WO2017097875A1 - Kit d'éléments pour utilisation dans le cadre d'une stratégie de primo-vaccination/rappel visant à protéger des animaux biongulés contre une infection par le virus de la fièvre aphteuse - Google Patents

Kit d'éléments pour utilisation dans le cadre d'une stratégie de primo-vaccination/rappel visant à protéger des animaux biongulés contre une infection par le virus de la fièvre aphteuse Download PDF

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WO2017097875A1
WO2017097875A1 PCT/EP2016/080185 EP2016080185W WO2017097875A1 WO 2017097875 A1 WO2017097875 A1 WO 2017097875A1 EP 2016080185 W EP2016080185 W EP 2016080185W WO 2017097875 A1 WO2017097875 A1 WO 2017097875A1
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fmdv
animal
kit
composition
seq
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PCT/EP2016/080185
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Graham John Belsham
Maria GULLBERG
Charlotta POLACEK
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Danmarks Tekniske Universitet
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • A61K2039/552—Veterinary vaccine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505—Inorganic adjuvants
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/14011—Baculoviridae
    • C12N2710/14041—Use of virus, viral particle or viral elements as a vector
    • C12N2710/14043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vectore
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/24011—Poxviridae
    • C12N2710/24111—Orthopoxvirus, e.g. vaccinia virus, variola
    • C12N2710/24141—Use of virus, viral particle or viral elements as a vector
    • C12N2710/24143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32111—Aphthovirus, e.g. footandmouth disease virus
    • C12N2770/32123—Virus like particles [VLP]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32111—Aphthovirus, e.g. footandmouth disease virus
    • C12N2770/32134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/36011—Togaviridae
    • C12N2770/36111—Alphavirus, e.g. Sindbis virus, VEE, EEE, WEE, Semliki
    • C12N2770/36141—Use of virus, viral particle or viral elements as a vector
    • C12N2770/36143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the present invention relates to a kit-of-parts for use in immunizing an animal against infection by foot-and-mouth disease virus (FMDV).
  • FMDV foot-and-mouth disease virus
  • the present invention relates to a kit-of-parts containing a priming composition and a boosting composition for use in a prime-boost FMDV-vaccination strategy.
  • FMDV is a virus that infects animals important for human food production such as cattle, pigs and sheep. It is currently circulating in Africa, Asia and likely South America, but sporadic outbreaks in FMDV-free countries makes it a global problem. The virus is highly contagious and can be transmitted readily via direct contact, contaminated materials and also through the air. This makes current vaccine production a challenge since it requires large scale growth of infectious virus, necessitating vaccine production in special, high containment facilities. Foot-and-mouth disease (FMD) is generally considered to be the most
  • FMD economically important viral disease of farm animals. It is estimated that FMD costs about US$ 10,000,000,000 annually around the globe (Knight-Jones
  • FMDV is an icosahedral virus of about 25 nm in diameter, containing a sing le- stranded RNA molecule consisting of about 8500 nucleotides, with a positive polarity.
  • This RNA molecule comprises a sing le large open read ing frame (ORF), encoding a sing le polyprotein containing, inter alia, the capsid precursor also known as protein P1 -2A.
  • the protein P1-2A is myristylated at its amino-terminal end .
  • the protein PI is cleaved by the protease 3C into three capsid proteins known as VP0, VP1 and VP3.
  • the viral capsids may be assembled without the presence of an RNA molecule inside it (so called "empty capsids”) . In these empty capsids, cleavage of the VP0 to VP4 and VP2 can occur (as found in the mature virus) .
  • Seven distinct serotypes of FMDV are known (O, A, C, SAT1, SAT2, SAT3 and Asia- 1 ), there is no cross protection between them and thus it is essential that a vaccine of the same virus serotype is used in the face of an outbreak of disease. In general, there is a considerable advantage in having a vaccine which produces the viral antigen within cells (e.g . as with a "live” vaccine) rather than simply administering non-infectious antigen .
  • WO06073431A2 discloses inter alia recombinant avipox vectors and viruses that express antigens of FMDV. Also disclosed is a prime-boost immunization or vaccination method of an animal against at least one FMDV antigen comprising administering to the animal e.g . a priming DNA vaccine followed by a boosting composition that comprises the FMDV antigen expressed by e.g . the DNA vaccine.
  • WO2011112945A2 discloses inter alia kits for use in vaccination against FMDV as well as FMDV polypeptides, antigens, epitopes or immunogens that elicit, induce or stimulate a response in e.g . bovines.
  • WO2011112945A2 also discloses a prime- boost method and a kit for performing said method, which can include a recombinant viral vector used to express an FMDV coding sequence followed by the ad ministration of vaccine or composition comprising FMDV antigen .
  • WO 11007339A2 discloses a chimeric FM DV nucleic acid molecule encoding a first FMDV strain, virus or isolate, wherein nucleotides encoding an outer capsid reg ion have been replaced with nucleotides encoding an outer capsid region of a second FMDV strain, virus or isolate which includes or has been mod ified so as to introduce a heparan sulfate proteog lycan binding site .
  • US20040001664 d iscloses FMD vaccine, using as antigen an efficient amount of empty capsids of FMDV.
  • WO 13001285 discloses modified VPl capsid protein from FMDV.
  • the modified VPl capsid protein comprises for example an epitope tag, an immunomod ulatory polypeptide or a target molecule.
  • WO 13001285 also relates to FMDV particles and vaccines, which comprise such a VPl capsid protein and uses thereof.
  • WO 13001285 also discloses a FMDV particle, which is an empty capsid FMDV-like particle.
