptide, nucleic acid molecule) but is not meant tolimit the method by which the component is made which can be, for example, by chemical synthesis or recombinant means. As used herein, the term “host cell” should be understood broadly without any limitation concerning particular organization in tissue, organ, or isolated cells. Such cells may be of a unique type of cells or a group of different types of cells such as cultured cell lines,primary cells, and dividing cells. In the context of the invention, the term “host cells”include prokaryotic cells, lower eukaryotic cells such as yeast, and other eukaryotic cells such as insect cells, plant, and mammalian (e.g., human or non-human) cells as well as cells allowing infection and replication of the recombinant poxvirus of the invention (these cells are designated as “permissive cells”). “Vector” refers to a carrier nucleic acid molecule or vehicle that can be introduced into a cell (a host cell) where it can be replicated. “Expression vector” refers to a vector containing a nucleic acid sequence encoding at least part of a gene product capable of being transcribed. Expression vectors typically contain one or more control sequences necessary for transcription and / or translation of an operably linked coding sequence. Vectors can be introduced into the desired host cells by known methods, including, but not limited to, transfection, transduction, cell fusion, and lipofection.The terms "virus", "viral particle", "viral vector particle" and “virion" are usedinterchangeably and are to be understood broadly as meaning a vehicle comprising at least one element of a wild-type virus genome and may be packaged into a viral particle or to a viral particle. Although, viral particles may or may not contain nucleic acid (i.e. the viral genome) it is preferred that a virus comprises a DNA or RNA viral genomepackaged into a viral particle (or virion) and is infectious. The term “infectious” refersto the ability of a viral vector to infect and enter into a host cell or subject. Desirably,the virus of this invention comprises a DNA genome, and most preferably a double- stranded DNA genome. In the context of the present disclosure, a "virus" includes wild- type and engineered (modified) viruses. Modification(s) can be within endogenous viral genes (e.g. coding and / or regulatory sequences) and / or within intergenic regions. Moreover, modification(s) can be silent or not (e.g. resulting in a modified viral gene product). Modification(s) can be made in a number of ways known to those skilled in the art using conventional molecular biology techniques. Desirably, the modifications encompassed by the present invention affect, for example virulence, toxicity, pathogenicity, or replication of the virus compared to a virus without such modification, but do not completely impair infection and production at least permissive cells. Viral vectors can be replication-competent or -selective (e.g. engineered to replicate better or selectively in specific host cells), or can be genetically disabled so as to be replication- defective or replication-impaired. The term "viral vector" as used herein refers to a nucleic acid vector that includes at least one element of a virus genome and may be packaged into a viral particle or to a viral particle. A particular suitable viral vector used herein is obtained from a poxvirus. A “poxvirus” refers to a virus of the Poxviridae family, including, e.g., viruses of the Orthopoxvirus genus. The terms “poxvirus”, “poxvirus particle”, “poxvirus vector”, “poxviral vector” and “poxvirus virion” are used interchangeably and are to be understood as meaning a vehicle comprising at least one element of a wild-type poxvirus genome. It is preferred that the poxvirus particle is infectious (i.e., capable of infecting and entering a host cell or subject). This term encompasses both native as well as genetically modified (e.g., engineered) poxvirus. The genome of a recombinant poxvirus as provided herein includes poxviruses genomes containing one or more deletions (removal) of endogenous sequences (genes or nucleotides), and / or addition of one or more heterologous sequences (genes and / or nucleotides). For example, the genome of a recombinant poxvirus can refer to the genome of an attenuated poxvirus.The terms “chimeric poxvirus” or “poxvirus chimera” are interchangeable and usedaccording to their ordinary meaning in virology: they refer to a hybrid poxvirus createdby joining nucleic acid fragments from two or more different poxvirus strains. Chimericpoxviruses can be obtained through a process of virus directed evolution, in which amixture of several poxviruses is contacted with producer cells of interest in order to generate recombination events between the genomes of several poxviruses, thusgenerating a pool of chimeric poxviruses. It is intended that the terms “chimericorthopoxvirus” or “orthopoxvirus chimera” applied to orthopoxvirus strains, and“chimeric vaccinia” or “vaccinia chimera” to vaccinia virus strains.The term “recombinant” when used with reference to a nucleic acid molecule, peptide, polypeptide, or protein means of, or resulting from, a new combination of genetic material that is not known to exist in nature. A recombinant molecule can be produced by any well-known technique available in the field of recombinant technology, including, but not limited to, polymerase chain reaction (PCR), gene splicing (e.g., using restriction endonucleases), and solid-phase synthesis of nucleic acid molecules, peptides, orproteins. In particular, the term “recombinant” as used herein in connection with thepoxvirus of the present invention indicates that the poxvirus has been modified by the introduction of at least one foreign nucleic acid (also called recombinant gene or nucleic acid, or heterologous gene or heterologous nucleic acid). As used herein, the term “oncolytic virus” refers to a virus capable of selectively replicating in dividing cells (e.g., a proliferative cell such as a cancer cell) with the aimof slowing the growth and / or lysing said dividing cell, either in vitro or in vivo, whileshowing no or minimal replication in non-dividing cells. Typically, an oncolytic virus contains a viral genome packaged into a viral particle (or virion) and is infectious (i.e.,capable of infecting and entering into a host cell or subject). Suitable oncolytic viralvectors may be selected from poxviruses, adenoviruses, herpes viruses, paramyxoviruses,and rhabdoviruses (see Kaufman, H. et al. Nat Rev Drug Discov. 2015:14(9): 642–62).The term “non-oncolytic virus” encompasses any virus which is not defined as anoncolytic virus. Suitable non-oncolytic viral vectors may be selected from poxviruses,preferably Pseudocowpox virus (PCPV), Modified vaccinia Virus Ankara (MVA), highly attenuated vaccinia virus strain (NYVAC), Swinepox virus (SWPV), Fowlpox virus (FPV) or chimeras thereof. “Oncolytic activity” refers to the ability of a virus to preferentially infect and kill cancer cells relative to normal cells. Cancer cell death can be caused by preferential infection, replication in and destruction of the cancer cells (referred to as “direct cytotoxic activity”) and by simulating and amplifying the host anti-cancer immune response, which, in addition to destroying existing cancer cells, can establish lasting immunity. Oncolytic activity can be detected by known methods, including, but not limited to, detecting celldeath, inhibition of cell proliferation and / or by detecting a reduction in tumor size.A virus is considered “cytotoxic” if it reduces cell viability in treated target cells relative to untreated target cells. Methods for determining cytotoxicity of viruses are known, and include, for example, cytotoxicity assays that measure cell necrosis and / or apoptosis following virus infection, such as MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assays and other related tetrazolium salt based assays (e.g., XTT, MTS or WST), ATP assays, apoptosis assays, such as TUNEL staining of infected cells, DNA fragmentation assays, DNA laddering assays, and cytochrome C release assays.Another method for determining cytotoxicity is to monitor tumor size and location before and after treatment. In some cases, it may be desirable to monitor size over several timepoints for information regarding the increase or decrease in size of a tumor or metastasis.“Attenuated virus” refers to a virus that is not pathogenic and has reduced toxicity towards normal or non-cancerous cells. An attenuated virus can be recombinantly modified to be less virulent, or non-virulent in normal tissues. In some aspects, modification does not or only minimally impacts the oncolytic ability of the virus.The terms “replication”, “viral replication” and “virus replication” refer to thereplication of the viral genome in target host cells (e.g.: tumors or healthy cells), or tothe synthesis of viral proteins in the target host cells. The steps of a viral life cycle include, but are not limited to, virus attachment to the host cell surface, penetration or entry of the host cell (e.g. through receptor mediated endocytosis or membrane fusion), uncoating (the process whereby the viral capsid is removed and degraded by viral enzymes or host enzymes thus releasing the viral genomic nucleic acid), genome replication, synthesis of viral messenger RNA (mRNA), viral protein synthesis, and assembly of viral ribonucleoprotein complexes for genome replication, assembly of virus particles, post- translational modification of the viral proteins, and release from the host cell by lysis or budding and acquisition of a phospholipid envelope which contains embedded viral glycoproteins. In a cell, there is a viral replication when the viral titer (measured intra- and extra-cellularly) is multiplied by a number higher than 1. In a permissive tumor cell line, the level of virus replication can be low (e.g.: 48 hours post-infection, multiplication of the viral titer by a number higher than 1 and lower than 20000), medium (e.g.: 48 hours post-infection, multiplication of the viral titer by a number comprised between 20000 to 40000) or high (e.g.: 48 hours post-infection, multiplication of the viral titer by a number higher than 40000). “Replication competent” refers to the ability of a virus to replicate in a cell or cell line and produce infectious progeny virions. A virus that can produce infectious progeny virions in a cell or cell line is considered “replication competent,” whereas a virus that is not able to produce infectious progeny virus in the cell or cell line is considered “replicationdefective”. Viral replication can be expressed by the ratio of virus produced by aninfected cell to the amount used to infect the cell, referred to as the “amplification ratio”. An amplification ratio of 1 or more means that the amount of virus produced from the infected cells is the same or more than the amount used to infect the cell, which indicates that replication has taken place, whereas an amplification ratio of less than 1 means that the amount of virus produced from the infected cells is less than the amount used to infect the cell, which indicates a lack of replication in the cell. “Transfection” refers to the introduction of an exogenous nucleic acid molecule into a cell. A “transfected cell” includes an exogenous nucleic acid molecule inside the cell, and a “transformed cell” is one in which the exogenous nucleic acid molecule within the cell induces a phenotypic change in the cell.As used herein, the term “tumour” or “tumor” may be used interchangeably with any ofthe terms “cancer”, “malignancy”, “neoplasm” and encompasses any disease orpathological condition resulting from uncontrolled cell growth and spread (i.e.,proliferative diseases). These terms are meant to include any type of tissue, organ orcell, any stage of malignancy (e.g., from a prelesion to stage IV). Typically, tumors,especially malignant tumors, show partial or complete lack of structural organization and functional coordination as compared to normal tissue and generally show a propensity to invade surrounding tissues (spreading) and / or metastasize to farther sites. The presentinvention is also designed for the treatment of a solid tumor. The term “solid tumor”refers to an abnormal masse of tissue that typically do not contain cysts or areas of fluid.The different types of solid tumors are named after the type of cell that forms them,such as sarcomas, carcinomas, and lymphomas. Examples of solid tumors include renalcancer, prostate cancer, breast cancer, bladder cancer, colorectal cancer, lung cancer, liver cancer, gastric cancer, bile duct carcinoma, endometrial cancer, pancreatic cancer, ovarian cancer, thyroid cancer, head and neck cancer, melanoma, glioblastoma, neuroblastoma, multiple myeloma, and malignant glioma cells.A “tumour cell”, “tumor cell”, “cancer cell”, “malignant cell”, or “neoplastic cell” canbe used interchangeably to refer to a cell that divides at an abnormal (i.e., increased)rate. The term “treatment” (and any form of treatment such as “treating”, “treat”, etc.,) asused herein encompasses prophylaxis (e.g. preventive measure in a subject at risk ofhaving the pathological condition to be treated) and / or therapy (e.g. in a subject diagnosed as having the pathological condition), optionally in association withconventional therapeutic modalities. Typically, therapy refers to an existent pathologicalcondition with the purpose to improve at least one clinical or biochemical symptom (size of tumor, expression level of associated biomarker, etc.), to slow down or control the progression of the targeted pathological condition, symptom(s) thereof, or a secondary state to the pathological condition in the subject treated in accordance with the presentinvention. For example, a subject is successfully treated for a cancer if afteradministration of a recombinant poxvirus of the present invention as described herein,the subject shows an observable improvement of its clinical status or biomarkersassociated to cancer progression. In reference to a cancer (“treatment of cancer” or“cancer treatment” herein), the term “treatment” refers to the various methods used tomanage, control, or eradicate tumor cells within the body of a subject in need thereof.It encompasses a range of treatments designed to reduce the development or progressionof a cancer, avoid recurrence, alleviate the symptoms of a cancer, and / or improve overallquality of life for the subject in need thereof. Further, a treatment of cancer may alsopreserve healthy tissues (non-cancerous tissues), minimize side effects, and enhance thewell-being of the subject in need thereof during and after treatment. A treatment ofcancer can have various effects on the tumor of a subject in need thereof. Its impactdepends on the type of the cancer treatment, the characteristics of the tumor, and / oron the individual's response to said cancer treatment. For example, a treatment of cancermay be effective in reducing the size of at least one tumor, in inducing cell death (e.g.,apoptosis or necrosis) of tumor cells, in killing tumor cells, in inhibiting tumor cell growthin vitro and / or in vivo, in inducing changes in the TME (e.g., turning a “cold” tumor to a“hot” tumor), in enhancing sensitivity to other treatments, or enhancing the immune response to tumor cells. The terms “toxic for a host cell or a mammalian host” as used herein means that thecontinuous expression and optionally secretion of the conditional gene product cangenerate adverse clinical events (or as used herein as “adverse effects”) that can lead to life-threatening organ damage, like, but not limited to, liver toxicity, lung oedema, cytokines storm and ultimately death. This toxicity also limits efficacy, due to the impossibility to reach the appropriate concentrations in targets organs.The terms “prevention” (and any form of treatment, such as “preventing”, “prevent”,etc.,) and “prophylaxis” are used interchangeably in the context of a not yet existent pathological condition or pathological condition that has been successfully treated andrefer to preventing, delaying the onset, or decreasing the severity of the first occurrenceor relapse of at least one clinical or biochemical symptom (size of tumor, expression levelof associated biomarker, stage progression…) of a pathological condition. In reference toa cancer (prevention of a cancer), “prevention” may refer to prevention of a worseningof the condition, or prevention of the development of the cancer, e g, preventing anearly-stage cancer developing to a later-stage. In some aspects, the treatment of a cancermay be aimed at preventing the growth of at least one tumor in the subject.The term “administering” (or any form of administration, such as “administered”, etc.,)as used herein, refers to the delivery to a subject of a component (e.g., a recombinantpoxvirus,) according to the modalities described herein. The term “combination” or “association” as used herein refers to any arrangement possible of various components (e.g. the fusion polypeptide according to the invention and another treatment). Such an arrangement includes mixture of said components as well as separate combinations for concomitant or sequential administrations. The present invention encompasses combinations comprising equal molar concentrations of each component as well as combinations with very different concentrations. It is appreciated that optimal concentration of each component of the combination can be determined by the artisan skilled in the art.The term “subject” generally refers to an organism for whom any of the product ormethods disclosed herein is needed or may be beneficial. Typically, the organism is a mammal, particularly a mammal selected from the group consisting of domestic animals, farm animals, sport animals, and primates (human and non-human). The terms “subject”,“individual”, and “patient” may be used interchangeably when referring to a humanorganism and covers male and female as well as foetuses, new-born, infant, young adult, adult, and elderly. The terms “combination treatment”, "combination therapy", "combined treatment” or “combinatorial treatment”, may be used interchangeably and refer to a treatment of asubject with a recombinant poxvirus as described herein and at least an additionaltherapeutic modality for concomitant or sequential administrations. The additionaltherapeutic modality may be selected from the group consisting of surgery, radiotherapy, chemotherapy, cryotherapy, hormonal therapy, toxin therapy, immunotherapy, cytokine therapy, targeted cancer therapy, gene therapy, photodynamic therapy, transplantation, etc. A combinatorial treatment may include a third or even further therapeutic modality. For combination treatment, it is appreciated that optimal concentration of each component of the combination can be determined by the artisan skilled in the art. The terms “chemotherapeutic drugs” or “immunotherapeutic products” as used herein refer to a product comprising one or more antigen(s) which is expected to induce or activate an immune response, whether specific or non-specific, humoral, or cellular, when delivered appropriately to a subject.Recombinant poxviruses expressing a conditional gene productRecombinant poxvirus for regulating the expression of toxic conditional gene products of said recombinant poxvirus in a producing cellIn a first aspect, the present invention relates to a recombinant poxvirus which repressthe conditional gene product to not interfere with the said recombinant poxvirus’production. Such recombinant poxvirus is especially advantageous in that the conditionalgene product expression does not affect its viability, replication, growth, and genomicand / or genetic stability. In the first aspect, the invention thus relates to: A recombinant poxvirus comprising in its genome at least one nucleic acid sequence encoding a conditional gene product, wherein the nucleic acid sequence encoding a conditional gene product is operably linked to at least one poxviral promoter and at least one Tetracycline operator (TetO) sequence; wherein expression of the nucleic acid sequence encoding a conditional gene product is inducible or repressible by the conditional binding of a transcriptional regulator protein; wherein said TetO sequence is inserted located upstream (5’ end), downstream (3’ end) and / or within of the poxviral promoter operably linked to said nucleic acid sequence encoding a conditional gene product; wherein the conditional gene product affects the viability of the recombinantpoxvirus. The TetO sequence is preferably located upstream (5’ end) of the poxviralpromoter operably linked to said nucleic acid sequence encoding a conditional gene product. Recombinant poxvirus for regulating the expression of conditional gene products of said recombinant poxvirus with an improved safety profile In a second aspect, the present invention relates to a recombinant poxvirus which regulate accurately the conditional gene product expression, including time and level of expression. Such recombinant poxvirus is especially advantageous in that it exhibits temporal control of conditional gene product expression under an exogenous signal to render safer the use of the recombinant poxvirus and which may be safely administered to subjects.In the second aspect, the invention thus relates to:A recombinant poxvirus comprising in its genome at least one nucleic acid sequence encoding a conditional gene product; wherein the nucleic acid sequence encoding a conditional gene product is operably linked to at least one poxviral promoter and at least one TetO sequence; and at least one nucleic acid sequence encoding a transcriptional regulator protein that conditionally binds to the TetO sequence; wherein said TetOsequence is located upstream (5’ end), downstream (3’ end) and / or within of the poxviralpromoter operably linked to said nucleic acid sequence encoding a conditional gene product; wherein expression of the conditional gene product is inducible or repressibleby a tetracycline antibiotic or a derivative thereof. The TetO sequence is preferablylocated upstream (5’ end) of the poxviral promoter operably linked to said nucleic acid sequence encoding a conditional gene product. PoxvirusIn the context of the invention (i.e. either the first aspect relating to a recombinantpoxvirus which repress the conditional gene product to not interfere with the said recombinant poxvirus’ production or the second aspect relating to a recombinant poxvirus which regulate accurately the conditional gene product expression, including time andlevel of expression), poxviruses form a broad family of DNA viruses containing a double-stranded genome. Over the course of their evolution, poxviruses have developed self-defence mechanisms through a repertoire of proteins involved in immune evasion andimmune modulation aimed at blocking many of the strategies employed by the host tocombat viral infections (Smith, S. A. and Kotwal, G. J. Crit. Rev. Microbiol. 2002;28(3):149-85). Typically, the poxvirus genome encodes more than 20 host response modifiers that allow the virus to manipulate host immune responses and, thus facilitate virus replication, spread, and transmission. These include growth factors, anti-apoptoticproteins, inhibitors of the NF-κΒ pathway and interferon signalling, and down-regulatorsof the major histocompatibility complex (MHC). In the native context, the poxvirus genome is a double-stranded DNA of approximately 200kb that has the potential of encoding nearly 200 proteins with different functions. Its genomic sequence and the encoded open reading frames (ORFs) are well known. The poxvirus of the invention comprises a genome which has been modified (in a laboratory,compared to the native form to provide a recombinant poxvirus) according to the presentdisclosure.In one embodiment, the recombinant poxvirus is a poxvirus of the Chordopoxvirinaefamily, preferably selected from the group consisting of Avipoxvirus genus ((includingCanarypoxvirus (e.g., ALVAC) and Fowlpoxvirus (e.g., the FP9 vector)), Capripoxvirusgenus, Leporipoxvirus genus, Molluscipoxvirus genus, Orthopoxvirus genus, Parapoxvirusgenus, Suipoxvirus genus, Cervidpoxvirus genus, Yatapoxvirus genus and chimeric poxvirusthereof.In a preferred embodiment, the recombinant poxvirus is a member of the Orthopoxvirusgenus, preferably selected from the group consisting of Vaccinia virus (VV), Cowpox virus(CPXV), raccoonpox virus (RCN), Rabbitpox virus (RPX), Monkeypox virus, Horsepox virus,Volepox virus, Skunkpox virus, Variola virus, Camelpox virus, Canarypox virus, ectromeliavirus and chimeric Orthopoxvirus thereof. Sequences of the genome of the various poxviruses are available in the art and in specialized databases (i.e., Genbank). For example, the Vaccinia virus, Cowpox virus, Canarypox virus, Myxoma virus genomes are available in specialized databases such asGenbank (accession number NC_006998.1 – last update on August 13, 2018; NC_003663.2- last update on January 7, 2023; NC_005309.1 – last update on January 7, 2023;NC_001132.2 – last update on January 7, 2023, respectively), genome of chimeric poxvirusreferenced as POXSTG19503 clone 7 deposited at the Collection Nationale de Cultures de Microorganismes (CNCM), Institut Pasteur, 25, rue du Docteur Roux, 75724 Paris Cedex 15, on 20 October 2022 under Accession Number CNCM I-5913 is disclosed in WO2024 / 038175.In a particular embodiment, the recombinant poxvirus of the invention is a Vaccinia virus.The terms “vaccinia virus”, “vaccinia virus particle”, “vaccinia virus vector” and “vaccinia virus virion” (also designated under “VACV” or “VV”) are used interchangeably.Vaccinia viruses are accessible via culture collections, like ATCC (e.g., VR-1354, VR-1549, VR-156, VR-117, VR-118). These terms encompass both wild-type, recombinant andchimeric vaccinia viruses thereof.In the native context, vaccinia viruses are large, complex, and enveloped viruses with a linear, double-stranded DNA genome of approximately 200kb in length that encodes numerous viral enzymes and factors that enable the virus to replicate independently fromthe host cell machinery. Two distinct infectious viral particles exist: the intracellularmature virion (IMV), surrounded by a single lipid envelop that remains in the cytosol ofinfected cells until lysis, and the double enveloped EEV (for extracellular envelopedvirion) that buds out from the infected cell. Any vaccinia virus strain can be used in the context of the present invention including Copenhagen (Cop), Western Reserve (WR),Elstree (also known as Lister), LIVP, Wyeth, Tian Tan, IHD, Modified Vaccinia virus Ankarastrains, etc., and any derivative thereof. The gene nomenclature used herein is that of Copenhagen vaccinia strain. It is also used herein for the homologous genes of other poxviridae unless otherwise indicated. However, gene nomenclature may be different according to the poxvirus strain but correspondence between Copenhagen and other vaccinia strains are generally available in the literature. Any vaccinia virus strain can be used in the context of the present invention including,without limitation, Copenhagen strain (Cop), Western Reserve strain (WR), Elstree strain,LIVP strain, Wyeth strain, IHD strain, Modified Vaccinia Virus Ankara and chimeric vaccinia virus thereof. In a particular embodiment, the recombinant poxvirus of the invention is a Vaccinia virus strain Copenhagen.In the context of the invention, poxviruses can be also used with modifications, includingmodifications aimed at improving safety (e.g., increased attenuation) and / or efficacy,and / or tropism of the resulting virus. One may cite also defective modifications withinthe thymidine kinase (J2R gene; see Buller, R. M. et al. Nature. 1985;317(6040):813-5);Genbank accession number AAA48082.1 – last update on March 15, 2006), the deoxyuridinetriphosphatase (F2L gene), the viral hemagglutinin (A56R gene), the small (F4L gene)and / or the large (I4L gene) subunit of the ribonucleotide reductase, the serine proteaseinhibitor (B13R / B14R gene), the complement 4b binding protein (C3L gene), the scaffoldassembly protein (D13L gene), and within genes like K1L, C7L, A39R and B7R-B8R. Exemplary modifications preferably concern viral genes involved in DNA metabolism, hostvirulence or IFN pathway (see e.g., Guse, K. et al., Expert Opinion Biol. Ther. 2011;11(5):595-608). A particularly suitable gene to be disrupted is the thymidine kinase (TK)-encoding gene(J2R gene; see Buller, R. M. et al. Nature. 1985;317(6040):813-5; Genbank accessionnumber AAA48082.1 – last update on March 15, 2006). The TK enzyme is involved in thesynthesis of deoxyribonucleotides. The TK is needed for viral replication in normal cellsas these cells have generally low concentration of nucleotides, whereas it is dispensablein dividing cells which contain high nucleotide concentration. Further, TK-defectiveviruses are known to have an increased selectivity to tumor cells. In some embodiments,the recombinant poxvirus is modified in the J2R gene (preference for modificationresulting in a suppressed expression of the viral TK protein), resulting in a recombinantpoxvirus defective for TK activity (TK- or ΔTK). Partial or full deletion of said J2R gene aswell as insertion of foreign nucleic acid in the J2R gene are contemplated in the contextof the present invention to inactivate TK function.Alternatively to or in combination with, the recombinant poxvirus may be modified in theI4L and / or F4L gene / genes (preference for modification leading to a suppressedexpression of the viral ribonucleotide reductase (RR) protein), resulting in a recombinantpoxvirus defective for RR activity (RR- or ΔRR). In the natural context, this enzymecatalyses the reduction of ribonucleotides to deoxyribonucleotides that represents acrucial step in DNA biosynthesis. The viral enzyme is similar in subunit structure to the mammalian enzyme, being composed of two heterologous subunits, designed R1 and R2encoded respectively by the I4L and F4L genes. Sequences for the I4L and F4L genes andtheir location (locus) in the genome of various poxvirus are available in public databases(see e.g., WO2009 / 065546). In the context of the invention, the recombinant poxviruscan be modified either in the I4L gene (encoding the R1 large subunit) or in the F4L gene(encoding the R2 small subunit) or both to provide a RR- recombinant poxvirus, forexample, by partial or full deletion of said I4L and / or F4L gene / genes.Also provided is a recombinant poxvirus modified in the J2R and in the I4L and / or F4Lgenes (double defective poxvirus with modifications in the J2R and I4L genes; J2R andF4L genes; or J2R, I4L and F4L genes), resulting in a recombinant poxvirus defective forTK and RR activities (TK- RR- or ΔTK ΔRR).In some embodiments, the simple, or double defective recombinant poxvirus is a chimericpoxvirus, a chimeric orthopoxvirus or a vaccinia virus. A chimeric poxvirus, a chimericorthopoxvirus or a vaccinia virus defective for TK and RR activities (oVV ΔTKΔRR) areparticularly preferred, especially for use for stimulating or improving an immune response(e.g., a lymphocyte-mediated response against an antigen or epitope thereof), or for usefor treating a cancer as described herein.Alternatively, or in combination with, the recombinant poxvirus modified in J2R locus, inone or both of the I4L and F4L loci, or in the J2R locus and in one or both of the I4L andF4L loci, the recombinant poxvirus may be further modified in the M2L gene (preferencefor modification leading to a suppressed expression of the viral m2 protein, such as M2L locus deletion).In one embodiment, the recombinant poxvirus is modified in J2R locus and in the M2Llocus, resulting in a recombinant poxvirus defective for both m2 and TK activities (TK-M2- or ΔTK ΔM2). Partial or complete deletion of said M2L locus and / or J2R locus as wellas insertion of foreign nucleic acid in the M2L locus and / or J2R locus are contemplated in the context of the present invention to inactivate m2 and tk functions.In another embodiment the recombinant poxvirus is modified in one or both of the I4Land F4L loci and in M2L locus, resulting in a recombinant poxvirus defective for both m2 and RR activities. In the context of the invention, the recombinant poxvirus can be modified either in the I4L gene (encoding the R1 large subunit) or in the F4L gene (encoding the R2 small subunit) or both to provide a RR-defective recombinant poxvirus. E.g.: by partial or complete deletion of said I4L and / or F4L locus / loci. In another embodiment, the recombinant poxvirus is defective in the J2R locus, in one or both of the I4L and F4L loci, and in the M2L locus (triple defective virus with modifications in the M2L, J2R and I4L loci; M2L, J2R and F4L loci or M2L, J2R, I4L and F4L loci), resultingin a recombinant poxvirus defective for M2, TK and RR activities (m2-, tk-, rr-recombinant poxvirus). Other suitable additional modifications include those resulting in suppressed expression of one or more viral gene product(s) selected from the group consisting of the viralhemagglutinin (A56R gene), the serine protease inhibitor (B13R / B14R gene), thecomplement 4b binding protein (C3L gene), the VGF-encoding gene and the interferonmodulating gene(s) (B8R or B18R / B19R gene). Another suitable modification comprisesthe inactivation of the F2L gene resulting in suppressed expression of the viral dUTPase(deoxyuridine triphosphatase) involved in both maintaining the fidelity of DNA replicationand providing the precursor to produce thymidine monophosphate (TMP) by thymidylatesynthase (WO2009 / 065547). As for B19R, the gene nomenclature used herein is that of Vaccinia virus strain Copenhagen. It is also used herein for the homologous genes of other poxviridae unless otherwise indicated and correspondence between Copenhagen and other poxviruses is available to the skilled person. Preferred modifications include: (i) inactivating mutations in the J2R gene,(ii) inactivating mutations in the I4L and / or F4L gene(s),(iii) inactivating mutations in the J2R gene and inactivating mutations in the I4Land / or F4L gene(s),(iv) inactivating mutations in the J2R gene, and inactivating mutations in the M2Lgene, (v) inactivating mutation in the I4L and / or F4L gene(s), and inactivating mutationsin the M2L gene, or(vi) inactivating mutations in the J2R gene, inactivating mutations in the I4Land / or F4L gene(s), and inactivating mutations in M2L gene.In one embodiment, the recombinant poxvirus is advantageously an orthopoxvirus,preferably selected from the group consisting of Vaccinia virus, Cowpox virus, Raccoonpoxvirus, Rabbitpox virus, Monkeypox virus, Horsepox virus, Volepox virus, Skunkpox virus, Variola virus, Camelpox virus, canarypox virus, ectromelia virus and chimeric Orthopoxvirus thereof, which preferably comprises: (i) inactivating mutations in the J2R gene,(ii) inactivating mutations in the I4L and / or F4L gene(s), or(iii) inactivating mutations in the J2R gene and inactivating mutations in the I4Land / or F4L gene(s),(iv) inactivating mutations in the J2R gene, and inactivating mutations in the M2Lgene,(v) inactivating mutations in the I4L and / or F4L gene(s), and inactivatingmutations in the M2L gene, or(vi) inactivating mutations in the J2R gene, inactivating mutations in the I4Land / or F4L gene(s), and inactivating mutations in the M2L gene.In one embodiment, the recombinant poxvirus is advantageously a Vaccinia virus,preferably selected from the group consisting of Copenhagen, Western Reserve, Elstree,LIVP, Wyeth, Tian Tan, IHD, Modified Vaccinia Virus Ankara and chimeric vaccinia virus thereof, which preferably comprises: (i) inactivating mutations in the J2R gene,(ii) inactivating mutations in the I4L and / or F4L gene(s),(iii) inactivating mutations in the J2R gene and inactivating mutations in the I4Land / or F4L gene(s),(iv) inactivating mutations in the J2R viral gene, and inactivating mutations in theM2L gene,(v) inactivating mutations in the I4L and / or F4L gene(s), and inactivatingmutations in the M2L gene, or(vi) inactivating mutations in the J2R gene, inactivating mutations in the I4Land / or F4L gene(s), and inactivating mutations in the M2L gene.In a particularly preferred embodiment, the recombinant poxvirus is a Vaccinia virusstrain Copenhagen comprising inactivating mutations in the J2R gene and inactivatingmutations in the I4L and / or F4L gene(s).In another particularly preferred embodiment, the recombinant poxvirus is a chimericorthopoxvirus comprising inactivating mutations in the J2R gene and inactivatingmutations in the I4L and / or F4L gene(s). Even more preferably, the recombinant poxvirusis a POXSTG19503 clone 7 comprising inactivating mutations in the J2R gene andinactivating mutations in the I4L and / or F4L gene(s).Conditional gene product of the recombinant poxvirus and / or heterologous nucleicacid of interestThe nucleic acid sequence encoding the conditional gene product as defined below isinserted into the genome of the recombinant poxvirus by any appropriate technique known in the art.As used herein, a “conditional gene product” refers to a heterologous gene or a foreigngene inserted into the viral genome for which the expression is inducible or repressibleby an exogeneous signal. Recombinant poxvirus for regulating the expression of toxic conditional gene products of said recombinant poxvirus in a producing cellIn the context of the first aspect of the invention (recombinant poxvirus which repressthe conditional gene product to not interfere with the said recombinant poxvirus’production), it is intended that if the conditional gene product is not downregulated, itaffects the viability of the recombinant poxvirus by interfering with the replication and / orthe genomic / genetic stability of the recombinant poxvirus. In the first aspect of theinvention, a conditional gene product may also be referenced as a detrimental heterologous gene product.In some embodiments of the first aspect, the conditional gene product is a toxicconditional gene product. In particular embodiments, the conditional gene product istoxic for a host cell. As used herein, the term “toxic” refers to the activity of a compoundto have a deleterious effect on the host cell by inhibiting its proliferation or for therecombinant poxvirus, for example by inhibiting its replication. In one embodiment, the conditional gene product is selected from the group consistingof bacterial toxins, plant toxins, enzymes, cytokines, self-antigens, virus genes. Inanother embodiments, the conditional gene product interferes with the replication of the recombinant poxvirus. Examples of conditional gene product defined as toxic according to the first aspect of theinvention include without limitation gene products selected from the groups consistingof:- bacterial toxins, such as diphtheria toxin (DT-A), Pseudomonas exotoxin,Clostridium perfringens enterotoxin, Streptolysin O, Enterotoxin H; -plant toxins such as ricin, abrin, pokeweed antiviral protein, Gypsophilin-S,saporin or gelonin; -enzymes such as SAMHD1, nitric oxide synthetases eNOS or iNOS;- cytokines such as IL-12, TGF beta or TGF gamma;- self-antigens such as HER2 / neu, CEA, Hepcam, PSA, PSMA, Telomerase, gplOO,Melan- A / MART- 1, Muc-1, NY-ESO-1, Survivin, Stromelysin 3, Tyrosinase, MAGE3,CML6S, CML66, OY-TES-1, SSX- 2, SART-1, SART-2, SART-3, NYC0-5S, NY-BR-62,hKLP2 and VEGF; -virus genes such as HBV Core-Envelope protein, human immunodeficiency virus(HIV) envelope glycoprotein, HCV E1-E2 protein, rabies glycoprotein, HIV-1 gp160, HIV-1 gp140, vesicular stomatitis virus G glycoprotein; and -any polypeptides that are toxic for the host cell or interfere with the replicationof the recombinant poxvirus. In one embodiment, the recombinant poxvirus of the first aspect of the invention further comprises in its genome one or more heterologous nucleic acid of interest, preferably a therapeutic molecule. In particular embodiments, the therapeutic molecule is selected from the list consisting of immune checkpoint inhibitors, cytokines, agents that affect the regulation of cell surface receptors, agents that affect angiogenesis, agents thatstimulates stem cells to produce granulocytes and / or macrophages or a combinationthereof. Recombinant poxvirus for regulating the of conditional of said recombinant In the context of the second aspect of the invention (recombinant poxvirus which regulateaccurately the conditional gene product expression, including time and level of express),it is intended that if the conditional gene product presents a risk or produces adverseeffects for the subject, it may be regulable by tetracycline or derivative thereof. In thecontext of the second aspect of the invention, the conditional gene product is then atherapeutic molecule. In some embodiments, the therapeutic molecule is selected from the list consisting of immune checkpoint inhibitors, cytokines, agents that affect the regulation of cell surface receptors, agents that affect angiogenesis, agents that stimulates stem cells to produce granulocytes and / or macrophages and a combination thereof. In a particular embodiment, the conditional gene product is toxic for a host cell or a mammalian host. Therapeutic polypeptideA “therapeutic polypeptide” or “therapeutic molecule” refer to a polypeptide ormolecule which is of therapeutic or prophylactic interest when administered appropriately to a subject, leading to a beneficial effect on the course or a symptom of the pathological condition to be treated or prevented. The term “immunomodulatory polypeptide” encompasses polypeptides targeting a component of a signalling pathway that can be involved in modulating, regulating, or modifying an immune response (up ordownregulation) either directly or indirectly. “Modulating”, “regulating”, or“modifying” an immune response refers to any alteration in an immune or in the activity of said immune cell (e.g., a T cell). Such modulation, interchangeably referred to as regulation or modification, includes stimulation or suppression of the immune system which can be manifested by an increase or decrease in the number of various cell types, an increase or decrease in the activity of these cells, or any other changes which can occur within the immune system. Preferably, such a polypeptide is capable of down- regulating at least partially an inhibitory pathway (antagonist) and / or up-regulating at least partially a stimulatory pathway (agonist); in particular, the immune pathway existing between effector immune cells, such as an antigen presenting cell (APC) or a cancer cell and an effector T cell. In some embodiments, the immunomodulatory polypeptide provides favourable conditions for the activation, recruitment, proliferation, activity and / or survival of effector immune cells (e.g., cytotoxic T cells (CTLs), T Helper 1 (TH1) cells, Natural Killer (NK) cells or Natural Killer T (NKT) cells). According to the first or second aspect of the invention, the nucleic acid(s) sequence(s) encoding the therapeutic molecule(s) can originate from Prokaryotes (comprising the kingdoms of Bacteria, Archaea), Acaryotes (comprising the viruses) or Eukaryotes (comprising the kingdoms of Protista, Fungi, Plantae, Animalia). Advantageously, said nucleic acid(s) of interest encodes all or part of a polypeptide. A polypeptide is understood to be any translational product of a polynucleotide regardless of size, and whether glycosylated or not, and includes peptides and proteins.In one embodiment of the first or second aspect of the invention, the nucleic acid ofinterest encodes a polypeptide of therapeutic interest, which is capable of providing a biological activity when administered appropriately to a subject or which is expected to cause a beneficial effect on the course or a symptom of the pathological condition to be treated. A vast number of nucleic acids of interest may be envisaged in the context of the invention such as those encoding polypeptides that can compensate for defective or deficient proteins in the subject, or those that act through toxic effects to limit or remove harmful cells from the body or those that encode immunity conferring polypeptides. They may be native or obtained from the latter by mutation, deletion, substitution and / or addition of one or more nucleotides. Representative examples of suitable polypeptides of therapeutic interest include, without limitation, polypeptides capable of potentiating anti-tumor efficacy (such as immunostimulatory polypeptides), as well as antigens for inducing or activating an immune humoral and / or cellular response, suicide polypeptideswhich are capable of reinforcing the nature of the recombinant poxvirus of the presentinvention, or permease to increase the cellular nucleoside or nucleotide pool among many others. The present invention also encompasses recombinant poxvirus expressing two or more polypeptides of interest as described herein, e.g.: at least two antigens, at least one antigen and one cytokine, at least two antigens and one cytokine, etc. Immunostimulatory polypeptide One embodiment of the invention (first or second aspect) is directed to a recombinantpoxvirus further comprising an immunostimulatory polypeptide. As used herein, the term“immunostimulatory polypeptide” refers to a polypeptide, or protein, which has theability to stimulate the immune system, in a specific or non-specific way. A vast number of proteins are known in the art for their ability to exert an immunostimulatory effect. Examples of suitable immunostimulatory proteins in the context of the invention include, without limitation, immune checkpoint inhibitors, including, but not limited to anti-PD1, anti-PDL1, anti-PDL-2, anti-CTLA4, anti-Tim3, anti-LAG3, anti-BTLA; cytokines, like alpha, beta or gamma interferon, interleukins or tumor necrosis factor; agents that affect the regulation of cell surface receptors such as, e.g. inhibitors of Epidermal Growth Factor Receptor (in particular cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, gefitinib, erlotinib or lapatinib) or inhibitors of Human Epidermal Growth Factor Receptor-2 (in particular trastuzumab); agents that affect angiogenesis such as, e.g. inhibitor of Vascular Endothelial Growth Factor (in particular bevacizumab or ranibizumab) ; agents that stimulate stem cells to produce granulocytes, macrophagessuch as, e.g. granulocyte macrophage – colony stimulating factor and B7 proteins.Antigens Another embodiment of the invention (first or second aspect) is directed to a poxvirusfurther encoding an antigen. The term “antigen” generally refers to a substance that isrecognized and selectively bound by an antibody or by a T cell antigen receptor, in order to trigger an immune response. It is contemplated that the term antigen encompasses native antigen as well as fragment (e.g.: epitopes, immunogenic domains, etc.) and analogue thereof, provided that such fragment or analogue is capable of being the target of an immune response. Suitable antigens in the context of the invention are preferably polypeptides (e.g.: peptides, polypeptides, post translationally modified polypeptides, etc.) including one or more B cell epitope(s) or one or more T cell epitope(s) or both B and T cell epitope(s) and capable of raising an immune response, preferably, a humoral or cell response that can be specific for that antigen. Typically, the one or more antigen(s) is selected in connection with the disease to treat. Preferred antigens for use herein are cancer antigens and antigens of tumor-inducing pathogens. In certain embodiments, the antigen(s) encoded by the recombinant poxvirus is / are cancer antigen(s) (also called tumor-associated antigens) that is associated with and / or serve as markers for cancers. Cancer antigens encompass various categories of polypeptides, e.g. those which are normally silent (i.e. not expressed) in healthy cells (preferably primary cells), those that are expressed only at low levels or at certain stages of differentiation and those that are temporally expressed such as embryonic and fetalantigens as well as those resulting from mutation of cellular genes, such as oncogenes(e.g. activated ras oncogene), proto-oncogenes (e.g. ErbB family), or proteins resulting from chromosomal translocations. The cancer antigens also encompass antigens encoded by pathogenic organisms (bacteria, viruses, parasites, fungi, viroids or prions) that are capable of inducing a malignant condition in a subject (especially chronically infected subject) such as RNA and DNA tumor viruses (e.g.: HPV, HCV, EBV, etc.) and bacteria (e.g.: Helicobacter pilori). Cancer antigens can also be neoantigens, which are specific for a patient’s tumor, and used for personalized medicine (WO2018 / 234506). Some non-limiting examples of cancer antigens include, without limitation, MART- 1 / Melan-A, gp100, Dipeptidyl peptidase IV (DPPIV), cyclophilin b, Colorectal associated antigen, Carcinoembryonic Antigen (CEA) , Prostate Specific Antigen (PSA) , prostate- specific membrane antigen (PSMA), T-cell receptor / CD3-zeta chain, MAGE-family of tumor antigens, GAGE-family of tumor antigens, BAGE, RAGE, LAGE-1, NAG, GnT-V, MUM- 1, CDK4, tyrosinase, p53, MUC family (e.g. MUC1, MUC16, etc.; see e.g. US6,054,438; WO98 / 04727; or WO98 / 37095), HER2 / neu, p21ras, alpha-fetoprotein, E-cadherin, catenin family, and viral antigens such as the HPV-16 and HPV-18 E6 and E7 antigens. Other antigens suitable for use in this invention are marker antigens (beta-galactosidase, luciferase, green fluorescent proteins, etc.). Suicide polypeptide In one embodiment, the recombinant poxvirus of the invention (first or second aspect)may further encode at least a suicide polypeptide. The term “suicide polypeptide” refersto a polypeptide able to convert a precursor of a drug, also named “prodrug”, into a cytotoxic compound. Examples of suicide polypeptides suitable for use herein and corresponding prodrugs are disclosed in the following table: Suicide polypeptideProdrugThymidine Kinase Ganciclovir;Ganciclovir elaidic acid ester; Penciclovir; Acyclovir; Valacyclovir; I-5-(2-bromovinyl)-2’-deoxyuridine; Zidovudine; 2’-Exo-methanocarbathymidine Cytosine deaminase 5-Fluorocytosine Purine nucleoside phosphorylase 6-Methylpurine deoxyriboside ;Fludarabine Uracil phosphoribosyl transferase 5-Fluorocytosine ;5-Fluorouracil Thymidylate kinase Azidothymidine Permease According to another embodiment, the recombinant poxvirus of the invention (first or second aspect) may further comprise a nucleic acid sequence(s) encoding a therapeutic molecule which is a permease. As used herein, the term “permease” refers to trans-membranous proteins involved in the translocation of nucleoside and nucleobases. Examples of permeases which are involved in the translocation of nucleosides, nucleoside analogues and nucleobases are hCNT1, hCNT2, hCNT3, hENT1 and hENT2. hCNT1, hCNT2 and hCNT3 proteins translocate nucleosides in a Na+ coupled manner with high affinity and some substrate selectivity,being hCNT1 and hCNT2 pyrimidine – and purine – preferring, respectively, and hCNT3abroad selectivity transporter. hENT1 and hENT2 are unequivocally implicated in the translocation of nucleosides and nucleobases (Pastor-Anglada et al, 2015, Front. Pharmacol., 6(13):1-14). Other nucleic acids of interest Other nucleic acids of interest include, but are not limited to: -Nucleoside pool modulators (e.g.: cytidine deaminase, like yeast cytidinedeaminase (CDD1) or human cytidine deaminase (hCD) (see EP3562946)) -Agents targeting metabolic immune modulators (e.g.: adenosine deaminase likehuman adenosine deaminase (huADA1 or huADA2) (see EP17306012.0)) -Apoptotic genes, including pro-apoptotic genes, inhibitors of pro-apoptotic genes,anti-apoptotic genes and inhibitors of anti-apoptotic genes, -Nucleic acid coding for endonuclease, like restriction enzymes, CRISPR / Cas9- RNA, including but not limited to target-specific miRNA, shRNA, siRNA.The nucleic acid(s) of interest (herein conditional gene product and / or heterologousnucleic acid of interest) sequences may be easily obtained by cloning, by PCR or bychemical synthesis using conventional techniques. They may be native nucleic acid(s) sequences (e.g.: cDNA) or sequences derived from the latter by mutation, deletion, substitution and / or addition of one or more nucleotides. Moreover, their sequences are described in the literature which can be consulted by persons skilled in the art. Insertion of the nucleic acid sequences encoding the conditional gene product and / or the heterologous nucleic acid of interest into the poxvirusThe nucleic acid sequences encoding the conditional gene product and / or theheterologous nucleic acid of interest may be inserted in any suitable location withingenome of the recombinant poxvirus of the invention (first or second aspect), e.g., withina viral gene, an intergenic region, in a non-essential gene or region or in place of viral sequences. Preference is given to insertion within the viral genome in a non-essentiallocus (e.g.: within J2R, I4L, F4L, M2L or VEGF loci), in an intergenic region, in a portionof the viral genome which does not encode gene products or in a duplicated locus.Insertion into the genome of the recombinant poxvirus can be performed by routinemolecular biology, e.g., as described in Sambrook et al. (Sambrook, J. and Russell, D. W.Cold Spring Harbor Laboratory Press. 2001;3rd ed.). Particularly, it can be performedthrough homologous recombination as described respectively in Chartier et al. (Chartier, C. et al. J. Virol. 1996;70(7): 4805-10) and Paul et al. (Paul, S. Cancer gene Ther. 2002; 9(5): 470-7). In the embodiment wherein the recombinant poxvirus further comprises in its genome one or more heterologous nucleic acid of interest, the nucleic acid(s) encoding the therapeutic molecule(s) of interest can be independently optimized for providing high level expression in a particular host cell or subject. It has been indeed observed that, thecodon usage patterns of organisms are highly non-random, and the use of codons may bemarkedly different between different hosts. As such nucleic acid(s) might be from bacterial or lower eukaryote origin, they may have an inappropriate codon usage pattern for efficient expression in higher eukaryotic cells (e.g.: human). Typically, codon optimization is performed by replacing one or more “native” (e.g.: bacterial or yeast) codon, corresponding to a codon infrequently used in the host organism of interest, by one or more codon encoding the same amino acid which is more frequently used. It is not necessary to replace all native codons corresponding to infrequently used codons since increased expression can be achieved even with partial replacement. Further to optimization of the codon usage, expression in the host cell or subject can further be improved through additional modifications of the nucleic acid sequence(s) of interest. For example, it may be advantageous to prevent clustering of rare, non-optimal codons being present in concentrated areas and / or to suppress or modify “negative” sequence elements which are expected to negatively influence expression levels. Such negative sequence elements include without limitation the regions having very high (>80%) or very low (<30%) GC content; AT-rich or GC-rich sequence stretches; unstable direct or inverted repeat sequences; and / or internal cryptic regulatory elements such as internal TATA-boxes, chi-sites, ribosome entry sites, and / or splicing donor / acceptor sites. In a specific embodiment of the present invention, the recombinant poxvirus comprises the elements necessary for the expression of the nucleic acid(s) of interest in a host cellsubject. Specifically, such nucleic acid(s) is / are operably linked to suitable regulatoryelements that allow, contribute or modulate expression in a given host cell or subject, including replication, duplication, transcription, splicing, translation, stability and / or transport of the nucleic acid(s) or its derivative (i.e.: mRNA). It will be appreciated by those skilled in the art that the choice of the regulatory sequences can depend on such factors as the nucleic acid molecule itself, the virus into which it is inserted, the host cell or subject, the level of expression desired, etc. The promoter is of special importance. In the context of the invention, it can be constitutive directing expression of the encoded product (e.g.: polypeptide(s) encoded by a cytidine gene) in many types of host cells or specific to certain host cells (e.g.: liver-specific regulatory sequences) or regulated in response to specific events or exogenous factors (e.g.: by temperature, nutrient additive, hormone, etc.) or according to the phase of a viral cycle (e.g.: late or early). One may also use promoters that are repressed during the production step in response to specific events or exogenous factors, in order to optimize the chimeric poxvirus production and circumvent potential toxicity of the expressed polypeptide(s). Vaccinia virus promoters are particularly adapted in the context of the invention. Representative examples include without limitation the vaccinia p7.5K, pH5R, p11k7.5 (Erbs et al., 2008, Cancer Gene Ther. 15(1): 18-28), pSE, pTK, p28, p11, pB2R, pF17R, pA14L, pSE / L, pA35R, pK1L, pPr13.5 (WO2014 / 063832), pB8R, pF11L, pA44L, pC11R (WO2011 / 128704), as well as synthetic promoters such as those described in Chakrabarti et al. (1997, Biotechniques, 23: 1094-7; Hammond et al., 1997, J. Virol. Methods, 66: 135-8; and Kumar and Boyle, 1990, Virology, 179: 151-8) as well as early / late chimeric promoters (e.g.: US 8,394,385; US 8,772,023). Cowpox promoters are also suitable as well (e.g.: the ATI promoter). Those skilled in the art will appreciate that the regulatory elements controlling the nucleic acid expression may further comprise additional elements for proper initiation, regulation and / or termination of transcription (e.g. a transcription termination sequences), mRNA transport (e.g. nuclear localization signal sequences), processing (e.g. splicing signals), and stability (e.g. introns and non-coding 5’ and 3’ sequences), translation (e.g. an initiator Met, tripartite leader sequences, IRES ribosome binding sites, signal peptides, etc.), targeting sequences, transport sequences, secretion signal, andsequences involved in replication or integration. Said sequences have been reported inthe literature and can be readily obtained by those skilled in the art. Inducible or repressible expression of the conditional gene productIn the context of the invention (first or second aspect), the conditional gene product isoperably linked to at least one poxviral promoter and at least one TetO sequencerendering the expression of the nucleic acid sequence encoding the conditional gene product inducible or repressible by the conditional binding of a transcriptional regulator protein.The term “conditional binding” as used herein refers to the ability of the transcriptionalregulator protein to bind to the TetO sequence in response to specific events or exogenousfactors (e.g.: by temperature, nutrient additive, hormone, etc.). In the context of the invention, the transcriptional regulator protein conditionally binds to the TetO sequence either in the presence or absence of a tetracycline antibiotic or a derivative thereto, according to the nature of the transcriptional regulator protein.In the context of the invention (first or second aspect), it is intended that the term“promoter” includes full-length promoter or at least a functional fragment thereof.In some embodiments, the poxviral promoter is selected from late, intermediate, orearly / late poxviral promoters. A “late promoter” is a promoter that is naturally associated with expression of a late gene. An “intermediate promoter” is one that controls the expression of a gene that follows early gene expression but is not controlled by a late promoter. Genes expressed early in the viral lifecycle preceding intermediate and late gene expression are termed “early promoters”. The expression of late and intermediate genes controlled by intermediate / late promoters depends on viral replication (as opposed to expression of an early gene whose expression does not depend on viral replication). The timeframe of expression of early, intermediate, and late promoters is a distinguishing factor, asdiscussed in Yang, Z. et al. J Virol. 2011;85(19): 9899-908, citing Baldick, C. J. Jr., andMoss, B. J Virol. 1993;67(6): 3515-27, each of which is incorporated by reference herein. Baldick and Moss disclosed that early-, intermediate-, and late-class mRNAs can be detected in 20, 100, and 140 mins respectively, after synchronous infection of HeLa cells with vaccinia viruses. Yang prepared a genome-wide early, intermediate, and late transcription map which revealed distinctive characteristics of intermediate and late promoters. As used herein, the terms “intermediate promoter” and “late promoter” can refer to any of the intermediate and late promoters discussed in Yang, Z. et al (Yang, Z.et al. J Virol. 2011;85(19): 9899-908).Exemplary poxviral late and intermediate promoters include but are not limited to: pI1L, pA3L, pA10L, pA11R, pA12L, pA13L, pA14L, pA19L, pA26L, pA27L, pA42R, pD13L, pG7L, pF17R, and pWR148. Exemplary poxviral early promoters include but are not limited to:pB2R, pC11R, and pA35R. Exemplary poxviral early / late promoters include but are notlimited to: p11K7.5, pH5R, pSE / L and p7.5K.In one embodiment, the poxviral promoter is a late or an intermediate poxviral promoterselected from the list consisting of pF17R, pA14L, pA3L, pA10L, pA13L, pA19L, pA42R, pD13L, pI1L and pWR148 promoters, preferably pF17R and pA14L promoters. In particularembodiments, the late or intermediate poxviral promoter comprises a nucleic acidsequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or even 100% of identity with SEQ ID NO: 4, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 87, or SEQ ID NO: 89. In a preferred embodiment, the late or intermediate poxviral promoter comprises atranscriptional initiator element. As used herein, the term “transcriptional initiatorelement” refers to a nucleic acid sequence that overlaps a transcription start site and issufficient to initiate a basal transcription without a functional TATA box in the promoter.In a particularly preferred embodiment, the transcriptional initiator element is anucleotides sequence of TAAATG or TAAATA, and preferably TAAATA.In another embodiment, the poxviral promoter is an early / late poxviral promoter selectedfrom the list consisting of pSE / L, p11K7.5, p7.5K and pH5R promoters. In particularembodiments, the early / late poxviral promoter comprises a nucleic acid sequence havingat least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or even 100% of identity with SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 18, or SEQ ID NO: 25. In a preferred embodiment, the early / late poxviral promoter comprises a transcriptional initiator element. In a particularly preferred embodiment,the transcriptional initiator element is a nucleotides sequence of TAAATA, ATTTATTGCA(SEQ ID NO: 107) or GTTCTTGAGG (SEQ ID NO: 108).In some embodiments, the TetO sequence is positioned upstream (5’ end) or downstream(3’ end) of the transcriptional initiator element. In particular embodiments, the TetOsequence positioned upstream or downstream of the transcriptional initiator element isseparated to the transcriptional initiator element by an interval of 0 to 100 nucleotides,preferably 0 to 80 nucleotides, more preferably 0 to 60 nucleotides.In a preferred embodiment, the TetO sequence is positioned upstream of the 5’ end ofthe transcriptional initiator element. In a preferred embodiment, the TetO sequencepositioned upstream is separated to the 5’ end of the transcriptional initiator element by an interval of 30 to 100 nucleotides, preferably 30 to 80 nucleotides, more preferably 30to 60 nucleotides. In a more preferred embodiment, the TetO sequence positionedupstream is separated to the 5’ end of the transcriptional initiator element by an interval of 30 to 100 nucleotides, preferably 30 to 80 nucleotides, more preferably 30 to 60 nucleotides, wherein the poxviral promoter is a late or an intermediate poxviral promoter, preferably a pF17R or a pA14L promoter.In another embodiment, the TetO sequence is positioned downstream of the 3’ end of thetranscriptional initiator element. In a preferred embodiment, the TetO sequencepositioned downstream is separated to the 3’ end of the transcriptional initiator elementby an interval of 0 to 50 nucleotides, preferably 0 to 30 nucleotides, more preferably 0 to 20 nucleotides.As used herein, the terms “Tetracycline operator” or “TetO” refers to a nucleic acidsequence to which a transcriptional regulator protein specifically and conditionally binds.Once coupled, associated or fused to a poxviral promoter, it induces or represses thetranscription of the conditional gene product to which they are operably linked. The binding sites for the transcriptional regulator protein in the TetO consist of 19 bp sequences.In some embodiments, the TetO sequence is selected from the group consisting of TetO1and TetO2 sequences, preferably the TetO sequence is TetO2 sequence. In oneembodiment, the TetO sequence is a TetO2 sequence and comprises or consists of anucleic acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least96%, at least 97%, at least 98%, at least 99%, or even 100% of identity with SEQ ID NO: 109or SEQ ID NO: 110. In a further embodiment, the TetO sequence is a TetO1 sequence andcomprises or consists of a nucleic acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or even 100% ofidentity with SEQ ID NO: 111 or SEQ ID NO: 112.In a further embodiment, the recombinant poxvirus comprises in its genome at least two nucleic acid sequences encoding respectively two conditional gene products, wherein the nucleic acid sequences encoding the two conditional gene products are operably linked respectively to two poxviral promoters and one TetO sequence. In a preferredembodiment, the TetO sequence is located upstream of the two poxviral promotersoperably linked to the two nucleic acid sequences encoding two conditional gene products. In a further preferred embodiment, the two poxviral promoters operably linked to the two nucleic acid sequences encoding two conditional gene products are oriented in back-to-back, with said TetO sequence located between the two poxviral promoters.Recombinant poxvirus comprising nucleic acid sequences encoding respectively aconditional gene product and a transcriptional regulator proteinIn one embodiment, the recombinant poxvirus further comprises a nucleic acid sequenceinserted in its genome encoding at least a transcriptional regulator operably linked to aconstitutive poxviral promoter. This embodiment is particularly preferred in the secondaspect of the invention (recombinant poxvirus which regulate accurately the conditional gene product expression, including time and level of express), and may also apply to thefirst aspect of the invention. In a preferred embodiment, the transcriptional regulatoroperably linked to a constitutive poxviral promoter is inserted in the I4L or F4L locus.As used herein, a “transcriptional regulator protein” or “transcriptional factorprotein” refer to a protein that binds to a DNA locus, herein the TetO sequence, to repress the transcription of a DNA sequence. The binding of the transcriptional regulatorprotein to the DNA may be lifted in the presence or absence (depending of the variant ofthe transcriptional regulator protein) of a substance, for example a tetracycline antibioticor a derivative thereof. In the present disclosure, it is referred to an “inducible transcriptional regulator” wherein such protein is bound to the DNA in absence of thesubstance, for example the tetracycline antibiotic or a derivative thereof, and whereinthe transcription of the associated gene may be induced by the addition of such substance(thereby reverting the binding of the protein to the DNA). In another embodiment, in thepresent disclosure, it is referred to an “repressible transcriptional regulator” whereinsuch protein is bound to the DNA in presence of the substance for example thetetracycline antibiotic or a derivative thereof and wherein the transcription of theassociated gene may be repressed by the addition of such substance (thereby allowingthe binding of the protein to the DNA). The transcriptional regulator proteins may beactivated or deactivated by a number of mechanisms including binding of a substance,interaction with other transcription factors (e.g., homo- or heterodimerization) orcoregulatory proteins, phosphorylation, and / or methylation. In the context of the invention, the transcriptional regulator protein conditionally binds to the said TetO sequence either in the presence or absence of a tetracycline antibiotic or a derivative thereto. In one embodiment, the transcriptional regulator protein is an inducible transcriptionalregulator protein in which the induction would be effective in the presence of atetracycline antibiotic or a derivative thereof. In such embodiment of the presentinvention, an inducible transcriptional regulator protein is a TetR protein and is selectedfrom the group consisting of TetR (SEQ ID NO: 73) and TetR_BD (SEQ ID NO: 74) variants.In a preferred embodiment, the inducible transcriptional regulator protein is TetR defined by SEQ ID NO: 73.Another interest of the invention is to use alternatively to the TetR protein a reverse TetRprotein (also known as RevTetR protein or revTetR protein), thus creating a repressibletranscriptional regulator in which the repression would be effective in the presence oftetracycline antibiotic or a derivative thereof. Indeed, the mutagenesis studies haveshown that the response of TetR can be reversed, causing such revTetR to act as arepressible transcriptional regulator. In such embodiment, the transcriptional regulatorprotein is a repressible transcriptional regulator protein in which the repression would beeffective in the presence of a tetracycline antibiotic or a derivative thereof. In thecontext of such embodiment, the repressible transcriptional regulator protein is aRevTetR protein and is selected from the list consisting of revTetR(B) and revTetR(BD)proteins. In one embodiment, the RevTetR(B) protein may be selected among M2_72P(SEQ ID NO: 65) and M2_72A (SEQ ID NO: 66) variants. In another embodiment, theRevTetR(DB) protein may be selected among RevTetR r6.2 (SEQ ID NO: 69), revTetR r1.7(SEQ ID NO: 70), revTetR r6.39 (SEQ ID NO: 72) and revTetR r4.29 (SEQ ID NO: 71) variants.In such embodiments, the transcriptional regulator conditionally binds to the TetO sequence either in the presence or absence of a tetracycline antibiotic or a derivative thereof, therefore the conditional gene product is expressed or repressed either in the presence or absence of a tetracycline antibiotic or a derivative thereof. In preferred embodiments, the tetracycline antibiotic is selected from the group consisting of tetracycline, doxycycline, minocycline, anhydrotetracycline, tigecycline, or acombination thereof. In a preferred embodiment, the tetracycline antibiotic isdoxycycline or tetracycline. In a more preferred embodiment, the tetracycline antibiotic is doxycycline.In a preferred embodiment, the recombinant poxvirus comprises in its genome twonucleic acid sequences encoding respectively a conditional gene product and atranscriptional regulator protein. The nucleic acid sequences encoding respectively the conditional gene product and the transcriptional regulator protein as defined above are inserted into the genome of the recombinant poxvirus by any appropriate technique known in the art.The nucleic acid sequences encoding the conditional gene product and the transcriptionalregulator protein may be inserted in any suitable location within genome of therecombinant poxvirus, e.g., within a viral gene, an intergenic region, in a non-essential gene or region or in place of viral sequences. Preference is given to insertion within the viral genome in a non-essential locus. Insertion into the genome of the recombinant poxvirus can be performed by routinemolecular biology as described above for the said nucleic acid(s) of interest.When the recombinant poxvirus comprises the two nucleic acid sequences encodingrespectively a conditional gene product and a transcriptional regulator protein, said twonucleic acid sequences encoding respectively a conditional gene product and atranscriptional regulator protein may be inserted into the viral genome at the samelocation or distinct location. Preference is given to insertion of the two acid nucleicsequences according to the invention at different locations, e.g., insertion in the TK locusand the RR locus of a recombinant poxvirus respectively.In some embodiments, one of the two nucleic acid sequences encoding respectively aconditional gene product and a transcriptional gene product is inserted within the J2Rgene of the recombinant poxvirus. Preferably, the J2R gene is partially or fully deletedby the insertion. More preferably, said insertion renders the J2R gene non-functional.In some embodiments, one of the two nucleic acid sequences encoding respectively aconditional gene product and a transcriptional regulator protein is inserted within the I4Lor F4L gene of the recombinant poxvirus. Preferably, the I4L or F4L gene is partially orfully deleted by the insertion. More preferably, said insertion renders the I4L or F4L genenon-functional.In preferred embodiments, one of the two nucleic acid sequences encoding respectivelyconditional gene product and a transcriptional regulator protein is inserted within the J2Rgene of the recombinant poxvirus, and the other is inserted within the I4L and / or F4Lgene of the recombinant poxvirus. Preferably, the J2R gene and the I4L or F4L gene arepartially deleted by the insertion. More preferably, said insertions render the J2R and theI4L or F4L gene non-functional.The general conditions for constructing recombinant poxviruses are well known in the art (see for example WO2007 / 147528; WO2010 / 130753; WO03 / 008533; US 6,998,252; US5,972,597 and US 6,440,422). Typically, a nucleic acid sequence to be inserted is clonedin a transfer plasmid surrounded by two recombination arms, corresponding to stretchesof poxviral sequences homologous (e.g., 90-100% identical) to those present in theparental genome on both sides of the insertion site. The length of the recombination arms may vary within the transfer plasmid. Desirably, each of the recombination armscomprises at least 150 bp, preferably at least 200 bp, more preferably, at least 300 bp,even more preferably from 300 to 600 bp with a specific preference for 350 to 500 bp(e.g., approximately 350 bp or 500 bp), or for 300 to 400 bp of homologous poxvirussequences. The parental poxvirus may be a wild-type poxvirus or a modified one (e.g., attenuated, tumor-specific, etc.) as described above in connection with the term “poxvirus”. Insertion is then performed by homologous recombination between the stretch of homologous sequences present both in the parental genome and the linearized transfer plasmid, requiring transfection of permissive cells with the linearized transfer plasmid and infection with the parental poxvirus.The step of generating the recombinant poxvirus encompasses the use of a poxviruscomprising a reporter gene and, notably, a fluorescent reporter gene, cloned at the siteof insertion that is selected for the nucleic acid sequence(s). Preferably, the reporter gene is placed under the transcriptional control of a promoter allowing its expressionwithin the permissive cells, e.g., a poxviral promoter. In the context of the presentinvention, such embodiment facilitates the selection of the recombinant poxvirus withrespect to the parental poxvirus. Representative examples of fluorescent reporters that can be used in the context of the present invention include, without limitation, Firefly Luciferase, Renilla Luciferase, NanoLuc® luciferase, GFP (Green Fluorescent Protein), eGFP (Enhanced Green Fluorescent Protein), AmCyan 1 fluorescent protein and mCherry. For instance, when relying on mCherry (a monomeric fluorescent protein that originatesfrom a Discosoma mushroom with peak absorption / emission at 587 nm and 610 nm), therecombinant poxviruses having inserted the heterologous nucleic acid sequence(s) inplace of the mCherry-encoding sequences, will give rise to white plaques whereas theparental poxviruses retaining the mCherry expression cassette will give rise to redplaques. The selection of the recombinant poxvirus may be by direct visualization (whiteplaques) or may also be facilitated by sorting means such as FACS after labelling with an APC (Allophycocyanin)-tagged anti-vaccinia virus antibody. A vast number of anti-poxvirusantibodies, including anti-vaccinia antibodies, is available from commercial sources.Usually, one recombinant is obtained for 50 to 100 parental and the whole process fromthe insertion step to the generation of the recombinant poxvirus takes 5 to 6 weeks.Producer cell comprising the recombinant poxvirus thereofIn a third aspect, the present invention also relates to a producer cell comprising therecombinant poxvirus according to the invention (first or second aspect) as defined aboveand wherein a transcriptional regulator is expressed.As used herein, a “producer cell” designates a permissive cell, especially a host cell (asdefined above) permissive for infection and replication of the recombinant poxvirus. Thechoice of the producer cell depends on the type of viral vector to be produced, and those skilled in the art know which producer cells or cell lines are suitable for which viral vector. Among poxviruses, choice of the producer cell also depends on the type of poxviral vectorto be produced. For example, for poxvirus strains, such as non-MVA vaccinia virus, inaddition to avian primary cells (such as CEF) and avian cell lines such as AGE1.CR®,AGE1.CR.PIX®, EB66®, DF1 (ATCC: CRL-3586), or those described in WO2005 / 042728,WO2007 / 054516, WO2006 / 108846, WO2008 / 129058, WO2010 / 130756, WO2012 / 001075, etc.), many other non-avian cell lines are available for production, including human cell lines such as HeLa (ATCC-CRM-CCL-2TMor ATCC-CCL-2.2TM), MRC-5, HEK-293; hamster celllines such as BHK-21 (ATCC CCL-10), and Monkey cells such as Vero (ATCC CCL-081), CV-1 (ATCC-70) and BSC1 (ATCC CCL-26) cell lines. A poxvirus is also generally amplified inHeLa cells (see e.g., WO2010 / 130753).In the context of the invention (first or second aspect), the producer cell may thus includeprokaryotic cells, lower eukaryotic cells such as yeast, and other eukaryotic cells such as insect cells, plant, and mammalian (e.g., human or non-human) cells. In a preferredembodiment, the producer cell is a permissive cell. In a more preferred embodiment, thepermissive cell is a mammalian cell, preferably a human or a non-human cell. In onepreferred embodiment, the human cell is selected from the group consisting of HEK293(Human embryonic kidney 293), HaCaT, MRC-5. Suitable human cells may still includehuman tumoral cell preferably selected from the group consisting of A549, CAL-33,HepG2, HCT116, HeLa, SK-MEL-1, PANC-1, Hs746T and SK-OV-3 cell lines, with apreference for HeLa cell lines. In another preferred embodiment, the non-human cell isselected between BGMK (Buffalo green monkey kidney), CV-1, COS, CEF (chicken embryo fibroblast), CEK (Chicken embryo kidney), BHK-21 (Baby Hamster Kidney), CHO (Chinese hamster ovary), BRL3A (Buffalo Rat Liver-3A), BSC-40 (Monkey kidney epithelial), MDCK(Madin-Darby Canine Kidney), NIH / 3T3, AGE1.CR®, AGE1.CR.PIX®, EB66®, DF1 (ATCC: CRL-3586) and Vero cell lines, preferably CEF, CEK and BHK-21. In a further embodiment thetranscriptional regulator is a TetR protein. In another embodiment the transcriptional regulator is a RevTetR protein. In some embodiments, the transcriptional regulator isintegrated into the genome of the producer cell. For example, some TetR-expressing celllines are available including T-RexTM-293 (Invitrogen # R71007) and T-RexTM-HeLa (Invitrogen # R71407).Such transcriptional regulator can be expressed in the producer cell under the control ofa cellular or partly cellular promoter in at least 70% of the producer cell, preferably atleast 75% of the producer cell, more preferably at least 80% of the producer cell, andmore preferably at least 85% of the producer cell, and more preferably at least 90% ofthe producer cell and most preferably at least 95% of the producer cells. The percentageof producer cells that express transcriptional regulator can be measured by art knownmethods including fluorescent staining of proteins or mRNA and FACS analysis.Such transcriptional regulator can be expressed in the producer cell at a level of at least103protein molecules / cell, preferably at least 104protein molecules / cell, preferably at least 105protein molecules / cell, preferably at least 106protein molecules / cell, more preferably at least 107protein molecules / cell, such as from 103to 106, 104to 105protein molecules / cell. Recombinant nucleic acid molecule and poxviral transfer plasmid According to another aspect, the present invention also relates to a recombinant nucleic acid molecule comprising at least one nucleic acid sequence encoding a conditional gene product, wherein the nucleic acid sequence encoding a conditional gene product is operably linked to at least one poxviral promoter and at least one Tetracycline operator (TetO) sequence; wherein expression of the nucleic acid sequence encoding a conditional gene product is inducible or repressible by the conditional binding of a transcriptional regulator protein; wherein said TetO sequence is located upstream (5’ end), downstream (3’ end) and / or within of the poxviral promoter operably linked to said nucleic acidsequence encoding a conditional gene product. The TetO sequence is preferably locatedupstream (5’ end) of the poxviral promoter operably linked to said nucleic acid sequence encoding a conditional gene product. When the recombinant nucleic acid molecule is intended to produce a recombinant poxvirus according to the first aspect of the invention (recombinant poxvirus which repress the conditional gene product to not interfere with the said recombinant poxvirus’ production as disclosed herein), the conditional gene product affects the viability of the recombinant poxvirus. When the recombinant nucleic acid molecule is intended to produce a recombinant poxvirus according to the second aspect of the invention (recombinant poxvirus which regulate accurately the conditional gene product expression, including time and level of expression as disclosed herein), the recombinant nucleic acid molecule may further comprise at least one nucleic acid sequence encoding a transcriptional regulator protein that conditionally binds to the TetO sequence and expression of the conditional gene product is then inducible or repressible by a tetracycline antibiotic or a derivative thereof. Any embodiment relating to the conditional gene, the poxviral promoter, the Tetracycline operator (TetO) sequence, or the transcriptional regulator protein disclosed herein in the context of the recombinant poxvirus according to the invention (first or second embodiment) may also apply similarly to the recombinant nucleic acid molecule according to the invention. The present invention also relates to a poxviral transfer plasmid comprising therecombinant nucleic acid molecule according to the invention. Such a poxviral transferplasmid may be used for producing the recombinant poxvirus according to the invention from a parental poxvirus. In addition to the recombinant nucleic acid molecule according to the invention, the poxviral transfer plasmid comprises conventional elements of a poxviral transfer plasmid. In particular, the poxviral transfer plasmid further comprises at both ends of the recombinant nucleic acid molecule according to the invention flanking sequencespermitting insertion into a poxviral locus of interest. Such flanking sequences aresequences from the genome of the parental poxvirus into which the recombinant nucleic acid molecule according to the invention is to be inserted. Flanking sequences generally consist of a fragment (e.g. 500–1000 base pairs (bp)) of dsDNA homologous to the sequence in the parental virus genome into which the recombinant nucleic acid molecule according to the invention is to be inserted. Preference is given to fragments of a non- essential locus (e.g.: within J2R, I4L, F4L, M2L or VEGF loci), of an intergenic region, of a portion of the viral genome which does not encode gene products or of a duplicated locus. The poxviral transfer plasmid may further comprise a reporter gene, such as a fluorescent gene. Methods for producing the recombinant poxvirusAccording to another aspect, the present invention also relates to a method for producingthe recombinant poxvirus of the invention (first or second aspect), said methodcomprising the steps of: a) infecting a producer cell with a parental poxvirus, so as to obtain an infectedproducer cell, b) transfecting the infected producer cell with a poxviral transfer plasmid accordingto the invention, so as to obtain a transfected producer cell,c) culturing the transfected producer cell under conditions which are appropriate forenabling the recombinant poxvirus to be produced, so as to obtain an infectedproducer cell culture comprising the recombinant poxvirus,d) recovering the recombinant poxvirus from said infected producer cell culture; andoptionally e) purifying said recovered recombinant poxvirus.Once generated the recombinant poxvirus of the invention may be produced / amplified using conventional techniques. It is understood that this method could comprise additional steps, optional and not indicated here. Furthermore, according to a particular embodiment, this method could consist exactly inthe aforementioned successive steps (a), (b), (c) and (d). According to another particularembodiment, this method could consist exactly in the aforementioned successive steps (a), (b), (c), (d) and (e).Step (a) of infection of producer cell lines with a parental poxvirus is made underappropriate conditions (in particular, using an appropriate multiplicity of infection (MOI)) to permit productive infection of producer cells. Step (b) of transfecting the infected producer cell with a poxviral transfer plasmid is also made under appropriate conditions to allow productive transfection of infected producer cells.Step (c) of culturing the transfected producer cells is made under appropriate conditionswell known to those skilled in the art until progeny recombinant poxviruses are produced. Culture of transfected producer cells is also preferably performed in a medium (which may be the same as or different from the medium used for culture of producer cellsand / or for infection step) free of animal- or human-derived products (using a chemicallydefined medium with no product of animal or human origin) at a temperature between 30°C and 37°C, for 1 to 5 days. The choice of the producer cell depends on the type of viral vector to be produced, and those skilled in the art know which producer cells or cell lines are suitable for which viral vector. Producer cells can be cultured in conventional fermentation bioreactors, flasks, and petri plates. Culturing can be carried out at a temperature, pH, and oxygen content appropriate for a given host cell. No attempts will be made here to describe in detail the various prokaryote and eukaryotic host cells and methods known to produce the viral vectors for use in the invention. Producer cells are preferably cultured in a medium freeof animal- or human-derived products, using a chemically defined medium with noproduct of animal or human origin. In particular, while growth factors may be present, they are preferably recombinantly produced and not purified from animal material. An appropriate animal-free medium may be easily selected by those skilled in the art depending on selected producer cells. Such media are commercially available. In particular, when CEFs are used as producer cells, they may be cultivated in VP-SFM cell culture medium (Invitrogen). Producer cells are preferably cultivated at a temperature comprised between 30°C and 38°C (more preferably at around 37°C) for between 1 and 8 days before infection. If needed, several passages of 1 to 8 days may be made to increase the total number of cells. The recombinant poxvirus of the invention can be collected from the infected producercell culture, including cell culture supernatant and transfected producer cells. The cellculture supernatant and the transfected producer cells can be pooled or collectedseparately. Recovery from transfected producer cells (and optionally also from culturesupernatant) may require a step allowing the disruption of the transfected producer cellmembrane to allow the liberation of the recombinant poxvirus. Various techniques are available to those skilled in the art, including but not limited to freeze / thaw, hypotonic lysis, sonication, micro fluidization, or high-speed homogenization. According to a preferred embodiment, the step of recovery of the recombinant poxvirus comprises a lysis step wherein the producer cell membrane is disrupted, preferably by using a high-speed homogenizer. High speed homogenizers are commercially available from Silverson Machines lnc. (East Longmeadow, USA) or Ika-Labotechnik (Staufen, Germany). According to particularly preferred embodiment, said High Speed homogenizer is a SILVERSON L4R. The recovered recombinant poxvirus of the invention may then be further purified, using purification steps well known in the art. Various purification steps can be envisaged, including clarification, enzymatic treatment (e.g., endonuclease, protease, etc.), chromatographic and filtration steps. Appropriate methods are described in the art (e.g., WO2007 / 147528; WO2008 / 138533, WO2009 / 100521, WO2010 / 130753, WO2013 / 022764). In a preferred embodiment, the purification step comprises a tangential flow filtration (TFF) step that can be used to separate the virus from other biomolecules, to concentrate and / or desalt the virus suspension. Various TFF systems and devices are available in the art depending on the volume to be filtered including, without limitation, Spectrumlabs, Pall Corp, PendoTech and New Pellicon among others. The recombinant poxvirus of the invention may then be protected by any method known in the art, to extend the recombinant poxvirus persistence in the subject blood circulation. Said methods comprise, but are not limited to, chemical shielding like PEGylation (Tesfay, M. Z. et al. J. of Virology. 2013;87(7): 3752-9; Nguyen, T. V. et al. Molecular therapy oncolytics. 2016;3: 15021–), viroembolization (WO2017 / 037523), etc.According to a particular embodiment, a tetracycline antibiotic is added to induce orrepress expression of the conditional gene product. In a preferred embodiment, thetetracycline antibiotic is added into the culture medium at the step b, c or d, and morepreferably at the step c or d. In some embodiments, the tetracycline antibiotic is selectedfrom the list consisting of tetracycline, doxycycline, minocycline, anhydrotetracycline,tigecycline, or a combination thereof. In certain embodiments, the tetracycline antibioticis doxycycline or tetracycline. In a preferred embodiment, the tetracycline antibiotic isdoxycycline.According to the invention, the tetracycline antibiotic is added to a concentrationcomprised between 0.05 µg / mL and 5 µg / mL, preferably between 0.075 µg / mL and 2.5µg / mL, even more preferably between 0.1 µg / mL and 1 µg / mL (e.g. dose of 0.1 µg / mL,0.2 µg / mL, 0.3 µg / mL, 0.4 µg / mL, 0.5 µg / mL, 0.6 µg / mL, 0.7 µg / mL, 0.8 µg / mL, 0.9 µg / mL, 1.0 µg / mL ).In one embodiment, the producer cell expresses a transcriptional regulator encodedwithin its genome. In a preferred embodiment the transcriptional regulator is a TetRprotein. In another preferred embodiment the transcriptional regulator is a RevTetRprotein. In some embodiments, the transcriptional regulator is integrated into thegenome of the producer cell. For example, some TetR-expressing cell lines are availableincluding T-RexTM-293 (Invitrogen # R71007) and T-RexTM-HeLa (Invitrogen # R71407). In another embodiment, the recombinant poxvirus further comprises a nucleic acid sequence encoding at least a transcriptional regulator selected among TetR and RevTetR proteins.According to the invention, the transcriptional regulator protein (expressed by theproducer cell itself or by the recombinant poxvirus) is an inducible transcriptionalregulator protein in which the induction would be effective in the presence of a tetracycline antibiotic or a derivative thereof. In another embodiment, the transcriptional regulator protein is a repressible transcriptional regulator protein in which the repression would be effective in the presence of a tetracycline antibiotic or a derivative thereof. Composition The invention also relates to a composition (preferentially a pharmaceutical composition) that comprises a therapeutically effective amount of the recombinant poxvirus of thepresent invention (first or second aspect). In one embodiment, the invention also relatesto a composition (preferentially a pharmaceutical composition) that comprises a therapeutically effective amount of the recombinant poxvirus of the second aspect of theinvention and a therapeutically effective amount of a tetracycline antibiotic or aderivative thereof. In another embodiment, the invention relates to a composition (preferentially a pharmaceutical composition) that comprises a therapeutically effective amount of the recombinant poxvirus of the second aspect of the invention and a separate composition (preferentially a pharmaceutical composition) that comprises atherapeutically effective amount of a tetracycline antibiotic or a derivative thereof.Preferably, the composition further comprises a pharmaceutically acceptable vehicle. Such a composition may be administered once or several times (e.g.: 2, 3, 4, 5, 6, 7 or 8 times etc.) and via the same or different routes.A “therapeutically effective amount” corresponds to the amount of each of the activeagents comprised in the composition of the invention that is sufficient for producing one or more beneficial results. Such a therapeutically effective amount may vary as a function of various parameters, e.g.: the mode of administration; the disease state; the age and weight of the subject; the ability of the subject to respond to the treatment; kind of concurrent treatment; the frequency of treatment; and / or the need for therapy. For “therapeutic” use, the composition of the invention is administered to a subject diagnosed as having a pathological condition (e.g.: a proliferative disease such as cancer) with the goal of treating the disease, optionally in association with one or more conventional therapeutic modalities. In particular, a therapeutically effective amount could be that amount necessary to cause an observable improvement of the clinical status over the baseline status or over the expected status if not treated, as described hereinafter. An improvement of the clinical status can be easily assessed by any relevant clinical measurement typically used by physicians and skilled healthcare staff. For example, techniques routinely used in laboratories (e.g.: flow cytometry, histology, imaging techniques, etc.) may be used to perform tumor surveillance. A therapeutically effective amount could also be the amount necessary to cause the development of an effective non-specific (innate) and / or specific anti-tumor response. Typically, development of an immune response, in particular a T cell response, can be evaluated in vitro, in suitable animal models or using biological samples collected from the subject. One may also use various available antibodies so-as to identify different immune cell populations involved in anti-tumor response that are present in the treated subjects, such as cytotoxic T cells, activated cytotoxic T cells, natural killer cells and activated natural killer cells.The appropriate dosage of the recombinant poxvirus can be adapted as a function ofvarious parameters and may be routinely determined by a practitioner in the light of therelevant circumstances. Suitably, individual doses for the recombinant poxvirus may varywithin a range extending from approximately 103to approximately 1012vp (viral particles), iu (infectious unit) or PFU (plaque-forming units) depending on the virus and the quantitative technique used. For illustrative purposes, a suitable dose of recombinant poxvirus for human use is comprised between approximately 104to approximately 1011PFU, preferably between approximately 105PFU to approximately 1010PFU; doses of approximately 106PFU to approximately 5x109PFU being particularly preferred (e.g. dose of 106, 2x106, 3x106, 4x106, 5x106, 6x106, 7x106, 8x106, 9x106, 107, 2x107, 3x107, 4x107, 5x107, 6x107, 7x107, 8x107, 9x107, 108, 2x108, 3x108, 4x108, 5x108, 6x108, 7x108, 8x108, 9x108, 109, 2x109, 3x109, 4x109or 5x109PFU). The quantity of virus present in a sample can be determined by routine titration techniques, e.g.: by counting the number of plaques following infection of permissive cells (e.g.: BHK-21 or CEF), immunostaining (e.g.: using anti-virus antibodies; Caroll et al., 1997, Virology 238: 198-211), by measuring the A260 absorbance (vp titers), or still by quantitative immunofluorescence (iu titers). In the context of the second aspect of the invention, the appropriate dosage of the tetracycline antibiotic or derivative thereof can be adapted as a function of various parameters. Suitably, individual doses for the tetracycline antibiotic or a derivative thereof may vary within a range extending from approximately 1.0 mg / Kg and the quantitative technique used and depending on the patient’s weight. For illustrative purposes, a suitable dose of tetracycline antibiotic or a derivative thereof for human useis comprised between approximately 1.0 mg / Kg to approximately 100.0 mg / Kg ,preferably between approximately 2.0 mg / Kg to approximately 20.0 mg / Kg , doses ofapproximately 3.0 mg / Kg to approximately 10.0 mg / Kg being particularly preferred (e.g.dose of 3.0 mg / Kg, 3.1 mg / Kg, 3.2 mg / Kg, 3.3 mg / Kg, 3.4 mg / Kg, 3.5 mg / Kg, 3.6 mg / Kg, […], 4.0 mg / Kg, 4.1 mg / Kg, 4.2 mg / Kg, 4.3 mg / Kg, 4.4 mg / Kg, 4.5 mg / Kg, 4.6 mg / Kg, […], 9.5 mg / Kg, 9.6 mg / Kg, 9.7 mg / Kg, 9.8 mg / Kg, 9.9 mg / Kg, 10.0 mg / Kg ).The term“pharmaceutically acceptable vehicle” is intended to include any and all carriers,solvents, diluents, excipients, adjuvants, dispersion media, coatings, antibacterial and antifungal agents, absorption agents and the like compatible with administration in mammals and in particular human subjects.The recombinant poxvirus of the invention can independently be placed in a solvent ordiluent appropriate for human or animal use. The solvent or diluent is preferably isotonic, hypotonic or weakly hypertonic and has a relatively low ionic strength. Representative examples include sterile water, physiological saline (e.g.: sodium chloride), Ringer’s solution, glucose, trehalose or saccharose solutions, Hank’s solution, and other aqueous physiologically balanced salt solutions (see for example the most current edition of Remington: The Science and Practice of Pharmacy, A. Gennaro, Lippincott, Williams&Wilkins). In one embodiment, recombinant poxviruses are suitably buffered for human use. Suitable buffers include without limitation phosphate buffer (e.g.: PBS), bicarbonate buffer and / or Tris buffer capable of maintaining a physiological or slightly basic pH (e.g. from approximately pH 7 to approximately pH 9). The composition of the invention may also contain other pharmaceutically acceptable excipients for providing desirable pharmaceutical or pharmacodynamic properties, including for example osmolarity, viscosity, clarity, colour, sterility, stability, rate of dissolution of the formulation, modifying or maintaining release or absorption into a human or animal subject, promoting transport across the blood barrier or penetration in a particular organ. In one embodiment, the composition of the invention can also comprise one or more adjuvants capable of stimulating immunity (especially a T cell-mediated immunity) or facilitating infection of tumor cells upon administration, e.g. through toll-like receptors (TLR) such as TLR-7, TLR-8 and TLR-9, including without limitation alum, mineral oil emulsion such as, Freunds complete and incomplete (IFA), lipopolysaccharide or a derivative thereof (Ribi et al., 1986, Plenum Publ. Corp., 407-419), saponins such as QS21 (Sumino et al., 1998, J.Virol. 72: 4931; WO98 / 56415), imidazoquinoline compounds such as Imiquimod (Suader, 2000, J. Am Acad Dermatol. 43:S6), S-27609 (Smorlesi, 2005, Gene Ther. 12: 1324) and related compounds such as those described in WO2007 / 147529, polysaccharides such as Adjuvax and squalenes, oil in water emulsions such as MF59, double-stranded RNA analogs such as poly(I:C), single stranded cytosine phosphate guanosine oligodeoxynucleotides (CpG) (Chu et al., 1997, J. Exp. Med., 186: 1623; Tritel et al., 2003, J. Immunol., 171: 2358) and cationic peptides such as IC-31 (Kritsch et al., 2005, J. Chromatogr. Anal. Technol. Biomed. Life Sci., 822: 263-70). In one embodiment, the composition of the invention may be formulated with the goal of improving its stability, in particular under the conditions of manufacture and long-term storage (i.e.: for at least 6 months, with a preference for at least two years) at freezing (e.g.: -70°C, -20°C), refrigerated (e.g.: 4°C) or ambient temperatures. Various virus formulations are available in the art either in frozen, liquid form or lyophilized form (e.g.: WO98 / 02522, WO01 / 66137, WO03 / 053463, WO2007 / 056847 and WO2008 / 114021, etc.). Solid (e.g.: dry powdered or lyophilized) compositions can be obtained by a process involving vacuum drying and freeze-drying (see e.g.: WO2014 / 053571). For illustrativepurposes, buffered formulations including NaCl and / or sugar are particularly adapted tothe preservation of viruses (e.g. S01 buffer: 342,3 g / L saccharose, 10 mM Tris, 1 mM MgCl2, 150 mM NaCl, 54 mg / L, Tween 80; ARME buffer: 20 mM Tris, 25 mM NaCl, 2.5% Glycerol (w / v), pH 8.0; S520 buffer: 100 g / L saccharose, 30 mM Tris, pH 7.6; S08 buffer: 10 mM Tris, 50 mM NaCl, 50 g / L saccharose, 10 mM Sodium glutamate, pH 8.0). The composition (either in the presence or absence of the tetracycline antibiotic or aderivative thereof in the context of the second aspect of the invention) is preferablyformulated in a way adapted to the mode of administration to ensure proper distribution and release in vivo. For example, gastro-resistant capsules and granules are particularly appropriate for oral administration, suppositories for rectal or vaginal administration, optionally in combination with absorption enhancers useful to increase the pore size of the mucosal membranes. Such absorption enhancers are typically substances having structural similarities to the phospholipid domains of the mucosal membranes (such as sodium deoxycholate, sodium glycocholate, dimethyl-beta-cyclodextrin, lauryl-1- lysophosphatidylcholine). Another example relates to the use of cell carriers (e.g.: mesenchymal stem cells, neural stem cells) as a vehicle for virus delivery. Another and particularly appropriate example is a formulation adapted to the administration through microneedle means (e.g. transcutaneous or intradermal patches). Such a formulation may comprise resuspension of the immunotherapeutic product in endotoxin-free phosphate- buffered saline (PBS). It can also be formulated in liposomes. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoester, and polylactic acid. Many methods for the preparation of such formulations are described by e.g.: J. R. Robinson in “Sustained and Controlled Release Drug Delivery Systems”, ed., Marcel Dekker, Inc., New York, 1978. AdministrationThe recombinant poxvirus (first or second aspect of the invention), the compositioncomprising the recombinant poxvirus (first or second aspect of the invention), thecomposition comprising the tetracycline antibiotic or a derivative thereof (second aspectof the invention), or the composition comprising the recombinant poxvirus and thetetracycline antibiotic or a derivative thereof (first or second aspect of the invention)may be administered in a single dose or multiple doses. If multiples doses are contemplated, administrations may be performed by the same or different routes and may take place at the same site or at alternative sites. Intervals between each administration can vary from approximately 1 day to approximately 8 weeks (e.g.: 24h, 48h, 72h, weekly, every two or three weeks, monthly, etc.), advantageously from approximately 2 days to approximately 6 weeks, preferably from approximately 3 days to approximately 4 weeks and even more preferably from approximately 1 week to approximately 3 weeks (e.g.: every two weeks for example). Intervals can also be irregular. It is also possible to proceed via sequential cycles of administrations that are repeated after a rest period (e.g.: cycles of 3 to 6 weekly administrations followed by a rest period of 3 to 6 weeks). The dose can vary for each administration within the range described above. Any of the conventional administration routes are applicable in the context of the invention including parenteral, topical or mucosal routes. Parenteral routes are intended for administration as an injection or infusion and encompass systemic as well as local routes. Common parenteral injection types are intravenous (into a vein), intra-arterial (into an artery), intradermal (into the dermis), subcutaneous (under the skin), intramuscular (into a muscle) and intratumoral (into a tumor or at its proximity). Infusions typically are given by intravenous route. Topical administration can be performed using transdermal means (e.g.: patch and the like). Mucosal administrations include without limitation oral / alimentary, intranasal, intratracheal, intrapulmonary, intravaginal or intra-rectal route. In the case of intranasal, intrapulmonary and intratracheal routes, it is advantageous for administration to take place by means of an aerosol or by means ofinstillation. Preferred routes of administration for the recombinant poxvirus of theinvention include intravenous and intratumoral routes. Administrations may use conventional syringes and needles (e.g.: Quadrafuse injection needles) or any compound or device available in the art capable of facilitating or improving delivery of the active agent(s) in the subject. Transdermal systems are also appropriate, e.g.: using solid, hollow, coated or dissolvable microneedles (e.g.: Van der Maaden et al., 2012, J. Control release 161: 645-55) and preferred are silicon and sucrose microneedle patches (see, e.g., Carrey et al., 2014, Sci Rep 4: 6154 doi 10.1038; and Carrey et al., 2011, PloS ONE, 6(7) e22442).A particularly preferred composition comprises 103 to 1012 pfu, preferably 104 to 1011 pfu,preferably 105 to 1010 pfu, more preferably 106 to 5x109 pfu of a recombinant poxvirusaccording to the invention; and notably individual doses of approximately 106, 5x106, 107, 5x107, 108, 5x108, 109or 5x109of a recombinant poxvirus according to the inventionformulated for intravenous or intratumoral administration. Another preferredcomposition comprises 106PFU to 5x109PFU of a recombinant poxvirus according to the invention. Method for regulating the expression of conditional gene products of said recombinant poxvirus according to the second aspect of the invention with an improved safety profile In the context of the second aspect of the invention, the recombinant poxvirus may be administered either in the presence or absence of a tetracycline antibiotic or a derivative thereof.The appropriate dosage of recombinant poxvirus and / or the tetracycline antibiotic or aderivative thereof can be adapted as a function of various parameters and as defined above. In the context of the second aspect of the invention, the recombinant poxvirus may be administered once or several time (e.g. 2, 3, 4, 5, 6, 7 or 8 times etc.) at a dose within the range of from 107to 5x109pfu. The time interval between each recombinant poxvirus administration can vary from approximately 1 day to approximately 8 weeks (e.g. 2, 3, 4, 5, 6 days, 1, 2, 3, 4, 5, 6 or 7 weeks), advantageously from approximately 2 days to approximately 6 weeks, preferably from approximately 3 days to approximately 4 weeks and even more preferably from approximately 1 week to approximately 3 weeks. In combination, the tetracycline antibiotic or a derivative thereof is administered once or several time (e.g. 2, 3, 4, 5, 6, 7, or 8 times etc.) at a dose within the range of from 1.0 mg / Kg to approximately 100.0 mg / Kg, preferably from about 3.0 mg / Kg to approximately 10.0 mg / Kg. The time interval between each administration of the tetracycline antibiotic or a derivative thereof can vary from approximately 1 day to approximately 8 weeks, advantageously from approximately 2 days to approximately 6 weeks, preferably from approximately 3 days to approximately 4 weeks and even more preferably from approximately 3 days to approximately 3 weeks. In one embodiment, the recombinant poxvirus is administered alone to the subject. Accordingly, to the clinical status of the subject assessed by any relevant clinical measurement typically used by clinicians, the tetracycline antibiotic or a derivative thereof can be administered to invert the expression of the conditional gene product. For illustrative purposes, when the transcriptional regulator protein is RevTetR protein, the conditional gene product is expressed until the administration of the tetracycline antibiotic or derivative thereof that will repress the expression of the conditional gene product. In another embodiment the recombinant poxvirus and the tetracycline antibiotic or a derivative thereof may be administered together in a single composition or concurrently in separation compositions, optionally comprising a pharmaceutically acceptable vehicle in addition to a therapeutically effective amount of such active agent(s). Single composition encompasses the case where the recombinant poxvirus and the tetracycline antibiotic or derivative thereof are mixed together (e.g. a mixture of the recombinant poxvirus and the tetracycline antibiotic or a derivative thereof). Separate compositions of the recombinant poxvirus and the tetracycline antibiotic or derivative thereof may be administered at the same time or sequentially, each once or several times (separately or in an interspersed manner), via the same or different routes and may take place at the same site or at alternative sites. Accordingly, to the clinical status of the subject assessed by any relevant clinical measurement typically used by clinicians, the tetracycline antibiotic or a derivative thereof administration can be suspended to invert the expression of the conditional gene product. In one embodiment, the recombinant poxvirus and the tetracycline antibiotic or a derivative thereof can be administered sequentially, such as the recombinant poxvirus being administered first and the tetracycline antibiotic or a derivative thereof second, or vise-versa (tetracycline antibiotic or a derivative thereof first and the recombinant poxvirus second). Furthermore, if more than one dose of the combination therapy is administered sequentially, the order of the sequential administration can be reversed or kept in the same order at each time point of administration. Moreover, sequential administrations may be combined with concurrent administrations. It is also possible to proceed via sequential cycles of administrations that are repeated after a rest period. Intervals between each administration can be from several hours to one year (e.g. 24h, 48h, 72h, weekly, every two weeks, monthly or yearly). Intervals can also be irregular. The doses can vary for each administration within the range described above. Accordingly, to the clinical status of the subject assessed by any relevant clinical measurement typically used by clinicians, the tetracycline antibiotic or a derivative thereof administration can be suspended to invert the expression of the conditional gene product. For illustrative purposes, in such embodiments, when the transcriptional regulator protein is a TetR protein, the conditional gene product is expressed until the administration of the tetracycline antibiotic or derivative thereof is suspended that will repress the expression of the conditional gene product (accordingly, to the clinical status of the subject assessed by any relevant clinical measurement typically used by clinicians). In one embodiment, the recombinant poxvirus may be administered once and the tetracycline antibiotic or a derivative thereof may also be administered once 1, 2, 3, 4, 5, 6 or 7 day(s) after the recombinant poxvirus administration. In another embodiment, the tetracycline antibiotic or a derivative thereof may be administered several times (e.g. 2, 3, 4, 5, 6, 7 or 8 times etc.) and the recombinant poxvirus may be administered before the first or after the last tetracycline antibiotic or derivative thereof administration. In another embodiment, the tetracycline antibiotic or a derivative thereof may be administered several times (e.g. 2, 3, 4, 5, 6, 7 or 8 times etc.) and the recombinant poxvirus may be administered before the first or after the last tetracycline antibiotic or derivative thereof administration. In another embodiment, the tetracycline antibiotic or a derivative thereof may be administered several times (e.g. 2, 3, 4, 5, 6, 7 or 8 times etc.) and the recombinant poxvirus may be administered concurrently with the first, with each or with the last tetracycline antibiotic or derivative thereof administration. In a further embodiment, the tetracycline antibiotic or derivative thereof may be administered several times (e.g. 2, 3, 4, 5, 6, 7 or 8 times etc.) and the recombinant poxvirus may be administered between two tetracycline antibiotic or derivative thereof administrations or concurrently with a tetracycline antibiotic or a derivative thereof administration. For illustrative purposes, the tetracycline antibiotic or a derivative thereof may be administered 4 times, each administration separated by approximately 1 day and the recombinant poxvirus may be administered concurrently to the second tetracycline antibiotic or derivative thereof administration (i.e. at the day 2). The doses can vary for each administration within the range described above. In a preferred embodiment, the recombinant poxvirus and the tetracycline antibiotic or a derivative thereof can be administered sequentially, such as the recombinant poxvirus being administered first and the tetracycline antibiotic or a derivative thereof second wherein the expression of the conditional gene product is induced or repressed by the antibiotic tetracycline or a derivative thereof administration according to the clinical status of the subject assessed by any relevant clinical measurement typically used by physicians or other skilled healthcare staff (independently to a defined timing or interval). For illustrative purposes, the tetracycline antibiotic or a derivative thereof may be administered 2 days after the administration of the recombinant poxvirus. In further preferred embodiment, the recombinant poxvirus and the tetracycline antibiotic or a derivative thereof can be administered sequentially, such as the tetracycline antibiotic being administered first and the recombinant poxvirus secondwherein the expression of the conditional gene product is induced or repressed bysuspending the tetracycline antibiotic or a derivative thereof administrations according to the clinical status of the subject assessed by any relevant clinical status of the subject assessed by any relevant clinical measurement typically used by clinicians. It will be appreciated that features of administration described herein may be employed in the context of methods of treatment and medical uses described herein. Combinations The recombinant poxvirus of the invention (first or second aspect) can be associated with one or more substances effective in anticancer therapy. Among pharmaceutical substances effective in anticancer therapy which may be used in association or incombination with the recombinant poxvirus of the invention, there may be mentionedmore specifically: -alkylating agents such as e.g.: mitomycin C, cyclophosphamide, busulfan,ifosfamide, melphalan, hexamethylmelamine, thiotepa, chlorambucil, or dacarbazine; -antimetabolites such as, e.g.: gemcitabine, capecitabine, 5-fluorouracil,cytarabine, 2-fluorodeoxy cytidine, methotrexate, idatrexate, tomudex or trimetrexate; -topoisomerase Il inhibitors such as, e.g.: doxorubicin, epirubicin, etoposide,teniposide or mitoxantrone; -topoisomerase I inhibitors such as, e.g.: irinotecan (CPT-11), 7-ethyl-10-hydroxy-camptothecin (SN-38) or topotecan; -antimitotic drugs such as, e.g.: paclitaxel, docetaxel, vinblastine, vincristine orvinorelbine; -platinum derivatives such as, e.g.: cisplatin, oxaliplatin, spiroplatinum orcarboplatinum; -inhibitors of tyrosine kinase receptors such as sunitinib (Pfizer) and sorafenib(Bayer); and -anti-neoplastic antibodies- cell carriers such as neural stem cells or mesenchymal stem cells- sodium Iodide Symporter-Radioiodine Gene TherapyThe recombinant poxvirus of the invention may also be used in association with one ormore other agents including but not limited to immunomodulatory agents such as, e.g. alpha, beta or gamma interferon, interleukin (in particular IL-2, IL-6, IL-10 or IL-12) or tumor necrosis factor; CAR-T cells; agents that affect the regulation of cell surface receptors such as, e.g. inhibitors of Epidermal Growth Factor Receptor (in particular cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, gefitinib, erlotinibor lapatinib) or inhibitors of Human Epidermal Growth Factor Receptor-2 (in particulartrastuzumab); agents that affect angiogenesis such as, e.g. inhibitor of Vascular Endothelial Growth Factor (in particular bevacizumab or ranibizumab); Immune Checkpoint Inhibitor (ICI), also designated as Immune Checkpoint Modulator (ICM), e.g. anti-PD1, anti-PD-L1, anti-PD-L2, anti-CTLA4, anti-Lag3, anti-BTLA and anti-Tim3. Such substances effective in anticancer therapy may be administered to the subject sequentially or concomitantly with the recombinant poxvirus of the invention. In the case of a product combination, the present invention also provides kits including the active agent(s) of the combination of the invention in kit form. In one embodiment, a kit includes at least a recombinant poxvirus as described herein in one container (e.g., in a sterile glass or plastic vial), and one or more pharmaceutical substances effective in anticancer therapy in another container (e.g., in a sterile glass or plastic vial). Optionally, the kit can include a device for performing the administration of the active agents. The kit can also include a package insert including information concerning the compositions or individual component and dosage forms in the kit.Alternatively, or in combination, the recombinant poxvirus of the invention can also beused in association with radiotherapy. Treatment or prevention of a proliferative disease such as cancer The medicament or vaccine comprising a recombinant poxvirus according to the invention (first or second aspect of the invention, any embodiment disclosed herein), or a (pharmaceutical) composition is preferably used in the treatment or prevention of aproliferative disease, especially cancer. In the context of the second aspect of theinvention, the recombinant virus may be used in the treatment or prevention of cancer either in the presence or absence of a tetracycline antibiotic or a derivative thereof.The present invention therefore also relates to a recombinant poxvirus according to theinvention (first or second aspect of the invention, any embodiment disclosed herein), or a (pharmaceutical) composition comprising the recombinant poxvirus according to the invention (first or second aspect of the invention, any embodiment disclosed herein), foruse in the treatment or prevention of a proliferative disease, especially cancer. In thecontext of the second aspect of the invention, the recombinant virus may be used in thetreatment or prevention of cancer either in the presence or absence of a tetracyclineantibiotic or a derivative thereof. The present invention also relates to the use of a recombinant poxvirus according to the invention (first or second aspect of the invention, any embodiment disclosed herein), or of a (pharmaceutical) composition comprising the recombinant poxvirus according to the invention (first or second aspect of the invention,any embodiment disclosed herein), for the manufacture of a medicament for use in a method of treatment or prevention of aproliferative disease, especially cancer. In the context of the second aspect of theinvention, the recombinant virus may be used either in the presence or absence of a tetracycline antibiotic or a derivative thereof.The present invention also relates to the use of a recombinant poxvirus according to theinvention (first or second aspect of the invention, any embodiment disclosed herein), or of a (pharmaceutical) composition (first or second aspect of the invention, any embodiment disclosed herein), in the treatment or prevention of a proliferative disease,especially cancer. In the context of the second aspect of the invention, the recombinantvirus may be used either in the presence or absence of a tetracycline antibiotic or aderivative thereof. The recombinant poxvirus according to the invention (first or second aspect of the invention, any embodiment disclosed herein) or the (pharmaceutical) composition (first or second aspect of the invention, any embodiment disclosed herein), may also be for use or used in the manufacture of a medicament for use, or used in any method of treatmentdisclosed herein. In the context of the second aspect of the invention, the recombinantvirus may be used either in the presence or absence of a tetracycline antibiotic or aderivative thereof.Provided herein is a method for treating or preventing a proliferative disease, especiallycancer in a subject, the method comprising (a) administering a recombinant poxvirusaccording to the invention (first or second aspect of the invention, any embodimentdisclosed herein), or of a (pharmaceutical) composition comprising the recombinant poxvirus according to the invention (first or second aspect of the invention,any embodiment disclosed herein) to the subject in an amount effective to treat theproliferative disease, especially cancer. In the context of the second aspect of theinvention, the recombinant virus may be used either in the presence or absence of atetracycline antibiotic or a derivative thereof in an amount sufficient to induce or repressexpression of the conditional gene product. The cancer to be treated / prevented in accordance with the present invention may be a solid cancer. Preferably, the solid cancer is selected from the group consisting of renal cancer, prostate cancer, breast cancer, bladder cancer, colorectal cancer, lung cancer, liver cancer, gastric cancer, bile duct carcinoma, endometrial cancer, pancreatic cancer, ovarian cancer, thyroid cancer, head and neck cancer, melanoma, glioblastoma, neuroblastoma, multiple myeloma, or malignant glioma cells. The cancer that may be treated / prevented in the invention may also include cancers typically responsive to immunotherapy. Non-limiting examples of such cancers generally responsive to immunotherapy include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), breast cancer, colorectal cancer, lung cancer (e.g., non-small cell lung cancer) and liver cancer (e.g., hepatocarcinoma). The cancer to be treated / prevented in accordance with the present invention may also be a primary cancer or a metastatic cancer. In particular, the present invention is useful for treatment of metastatic cancers, including metastatic solid cancers (any one of those disclosed herein), especially metastatic cancers that express PD-L1 (Iwai, Y. et al. Int. Immunol. 2005;17(2): 133-44). Preferably, the treated cancer is a PD-L1 positive cancer, meaning that PD-L1 may be detected (at the mRNA or protein level) in a tumor sample, so that at least part of the tumor cells expresses PD-L1. Cancers known to be generally PD-L1 positive comprise lung cancer (including adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and neuroendocrine carcinoma), ovarian cancer (including adenocarcinoma and carcinosarcoma), melanoma, skin cancer, and colon cancer (Yarchoan, M. et al. JCI Insight. 2019; 4(6): e126908A), and those cancers are thus particularly preferred in the context of the present invention. Methods and UsesIn another aspect, the present invention provides a recombinant poxvirus according tothe invention (first or second aspect of the invention, any embodiment disclosed herein) or a composition comprising it (in particular a pharmaceutical composition) for use as adrug or a vaccine, for treating a disease or a pathologic condition in a subject in needthereof. The present invention also relates to the use of a recombinant poxvirus according to the invention (first or second aspect of the invention, any embodiment disclosed herein) or composition comprising it for the manufacture of a medicament or a vaccine for treating a disease or a pathologic condition in a subject in need thereof. The present invention also relates to a method of treatment comprising administering therecombinant poxvirus according to the invention (first or second aspect of the invention, any embodiment disclosed herein) or a composition comprising it in an amount sufficient for treating a disease or a pathologic condition in a subject in need thereof. The presentinvention also relates to the use of a recombinant poxvirus according to the invention(first or second aspect of the invention, any embodiment disclosed herein) or composition comprising it for treating a disease or a pathologic condition in a subject in need thereof.A “disease” (and any form of disease such as “disorder” or “pathological condition”) istypically characterized by identifiable symptoms.Examples of diseases that may be treated using the recombinant poxvirus of theinvention, or the composition thereof include proliferative diseases such as cancers, tumors or restenosis. The present invention is particularly suited for treating cancers, and particularly Adrenocortical Carcinoma, Adrenal Cortex Cancer, Anal Cancer, Gastrointestinal Carcinoid Tumors (for example Appendix Cancer and Carcinoid Tumor), Bile Duct Cancer (for example Cholangiocarcinoma), Bladder Cancer, Bone Cancer (for example Ewing Sarcoma, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma), Brain Tumors (for example Astrocytomas, Embryonal Tumors, Germ Cell Tumors, Central Nervous System Atypical Teratoid / Rhabdoid Tumor, Craniopharyngioma, Ependymoma, Gliomas and Glioblastoma), Breast Cancer (for example Ductal Carcinoma In Situ), Bronchial Tumors, Carcinoma of Unknown Primary, Cardiac (Heart) Tumors, Cervical Cancer, Chordoma, Chronic Myeloproliferative Neoplasms, Colorectal Cancer (for example Colon Cancer or Rectal Cancer), Esthesioneuroblastoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Retinoblastoma, Gallbladder Cancer, Gastrointestinal Carcinoid Tumor, Testicular Cancer, Gestational Trophoblastic Disease, Head and Neck Cancer (for example Hypopharyngeal Cancer, pharyngeal Cancer, Laryngeal Cancer, Lip and Oral Cavity Cancer, Metastatic Squamous Neck Cancer with Occult Primary, Mouth Cancer, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Salivary Gland Cancer, Throat Cancer, Esophageal Cancer), Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell, Kidney cancer (for example Wilms Tumor, Renal Cell Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter), Langerhans Cell Histiocytosis, Laryngeal Cancer and Papillomatosis, Leukemia (for example Hairy Cell Leukemia, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL)), Liver Cancer, Lung Cancer (Small Cell Lung Cancer and Non-Small Cell Lung Cancer), Lymphoma (for example AIDS-Related Lymphoma, Primary CNS Lymphoma, Cutaneous T-Cell Lymphoma, Hodgkin Lymphoma, Burkitt Lymphoma, Primary Lymphoma, Mycosis Fungoides, Non-Hodgkin Lymphoma, Macroglobulinemia, Waldenström, Primary Central Nervous System (CNS) Lymphoma, Sézary Syndrome, T-Cell Lymphoma), Intraocular Melanoma, Mesothelioma, Midline TractCarcinoma Involving NUT Gene, Multiple Endocrine Neoplasia Syndromes, MultipleMyeloma / Plasma Cell Neoplasms Myelodysplastic Syndromes, Chronic Myeloproliferative Neoplasms, Neuroblastoma, Ovarian Cancer (for example Primary Peritoneal Cancer and Fallopian Tube Cancer), Pancreatic Cancer and Pancreatic Neuroendocrine Tumors (Islet Cell Tumors), Papillomatosis, Paraganglioma, Parathyroid Cancer, Penile Cancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm / Multiple Myeloma, Pleuropulmonary Blastoma, Prostate Cancer, Retinoblastoma, Vascular Tumors, Skin Cancer (for example Basal Cell Carcinoma, Melanoma, Squamous Cell Carcinoma and Merkel Cell Carcinoma), Small Intestine Cancer, Soft Tissue Sarcoma (for example Gastrointestinal Stromal Tumors (GIST), AIDS-Related Cancers Kaposi Sarcoma, KaposiSarcoma and Rhabdomyosarcoma), Stomach (Gastric) Cancer, Testicular Cancer,Thymoma and Thymic Carcinoma, Thyroid Cancer, Urethral Cancer, Uterine Cancer, Endometrial and Uterine Sarcoma, Vaginal Cancer and Vulvar Cancer. The present invention is also useful for treatment of metastatic cancers. In a preferred embodiment, the present invention is particularly suited for treating solid cancers (including for example carcinomas and sarcomas) or hematological malignancies (including for example lymphoma, leukemia and myelomas). In a preferred embodiment, the present invention is particularly suited for treating lung cancer, renal cancer, bladder cancer, prostate cancer, breast cancer, colorectal cancer, colon cancer, hepatic cancer, hepatocarcinoma, gastric cancer, pancreatic cancer, melanoma, ovarian cancer and glioblastoma. In a more preferred embodiment, the present invention is particularly suited for treating lung cancer, colon cancer, hepatocarcinoma, pancreatic cancer, melanoma and glioblastoma. In another preferred embodiment, the present invention is particularly suited for treating cancers refractory or resistant to at least one oncolytic virus-based therapy, or to at least one oncolytic vaccinia virus-based therapy.A particularly preferred method comprises 1 to 6 (e.g.: 2, 3, 4 or 5) intravenous orintratumoral administrations of the recombinant poxvirus of the invention or thecomposition thereof given at weekly to monthly intervals with a specific preference for 3 bi-weekly administrations (e.g.: at approximately D1, D14 and D29) of a compositioncomprising 106 to 5x109 PFU of a recombinant poxvirus according to the invention. Another particularly preferred method comprises 1 to 6 (e.g.: 2, 3, 4 or 5) intravenous or intratumoral administrations of the recombinant poxvirus of the invention or the composition thereof given at weekly to monthly intervals with a specific preference for 3 bi-weekly administrations (e.g.: at approximately D1, D14 and D29) of a composition comprising 106to 5x109PFU of a recombinant poxvirus, the latter being preferably defective in J2R locus and / or in the I4L or F4L locus, and encoding a therapeutic molecule. The beneficial effects provided by the methods of the present invention can be evidenced by an observable improvement of the clinical status over the baseline status or over the expected status if not treated according to the modalities described herein. An improvement of the clinical status can be easily assessed by any relevant clinical measurement typically used by physicians and skilled healthcare staff. In the context of the invention, the therapeutic benefit can be transient (for one or a couple of months after cessation of administration) or sustained (for several months or years). As the natural course of clinical status which may vary considerably from a subject to another, it is not required that the therapeutic benefit be observed in each subject treated but in a significant number of subjects (e.g. statistically significant differences between twogroups can be determined by any statistical test known in the art, such as a Tukeyparametric test, the Kruskal-Wallis test the U test according to Mann and Whitney, the Student’s t-test, the Wilcoxon test, etc.). In a particular embodiment, as the methods according to the present invention are particularly appropriate for treating cancer, such methods can be correlated with one or more of the followings: inhibiting or slowing tumor growth, proliferation and metastasis, preventing or delaying tumor invasion (spread of tumor cells in neighboring tissues), reducing the tumor number; reducing the tumor size, reducing the number or extent of metastases, providing a prolonged overall survival rate (OS), increasing progression free survival (PFS), increasing the length of remission, stabilizing (i.e. not worsening) the state of disease, providing a better response to the standard treatment, improving quality of life and / or inducing an anti-tumor response (e.g. non-specific (innate) and / or specific such as a cytotoxic T cell response) in the subject treated in accordance with the present invention. The appropriate measurements that can be used to assess a clinical benefit such as blood tests, analysis of biological fluids and biopsies as well as medical imaging techniques are evaluated routinely in medical laboratories and hospitals and a large number of kits is available commercially. They can be performed before the administration (baseline) and at various time points during treatment and after cessation of the treatment. The present invention also relates to a method for treating a disease or a pathologicalcondition in a subject in need thereof comprising administering the recombinant poxvirusor the composition of the present invention or prepared according to the method described herein. In one embodiment, said disease is a proliferative disease such as cancers, tumors and restenosis. More precisely, the present invention relates to a methodfor inhibiting tumor cell growth in vivo comprising administering a recombinant poxvirusor a composition thereof in a subject in need thereof so-as to inhibit the growth of a tumor. For general guidance, inhibition of tumor cell growth can be evaluated routinely, for example by radiography means. The administration(s) of the recombinant poxvirus or the composition thereof desirably result(s) in at least a 10% decrease of the tumor mass. Preferred embodiments of the second aspect of the present invention Regarding the second aspect of the present invention, preferred embodiments are as follows: 1. A recombinant poxvirus comprising in its genome at least one nucleic acidsequence encoding a conditional gene product; wherein the nucleic acid sequence encoding a conditional gene product is operably linked to at least one poxviral promoter and at least one TetO sequence; and at least one nucleic acid sequence encoding a transcriptional regulator protein that conditionally binds to the TetO sequence; wherein said TetO sequence is located upstream (5’ end), downstream (3’ end)and / or within of the poxviral promoter operably linked to said nucleic acid sequence encoding a conditional gene product; wherein expression of the conditional gene product is inducible or repressible by a tetracycline antibiotic or a derivative thereof. 2. The recombinant poxvirus according to embodiment 1, wherein the recombinantpoxvirus is a poxvirus of the Chordopoxvirinae family, preferably selected from the group consisting of Avipoxvirus genus, Capripoxvirus genus, Leporipoxvirus genus, Molluscipoxvirus genus, Orthopoxvirus genus, Parapoxvirus genus, Suipoxvirus genus, Cervidpoxvirus genus, Yatapoxvirus genus and chimeric poxvirus thereof.3. The recombinant poxvirus according to embodiment 2, wherein the recombinantpoxvirus is a member of the Orthopoxvirus genus preferably selected from the group consisting of Vaccinia virus, Cowpox virus, Raccoonpox virus, Rabbitpox virus, Monkeypox virus, Horsepox virus, Volepox virus, Skunkpox virus, Variola virus, Camelpox virus, canarypox virus, ectromelia virus and chimeric Orthopoxvirus thereof.4. The recombinant poxvirus according to embodiment 3, wherein the recombinantpoxvirus is a Vaccinia virus preferably selected from the group consisting of Copenhagen, Western Reserve, Elstree, LIVP, Wyeth, Tian Tan, IHD, Modified Vaccinia Virus Ankara and chimeric vaccinia virus thereof.5. The recombinant poxvirus according to embodiment 4, wherein the recombinantpoxvirus is a Vaccinia virus strain Copenhagen.6. The recombinant poxvirus according to any one of embodiments 1 to 5, whereinthe conditional gene product is a therapeutic molecule.7. The recombinant poxvirus according to embodiment 6, wherein said therapeuticmolecule is selected from the list consisting of immune checkpoint inhibitors, cytokines, agents that affect the regulation of cell surface receptors, agents that affect angiogenesis, agents that stimulates stem cells to produce granulocytes and / or macrophages and a combination thereof.8. The recombinant poxvirus according to embodiment 6 to embodiment 7, whereinthe conditional gene product is toxic for a host cell or a mammalian host.9. The recombinant poxvirus according to any one of embodiments 1 to 5, whereinthe conditional gene product is selected from the group consisting of bacterial toxins, plant toxins, enzymes, cytokines, self-antigens, virus genes.10. The recombinant poxvirus according to any one of embodiments 1 to 9, whereinthe poxviral promoter is selected from late, intermediate, or early / late poxviral promoters.11. The recombinant poxvirus according to embodiment 10, wherein the poxviralpromoter is a late or an intermediate poxviral promoter selected from the list consisting of pF17R, pA14L, pA3L, pA10L, pA13L, pA19L, pA42R, pD13L, pI1L and pWR148 promoters, preferably pF17R and pA14L promoters.12. The recombinant poxvirus according to embodiment 11, wherein the late orintermediate poxviral promoter comprises a nucleic acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or even 100% of identity with SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 87, or SEQ ID NO: 89.13. The recombinant poxvirus according to any one of embodiments 11-12, whereinthe late or intermediate poxviral promoter comprises a transcriptional initiator element.14. The recombinant poxvirus according to embodiment 13, wherein thetranscriptional initiator element is a nucleotides sequence of TAAATG or TAAATA, preferably TAAATA.15. The recombinant poxvirus according to embodiment 10 wherein the poxviralpromoter is an early / late poxviral promoter selected from the list consisting of pSE / L, p11K7.5, p7.5K and pH5R promoters.16. The recombinant poxvirus according to embodiment 15, wherein the early / latepoxviral promoter comprises a nucleic acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or even 100% of identity with SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 18, or SEQ ID NO: 25.17. The recombinant poxvirus according to any one of embodiments 15-16, whereinthe early / late poxviral promoter comprises a transcriptional initiator element.18. The recombinant poxvirus according to embodiment 17, wherein thetranscriptional initiator element is a nucleotides sequence of TAAATA, ATTTATTGCA (SEQ ID NO: 107) or GTTCTTGAGG (SEQ ID NO:108).19. The recombinant poxvirus according to any one of embodiments 13-14 and 17-18,wherein the TetO sequence is positioned upstream (5’ end) or downstream (3’ end) of the transcriptional initiator element.20. The recombinant poxvirus according to embodiment 19, wherein the TetOsequence positioned upstream or downstream of the transcriptional initiator element is separated to the transcriptional initiator element by an interval of 0 to 100 nucleotides, preferably 0 to 80 nucleotides, more preferably 0 to 60 nucleotides.21. The recombinant poxvirus according to embodiment 19 or embodiment 20,wherein the TetO sequence is positioned upstream of 5’ end of the transcriptional initiator element.22. The recombinant poxvirus according to embodiment 21, wherein the TetOsequence positioned upstream is separated to the 5’ end of the transcriptional initiator element by an interval of 30 to 100 nucleotides, preferably 30 to 80, more preferably 30 to 60 nucleotides.23. The recombinant poxvirus according to embodiment 19 or embodiment 20,wherein the TetO sequence is positioned downstream of the 3’ end of the transcriptional initiator element.24. The recombinant poxvirus according to embodiment 23, wherein the TetOsequence positioned downstream is separated to the 3’end of the transcriptional initiator element by an interval of 0 to 50 nucleotides, preferably 0 to 30, more preferably 0 to 20 nucleotides.25. The recombinant poxvirus according to any one of embodiments 1 and 19-24,wherein the TetO sequence is selected from the group consisting of TetO1 and TetO2 sequences, preferably the TetO sequence is TetO2 sequence.26. The recombinant poxvirus according to embodiment 25, wherein the TetO2sequence comprises or consists of a nucleic acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or even 100% of identity with SEQ ID NO: 109 or SEQ ID NO: 110.27. The recombinant poxvirus according to embodiment 25, wherein the TetO1sequence comprises or consists of a nucleic acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or even 100% of identity with SEQ ID NO: 111 or SEQ ID NO: 112.28. The recombinant poxvirus according to any one of embodiments 1 to 27, whereinthe recombinant poxvirus comprising in its genome at least two nucleic acid sequences encoding respectively two conditional gene products, wherein the nucleic acid sequences encoding the two conditional gene products are operably linked respectively to two poxviral promoters and one TetO sequence.29. The recombinant poxvirus according to embodiment 28, wherein the TetOsequence is located upstream of the two poxviral promoters operably linked to the two nucleic acid sequences encoding two conditional gene products.30. The recombinant poxvirus according to any one of embodiments 28-29, whereinthe two poxviral promoters operably linked to the two nucleic acid sequences encoding two conditional gene products are oriented in back-to-back, with said TetO sequence located between the two poxviral promoters.31. The recombinant poxvirus according to any one of embodiments 1-30, wherein thenucleic acid sequence encoding a transcriptional regulator is operably linked to a constitutive poxviral promoter.32. The recombinant poxvirus according to embodiment 31, wherein the nucleic acidsequence encoding a transcriptional regulator operably linked to a constitutive poxviral promoter is inserted in the I4L or F4L locus.33. The recombinant poxvirus according to any one of embodiments 1 to 32, whereinthe transcriptional regulator is a TetR protein and is selected from the group consisting of TetR of SEQ ID NO: 73 and TetR_BD of SEQ ID NO: 74 variants.34. The recombinant poxvirus according to any one of embodiments 1 to 32, whereinthe transcriptional regulator is a RevTetR protein and is selected from the group consisting of revTetR(B) and revTetR(BD) proteins.35. The recombinant poxvirus according to embodiment 34, wherein thetranscriptional regulator is a revTetR (B) protein and is selected from the group consisting of M2_72P of SEQ ID NO: 65 and M2_72A of SEQ ID NO: 66 variants.36. The recombinant poxvirus according to embodiment 34, wherein thetranscriptional regulator is a revTetR (DB) protein and is selected from the group consisting of revTetR r6.2 of SEQ ID NO: 69, revTetR r1.7 of SEQ ID NO: 70, revTetR r6.39 of SEQ ID NO: 72 and revTetR r4.29 of SEQ ID NO: 71 variants.37. The recombinant poxvirus according to any one of embodiments 1 to 36 whereinthe conditional gene product is expressed or repressed either in the presence or absence of a tetracycline antibiotic or a derivative thereof.38. The recombinant poxvirus according to the embodiment 37, wherein thetetracycline antibiotic is selected from the list consisting of tetracycline, doxycycline, minocycline, anhydrotetracycline, tigecycline, or a combination thereof.39. A recombinant nucleic acid molecule comprising at least one nucleic acidsequence encoding a conditional gene product, wherein the nucleic acid sequence encoding a conditional gene product is operably linked to at least one poxviral promoter and at least one Tetracycline operator (TetO) sequence; wherein expression of the nucleic acid sequence encoding a conditional gene product is inducible or repressible by the conditional binding of a transcriptional regulatorprotein; wherein said TetO sequence is located upstream (5’ end), downstream (3’ end) and / or within of the poxviral promoter operably linked to said nucleic acid sequence encoding a conditional gene product.40. The recombinant nucleic acid molecule according to embodiment 39, whichfurther comprises at least one nucleic acid sequence encoding a transcriptional regulator protein that conditionally binds to the TetO sequence and expression of the conditional gene product is inducible or repressible by a tetracycline antibiotic or a derivative thereof.41. The recombinant nucleic acid molecule according to embodiment 47, wherein:a) the conditional gene product is as defined in any one of embodiments 6 to 9;b) the poxviral promoter is as defined in any one of embodiments 10 to 18 and 28to 30; c) the Tetracycline operator (TetO) sequence is as defined in any one ofembodiments 19 to 30; d) the transcriptional regulator protein is as defined in any one of embodiments31 to 36; or e) any combination of a) to e).42. The recombinant nucleic acid molecule according to any one of embodiments 39to 41, which comprises at least two nucleic acid sequences encoding respectively two conditional gene products, wherein the nucleic acid sequences encoding the two conditional gene products are operably linked respectively to two poxviral promoters and one TetO sequence.43. The recombinant nucleic acid molecule according to embodiment42, wherein theTetO sequence is located upstream of the two poxviral promoters operably linked to the two nucleic acid sequences encoding two conditional gene products.44. The recombinant nucleic acid molecule according to embodiment43, wherein thetwo poxviral promoters operably linked to the two nucleic acid sequences encoding two conditional gene products are oriented in back-to-back, with said TetO sequence located between the two poxviral promoters.45. A poxviral transfer plasmid comprising the recombinant nucleic acid moleculeaccording to any one of embodiments 39 to 44.46. A method for producing the recombinant poxvirus according to any one ofembodiments 1 to 38 comprising the steps of:a) infecting a producer cell with a parental poxvirus, so as to obtain an infectedproducer cell,b) transfecting the infected producer cell with a poxviral transfer plasmid accordingto embodiment 45, so as to obtain a transfected producer cell,c) culturing the transfected producer cell under conditions which are appropriate forenabling the recombinant poxvirus to be produced, so as to obtain an infected producer cell culture comprising the recombinant poxvirus,d) recovering the produced recombinant poxvirus from the infected producer cellculture and optionally;e) purifying said recovered recombinant poxvirus.47. A composition comprising the recombinant poxvirus according to any one ofembodiments 1 to 38, or the recombinant poxvirus obtained according to the method of embodiment 46, and a pharmaceutically acceptable vehicle.48. The composition according to the embodiment 47, wherein the compositioncomprises a therapeutically effective amount of said recombinant poxvirus and a pharmaceutically acceptable vehicle.49. The composition according to embodiment 47 or embodiment 48, comprising from103to 1012pfu, preferably 104to 1011pfu, preferably 105to 1010pfu, more preferably 106to 5x109pfu of the poxvirus; and notably individual doses of approximately 106, 5x106, 107, 5x107, 108, 5x108, 109or 5x109.50. The composition according to any one of embodiments 47 to 49, which isformulated for intravenous, intramuscular, subcutaneous, oral, intranasal, transdermal, or intratumoral administration.51. The recombinant poxvirus according to any one of embodiments 1 to 38, or thecomposition according to any one of embodiments 47 to 50, for use as a medicament or a vaccine.52. The recombinant poxvirus according to any one of embodiments 1 to 38, or thecomposition according to any one of embodiments 47 to 50, for use for treating or preventing a proliferative disease, preferably a cancer.53. The recombinant poxvirus or the composition for use according to embodiment 52,wherein the cancer is selected from the group consisting of renal cancer, prostate cancer, breast cancer, bladder cancer, colorectal cancer, lung cancer, liver cancer, gastric cancer, bile duct carcinoma, endometrial cancer, pancreatic cancer, ovarian cancer, head and neck cancer, melanoma, glioblastoma, multiple myeloma, or malignant glioma cells.54. A method of treating or preventing a proliferative disease comprisingadministering to a subject the recombinant poxvirus according to any one of embodiments 1 to 38 or the composition according to any one of embodiments 47 to 50. 55. The method according to embodiment 54, further comprising administering atetracycline antibiotic in an amount sufficient to induce or repress expression of the conditional gene product. 56. The method according to embodiment 55, wherein the amount sufficient to induceor repress expression of the conditional gene product is comprised between approximately 1.0 mg / Kg to approximately 100.0 mg / Kg, preferably between approximately 2.0 mg / Kg to approximately 20.0 mg / Kg, more preferably between approximately 3.0 mg / Kg to approximately 10.0 mg / Kg. All of the above cited disclosures of patents, publications and database entries are specifically incorporated herein by reference in their entirety. Other features, objects, and advantages of the invention will be apparent from the description, drawings and from the claims. The following examples are incorporated to demonstrate preferred embodiments of the invention. However, in light of the present disclosure, those skilled in the art should appreciate that changes can be made in the specific embodiments thatare disclosed without departing from the spirit and scope of the invention. The followingexamples merely intend to illustrate the present invention. EXAMPLES MATERIAL AND METHODS Viruses VVTG18058 (empty VACV, VACV control, or unarmed control VACV) is a Copenhagen Vaccinia virus (VACV) deleted in J2R and I4L genes. VVTG18058 was used as an unarmed control VACV. VVTG18058 was produced on chicken embryo fibroblasts (CEF). Titration was performed by plaque assay on Vero cells. For example, a non-purified research stock tittered at 1.3E+07 PFU / mL was used for infection / transfection experiment as an unarmed control VACV. COPTG19104 is a Vaccinia virus strain Copenhagen expressing the fluorescent proteinmCherry under the control of pH5R promoter at J2R locus and deleted in I4L gene.COPTG19104 is used as the parental virus for generation of recombinant virus.POXSTG19834 is a chimeric poxvirus, derived from POXSTG19503 clone 7 and expressingGFP::FCU1 under the control of p11K7.5 promoter at J2R locus and deleted in I4L gene.POXSTG19730 is a chimeric poxvirus, also derived from POXSTG19503 clone 7 andexpressing GFP::FCU1 under the control of p11K7.5 promoter at the J2R locus and thefluorescent protein mCherry under the control of pH5R promoter at I4L locus.Hereafter, virus POXSTG19503 clone 7, and derivatives thereof, are referred to as POXSTG virus.Cells and Cell lines Chicken embryo fibroblasts (CEF) were isolated from 11 to 12 day-oldembryonated and specific pathogen free (SPF) eggs (Charles River). The embryos were mechanically dilacerated, solubilized in a Tryple Select solution (Invitrogen) and dissociated cells cultured in BME (Basal Medium Eagle; Gibco) supplemented with 5% FCS (Gibco), 2 mM L-glutamine and 40 mg / L of gentamicin. CEF used to produce pre-clinical batches were seeded in VP-SFM medium (Invitrogen) supplemented with 4 mM L- Glutamine and containing gentamicin at a final concentration of 40 mg / L. CEF cells were grown at 37 °C, 5 % CO2before virus infection.The Cercopithecus aethiops (African green) kidney cell line Vero (ATCC® CCL-81™) wasgrown in DMEM (Gibco) supplemented with 10 % FBS, 2mM L-glutamine and 40 mg / L of gentamicin. The human cervix tumor cell line HeLa (ATCC® CCL-2™) was grown in DMEM (Gibco) supplemented with 10 % FBS, 2mM L-glutamine and 40 mg / L of gentamicin. T-REx™-HeLa cells stably express a transcriptional regulator, specifically TetR protein (Invitrogen # R71407). They were grown in MEM (Gibco) supplemented with 10 % FBS, 2mM L-glutamine, 40 mg / L of gentamicin and 5 µg / mL blasticidin. BacteriaEscherichia coli DH5α strain (Library Efficiency™ DH5α Competent Cells Invitrogen #18263012) was used for cloning and plasmid amplification in LB media supplemented with 100 µg / mL ampicillin. This strain was grown at 37°. Construction of reporter transfer plasmids Reporter transfer plasmids were designed to assess the ability of the transcriptionalregulator protein (TetR) to modulate the expression of the Firefly luciferase locateddownstream of and operably linked to a poxviral promoter and a TetO sequence. Thepoxvirus reporter and transfer plasmids also included the Renilla luciferase codingsequence placed under the control of the poxviral promoter ATI. Renilla luciferase wasused as an internal standard to normalize expression. Firefly and Renilla luciferasesoriginated from the plasmid pmirGLO Dual-Luciferase miRNA Target Expression Vector(Promega). Both expression cassettes were inserted in a poxvirus transfer plasmid designed to allowinsertion of the nucleotide sequence of said expression cassettes in J2R locus of thevaccinia virus or chimeric poxvirus genomes by homologous recombination. Therefore,this plasmid contains the flanking sequences (referenced as “R arm” for right arm and “Larm” for left arm into Figures 1 and 7) surrounding the J2R locus.pTG19520 reporter transfer plasmid (Figure 1) was used to generate further transfer plasmids varying in their upstream sequences (different promoters with or without a TetOsequence of the Firefly luciferase coding sequence. Fragments (Table 1 and Table 2)containing the different promoters with or without the TetO sequence were generated bya synthetic way and inserted in pTG19520 restricted with AvrII and ApaI by homologousrecombination. Transfer plasmid carrying the different combinations of poxviral promoter and TetOaccording to the invention are described in Table 1 below.SEQ ID NO of poxviral promoter and TetO Plasmid ID Descriptioncombination encoded by the plasmid pTG19695 pA14L 1pTG19654 pA14L-O2 2pTG19719 O2-pA14L 3pTG19694 pF17R 4pTG19653 pF17R-O2 5pTG19714 O2-pF17R 6pTG19715 O2-pF17R[6-45] 7pTG19687 pSE / L 8pTG19688 pSE / L-O2 9pTG19689 O2-pSE / L 10pTG19690 p11K7.5 11pTG19691 p11K7.5-O2 12pTG19692 O2[47-55]-p11K7.5 13pTG19693 O2[47-55]-p11K7.5-O1 14pTG19716 O2-p11K7.5 15pTG19717 O2-p11K7.5[4-45] 16pTG19718 O2-p11K7.5[9-45] 17pTG19684 p7.5K 18pTG19652 p7.5K-O2 19pTG19685 O2

[0106] -p7.5K 20pTG19686 p7.5K[1-106]-O2 21pTG19711 O2-p7.5K 22pTG19712 O2-p7.5K[29-124] 23pTG19713 O2-p7.5K[55-124] 24pTG19681 pH5R 25pTG19651 pH5R-O2 26pTG19682 O2

[0060] -pH5R 27pTG19683 pH5R[1-60]-O2 28pTG19708 O2-pH5R 29pTG19709 O2-pH5R[5-114] 30pTG19710 O2-pH5R[9-114] 31pTG19751 O2

[0014] -pH5R 32pTG19752 O2

[0031] -pH5R 33pTG19753 O2

[0052] -pH5R 34pTG19754 O2

[0073] -pH5R 35pTG19755 O2

[0092] -pH5R 36pTG19756 O2

[0104] -pH5R 37Table 1: Design of poxviral promoter and TetO combination according to the inventionand corresponding plasmid ID. In the case of O2 is followed by [X], it means the TetOsequence (herein defined as O2) has been inserted after the position X of the associatedpoxviral promoter sequence, X being expressed as a number of nucleotides. In the caseof O2 is followed by [X-Y], it means the TetO sequence (herein defined as O2) has beeninserted within the associated promoter and is replacing the sequence between theassociated nucleotides defined by [X-Y]. In the case of [X-Y] followed the associatedpromoter, it means the promoter consists of the fragment defined by [X-Y] nucleotidesof the associated promoter. X and Y are a sole number. As a non-limiting example, O2

[0073] -pH5R means the TetO2 sequence has been inserted in the 5’ position of the pH5R sequence, with 73 nucleotides separating the 5’ end of the TetO2 sequence and the 5’ end of the pH5R sequence. As another non-limiting example, O2[47-55]-p11K7.5-O1means the TetO2 sequence has been inserted within the p11K7.5 promoter sequence, byreplacing the 47 to 55 nucleotides position of said promoter by the TetO2 sequence, and that a TetO1 sequence has been inserted right after the 3’end of the promoter sequence.A first set of plasmids (Table 1) was designed to evaluate poxviral promoter and TetOcombinations to modulate the expression of the Firefly luciferase. The obtained reporter transfer plasmids were first tested in transient transfection / infection expression studies. In a second phase, some of them were used to generate recombinant poxvirus as described below.A second set of plasmids (Table 2) was designed to evaluate the position of the TetOsequence located upstream of pA14L or pF17R promoter still allowing efficienttranscription regulation. SEQ ID NO of poxviral promoter and TetO Plasmid ID Descriptioncombination encoded by the plasmid pTG19916 pA14L

[0100] 38pTG19922 O2-pA14L

[0100] 39pTG19911 pA14L

[0050] 40pTG19917 O2-pA14L

[0050] 41pTG19912 pA14L

[0060] 42pTG19918 O2-pA14L

[0060] 43pTG19913 pA14L

[0070] 44pTG19919 O2-pA14L

[0070] 45pTG19914 pA14L

[0080] 46pTG19920 O2-pA14L

[0080] 47pTG19915 pA14L

[0090] 48pTG19921 O2-pA14L

[0090] 49pTG19928 pF17R

[0100] 50pTG19934 O2-pF17R

[0100] 51pTG19923 pF17R

[0050] 52pTG19929 O2-pF17R

[0050] 53pTG19924 pF17R

[0060] 54pTG19930 O2-pF17R

[0060] 55pTG19925 pF17R

[0070] 56pTG19931 O2-pF17R

[0070] 57pTG19926 pF17R

[0080] 58pTG19932 O2-pF17R

[0080] 59pTG19927 pF17R

[0090] 60pTG19933 O2-pF17R

[0090] 61Table 2: Design of combinations of the promoter pA14L or pF17R with or without TetOsequence (herein specifically TetO2 sequence, also defined as O2 and corresponding SEQ ID NO reference). All sequences are preceded at 5’ end by a sequence defined by the SEQ ID NO: 113 and are followed at 3’ end by a sequence defined by the SEQ ID NO: 114. These constant sequences allow the cloning of the different modified promoters in the transfer plasmid. Numbers in square brackets after the promoter’s name indicate thelength of the promotor sequences in nucleotides number, additionally to the ATA codon(previous start codon ATG mutated into ATA for avoiding starting translation from thiscodon). The transcriptional regulator protein (TetR) is originated either from the cell lineT-REx™-HeLa or from the mammalian expression plasmid pTG19649 (SEQ ID NO: 115).Generation of said plasmid pTG19649: The transcriptional regulator protein (TetR) class B from transposon Tn10 (UniProtKB / Swiss-Prot accession number: P04483) coding sequence was codon-optimized, synthesized (GeneArt™), and cloned in pCI-neo mammalian expression plasmid (GenBank: U47120), generating pTG19649. Cloning, plasmid amplification and other molecular biology procedures were performed according to standard procedures. Transient transfection / infection Transient transfection-infection expression assays in HeLa or T-REx™-HeLa cells were carried out with the goal of selecting the most effective promoter and TetO combinations to be vectorized in VACV genome. Cells were cultured in 24-well culture plate before being transfected with a reporter transfer plasmid at 0.05 ng per well, together with 250 ng of the pTG19649 plasmid expressing TetR (if required) or of the GFP-expressing pTG15839 (control plasmid) complexed with 1.25 µL of lipofectamine 2000 (Invitrogen). After 6 hours, cells were infected at MOI 1 by VVTG18058, and further incubated 24 H at 37 °C and 5 % CO2. For luciferase measurements, supernatants were removed, and cells were lysed and processed according to the “Dual-Luciferase Reporter Assay System” (Promega). Luciferase Reporter Assays Reporter assays were performed by transfecting cells with reporter plasmids or viruses containing the TetO, in the presence or absence of TetR (expressed by a plasmid or by T-REx™-HeLa cells). In the same way, reporter assays were performed by transfecting cells with the control reporter plasmids or viruses missing the TetO in the presence or absence of TetR (expressed by a plasmid or by T-REx™-HeLa cells).In addition to the repression of the Firefly luciferase resulting from the binding of TetRto the TetO, other cellular factors, insertion of the TetO sequence and even TetR couldpotentially modulate in a nonspecific manner the Firefly and Renilla luciferase activities.To obtain the specific effect of TetR over the TetO, the method described by Campos-Melo, D., et al. (2014) for miRNAs was here adapted.Firefly luciferase activity value was firstly normalized with its respective Renillaluciferase activity value (to account for variations in the transfection or infection efficiency among experiments), and named F / R. A second step of normalization was applied by comparing the ratio F / R obtained after transfection with reporter plasmids or viruses containing the TetO, in the presence or absence of TetR (as described in Table 3, F / R 1 and F / R 2). Normalization 1 / 2 is performed (as described in Table 3, A) enabling cancellation of the cellular effects and of the indirect effects on promoter strength resulting from the TetO sequence insertion, leaving only the TetR effects on the expression of luciferase in presence of the TetO. A third step of normalization was applied by comparing the F / R ration obtained after transfection with the control reporter plasmids or viruses missing the TetO in the presence or absence of TetR (as described in Table 3, F / R 3 and F / R 4). Normalization 3 / 4 is performed (as described in Table 3, B) enabling cancellation of the cellular effects leaving only the TetR effects on the expression of luciferase (in absence of the TetO). Finally, any nonspecific TetR effects over the Firefly or Renilla luciferase activity was cancelled due to A / B normalization toobtain the specific effect of TetR over the TetO sequence. The percentage of repression was obtained by performing the following calculation (1-A / B) x100. Transfections / Infections F / R Normalization RepressionReporter plasmid / virus (with TetO) + plasmid 1 expressing TetR or T-Rex™-HeLa cells 1 / 2=A Reporter plasmid / virus (with TetO) 2 1-A / B Control reporter plasmid / virus (without TetO) + 3 plasmid expressing TetR or T-Rex™-HeLa cells 3 / 4=BControl reporter plasmid / virus (without TetO) 4Table 3: Normalization of luciferase reporter assays. Generation and production of recombinant vaccinia virus (recVACV) Recombinant vaccinia viruses (recVACVs) were generated by homologous recombination in CEF using COPTG19104 as parental virus and the transfer plasmid containing the expression cassette to be integrated with flanking sequences (R arm and L arm) surrounding the J2R locus. The homologous recombination between the transfer plasmid and the parental vaccinia virus enables the generation of recVACVs which has lost the mCherry expression cassette and gained the expression cassette resulting in whiteplaques. More specifically, a F175 flask of CEFs was infected at MOI 5E-02 with COPTG19104 for 1 hour at room temperature. The viral suspension was then discarded, and the infected cells were incubated 2 hours in MBE + 5 % FBS at 37 °C + 5 % CO2before being trypsinated and counted. 1E+07 infected cells were then transfected with 2µg of I- SceI-restricted transfer plasmid by nucleofection. The transfected cells were then transferred into a well of a 6-well plate incubated at 37 °C for 48 h before being frozen. After sonication, serial dilutions of the transfer mixture were used to infect CEF for selection of recombinant virus. Non-fluorescent white plaques were picked and used for a second round of plaque purification. Selected non-fluorescent white plaques were picked and amplified in a 6-well plate at 37 °C, 5 % CO2for 72h. Amplifications were used for PCR analysis followed by the selection of the recVACV. Primary stock was produced by infection of CEF grown during 72 h before infection with 100 µL of the selected clone. Viral amplification was performed in MBE supplemented with 5 % FBS, at 37 °C, 5 % CO2 for 72 h. Infected cells and media were submitted to afreeze / thaw cycle before being homogenized by sonication. This so-called primary stockwas then characterized and stored in aliquots until use. A purified bulk was produced following viral amplifications in F500 flasks seeded with CEF. Infected cells and medium were harvested to generate the crude harvest which was stored at -80 °C. The virus was purified according to a procedure described in WO2007 / 147528 patent application. RESULTS Example 1: Combinations of TetO2 and poxviral promoter in a transient transfection-infection expression assay. Reporter transfer plasmids were designed to assess the ability of a transcriptionalregulator protein (herein TetR) to modulate the expression of the Firefly luciferase placeddownstream a poxviral promoter and the TetO sequence, herein specifically TetO2. To evaluate effective TetO2 / poxviral promoter combinations suitable to modulate expression of transgene, various combinations were tested through their capacity toregulate the expression of the Firefly luciferase. The TetO2 was inserted at variousposition in the poxviral promoters pA14L, pF17R, pSE / L, p11K7.5, p7.5K and pH5R, as described in Table 1. The TetO2 was inserted at the 5’ end or at the 3’ end of each poxviral promoter. Moreover, for the early / late promoters p7.5K, p11K7.5 and pH5R, the TetO2 was also inserted at different locations, between the early and the late component of these promoters.The poxvirus reporter plasmids also included the Renilla luciferase coding sequenceplaced under the control of the poxviral promoter ATI, as the Renilla luciferase was usedas an internal standard to normalize expression. The plasmids were evaluated by transient transfection / infection experiments in HeLa cells, in presence or absence of a plasmid encoding the TetR. Both luciferases were measured after 24H.The results obtained with the promoter A14L are illustrated in Figure 2 that shows ratioF / R (Firefly luciferase / Renilla luciferase) for each poxviral pA14L promoter / TetO2combinations by infected / transfected HeLa cells. The ratio F / R (Firefly luciferase / Renilla luciferase) are reported for each promoter’sconfiguration, in presence or in absence of the TetR. The ratio obtained for the promoter devoid of the TetO2 in absence of TetR was arbitrarily set at 1. Addition of the TetO2 at the 3′ end of the pA14L promoter decreases the strength of the promoter (relative strength: 0.3) while expression is increased when the TetO2 is placed at the 5’ end of the promoter (relative strength: 1.6). After addition of the TetR, a very strong repression of expression was observed in both cases (99 and 92%), but the repression level was greater when the TetO2 was placed at the 3’ end of the promoter. The fold reduction, obtained by dividing the F / R ratio measured in absence of TetR by the ratio measured in presence of TetR, was 10-fold higher when the TetO2 was inserted at the 3’ end of the promoter (109-fold versus 12-fold). The results for all evaluated promoters are displayed in Table 4. Relative Poxviral Poxviral promoter and Fold Plasmid ID strength (prom. Repression promoter TetO2 combination reduction minus O2=1) pTG19695 pA14L 1.0pA14LpTG19654 pA14L-O2 0.3 99% 109pTG19719 O2-pA14L 1.6 92% 12pTG19694 pF17R 1.0pTG19653 pF17R-O2 0.7 100% 226pF17R pTG19714 O2-pF17R 1.0 91% 11pTG19715 O2-pF17R[6-45] 1.0 91% 11pTG19687 pSE / L 1.0pSE / LpTG19688 pSE / L-O2 0.7 100% 199pTG19689 O2-pSE / L 1.4 94% 17pTG19690 p11K7.5 1.0pTG19691 p11K7.5-O2 1.1 26% 1pTG19692 O2[47-55]-p11K7.5 0.3 98% 42p11K7.5 pTG19693 O2[47-55]-p11K7.5-O1 0.3 98% 60pTG19716 O2-p11K7.5 1.3 91% 11pTG19717 O2-p11K7.5[4-112] 1.2 90% 10pTG19718 O2-p11K7.5[9-112] 1.1 91% 10pTG19684 p7.5K 1.0pTG19652 p7.5K-O2 1.2 17% 1pTG19685 O2

[0106] -p7.5K 1.1 8% 1p7.5KpTG19686 p7.5K[1-106]-O2 1.0 10% 1pTG19711 O2-p7.5K 1.3 96% 20pTG19712 O2-p7.5K[29-124] 0.0 31% 1pTG19713 O2-p7.5K[55-124] 0.0 -20% 1pTG19681 pH5R 1.0pTG19651 pH5R-O2 1.1 42% 2pTG19682 O2

[0060] -pH5R 0.4 43% 2pTG19683 pH5R[1-60]-O2 0.4 37% 2pTG19708 O2-pH5R 0.9 1% 1pTG19709 O2-pH5R[5-114] 1.2 20% 1pH5RpTG19710 O2-pH5R[9-114] 0.7 25% 1pTG19751 O2

[0014] -pH5R 0.8 -4% 1pTG19752 O2

[0031] -pH5R 0.7 -16% 1pTG19753 O2

[0052] -pH5R 1.5 56% 2pTG19754 O2

[0073] -pH5R 0.5 7% 1pTG19755 O2

[0092] -pH5R 1.5 65% 3pTG19756 O2

[0104] -pH5R 1.2 19% 1Table 4: Evaluation of promoters’ combinations with TetO2 sequence by transienttransfection / infection experiments in HeLa cells. In the case of O2 is followed by [X], itmeans the TetO sequence (herein defined as O2) has been inserted after the position Xof the associated poxviral promoter sequence, X being expressed as a number of nucleotides. In the case of O2 is followed by [X-Y], it means the TetO sequence (herein defined as O2) has been inserted within the associated promoter and is replacing thesequence between the associated nucleotides defined by [X-Y]. In the case of [X-Y] followed the associated promoter, it means the promoter consists of the fragment defined by [X-Y] nucleotides of the associated promoter. X and Y are a sole number. As a non-limiting example, O2

[0073] -pH5R means the TetO2 sequence has been inserted in the 5’ position of the pH5R sequence, with 73 nucleotides separating the 5’ end of the TetO2 sequence and the 5’ end of the pH5R sequence. As another non-limiting example, O2[47-55]-p11K7.5-O1 means the TetO2 sequence has been inserted within the p11K7.5 promoter sequence, by replacing the 47 to 55 nucleotides position of said promoter by the TetO2 sequence, and that a TetO1 sequence has been inserted right after the 3’end of the promoter sequence. As for the pA14L promoter, presence of the TetO2 at the 3’ end led to very high repressionlevel (approximately 200- fold reduction) and to a slight decrease of the expression levelfor pF17R and pSE / L promoters (relative strength: 0.7). Promoter strengths were increased when the TetO2 is placed at the 5’ end of the promoter, but the fold reduction was lower (11 or 17 times lower). The p11K7.5 promoter strength was not affected by the addition of the TetO2 at 3’ end however the repression was weak (only 26%). Presence of the TetO2 at the 5′ end slightly improved the promoter strength (1.3) but allowed to reach a high repression level (over 90%). A strong repression (98%) along with a greatly reduced promoter strength (0.3) was observed when the TetO2 was inserted within the promoter, between the “late” component F17R and the “early / late” component of the p7.5K promoter. A slight repression (17%) was measured when the TetO2 was placed at the 3 ′ end of the p7.5K promoter. When the TetO2 was inserted at the 5’ end, a strong repression (96%) was observed along with an increase of the promoter strength (1.3). Promoter p7.5Kdeleted of the 5’ sequence [from nucleotide 1 to 28] totally lost its activity.Early / late promoters p11K7.5 and p7.5K can be regulated when the TetO2 is placed at their 5’ end. Twelve TetO2 / pH5R promoter combinations failed to produce a significative repression (best fold reduction reach only 3 times), i.e.the pH5R promoter cannot be regulated using a TetO.Plasmids comprising poxviral promoter and TetO2 combination displaying a decrease inexpression over 90% were selected for further evaluations. pA14L, pF17R and pSE / Lpromoters wherein the TetO2 is inserted at the 5’ or 3’ end as well as p11K7.5 and p7.5Kwherein the TetO2 is inserted at the 5’ end were chosen.Example 2: Position of the TetO located at the 5’ end of pA14L and pF17R promotersThe size of the late promoters pA14L and pF17R used in this study was respectively 40 nucleotides and 45 nucleotides. It was shown above that the insertion of the TetO2 at their 5’ end allowed to obtain a reduction of expression of about 90 % in presence of TetR. The influence of the position of the TetO, respective to the transcriptional initiator element, was studied by increasing the size of both promoters by adding sequence normally located at their 5’ end. Several reporter plasmids were generated, as described in Table 2. They were evaluated by transient transfection / infection in Hela cells and results are described in Table 5 and Table 6. Relative Poxviral Fold Plasmid ID strength Repression promoter reduction (pA14L=1) pTG19695 pA14L 1.0 1pTG19719 O2-pA14L 2.5 94% 13pTG19911 pA14L

[0050] 1.6 1pTG19917 O2-pA14L

[0050] 2.0 92% 10TG19912 pA14L

[0060] 2.9 1pTG19918 O2-pA14L

[0060] 2.7 61% 2pTG19913 pA14L

[0070] 2.6 1pTG19919 O2-pA14L

[0070] 2.4 12% 1pTG19914 pA14L

[0080] 2.8 1pTG19920 O2-pA14L

[0080] 2.4 20% 1pTG19915 pA14L-90 2.5 1pTG19921 O2-pA14L

[0090] 2.5 32% 1pTG19916 pA14L

[0100] 2.5 1pTG19922 O2-pA14L

[0100] 2.4 16% 1Table 5: TetO2 position located at the 5’ end of pA14L promoter. Numbers in squarebrackets after the promoter’s name indicate the length of the promotor sequences in nucleotides number additionally to the ATA codon (previous start codon ATG mutated into ATA for avoiding starting translation from this codon). Relative Poxviral Fold Plasmid ID strength Repression promoter reduction (pF17R=1) pTG19694 pF17R 1.0pTG19714 O2-pF17R 1.3 93% 12pTG19923 pF17R

[0050] 1.0pTG19929 O2-pF17R

[0050] 1.2 92% 11pTG19924 pF17R

[0060] 1.3pTG19930 O2-pF17R

[0060] 1.3 54% 2pTG19925 pF17R

[0070] 1.4pTG19931 O2-pF17R

[0070] 1.3 14% 1pTG19926 pF17R

[0080] 1.3pTG19932 O2-pF17R

[0080] 1.3 17% 1pTG19927 pF17R

[0090] 1.3pTG19933 O2-pF17R

[0090] 1.3 28% 1pTG19928 pF17R

[0100] 1.3pTG19934 O2-pF17R

[0100] 1.4 12% 1Table 6: TetO2 position located at the 5’ end of pF17R promoter. Numbers in squarebrackets after the promoter’s name indicate the length of the promotor sequences in nucleotides number additionally to the ATA codon (previous start codon ATG mutated into ATA for avoiding starting translation from this codon).When the TetO2 is located at the 5’ end, the herein used pA14L (of pTG19719) and pF17R(of pTG19714) promoters having respectively a length of 40 nucleotides and 45nucleotides as well as their 50 nucleotides counterparts (pTG19917 and pTG19929)showed repressions of Firefly luciferase expression over 92%. Presence of the TetO2 atthe 5’ end also enhanced promoter’s strength. Repression of the expression dropped approximatively by half for the pA14L and pF17R promoters having a length of 60nucleotides (61 and 54 % respectively) and were very low when promoter length exceeded70 nucleotides (less than 30%). When the promoter length reached 60 nucleotides or more, insertion of the TetO2 did not have any more effect on the strength of the promoters. Therefore, the size of the late promoter p14L and pF17R should not exceed 50 nucleotidesto keep an effective repression of the expression after addition of the TetO2 at the 5’end of these promoters. Example 3: Evaluation and comparison of repression level in HeLa cellsPlasmids comprising selected promoter / TetO2 combinations were compared in the sametransient transfection-infection experiment using HeLa cells, in the presence or absenceof the plasmid encoding the TetR protein. pA14L, pF17R and pSE / L promoters whereinthe TetO2 is inserted at the 5’ or 3’ end as well as the p11K7.5 and p7.5K promoterswherein the TetO2 is inserted at the 5’ end were evaluated. pH5R promoter without theTetO2 was also used for promoter strength normalization. The results are shown in Table 7. The expression levels were normalized for each poxviral promoter / TetO2 combination on one hand to the result obtained with the corresponding control promoter without the 5 TetO2, and on the other hand to the result obtained with the pH5R promoter. Placing the TetO2 at the 5’ end of the promoter enhanced the promoter strength while placing the TetO2 at the 3’ end decreased the promoter strength. Relative strength Relative Poxviral Fold Plasmid ID (prom. minus O2= strength Repression promoter reduction 1) (pH5R=1)pTG19695 pA14L 1.0 0.9pTG19654 pA14L-O2 0.3 0.2 99% 47pTG19719 O2-pA14L 1.6 1.4 92% 12pTG19694 pF17R 1.0 3.5pTG19653 pF17R-O2 0.7 2.4 99% 74pTG19714 O2-pF17R 1.1 3.7 92% 12pTG19687 pSE / L 1.0 2.6pTG19688 pSE / L-O2 0.7 1.7 99% 78pTG19689 O2-pSE / L 1.3 3.4 94% 15pTG19690 p11K7.5 1.0 2.3pTG19716 O2-p11K7.5 1.2 2.8 92% 13pTG19684 p7.5K 1.0 0.4pTG19711 O2-p7.5K 1.2 0.5 95% 18pTG19681 pH5R 1.0 1.0 na naTable 7: Evaluation of poxviral promoter / TetO2 combinations by transienttransfection / infection experiments in HeLa cells. 0Best repression levels were observed when the TetO2 is located at the 3' end of the pF17R,pA14L and pSE / L promoters (99%) although it leads to a decrease in the expression level in the absence of the transcriptional regulator. Eight TetR / TetO2 regulable poxviral promoters with different expression and repression levels were identified as shown in Table 8. Poxviral Relative strength Repression Fold reductionpromoter (pH5R=1) O2-pF17R 3.7 92% 12O2-pSE / L 3.4 94% 15O2-p11K7.5 2.8 92% 13pF17R-O2 2.4 99% 74pSE / L-O2 1.7 99% 78O2-pA14L 1.4 92% 12O2-p7.5K 0.5 95% 18pA14L-O2 0.2 99% 47Table 8: Ranking of poxviral promoter / TetO2 combinations according to their relative strength from transient transfection / infection experiments in HeLa cells. Example 4: Evaluation and comparison of repression level in T-REx™-HeLa cells Plasmids comprising selected poxviral promoter / TetO2 combinations were compared inthe same transient transfection-infection experiment using T-REx™-HeLa cells, in the presence or absence of doxycycline at 0.1 µg / µL. The T-REx™-HeLa cells expressed constitutively the TetR protein. When doxycycline is present, TetR will bind preferentiallyto the doxycycline drug and not to the TetO2, permitting transcription. The results are shown in Table 9. Relative Poxviral strength Relative strength Fold Plasmid ID Repression promoter (prom. minus (pH5R=1) reduction O2= 1)pTG19695 pA14L 1.0 1.2pTG19654 pA14L-O2 0.2 0.3 97% 30pTG19719 O2-pA14L 1.5 1.7 90% 10pTG19694 pF17R 1.0 4.2pTG19653 pF17R-O2 0.7 2.8 98% 41pTG19714 O2-pF17R 1.1 4.7 92% 12pTG19687 pSE / L 1.0 3.2pTG19688 pSE / L-O2 0.6 2.0 98% 42pTG19689 O2-pSE / L 1.3 4.2 92% 13pTG19690 p11K7.5 1.0 2.8pTG19716 O2-p11K7.5 1.2 3.4 91% 10pTG19684 p7.5K 1.0 0.6pTG19711 O2-p7.5K 1.2 0.7 94% 16pTG19681 pH5R 1.0 na naTable 9: Evaluation of poxviral promoter / TetO2 combinations by transienttransfection / infection experiments in T-REx™-HeLa cells. The expression levels determined in presence of doxycycline were normalized for each poxviral promoter / TetO2 combination on one hand to the result obtained with the corresponding control promoter without the TetO2, and on the other hand to the result obtained with the pH5R promoter. Placing the TetO2 at the 5’ end of the promoter enhanced the promoter strength while placing the TetO2 at the 3’ end decreased the promoter strength. In absence of doxycycline, the best repression was observed when the TetO2 is located at the 3' end of the pF17R, pA14L and pSE / L promoters (97 to 98 %). The repression observed in T-REx™-HeLa cells is slightly lower than that observed in HeLa cells transfected with the plasmid encoding the TetR. The results are shown in Table 10. Relative Poxviral strengthRepression Fold reductionpromoter (pH5R=1) O2-pF17R 4.7 92% 12O2-pSE / L 4.2 92% 13O2-p11K7.5 3.4 91% 10pF17R-O2 2.8 98% 41pSE / L-O2 2.0 98% 42O2-pA14L 1.7 90% 10O2-p7.5K 0.7 94% 16pA14L-O2 0.2 97% 30Table 10: Ranking of poxviral promoter / TetO2 combinations according to their relative strength from transient transfection / infection experiments in T-REx™-HeLa cells.Example 5: Evaluation and repression by VACV comprising regulable promotersThe inducible gene expression studies were also conducted when expression cassettes regulated by the TetR are inserted into the J2R locus of the parental virus. RecVACVs encoding the Firefly luciferase located downstream a poxviral promoter withor without the TetO2 sequence named for example VACV pF17R-O2 (COPTG19653) and the Renilla luciferase under the control of ATI promoter were generated by homologousrecombination performed between the transfer plasmids and the parental virus resulting in the insertion of the expression cassette into the J2R locus of the parental virus, as described in Materials and methods. VACVs containing the following promoters were generated: pA14L, pF17R, pSE / L, p11K7.5, p7.5K and pH5R. Evaluation in Hela and T-REx™-HeLa cells HeLa cells and T-REx™-HeLa cells were infected at a MOI of 10-4by recVACVs and corresponding control VACVs deprived of the TetO2 and incubated for 24 hours. Cells were lysed, and the luciferase activities were measured. The results of the luciferase assays are shown in Table 11. Poxviral promoter Relative Relative Fold Virus ID and TetO strength (prom. strength Repression reduction combination minus O2= 1) (pH5R=1)COPTG19695 pA14L 1.0 0.6COPTG19719 O2-pA14L 1.7 0.9 90% 9COPTG19694 pF17R 1.0 2.4COPTG19653 pF17R-O2 0.7 1.6 98% 38COPTG19714 O2-pF17R 1.1 2.7 92% 11COPTG19687 pSE / L 1.0 2.0COPTG19688 pSE / L-O2 0.6 1.3 93% 11COPTG19689 O2-pSE / L 1.2 2.4 81% 4COPTG19690 p11K7.5 1.0 1.8COPTG19716 O2-p11K7.5 1.2 2.1 75% 3COPTG19684 p7.5K 1.0 0.5COPTG19711 O2-p7.5K 1.1 0.5 48% 1.3COPTG19681 pH5R 1 na naTable 11: Evaluation of repression levels after infection of HeLa and T-REx™-HeLa cellswith recVACV. F / R ratios obtained in HeLa cells were used to evaluate expression levels. They were normalized for each poxviral promoter / TetO2 combination on one hand to the result obtained with the corresponding control promoter without the TetO2 (Relative strength (prom. Minus O2=1), and on the other hand to the result obtained with VACV pH5R (Relative strength (pH5R=1). As observed in infection / transfection experiments, placing TetO2 at the 5’ end of the promoter enhanced the promoter strength (ratio 1.1 to 1.7) while placing the TetO2 at the 3’ end decreased the promoter strength (ratio 0.6 to 0.7). Repression levels were calculated as described in Table 3, to obtain the specific effect of TetR over the TetO2 sequence. Fold reductions were obtained by dividing the F / R ratio measured in HeLa cells (absence of TetR) by the ratio measured in T-RExTM-HeLa cells (presence of TetR). Repression levels superior to 90 % were obtained for both late promoters pA14L and pF17R, and for pSE / L promoter. The repression levels observed with the early / late promoter p11K7.5 and p7.5K were clearly lower, 75% and 48%, respectively.Best repression levels were observed when the TetO2 is located at the 3’ end of thepF17R, and pSE / L promoters (98% and 93%) although it leads to a decrease in the expression level in the absence of the transcriptional regulator. As observed during infection / transfection experiments (Table 7), placing the TetO2 operator at the 5’ end of the promoter enhanced the promoter strength while placing the TetO2 at the 3’ end decreased the promoter strength. In Table 12, comparisons are made between the fold reduction measured during the transfection / infection experiments (data from Table 7) and during infections experiments (data from Table 11). Transfection / Infection recVACVs infectionPoxviral promoter Relative Fold Relative strength Fold and TetO strength reduction (pH5R=1) reduction combination (pH5R=1) O2-pF17R 3.7 12 2.7 11O2-pSE / L 3.4 15 2.4 4O2-p11K7.5 2.8 13 2.1 3pF17R-O2 2.4 74 1.6 38pSE / L-O2 1.7 78 1.3 11O2-pA14L 1.4 12 0.9 9O2-p7.5K 0.5 18 0.5 1pA14L-O2 0.2 47 nd ndTable 12: Comparisons between the fold reduction measured during the transfection / infection experiments and during infection experiments. Fold reduction obtained with recVACV containing late promoters O2-pF17R, pF17R-O2 and O2-pA14L are comparable to those obtained during infection / transfection experiments using their corresponding transfer plasmid. While fold reduction measured with recVACVsexpressing the Firefly luciferase under the control of an “early-late” promoter weresignificantly lower than those obtained during infection / transfection experiments using the transfer plasmid (approximately 7 times lower for the pSE / L-O2 promoter, 4 times lower for the O2-pSE / L and O2-p11K7.5 promoters and about 18 times lower for the O2- p7.5K promoter). These results showed that the “early” elements of promoters are tricky to control by using the TetO2 in combination with TetR. The early transcription cannot be regulated probably because during the replication cycle of the VACV the TetR is not integrated into the viral “Core” where the early transcription takes place. This is also a reason why the amplitude of the promoter strength obtained during transfection / infection experiments are larger than those measured after infection with the VACV, as the early / late promoter pH5R is used as the reference and it is more efficient in infection rather than in transfection / infection experiments. Evaluation in T-REx™-HeLa cells in presence or absence of doxycyclineT-RExTM-HeLa cells were infected at a MOI of 10-4 by recVACVs and corresponding controlVACVs deprived of the TetO2 and incubated for 24 hours in presence or absence of doxycycline at 0.1 µg / mL. Cells were lysed, and luciferase activities were measured. The results of the luciferase assays are shown in Table 13. Poxviral promoter Relative strength Relative Fold Virus ID and TetO (prom. minus O2= strength reduction combination 1) (pH5R=1) COPTG19695 pA14L 1.0 0.4COPTG19719 O2-pA14L 1.8 0.7 11COPTG19694 pF17R 1.0 1.8COPTG19653 pF17R-O2 0.7 1.2 38COPTG19714 O2-pF17R 1.0 1.8 11COPTG19687 pSE / L 1.0 1.5COPTG19688 pSE / L-O2 0.6 0.9 13COPTG19689 O2-pSE / L 1.1 1.7 5COPTG19690 p11K7.5 1.0 1.4COPTG19716 O2-p11K7.5 1.2 1.7 4COPTG19684 p7.5K 1.0 0.4COPTG19711 O2-p7.5K 1.0 0.4 2COPTG19681 pH5R 1.0Table 13: Evaluation of repression after infection of T-REx™-HeLa cells with recVACV in presence or absence of doxycycline. In this case, repression levels could not be calculated, as the controls in absence of the TetR are not available using the T-REx™-HeLa cells. Fold reductions were obtained by dividing the F / R ratio measured in presence of doxycycline by the ratio measured in absence of doxycycline. The fold reductions measured after infection of T-REx™-HeLa cells in presence or absence of doxycycline are similar to the fold reduction obtained after infection of HeLa cellsversus T- REx™-HeLa cells (Table 11). Therefore, the addition of doxycycline is able tofully induce the gene expression. Example 6: Evaluation of the repression of secreted protein by TetR As all the above experiments were performed using an intracellular protein, i.e Firefly luciferase, a set of experiments were designed to evaluate the regulation of expressionof a secreted protein, i.e the human IL-12 (hIL-12 or hIL12). It is unique amongst cytokinesin being a disulfide-linked heterodimer of two separately encoded subunits (p35 and p40). A single chain IL-12 protein was expressed from vaccinia constructs in which the full length p40 subunit was fused, via a G6S linker, to the p35 subunit truncated of its leadersequence (i.e. IL-12.p40.delta p35); (Lieschke, 1997). The sequence coding for the IL-12was introduced in poxviral transfer plasmids downstream poxviral promoter with or without the TetO2. RecVACVs were generated by homologous recombination performed between the transfer plasmids and parental virus VACV resulting in the insertion of the expression cassette into the J2R locus of VACV, as described in Materials and methods. The following viruses were generated: VACV pF17R-IL12, VACV pF17R-O2-IL12 and VACV pSE / L-O2-IL12. HeLa cells and T-REx™-HeLa cells were infected at a MOI of 10-2by recVACVs and corresponding control VACVs deprived of the TetO2 and incubated for 48 hours. The infection of T-REx™-HeLa cells was performed in absence or in presence of 0.1 µg / mL of doxycycline. The culture supernatants were harvested and the expression of IL-12 was analyzed by ELISA using the DuoSet®ELISA development system Human IL-12 (R&D Systems). The results are shown in Figure 3. Fold reductions were obtained by dividing the quantity of IL-12 measured in HeLa cells (absence of TetR) by the quantity measured in T-RExTM-HeLa cells (presence of TetR). A strong reduction of IL-12 expression was observed with the late promoter pF17R-O2 (17- fold), while a reduction of 6-fold was detected with the early / late pSE / L-O2 promoter. Fold reductions obtained comparing the level of expression in T-RExTM-HeLa cells in absence or in presence of doxycycline were even higher: 34-fold with the pF17R-O2 promoter and about 17-fold with the pSE / L-O2 promoter. These results were comparableto the results obtained with the VACV expressing the Firefly luciferase. Therefore, theTetR system is also able to regulate the expression of secreted protein. Example 7: Generation of recVACV encoding toxic protein In-house previous experiments had shown that it was not possible to generate a recVACV (MVA) encoding a functional fusion of the Core-Env proteins of the hepatitis B virus (HBV). Isolated recVACV expressed mutated and truncated Core-Env protein. The expressedfusion protein was either toxic for the host cells or for the VACV itself. Therefore,inhibiting transgene expression during recVACV generation by using the regulable TetR system should overcome this problem. Thus, a transfer plasmid containing the Core-Env sequence placed under the control ofthe pSE / L-O2 promoter (pTG19745 as defined by SEQ ID NO: 116) was used to generaterecVACV expressing the Core-Env protein (as defined as COPTG19745) in HeLa and in T- REx™-HeLa cells. The summary of these experiments is presented in Figure 4. HeLa and T-REx™-HeLa cells were infected with the COPTG19104 parental virus (encoding mCherry protein) and transfected with the plasmid pTG19745. The transfers were then used for selection of non-fluorescent recVACVs. Eleven clones were obtained for the experiment in T-REx™-HeLa cells, while only 6 clones were detected for the experiment in HeLa cells. These clones were analyzed by PCR to detect the presence of the expression cassette and the absence of COPTG19104 parental virus.No recVACV was obtained by using the HeLa cells but eight recVACVs were obtained byusing the T-Rex™-HeLa cells. A primary stock of COPTG19745 was obtained by amplification of one of the isolated virus clones in T-REx™-HeLa cells. Absence of parentalvirus and presence of the expression cassette were again assessed by PCR analysis.Moreover, the sequence of the expression cassette was in compliance with the theoretical sequence of Core-Env protein. The expression of Core-Env fusion was evaluated after infection of HeLa cells and T-REx™- HeLa cells by COPTG19745 in presence or absence of doxycycline (0.1 µg / mL). Cells were infected at MOI 1 with COPTG19745 or with VVTG18058. After 48 hours of infection, cellswere harvested and analyzed by Western blot after an electrophoresis under reducingconditions. Blots were developed by using the mouse monoclonal antibody Hep B cAg 10E11 (Santa Cruz, sc-23947) specific for the Core-Env fusion and by using a rabbit polyclonal raised again the MVA p14 protein (in house) specific for the VACV. The results are illustrated in Figure 5. Core-Env fusion protein expression is detected only after infection of Hela cells or T- REx™-HeLa cells in presence of doxycycline, as a specific band of 26.3 kDa. On the other hand, no expression is detected after infection of T-REx™-HeLa cells in absence of doxycycline. The intensity of the VACV specific signal (detection with anti p14) is strongly reduced when the Core-Env fusion protein is expressed (Hela cells and T-REx™-HeLa cells in presence of doxycycline, infected with COPTG19745) while no decrease is observed in T-REx™-HeLa cells infected with COPTG19745 in absence of doxycycline. Therefore, the expression of the Core-Env fusion under the control of the regulable pSE / L- O2 promoter is repressed in T-REx™-HeLa cells, expressing the TetR and the addition ofdoxycycline can lift the repression. The expression of Core-env is linked to a strongdecrease of the VACV replication, confirming the toxicity of the fusion protein. In conclusion, only the transfer carried out in T-Rex™-HeLa cells, in which the expression of the transgene is repressed, lead to recVACV COPTG19745 expressing a functional Core Env fusion protein. These results show that repressing a toxic transgene during the generation of recVACV allows to isolate a functional recVACV. Analysis of COPTG19745 genetic stability The genetic stability of the COPTG19745 was evaluated after 5 passages of the primary stock on T-REx™-HeLa cells in absence or in presence of doxycycline at 0.1 µg / µL. Briefly, cells were cultured in F75 flasks before being infected at MOI 10-4with COPTG19745. Cells were harvested after 72 hours, and successive passages were performed. COPTG19745 genetic stability was monitored at each passage by PCR amplification and sequencing of the expression cassette. After three passages in presence of doxycycline, the PCR products presented correct profiles (amplicons with the expected size). However, sequences of the Core-Env expression cassette showed a deletion of a G nucleotide located in a 6 G stretch, leading to a truncated protein (7.2 kDa). The recVACV isolated herein, when the transgene is expressed, is unstable and therefore no more passages were done in presence of doxycycline. COPTG19745 was passaged five times in T-Rex™-HeLa cells in absence of doxycycline and genetic stability was monitored at each passage as described before. At each passage the PCR products presented expected profiles and the integrity of the expression cassette was confirmed by sequencing. To confirm these positive results, 50 clones were isolated from passage 5. They were first tested by PCR to analyze the integrity of their expression cassette and all the clones gave rise to the expected profile. Then, the sequence of the expression cassette was determined for the 50 clones. They showed a sequence in compliance with the theoretical one. Therefore, the genetic stability of the expression cassette of COPTG19745 is equal to 100 % after 5 passages on T-REx™-HeLa cells. In conclusion, repressing the transgene expression during VACV amplification strongly increased the genomic stability of recVACV. Example 8: Identification and evaluation of revTetRVariants of the TetR protein developed in the prior art:A first variant of the TetR protein (revTetR) differing from the TetR protein at fourpositions (EK71 DN95 LS01 GD102) was obtained by random mutagenesis. Fusion to the activation domain of the VP16 protein allowed the generation of a reverse-tTA (rtTA) which binds the O2 operator and activates transcription exclusively in the presence ofdoxycycline when O2 operator sites are inserted upstream of a eukaryotic promoter(Gossen M et al, Science. 1995 Jun 23;268(5218):1766-9; Baron U et al, Nucleic Acids Res. 1997;25(14):2723-2729). However, this variant exhibited a low affinity for the doxycycline effector. To improve the control of expression (weak binding in the absence of doxycycline, strong in the presence of doxycycline) new variants of the rtTA protein havebeen selected in yeast and have been evaluated in human cells (Urlinger S et al, Proc NatlAcad Sci U S A. 2000 Jul 5;97(14):7963-8 ; Das AT et al, Curr Gene Ther. 2016;16(3):156- 67; Roney IJ et al, Sci Rep. 2016 Jun 21;6:27697). Six variants were selected: rtTA-M2,rtTA-S2 (Urlinger S et al, Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):7963-8), rtTA-V10,rtTA-V16 (Das AT et al, Curr Gene Ther. 2016;16(3):156-67), rtTA-M2-72P, rtTA-M2-72A(Roney IJ et al, Sci Rep. 2016 Jun 21;6:27697) and the modified Tet repressors present inthese rtTA were evaluated in the context of regulation of poxviral promoter. On the other hand, extensive mutagenesis of the repressor TetR (BD) resulting from the fusion of amino acids 1 to 50 of TetR (class B) and amino acids 51 to 208 of TetR (class D)(Schnappinger D et al, EMBO J. 1998 Jan 15;17(2):535-43) allowed the identification ofrepressor active in the presence of doxycycline (revTetR) in E.Coli (Scholz, O., et al.(2004). Mol Microbiol 53(3): 777-789). Four of them were selected for evaluation in poxviral context: revTetR r6.2, r1.7, r4.29, r6.39. Evaluation of those variants in the context of the invention:The coding sequences of these revTetR were codon-optimized, synthesized (GeneArt™),and cloned downstream the pH5R promoter in a poxvirus transfer plasmid designed to allow insertion of the nucleotide sequence to be transferred by homologous recombination in I4L locus of the vaccinia virus genome (Table 14).The revTetR variants according to the present disclosure are not fused to the activationdomain of the VP16 protein.SEQ ID NO of the RevTetR and TetR RevTetR and Plasmid ID protein variants TetR variants encoded within theplasmid pTG19768 RevTetR 62pTG19769 RevTetR_M2 63pTG19770 RevTetR_S2 64pTG19771 RevTetR_M2 72P 65pTG19772 RevTetR_M2 72A 66pTG19773 RevTetR_V10 67pTG19774 RevTetR_V16 68pTG19775 RevTetR_r6.2 69pTG19776 RevTetR_r1.7 70pTG19777 RevTetR_r4.29 71pTG19778 RevTetR_r6.39 72pTG19779 TetR 73pTG19780 TetR_BD 74Table 14: List of TetR and RevTetR proteins tested and corresponding plasmids expressingthereof. The evaluation of the various revTetR proteins was carried out by transient transfection / infection experiments with the plasmids expressing the revTetR variants andwith the plasmid expressing the Firefly luciferase under the control of the F17R-O2promoter (pTG19653) in HeLa cells cultured in presence or absence of doxycycline. The cells were also transfected with a GFP-expressing plasmid pTG15839 (as control plasmid) to evaluate the expression level in absence of repression. After 24 h the cells were lysed, and the luciferase activities were measured. The results of the luciferase assays are shown in Figure 6. All the revTetR proteins allow to obtain a strong repression of luciferase expression in presence of 1 µg / mL of doxycycline. However, the expression detected in absence of doxycycline was also strongly reduced for most of them, indicating that the binding of the transcriptional regulator to the TetO could occurred independently of the presence of doxycycline. Among the revTetR(B) proteins, only the revTetR_M2_72P variant allows strong expression in the absence of doxycycline (69%) as well as strong repression (25-fold) in the presence of doxycycline. Among the revTetR(BD) proteins, three of them (r6.2, r1.7 and r6.39) showed an expression level equivalent to that observed using the control plasmid pTG15839 in absence of doxycycline. The revTetR r1.7 (pTG19776) variant exhibits the better expression in the absence of doxycycline, and the strongest repression in presence of doxycycline (151-fold). Example 9: Generation and evaluation of “all in one” recVACVs “All in one” recVACVs constitutively expressing a transcriptional regulator (TetR orrevTet) and the Firefly luciferase gene under several different engineered induciblepromoters (containing the TetO2) were generated. In these cases, all the elements necessary for the regulation by the Tet regulable system (TetO2 and transcriptional regulator) are included in the same recombinant virus.The TetR, or the revTetR r1.7, were placed under the control of the early / late promoterpH5R and were introduced in the I4L locus of the VACV, giving rise to COPTG19779 and COPTG19776, respectively.In a second step, expression cassettes encoding the Firefly luciferase under the controlof regulable promoters and the Renilla luciferase under the control of pATI promoterwere introduced in the J2R locus of VACV encoding TetR or revTetR. The different VACVs generated are listed in Table 15. Poxviral promoter and Transcriptional Virus ID TetO combination into regulator into I4L J2R locus Locus COPTG19979 revTetR O2-pA14L COPTG19978 TetRCOPTG19865 revTetR pF17R-O2 COPTG19889 TetRCOPTG19863 revTetR pSE / L-O2 COPTG19890 TetRCOPTG19896 O2-p11K7.5 TetRCOPTG19895 O2-p7.5K TetRTable 15: Description of “all in one” recVACVs and corresponding virus ID. Evaluation of repression after infection of HeLa cells and CEP with “all in one” recVACVs HeLa cells and CEP were infected by “all in one” recVACVs and corresponding control VACVs which are deprived of transcriptional regulator at a MOI of 10-4and incubated for 24 hours in presence or absence of doxycycline at 0.1 µg / mL. Cells were lysed, and the luciferase activities were measured.The results of the luciferase assays are shown in Table 16 and Table 17. For the VACVcontaining the TetR, the fold reduction was calculated by dividing the F / R ratio obtained in presence of doxycycline by the ratio obtained in absence of doxycycline. The reverse calculation is applied to calculate the fold reduction for the VACV containing the revTetR. Poxviral promoter Transcriptional Virus ID and TetO Fold reduction regulator combination COPTG19719Ø 1COPTG19979O2-pA14LrevTetR 13COPTG19978 TetR 13COPTG19653Ø 1COPTG19865pF17R-O2revTetR 143COPTG19889 TetR 633COPTG19688Ø 1COPTG19863pSE / L-O2revTetR 10COPTG19890 TetR 32COPTG19716Ø 1O2-p11K7.5 COPTG19896 TetR 4COPTG19711Ø 1O2-p7.5K COPTG19895 TetR 2Table 16: Evaluation of repression after infection of HeLa cells with “all in one” recVACV. Poxviral promoter Transcriptional Virus ID and TetO Fold reduction regulator combination COPTG19653Ø 1COPTG19865pF17R-O2revTetR 90COPTG19889 TetR 390COPTG19688Ø 1COPTG19863pSE / L-O2revTetR 5COPTG19890 TetR 25 COPTG19716Ø 1O2-p11K7.5 COPTG19896 TetR 2COPTG19711Ø 1O2-p7.5K COPTG19895 TetR 1Table 17: Evaluation of repression after infection of CEP cells with “all in one” recVACV. On HeLa cells, fold reductions measured for VACV TetR O2-pA14L and for VACV TetR pSE / L-O2 were respectively 13-fold and 32-fold. The fold reduction yield over 600-fold for VACV TetR pF17R-O2. Comparing the herein results with those measured after infection of T-REx™-HeLa cells (Table 13), showed that repression is considerably improved when TetR is co-expressed by the recVACV TetR pF17R-O2. A slight increase is obtained when the promoter pSE / L-O2 is used in combination with TetR (fold reduction raised from 13 to 32). In contrast, co-expression of TetR by VACVs expressing Firefly Luciferase under the control of regulable promoters O2-pA14L, O2-p11K7.5 and O2-p7.5K did not improve the fold reduction (13, 4 and 2-fold only, respectively). Co-expression of the revTetR by the recVACV revTetR pSE / L-O2 and VACV revTetR O2- pA14L caused respectively a 10-fold reduction and a 13-fold reduction. The fold reduction reached 143-fold for VACV revTetR pF17R-O2. Fold reductions measured in CEP (Table 17) for the herein VAVCs were comparable to those observed in HeLa cells. Therefore, the ”all in one“ recVACV displayed a very efficient expression regulation by the Tet regulable system. Evaluation of repression after infection of HeLa cells with “all in one” recVACVs at different MOI HeLa cells were infected by recVACV TetR pF17R-O2 and VACV revTetR pF17R-O2 at different MOI ranging from MOI 10-3to MOI 1 and incubated for 24 hours in presence or absence of doxycycline at 0.1 µg / mL. Cells were lysed, and the luciferase activities were measured. As shown in Table 18, the same level of repression is observed, whatever the MOI, about 100-fold, for the virus expressing revTetR and more than 500-fold for the virus expressing TetR. Poxviral promoter Transcriptional Virus ID and TetOMOI Fold reductionregulator combination COPTG19865 revTetR-386 pF17R-O2 10 COPTG19889 TetR 481COPTG19865 revTetR-2125 pF17R-O2 10 COPTG19889 TetR 525COPTG19865 revTetR 0- 98 pF17R-O2 11COPTG19889 TetR 697COPTG19865 revTetR 104 pF17R-O2 1 COPTG19889 TetR 807Table 18: Evaluation of repression after infection of HeLa cells at different MOI with “allin one” recVACVs. Evaluation of repression at different time post-infection of HeLa cells with “all in one” recVACVs HeLa cells were infected by “all in one” recVACV TetR pF17R-O2 and corresponding control VACVs at MOI 10-4, in presence or absence of doxycycline at 0.1 µg / mL. Cells were lysed at different times post infection, and the luciferase activities were measured. As shown in Table 19, repression efficiencies are stable over time up to 72 hours post- infection (hpi). Poxviral promoter Fold reduction Transcriptiona Virus ID and TetO l regulator24 hpi 48 hpi 72 hpicombination COPTG19653Ø 1 1 1pF17R-O2 COPTG19889 TetR 811 935 1007Table 19: Evaluation of repression after infection of HeLa cells with “all in one” recVACVat different time post-infection Example 10: Evaluation of repression with additional intermediate or late promoters An additional set of eight late or intermediate promoters was tested for their capacity toregulate the expression of the Firefly luciferase when the TetO2 sequence is placed downstream these promoters and in presence of TetR or revTetR. The size of the promoters used was about 100 nucleotides and the TetO2 sequence was inserted after the identified putative late transcriptional initiator element sequence TAAATG, which was changed to TAAATA to ensure translation initiation only from the downstream luciferase open reading frame. The different poxviral promoter / TetO combinations (Table 20) were inserted in reportertransfer plasmid upstream the Firefly luciferase.SEQ ID NO of the poxviral promoter and Poxviral promoter and Plasmid ID TetO combination TetO combination encoded into the plasmid pTG19938 pA3L 75pTG20114 pA3L-O2 76pTG19942 pA10L 77pTG20115 pA10L-O2 78pTG19944 pA13L 79pTG20116 pA13L-O2 80pTG19948 pA19L 81pTG20117 pA19L-O2 82pTG19952 pA42R 83pTG20118 pA42R-O2 84pTG19954 pD13L 85pTG20119 pD13L-O2 86pTG19960 pI1L 87pTG20120 pI1L-O2 88pTG19964 pWR148 89pTG20124 pWR148-O2 90Table 20: Additional set of DNA sequences containing poxviral promoters with or withoutthe TetO2 sequence according to the invention and corresponding plasmids. All sequences are preceded at 5’ end by a sequence defined by the SEQ ID NO: 113 and are followed at 3’ end by a sequence defined by the SEQ ID NO: 114. These constant sequences allow thecloning of the different modified promoters into the transfer plasmid. The plasmids were evaluated by transient transfection / infection experiments in HeLa cells, in presence or absence of a plasmid encoding the TetR or the revTetR r1.7 (in presence of doxycycline at 0.1 µg / µL) placed under the control of the early / late promoter pH5R (pTG19779 and pTG19776, respectively). After 24 h the cells were lysed, and the luciferase activities were measured. The results are shown in Table 21. The expression levels were normalized for each poxviral promoter / TetO2 combination to the result obtained with the corresponding control promoter without the TetO2. As observed herein, insertion of the TetO2 at the 3’ end of the promoter decreased the promoter strength except for the promoters pA42R and pD13L. Poxviral promoter Relative strength Fold Fold red. Plasmid ID and TetO (prom. minus O2= reduction RevTetR + combination 1) TetR DOX pTG19695 pA14L 1.0pTG19654 pA14L-O2 0.3 126 105pTG19694 pF17R 1.0pTG19653 pF17R-O2 0.6 328 124pTG19938 pA3L 1.0pTG20114 pA3L-O2 0.9 154 118pTG19942 pA10L 1.0pTG20115 pA10L-O2 0.5 29 54pTG19944 pA13L 1.0pTG20116 pA13L-O2 0.3 243 146pTG19948 pA19L 1.0pTG20117 pA19L-O2 0.3 256 256pTG19952 pA42R 1.0pTG20118 pA42R-O2 1.1 129 61pTG19954 pD13L 1.0pTG20119 pD13L-O2 1.4 156 124pTG19960 pI1L 1.0pTG20120 pI1L-O2 0.2 75 56pTG19964 pWR148 1.0pTG20124 pWR148-O2 0.3 363 181Table 21: Evaluation and comparison of additional regulable promoters by transient transfection / infection experiments in HeLa cells. The efficacy of the regulation was estimated by the fold reduction of luciferase activity in presence of transcriptional regulators. All the additional promoters gave rise to similar level of repression to those obtained with the pA14L and pF17R promoters, except pA10L and p1L (fold reduction below 100). Best fold reductions were observed with the pWR148, pA19L and pA13L promoters (fold reduction over 200). The repression obtained with the TetR was generally higher than the repression induced by the RevTetR in presence of doxycycline. Eight additional TetR / TetO2 poxviral promoters with different expression and repression levels were identified as shown in Table 22. Poxviral promoter Fold Fold reduction Relative strength and TetO reduction RevTetR + (pA14L= 1) combinations TetR DOX pF17R-O2 2.6 328 124pA42R-O2 1.7 129 61pD13L-O2 1.2 156 114pWR148-O2 0.8 363 181pA3L-O2 0.7 154 118pA10L-O2 0.5 29 54pA19L-O2 0.4 256 256pA13L-O2 0.3 243 146pI1L-O2 0.3 75 56pA14L-O2 0.3 126 105Table 22: Ranking of poxviral promoter / TetO2 combinations according to their relativestrength in HeLa cells. Example 11: Evaluation of the TetO1 sequence The TetO1 as the TetO2 belongs to the DNA elements that control the Tn10-encoded tetracycline resistance operon of E.Coli. The nucleotide sequences of both TetO differ at four positions. The TetO1 and TetO2 are bound by the transcriptional regulator. The combination of the TetO1 sequence with the TetR or revTetR transcriptionalregulators to modulate the expression of the Firefly luciferase was also evaluated. TheTetO1 was inserted at the 3’ end of the pA14L, pF17R and pSE / L promoters as described in Table 23. SEQ ID NO of the poxviral promoter Poxviral promoter and and TetO Plasmid ID TetO combination combination encoded into the plasmid pTG20125 pA14L-O1 91pTG20126 pF17R-O1 92pTG20127 pSE / L-O1 93Table 23: DNA sequences containing poxviral promoter / TetO1 combinations andcorresponding plasmid ID comprising such. All sequences are preceded at 5’ end by asequence defined by the SEQ ID NO: 113 and are followed at 3’ end by a sequence defined by the SEQ ID NO: 114. These constant sequences allow the cloning of the differentmodified promoters into the transfer plasmid.The different poxviral promoter / TetO combinations were inserted into the reportertransfer plasmid in upstream position of the Firefly luciferase sequence.The plasmids were evaluated by transient transfection / infection experiments in HeLa cells, in presence or absence of a plasmid encoding the TetR or the revTetR r1.7 (in presence of doxycycline at 0.1 µg / µL). The pA14L, pF17R and pSE / L promoters wherein the TetO2 is inserted at the 3’ end were also evaluated for comparison. After 24 h the cells were lysed, and the luciferase activities were measured. The results are shown in Table 24. The expression levels were normalized for each poxviral promoter / TetO combination to the result obtained with the corresponding control promoter without the TetO. Relative Fold Poxviral promoter Fold Repression strength Repression Reduction Plasmid ID and TetO Reduction RevTetR + (prom. minus TetR RevTetR + combination TetR DOX O2= 1) DOXpTG19695 pA14L 1.0pTG20125 pA14L-O1 0.3 99,2% 259 98,1% 99pTG19654 pA14L-O2 0.3 98,4% 126 98,2% 105pTG19694 pF17R 1.0pTG20126 pF17R-O1 0.7 99,5% 361 98,0% 95pTG19653 pF17R-O2 0.6 99,4% 328 98,5% 124pTG19687 pSE / L 1.0pTG20127 pSE / L-O1 0.6 99,6% 396 98,2% 103PTG19688 pSE / L-O2 0.6 99,6% 403 98,7% 148Table 24: Evaluation of poxviral promoters with TetO1 or TetO2 by transient5 transfection / infection experiments in HeLa cells. Insertion of the TetO1 at the 3’ end of the promoters decreased the promoter strength equivalently to the insertion of the TetO2 at the 3’ end. Repressions and fold reductionsmeasured with plasmids wherein the TetO1 sequence is inserted at the 3’ end of thepA14L, pF17R and pSE / L promoters are comparable to those measured with their 10 counterpart plasmids using the TetO2 at the 3’ end.Therefore, the TetO1 is as efficient as the TetO2 to allow regulation of gene expression by TetR or RevTetR transcriptional regulators. Example 12: Evaluation of simultaneous repression of two transgenes with a unique TetO sequence 15 “Dual” reporter transfer plasmids were designed to assess the ability of a transcriptional regulator protein (herein TetR) to modulate simultaneously the expression of the Firefly luciferase and the expression of the Renilla luciferase placed downstream two poxviralpromoters oriented in the opposite direction in regard of the transcription orientation ofsaid two luciferase sequences (back-to-back orientation), with a unique TetO2 or TetO1 sequence inserted between both promoters. The poxvirus reporter and transfer plasmids also included the NanoLuc® luciferase coding sequence placed under the control the poxviral promoter pA26L. NanoLuc® luciferase was used as an internal standard tonormalize expression of Firefly luciferase and of Renilla luciferase. Firefly and Renillaluciferases originated from the plasmid pmirGLO Dual-Luciferase miRNA Target Expression Vector (Promega). NanoLuc® luciferase originated from plasmid pNL1.1.CMV (GenBank: JQ513379).The reporter transfer plasmid pTG20229 (Figure 7) wherein the Firefly luciferase and theRenilla luciferase are respectively placed under the control of the promoter pF17R andpromoter pA14L in combination with the TetO2, was used to generate three further transfer plasmids varying in their promoters’ sequences in combination with a unique TetO sequence (Table 25). The length of the promoters was set to 45 pb. The promoters were combined with TetO1 or TetO2. SEQ ID NO of the Poxviral promoters poxviral promoters Plasmid ID and TetO and TetO combination combination encoded into the plasmid pTG20229 pA14L_<O2_pF17R 94pTG20267 pA42R_<O1_pA19L 95pTG20266 pA14L_<O1_pF17R 96pTG20264 pA42R_<O2_pA19L 97Table 25: Design of DNA sequences containing the poxviral promoters with a TetO (TetO1or TetO2) to regulate two promoters oriented in opposite direction, correspondingplasmid ID and corresponding sequence of SEQ ID NO. The inequality symbols greater than(>) and less than (<) as used herein into the description of the plasmids indicates the 5’-3’ orientation of the TetO into the sequence in regard of the associated promoters. As anon-limitative example, pA14L_<O2_pF17R means the TetO2 sequence is encoded between the pA14L promoter and the pF17R promoter (said promoters are in a back-to-back orientation in regard of each other) and the TetO2 sequence is oriented in its 5’-3’orientation in the direction of the pA14L. Said otherwise, said TetO2 sequence 5’end islocated at the 5’ end of the pF17R promoter, and said TetO2 sequence 3’end is locatedat the 5’ end of the pA14L promoter.Single transfer plasmids were constructed as controls. A set of nine “single” plasmids were tested for their capacity to regulate the expression when the TetO / poxviral promoter sequences present in “dual plasmids” are not combined with another promoterin opposite direction. The nucleic acid sequences of the promoters, in combination witha TetO (Table 26), were cloned upstream of the Firefly luciferase gene into the poxviraltransfer plasmid pTG19520 (also expressing Renilla luciferase placed under the control ofthe ATI promoter). Renilla luciferase was used as an internal standard to normalize theexpression. The O2-pF17R or O2-pA19L sequences present in “dual plasmids” were alsoinserted into a transfer plasmid upstream the Firefly luciferase containing the NanoLuc®luciferase placed under the promoter pA26L and used as an internal standard to normalizeexpression. SEQ ID NO of the poxviral promoters and Poxviral promoter and Plasmid ID TetO combination TetO combination encoded into the plasmid pTG20342 <O1pF17R 98pTG20341 O1>pA42R 99pTG20340 <O1pA19L 100pTG20339 O1>pA14L 101pTG20338 O2>pA42R 102pTG20337 <O2pA19L 103pTG20336 <O2pF17R 104pTG20294 O2>pA14L 105pTG20217 O1>pF17R 106Table 26: Design of additional DNA sequences containing the promoter with TetOsequence. All sequences are preceded at 5’ end by a sequence defined by the SEQ ID NO: 113 and are followed at 3’ end by a sequence defined by the SEQ ID NO: 114. Theseconstant sequences allow the cloning of the different modified promoters into thetransfer plasmid. The inequality symbols greater than (>) and less than (<) as used herein into the description of the plasmids indicates the 5’-3’ orientation of the TetO into thesequence in regard of the associated promoter. As non-limitative example, <O1pF17Rmeans the TetO1 is encoded in a 5’-3’ orientation in opposite direction from the pF17Rpromoter. Said otherwise, said TetO1 sequence 5’end is located at the 5’ end of thepF17R promoter. As another non-limited example, O1>pA42R means the TetO1 is encoded in a 5’-3’ orientation in the same direction from the pF17R promoter. Said otherwise, said TetO1 sequence 3’end is located at the 5’ end of the pF17R promoter.“Dual” and “single” transfer plasmids contain the flanking sequences (R arm and L arm)surrounding the J2R locus allowing insertion of the nucleotide sequence to be transferred by homologous recombination in the J2R locus of the VACV virus genome. The plasmids were evaluated by transient transfection / infection experiments in HeLa cells, in presence or absence of a plasmid encoding the TetR (pTG19649: pCMV-TetR, of SEQ ID NO: 115). After 24 h the cells were lysed, and the luciferase activities were measured. The luminescence of the three luciferases was measured by two independentexperiments. Firstly, Firefly luciferase activity value (F) and Renilla luciferase activityvalue (R) were determined and the ratio r1=F / R calculated using Dual-Luciferase®Reporter Assay System (Promega). Secondly, Firefly luciferase activity value (F) andNanoLuc® luciferase activity value (N) were determined and the ratio r2=F / N calculatedusing Nano-Glo® Dual-Luciferase® Reporter Assay System (Promega). The efficacy of the regulation was estimated by the fold reduction of luciferase activity in presence of transcriptional regulators. The ratio r2 / r1 was determined to obtain the ratio R / N that corresponds to thenormalization of the Renilla luciferase activity value to its control NanoLuc® luciferaseactivity value. (Since F / R=r1 and F / N=r2 or F=r1.R and F=r2.N as a result r1.R= r2.N.) For each promoter studied, the reduction factor was obtained by dividing the F / R ratio(Firefly luciferase / Renilla luciferase) or the F / N ratio (Firefly luciferase / NanoLuc®luciferase) measured in the absence of the TetR by that measured in the presence of the TetR. The ability of a transcriptional regulator protein (herein TetR) to simultaneously regulatethe expression of Firefly luciferase and Renilla luciferase, positioned downstream of twopoxviral promoters oriented in the opposite direction with a unique TetO, was assessed and compared to the regulation of expression when the TetO / poxviral promoter sequences are not combined with another promoter in the opposite direction.The results are shown in Table 27 and Table 28.Relative Poxviral promoter Relative Fold Fold strength and TetOPlasmid Promoterstrength reduction reduction (O2pA14L=1) combination (O2pF17R=1) 12 1.1 pA14L_<O1(_pF17R) pTG20266 (pA14L_)<O1_pF17R 1.3 1412 1.0 pA14L_<O2(_pF17R) pTG20229 (pA14L_)<O2_pF17R 1.0 146 0.4 pA42R_<O1(_pA19L) pTG20267 (pA42R_)<O1_pA19L 0.4 128 0.4 pA42R_<O2(_pA19L) pTG20264 (pA42R_)<O2_pA19L 0.4 18Table 27: Evaluation of regulable promoters using TetO (TetO1 or TetO2) to regulate two promoters placed in opposite direction by transient transfection / infection experiments in HeLa cells. The data presented are the mean of three experiments. Same nomenclature5 used in regard of the inequality symbols greater than (>) and less than (<), as in Table 26.Poxviral promoter Relative Fold Plasmid and TetO strength reduction combination (pA14L=1) pTG19694 pF17R 3.8 1pTG19681 pH5R 1.5 1pTG20339 O1>pA14L 2.0 15pTG20294 O2>pA14L 1.6 12pTG20341 O1>pA42R 1.2 14pTG20338 O2>pA42R 1.1 13pTG20342 <O1pF17R 4.6 13pTG20336 <O2pF17R 4.0 12pTG20340 <O1pA19L 1.9 14pTG20337 <O2pA19L 2.2 21pTG20217 O1>pF17R 4.7 13pTG19714 O2>pF17R 3.9 12Table 28: Evaluation of regulable promoters using TetO1 or TetO2 by transient transfection / infection experiments in HeLa cells. The data presented are the mean of two experiments. Same nomenclature used in regard of the inequality symbols greaterthan (>) and less than (<), as in Table 26. Using a single TetO (TetO1 or TetO2) to regulate two promoters in opposite direction yields reduction factors comparable to those of "single" promoters. The presence of the TetO1 sequence at 5' end of the promoters results in higher expression levels than thoseobtained with the TetO2 except for the pA19L promoter. The orientation of the TetO hasno influence on promoter strength or repression levels (see pF17R “single” transferplasmids results in Table 28). The reduction factors for the pF17R and pA19L promotersobtained when using the “dual” plasmids are equivalent to those obtained with “single" plasmids. The reduction factors of the pA42R promoter obtained when using the “dual” plasmids were lower than those obtained with "single" plasmids.In conclusion, a single TetO sequence, TetO2 or TetO1, placed upstream two oppositelyoriented poxviral promoters is sufficient to allow the regulation of expression of the two promoters by the transcriptional regulator protein (TetR). The strength of promoters placed in "dual" plasmids is not comparable to that measured when the same promoters are placed in "single" plasmids, as luciferase activities are normalized for "dual" plasmids against NanoLuc® luciferase and for "single" plasmidsagainst Renilla luciferase. For this reason, the <O2pF17R and <O2pA19L sequences presentin the "dual" plasmids were also placed upstream of the Firefly luciferase gene in apoxviral transfer plasmid also expressing NanoLuc® luciferase placed under the pA26L promoter. By normalizing the results after measuring the two luciferase activities, the strength of the promoters when combined or not with another promoter in the opposite direction were compared in the same transient transfection-infection experiment using HeLa cells, in the presence or absence of the plasmid encoding the TetR. After 24 h the cells were lysed, and the luciferase activities were measured. The results are shown in Table 29. Relative strength Fold Plasmid Promoter(pA19L=1) reduction pTG20343 <O2_pF17R 2.1 14pTG20344 <O2_pA19L 1.0 23pTG20229 (pA14L_)<O2_pF17R 1.6 14pTG20264 (pA42R_)<O2_pA19L 0.7 18 Table 29: Evaluation and comparison of regulable promoters using TetO2 by transienttransfection / infection experiments in HeLa cells. Same nomenclature used in regard ofthe inequality symbols greater than (>) and less than (<), as in Table 25 and 26. The strength of the pF17R and pA19L promoters is reduced by around 25% when they are placed in "dual" plasmids, whereas fold reduction values remain comparable in the "single" plasmids and "dual" plasmids. Example 13: In vivo evaluation of “all in one” VACVFollowing in vitro characterization, the regulation of expression induced by Tet regulablesystem was analyzed in vivo in xenograft tumor model. Virus containing the late promoterpF17R were evaluated. Luciferase activities obtained after injection of VACV TetR pF17R-O2 (COPTG19889) and VACV revTetR pF17R-O2 (COPTG19865) were tested in comparison to injection of VACV pF17R-O2 (COPTG19653) using human colon cancer cells (HCT-116) xenografts model in nude mice. recVACVs were injected intravenously (i.v.) by tail vein injection, and Fireflyand Renilla luciferases were measured 3 days post-injection, in presence or in absence ofdoxycycline. As for in vitro experiments, the quantification of Renilla luciferase allowedto consider the various levels on viral infection and replication in each mouse. The fold reduction of expression was estimated by comparing the ratio F / R (Firefly / Renilla) obtained in inducing conditions compared to repressive conditions. Swiss nude mice were obtained from Charles River Laboratories. Animals used in the studies were uniform in age (6 and 7 weeks) and body weights ranged from 21-29 g (mean 24g). Swiss nude mice were injected subcutaneously into the flank with 5x106HCT-116 cells / 100 μL. When tumors reached a volume of 100-200 mm3, the mice were randomizedin a blinded manner and treated for in vivo experiments.In the first experiment two different ways were tested for the administration of doxycycline and two amounts (106pfu or 105pfu) of recVACVs were evaluated. To evaluate the repression caused by the revTetR, doxycycline was administrated for 4days and then stopped the day before the measurement of the Firefly luciferase.Four groups of 3 mice each were injected intraperitoneally (i.p.) daily with 10 µg / g doxycycline from day -1 before injection of VACVs to day 2 after injection of recVACVs. Groups (n=3) of mice were injected (i.v.) at day 0 with the VACV revTetR pF17R-O2 or VACV pF17R-O2 at an amount of 106pfu or 105pfu. Twelve control mice did not received doxycycline but were treated with the recVACVs at both concentrations (Figure 8). To evaluate the repression caused by TetR, doxycycline was administrated only one daybefore the measurement of the Firefly luciferase.Four groups of 3 mice each received a unique i.p. administration of doxycycline (10 µg / g) the second day after VACVs injection. Groups (n=3) of mice were injected i.v. with the recVACV TetR pF17R-O2 or VACV pF17R-O2 at an amount of 106pfu or 105pfu. Control mice did not received doxycycline but were treated with the recVACVs at both concentrations (Figure 9). Mice were sacrificed at day 3 post VACV injection, and the tumors were dissected out, mechanically divided into small pieces, and homogenized in PBS. Luciferase activitieswere measured in tumors. The results obtained are illustrated in Figure 10 and Figure11. The ratio F / R are reported for each VACV, in presence or absence of doxycycline treatment. The ratio obtained with VACV pF17R-O2 in absence of doxycycline was arbitrarily set at 1.Results in Figure 10 show that i.v. injection of VACV pF17R-O2 revTetR in mice thatreceived daily doxycycline i.p. administration allow to control the repression of Firefly luciferase. A 25-fold reduction was measured after injection of 105pfu of VACV pF17R-O2revTetR. Only a 7-fold reduction of Firefly luciferase expression was reached by using 106pfu of this virus, indicating that doxycycline amount becomes limiting. Moreover, foldreduction observed in vivo are lower than those measured in vitro (see Table 18 andTable 19, 143-fold in HeLa cells and 90-fold in CEP). A higher amount of doxycycline should improve the repression. The results obtained with the virus encoding the TetR was shown in Figure 11. A 260- fold and 297-fold reduction of luciferase expression was obtained after i.v. injection of VACV pF17R-O2 TetR at 105pfu and 106pfu, respectively in mice that received a unique doxycycline administration. Repression caused by TetR was not totally removed by doxycycline as F / R ratio of the VACV TetR pF17R-O2 is reduced by 70 % when compared to VACV pF17R-O2. Administration of higher concentrations of doxycycline should allow to increase the induction rate. In a second experiment, one dose of virus was injected (106pfu) and the use of higher dose of doxycycline was evaluated. Two groups of 6 mice were injected at day 0 with the VACV TetR pF17R-O2 or with the control VACV pF17R-O2. Each group was divided into 2. Groups (n=3) of mice were then treated i.p. at day 2 with 10 µg / g or 100 µg / g doxycycline (Figure 9). Three groups of 6 mice were injected at day 0 with the VACV TetR pF17R-O2, with the VACV revTetR pF17R-O2 or with the control VACV pF17R-O2. Each group was divided into 2. Groups (n=3) of mice were injected i.p. with 10 µg / g or 100 µg / g doxycycline from day -1 to day 2 post-injection (Figure 8). Mice were sacrificed at day 3 post-injection, and the tumors were dissected out, mechanically divided into small pieces and homogenized in PBS. Luciferase activities were measured in tumors.Results are showed in Figure 12 and Figure 13. The ratio F / R are reported for eachrecVACV. The ratio obtained with VACV pF17R-O2 using doxycycline at 10 µ / g or 100 µg / g was arbitrarily set at 1. The effect of the doxycycline concentration on the induction rate observed with viruscontaining the TetR is shown in Figure 12 and Figure 13. A higher doxycyclineconcentration increased the F / R ratio observed for the VACV TetR pF17R-O2 after a single injection of doxycycline (0.84 vs 0.59). Therefore, using a unique i.p. injection ofdoxycycline, high concentration is required to induce optimal Firefly luciferaseexpression when the promoter p17R-O2 is regulated by the TetR. Daily i.p. injection of doxycycline at 10 µg / g did not improve the induction rate compared to a single injection (0.46 vs 0.59). However, using a concentration of doxycycline at 100 µg / g allowed to recover the full strength of the promoter pF17R-O2 as the F / R ratio measured when TetR is expressed is equivalent to that when TetR is absent (1.16 vs 1.0). Therefore, repeated injections (4 days) of 100 µg / g of doxycycline are required to obtain a full induction rate after injection of recVACV containing the TetR. The effect of the doxycycline concentration on the repression rate observed with virus containing the RevTetR is shown in Figure 10. The F / R ratio drops dramatically when the promoter pF17R-O2 is used in combination with the RevTetR and by proceeding daily i.p.injection of doxycycline at 100 µg / g. The repression of the Firefly luciferase reached 287-fold, while it is only 22-fold when using only 10 µg / g of doxycycline.These in vivo experiments showed that the introduction of the TetR or the RevTetRtranscriptional regulators in a VACV could regulate the expression of a transgene driven by a regulable pF17R-O2 promoter in mice.Example 14: Evaluation of the Tet regulable system in chimeric poxvirusesThe functionality of the Tet regulable system was also evaluated in a chimeric poxvirus,hereafter referred to as POXSTG virus.Inducible gene expression studies were performed using expression cassettes regulatedby the TetR, inserted into the J2R locus of a POXSTG virus deleted for both the J2R andI4L genes.Recombinant POXSTG viruses encoding Firefly luciferase downstream of the poxviral latepromoter pF17R combined to a TetO2 sequence (also defined as O2), and Renillaluciferase under the control of the ATI promoter, were generated via homologous recombination between the transfer plasmid pTG19653 and POXSTG19834. This recombination resulted in the insertion of the expression cassette into the J2R locus of POXSTG20348 (hereafter referred to as POXSTG pF17R-O2). Evaluation in Hela and T-REx™-HeLa cellsHeLa and T REx™ HeLa cells were infected with POXSTG pF17R-O2 at a MOI of 10⁻⁴ andincubated for 24 hours. Following cell lysis, Firefly and Renilla luciferase activities weremeasured. The fold reduction in gene expression was calculated by dividing the F / R ratioobtained in HeLa cells (in absence of TetR) by the F / R ratio measured in T-REx™ HeLacells expressing TetR. The result is displayed in Table 30.Fold Virus ID Promoterreduction POXSTG20348 pF17R-O2 24Table 30: Evaluation of fold reduction after infection of HeLa and T-RExTM-HeLa cells withrecombinant POXSTG20348 (POXSTG pF17R-O2).A 24-fold reduction was observed for POXSTG pF17R-O2. This demonstrates that the TetR efficiently suppresses gene expression, with a repression level comparable to thatobserved for a recVACV carrying the same pF17R-O2 promoter configuration, whichexhibited a 38-fold reduction. Evaluation in T-REx™-HeLa cells in presence or absence of doxycyclineT-RExTM-HeLa cells were infected at a MOI of 10-4 by POXSTG pF17R-O2 and incubated for24 hours in presence or absence of doxycycline at 1 µg / mL. Cells were lysed, and luciferase activities were measured. Fold reduction in gene expression was calculated by dividing the F / R ratio obtained in the presence of doxycycline by the F / R ratio measuredin its absence. The result of the fold-reduction is shown in Table 31.Fold Virus ID Promoterreduction POXSTG20348 pF17R-O2 21Table 31: Evaluation of fold reduction after infection of T-REx™ HeLa cells withrecombinant POXSTG20348 (POXSTG pF17R-O2) in presence or absence of doxycyclineUnder these conditions, a 21-fold reduction was observed. This fold reduction measuredafter infection of T-REx™-HeLa cells in presence or absence of doxycycline is similar tothe fold reduction obtained after infection of HeLa cells versus T- REx™-HeLa cells,confirming that doxycycline treatment is able to fully induce the gene expression.Furthermore, the fold reduction observed with POXSTG pF17R-O2 is consistent with thatreported for a recVACV expressing the same promoter configuration, which showed a 38-fold reduction.These results validate the robustness and versatility of the Tet regulable system inchimeric poxvirus, such as POXSTG virus.Example 15: Generation and evaluation of “all in one” recombinant POXSTGAn ”all-in-one” recombinant POXSTG virus, hereafter referred as POXSTG20355 expressinga transcriptional regulator (revTetR) and the Firefly luciferase under a poxviral promotercombined to a TetO2 sequence was also generated and evaluated. A revTetR r1.7 placedunder the control of the pH5R promoter, was inserted into the I4L locus of POXSTG19730, resulting in the intermediate construct POXSTG20354. Then, POXSTG20355 (hereafter referred to as POXSTG revTetR pF17R-O2) was generated by homologous recombinationbetween the transfer plasmid pTG19653 and POXSTG20354 (the pF17R-O2 promotercarried by pTG19653 is inserted in the J2R locus of POXSTG20354). This constructconstitutively expresses a revTetR regulator and carries the Firefly luciferase genedownstream of the poxviral late promoter pF17R combined to a TetO2 sequence and theRenilla luciferase gene downstream of the ATI promoter. In this case, all the regulatoryelements necessary for the regulation by the Tet regulable system are integrated withinthe same recombinant virus. HeLa cells were infected by POXSTG revTetR pF17R-O2 recombinant at a MOI of 10-4and incubated for 24 hours in presence or absence of doxycycline at 1 µg / mL. Cells were lysed, and the luciferase activities were measured. The fold reduction in expression was calculated by dividing the F / R ratio measured in the absence of doxycycline by the F / Rratio measured in presence of doxycycline. The results of the fold-reduction are shown inTable 32. Transcriptional Virus ID PromoterFold reduction regulator POXSTG20348Ø 1pF17R-O2 POXSTG20355 revTetR367 Table 32: Evaluation of fold reduction after infection of HeLa cells by “all in one” POXSTG The POXSTG revTetR pF17R-O2 construct showed a fold reduction exceeding 300, indicating highly efficient repression. In comparison, infection of T-REx™-HeLa cells with POXSTG pF17R-O2 resulted in a significantly lower fold reduction of 21, highlighting the enhanced repression achieved through revTetR co-expression from the POXSTG virus itself. 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Claims

1. CLAIMS1. A recombinant poxvirus comprising in its genome at least one nucleic acidsequence encoding a conditional gene product, wherein the nucleic acid sequence encoding a conditional gene product is operably linked to at least one poxviral promoter and at least one Tetracycline operator (TetO) sequence; wherein expression of the nucleic acid sequence encoding a conditional gene product is inducible or repressible by the conditional binding of a transcriptional regulator protein; wherein said TetO sequence is located upstream (5’ end), downstream (3’ end)and / or within of the poxviral promoter operably linked to said nucleic acid sequence encoding a conditional gene product; wherein the conditional gene product affects the viability of the recombinant poxvirus.

2. The recombinant poxvirus according to claim 1, wherein the recombinant poxvirusis a poxvirus of the Chordopoxvirinae family, preferably selected from the group consisting of Avipoxvirus genus, Capripoxvirus genus, Leporipoxvirus genus, Molluscipoxvirus genus, Orthopoxvirus genus, Parapoxvirus genus, Suipoxvirus genus, Cervidpoxvirus genus, Yatapoxvirus genus and chimeric poxvirus thereof.

3. The recombinant poxvirus according to claim 2, wherein the recombinant poxvirusis a member of the Orthopoxvirus genus preferably selected from the group consisting of Vaccinia virus, Cowpox virus, Raccoonpox virus, Rabbitpox virus, Monkeypox virus, Horsepox virus, Volepox virus, Skunkpox virus, Variola virus, Camelpox virus, canarypox virus, ectromelia virus and chimeric Orthopoxvirus thereof.

4. The recombinant poxvirus according to claim 3, wherein the recombinant poxvirusis a Vaccinia virus preferably selected from the group consisting of Copenhagen, Western Reserve, Elstree, LIVP, Wyeth, Tian Tan, IHD, Modified Vaccinia Virus Ankara and chimeric vaccinia virus thereof.

5. The recombinant poxvirus according to claim 4, wherein the recombinant poxvirusis a Vaccinia virus strain Copenhagen.

6. The recombinant poxvirus according to any one of claims 1 to 5, wherein theconditional gene product is a toxic conditional gene product.

7. The recombinant poxvirus according to claim 6, wherein the toxic conditional geneproduct is toxic for a host cell.

8. The recombinant poxvirus according to claim 6 or claim 7, wherein the toxicconditional gene product is selected from the group consisting of bacterial toxins, plant toxins, enzymes, cytokines, self-antigens, virus genes.

9. The recombinant poxvirus according to any one of claims 6 to 8, wherein theconditional gene product interferes with the replication of the recombinant poxvirus.

10. The recombinant poxvirus according to any one of claims 1 to 9, wherein therecombinant poxvirus further comprises in its genome one or more heterologousnucleic acid of interest.

11. The recombinant poxvirus according to claim 10, wherein the heterologous nucleicacid of interest is selected from the list consisting of immune checkpoint inhibitors, cytokines, agents that affect the regulation of cell surface receptors, agents that affect angiogenesis, agents that stimulates stem cells to produce granulocytes and / or macrophages and a combination thereof.

12. The recombinant poxvirus according to any one of claims 1 to 11, wherein thepoxviral promoter is selected from late, intermediate, or early / late poxviral promoters.

13. The recombinant poxvirus according to claim 12, wherein the poxviral promoter isa late or an intermediate poxviral promoter selected from the list consisting of pF17R, pA14L, pA3L, pA10L, pA13L, pA19L, pA42R, pD13L, pI1L and pWR148 promoters, preferably pF17R and pA14L promoters.

14. The recombinant poxvirus according to claim 12 or claim 13, wherein the late orintermediate poxviral promoter comprises a nucleic acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or even 100% of identity with SEQ ID NO: 1, SEQ ID NO: 4, SEQID NO: 75, SEQ ID NO: 77, SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 87, or SEQ ID NO: 89.

15. The recombinant poxvirus according to claim 13 or claim 14, wherein the late orintermediate poxviral promoter comprises a transcriptional initiator element.

16. The recombinant poxvirus according to claim 15, wherein the transcriptionalinitiator element is a nucleotides sequence of TAAATG or TAAATA, preferably TAAATA.

17. The recombinant poxvirus according to claim 12, wherein the poxviral promoter isan early / late poxviral promoter selected from the list consisting of pSE / L, p11K7.5, p7.5K and pH5R promoters.

18. The recombinant poxvirus according to any one of claims 12 or 17, wherein theearly / late poxviral promoter comprises a nucleic acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or even 100% of identity with SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 18, or SEQ ID NO: 25.

19. The recombinant poxvirus according to claim 17 or claim 18, wherein theearly / late poxviral promoter comprises a transcriptional initiator element.

20. The recombinant poxvirus according to claim 19, wherein the transcriptionalelement is a nucleotides sequence of TAAATA, ATTTATTGCA (SEQ ID NO: 107) orGTTCTTGAGG (SEQ ID NO:108).

21. The recombinant poxvirus according to claim 15, wherein the TetO sequence ispositioned upstream (5’ end) or downstream (3’ end) of the transcriptional initiator element.

22. The recombinant poxvirus according to claim 21, wherein the TetO sequencepositioned upstream or downstream of the transcriptional initiator element is separated to the transcriptional initiator element by an interval of 0 to 100 nucleotides, preferably 0 to 80 nucleotides, more preferably 0 to 60 nucleotides.

23. The recombinant poxvirus according to claim 21 or claim 22, wherein the TetOsequence is positioned upstream of 5’ end of the transcriptional initiator element.

24. The recombinant poxvirus according to claim 24, wherein the TetO sequencepositioned upstream is separated to the 5’ end of the transcriptional initiator element by an interval of 30 to 100 nucleotides, preferably 30 to 80 nucleotides, more preferably 30 to 60 nucleotides.

25. The recombinant poxvirus according to claim 24, wherein the poxviral promoter isa late or intermediate poxviral promoter, preferably a pF17R or a pA14L promoter.

26. The recombinant poxvirus according to claim 19, wherein the TetO sequence ispositioned downstream of 3’ end of the transcriptional initiator element.

27. The recombinant poxvirus according to claim 26, wherein the TetO sequencepositioned downstream is separated to the 3’ end of the transcriptional initiator element by an interval of 0 to 50 nucleotides, preferably 0 to 30 nucleotides, more preferably 0 to 20 nucleotides.

28. The recombinant poxvirus according to any one of claims 1 to 27, wherein theTetO sequence is selected from the group consisting of TetO1 and TetO2 sequences, preferably the TetO sequence is TetO2 sequence.

29. The recombinant poxvirus according to claim 28, wherein the TetO2 sequencecomprises or consists of a nucleic acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or even 100% of identity with SEQ ID NO: 109 or SEQ ID NO: 110.

30. The recombinant poxvirus according to claim 28, wherein the TetO1 sequencecomprises or consists of a nucleic acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or even 100% of identity with SEQ ID NO: 111 or SEQ ID NO: 112.

31. The recombinant poxvirus according to any one of claims 1 to 30, wherein therecombinant poxvirus comprising in its genome at least two nucleic acid sequences encoding respectively two conditional gene products, wherein the nucleic acidsequences encoding the two conditional gene products are operably linked respectively to two poxviral promoters and one TetO sequence.

32. The recombinant poxvirus according to claim 31, wherein the TetO sequence islocated upstream of the two poxviral promoters operably linked to the two nucleic acid sequences encoding two conditional gene products.

33. The recombinant poxvirus according to claim 32, wherein the two poxviralpromoters operably linked to the two nucleic acid sequences encoding two conditional gene products are oriented in back-to-back, with said TetO sequence located between the two poxviral promoters.

34. The recombinant poxvirus according to any one of claims 1 to 33, wherein therecombinant poxvirus further comprises a nucleic acid sequence inserted in its genome encoding at least a transcriptional regulator operably linked to a constitutive poxviral promoter.

35. The recombinant poxvirus according to claim 34, wherein the nucleic acidsequence encoding the transcriptional regulator operably linked to a constitutive poxviral promoter is inserted in the I4L or F4L locus.

36. The recombinant poxvirus according to claim 34 or claim 35, wherein thetranscriptional regulator is a TetR protein and is selected from the group consisting of TetR of SEQ ID NO: 73 and TetR_BD of SEQ ID NO: 74 variants.

37. The recombinant poxvirus according to claim 34 or claim 35, wherein thetranscriptional regulator is a RevTetR protein and is selected from the group consisting of revTetR (B) and revTetR (BD) proteins.

38. The recombinant poxvirus according to claim 37, wherein the transcriptionalregulator is a revTetR (B) protein and is selected from the group consisting of M2_72P of SEQ ID NO: 65 and M2_72A of SEQ ID NO: 66 variants.

39. The recombinant poxvirus according to claim 37, wherein the transcriptionalregulator is a revTetR (DB) protein and is selected from the group consisting of revTetR r6.2 of SEQ ID NO: 69, revTetR r1.7 of SEQ ID NO: 70, revTetR r6.39 of SEQ ID NO: 72 and revTetR r4.29 of SEQ ID NO: 71 variants.

40. The recombinant poxvirus according to any one of claims 34 to 39, wherein thetranscriptional regulator conditionally binds to the TetO sequence either in the presence or absence of a tetracycline antibiotic or a derivative thereof.

41. The recombinant poxvirus according to claim 40, wherein the tetracyclineantibiotic is selected from the group consisting of tetracycline, doxycycline, minocycline, anhydrotetracycline, tigecycline, or a combination thereof.

42. A producer cell comprising the recombinant poxvirus according to any one ofclaims 1 to 42, wherein a transcriptional regulator is expressed.

43. The producer cell according to claim 42, wherein said cell is a permissive cell,preferably a mammalian cell selected between a human or a non-human cell, and more preferably a HeLa cell.

44. The producer cell according to claim 42 or claim 43, wherein the transcriptionalregulator is a TetR protein.

45. The producer cell according to claim 42 or claim 43, wherein the transcriptionalregulator is a RevTetR protein.

46. The producer cell according to any one of claims 42 to 45, wherein thetranscriptional regulator is integrated into the genome of the producer cell.

47. A recombinant nucleic acid molecule comprising at least one nucleic acidsequence encoding a conditional gene product, wherein the nucleic acid sequence encoding a conditional gene product is operably linked to at least one poxviral promoter and at least one Tetracycline operator (TetO) sequence; wherein expression of the nucleic acid sequence encoding a conditional gene product is inducible or repressible by the conditional binding of a transcriptional regulator protein; wherein said TetO sequence is inserted located upstream (5’ end), downstream (3’ end) and / or within of the poxviral promoter operably linked to said nucleic acid sequence encoding a conditional gene product, wherein the conditional gene product affects the viability of the recombinant poxvirus.

48. The recombinant nucleic acid molecule according to claim 47, wherein:a) the conditional gene product is as defined in any one of claims 6 to 9;b) the poxviral promoter is as defined in any one of claims 12 to 20 and 25;c) the Tetracycline operator (TetO) sequence is as defined in any one of claims21 to 24 and 26 to 30; d) the transcriptional regulator protein is as defined in any one of claims 36 to39; or e) any combination of a) to e).

49. The recombinant nucleic acid molecule according to claim 47 or claim 48, whichcomprises at least two nucleic acid sequences encoding respectively two conditional gene products, wherein the nucleic acid sequences encoding the two conditional gene products are operably linked respectively to two poxviral promoters and one TetO sequence.

50. The recombinant nucleic acid molecule according to claim 49, wherein the TetOsequence is located upstream of the two poxviral promoters operably linked to the two nucleic acid sequences encoding two conditional gene products.

51. The recombinant nucleic acid molecule according to claim 50, wherein the twopoxviral promoters operably linked to the two nucleic acid sequences encoding two conditional gene products are oriented in back-to-back, with said TetO sequence located between the two poxviral promoters.

52. A poxviral transfer plasmid comprising the recombinant nucleic acid moleculeaccording to any one of claims 47 to 51.

53. A method for producing a recombinant poxvirus according to any one of claims 1to 42, said method comprising the steps of: a) infecting a producer cell with a parental poxvirus, so as to obtain aninfected producer cell, b) transfecting the infected producer cell with a poxviral transfer plasmidaccording to claim 52, so as to obtain a transfected producer cell, c) culturing the transfected producer cell under conditions which areappropriate for enabling the recombinant poxvirus to be produced, so as to obtain an infected producer cell culture comprising the recombinant poxvirus,d) recovering the recombinant poxvirus from said infected producer cellculture; and optionally e) purifying said recovered recombinant poxvirus.

54. The method according to claim 53, wherein the producer cell expresses atranscriptional regulator encoded within its genome.

55. The method according to claim 54, wherein the transcriptional regulator is a TetRprotein.

56. The method according to claim 54, wherein the transcriptional regulator is aRevTetR protein.

57. The method according to any one of claims 53 to 56, wherein a tetracyclineantibiotic is added to induce or repress expression of the conditional gene product.

58. The method according to claim 57, wherein the tetracycline antibiotic is added atthe step b), c) or d), preferably at the step c) or d).

59. The method according to claim 57 or claim 58, wherein the tetracycline antibioticis selected from the list consisting of tetracycline, doxycycline, minocycline, anhydrotetracycline, tigecycline, or a combination thereof.

60. The method according to any one of claims 57 to 59, wherein the tetracyclineantibiotic is added to a concentration comprised between 0.05 µg / mL and 5 µg / mL, preferably between 0.075 µg / mL and 2.5 µg / mL, even more preferably between 0.1 µg / mL and 1 µg / mL61. Use of a producer cell according to any one of claims 42 to 46, a recombinantnucleic acid molecule according to any one of claims 47 to 51, a poxviral transfer plasmid according to claim 52 or a method according to any one of claims 53 to 60 for producing a recombinant poxvirus according to any one of claims 1 to 41.

62. A composition comprising the recombinant poxvirus according to any one of claims1 to 41, or the recombinant poxvirus obtained according to the method of any one of claims 53 to 60, and a pharmaceutically acceptable vehicle.

63. The composition according to the claim 62, wherein the composition comprises atherapeutically effective amount of said recombinant poxvirus.

64. The composition according to claim 63, comprising from 103 to 1012 pfu, preferably104to 1011pfu, preferably 105to 1010pfu, more preferably 106to 109pfu of the poxvirus; and notably individual doses of approximately 106, 5x106, 107, 5x107, 108or 5x108.

65. The composition according to any one of claims 62 to 65, which is formulated forintravenous, intramuscular, subcutaneous, oral, intranasal, transdermal, or intratumoral administration.

66. The recombinant poxvirus according to any one of claims 1 to 41, or thecomposition according to any one of claims 62 to 65, for use as a medicament or a vaccine.

67. The recombinant poxvirus according to any one of claims 1 to 41, or thecomposition according to any one of claims 62 to 65, for use for treating or preventing a proliferative disease, preferably a cancer.

68. The recombinant poxvirus or the composition for use according to claim 67,wherein the cancer is selected from the group consisting of renal cancer, prostate cancer, breast cancer, bladder cancer, colorectal cancer, lung cancer, liver cancer, gastric cancer, bile duct carcinoma, endometrial cancer, pancreatic cancer, ovarian cancer, head and neck cancer, melanoma, glioblastoma, multiple myeloma, or malignant glioma cells.

69. A method of treating or preventing a proliferative disease comprisingadministering to a subject the recombinant poxvirus according to any one of claims 1 to 41 or the composition according to any one of claims 62 to 65.

70. The method according to claim 69, further comprising administering a tetracyclineantibiotic in an amount sufficient to induce or repress expression of the conditional gene product.

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