  • kit-of-parts and the prime-boost strategy of the present invention differs from many of the existing vaccine technology in inter alia the following respects :
  • an object of the present invention relates to prime-boost FMDV-vaccination strategy by using a kit-of-parts comprising a priming composition and a boosting composition.
  • the inventors have established that a prime-boost vaccination strategy can achieve protection of cattle against FMDV challenge.
  • kits-of-parts for use in immunizing an animal against FMDV-infections, wherein the kit-of-parts comprises:
  • a vessel containing a priming composition which comprises a single-cycle alphavirus vector system expressing FMDV-antigens in vivo within cells of the animal;
  • a vessel containing a boosting composition which comprises non-infectious FMDV-capsid particles;
  • the priming composition is administered into the animal prior to the administration into said animal of the boosting composition.
  • An even further aspect of the invention relates to a prime-boost vaccination against FMDV in an animal, wherein a priming composition, which comprises a single-cycle alphavirus vector system expressing FMDV-antigens in vivo within cells of the animal, is administered to the animal prior to a subsequent priming composition, which comprises a single-cycle alphavirus vector system expressing FMDV-antigens in vivo within cells of the animal, is administered to the animal prior to a subsequent
  • a boosting composition which comprises noninfectious FMDV-capsid particles.
  • kit-of-parts according to the present invention makes use of a "single-cycle" RNA virus vector which is capable of expressing the FMDV antigens in vivo within cells of the animal (priming composition) and primes a surprisingly strong immune response upon subsequent administration of the boosting composition with non-infectious antigen.
  • High potency vaccines generated using current technology, can induce sterile immunity (i.e. no virus replication following virus challenge) whereas standard potency vaccines do not and limited virus replication can be detected post- challenge in animals given the lower dose of vaccine.
  • the prime-boost strategy on which the kit-of-parts of the invention is based, surprisingly showed a complete block on FMDV-dissemination after administration of the prime and boost compositions of the prime-boost
  • the single-cycle alphavirus of the priming composition of the invention such as Semliki Forest Virus (SFV)-FMDV, does result in the production of the FMDV- capsid proteins within cells (as would occur with a "live” virus rather than the antigen only being presented as an inactivated product) and this may elicit an immune response of a different nature than the current, inactivated vaccine.
  • SFV Semliki Forest Virus
  • the level of anti-FMDV antibodies elicited by the prime-boost strategy was significantly higher than that generated by a single FMDV-challenge of naive animals with infectious virus.
  • kits-of-parts of the present invention compared to the current FMDV-vaccines, is the ease of modifying the sequences of the priming- and/or boosting compositions in a wide range of different ways, e.g . to improve capsid stability, diversify antigenicity (to give protection against different strains) and to add specific markers which can be used to differentiate infected from vaccinated animals (DIVA) .
  • DIVA vaccinated animals
  • Other advantages of the prime-boost vaccination kit of the present invention are the potential for longer duration of immune response, inclusion of vaccine marker and lack of FMDV non-structural proteins, which in turn simplifies the
  • the prime-boost immunization protocol of the invention uses an infectious virus (albeit single cycle infection) in the priming step, which results in the production of the FMDV capsid proteins within the animal cells. This will generate a distinct immune response from that achieved using inactivated antigens. It is expected that this will achieve long-term immunity (c.f. "live" vaccines used to protect against poliovirus, measles virus, mumps virus and rubella virus) .
  • the nature of the immune response generated by this two-step strategy may be expected to have improved characteristics compared to that elicited by conventional, inactivated, FMDV vaccines.
  • the cell-mediated arm of the immune system may be stimulated more efficiently by the intracellular expression, processing and presentation on the cell surface of viral antigens. This may be particularly relevant with respect to the duration of immunity.
  • kit-of-parts of the invention relies on the use of a well-established "split helper" single-cycle viral vector system which preferably is based on SFV ( Figure 1) to express the correctly processed FMDV-capsid proteins (antigen) within cells of the animal as a priming step within a two stage prime-boost vaccination strategy (see Figure 2) .
  • the "split helper" single-cycle viral vector system provides the production of the SFV-capsid proteins from two separate RNA- transcripts whereas within the SFV they are produced from a single RNA- transcript. These transcripts are not packaged into the recombinant SFV (rSFV)- viruses and the potential for recombination between the SFV-capsid coding sequences and the modified rSFV is greatly diminished by "splitting" the capsid coding sequences into two transcripts.
  • rSFV vectors containing three different types of FMDV-cassette P1-2A, P1-2A- 3CC142S and Pl-2A-mIRES-3C
  • Figure 3 rSFV vectors containing three different types of FMDV-cassette (P1-2A, P1-2A- 3CC142S and Pl-2A-mIRES-3C) have been made ( Figure 3) . They have all been tested in cells, in culture, and shown to express the anticipated FMDV proteins that are required to induce an anti
  • the Pl-2A-mIRES-3C construct produces two proteins independently, i.e. P1-2A and 3Cwt.
  • the mIRES region does not encode any protein itself but allows two separate proteins to be made from one mRNA transcript.
  • the FMDV-particle consists essentially of a protein shell (capsid) around a single copy of the RNA genome.
  • the capsid consists of 60 copies of 4 different proteins, termed VP1, VP2, VP3 and VP4.
  • the VP1, VP2 and VP3 make up the outer surface of the capsid while VP4 is located internally within the FMDV-particle.
  • Each of the viral proteins is produced from a single polyprotein .
  • the capsid protein precursor is termed P1-2A, as described and shown in Figure 3, which is processed by the virus encoded 3C protease (3CP ro ) to make VP1, VP3 and VP0 (the precursor of VP2 and VP4) . Processing of the VP0 to VP2 and VP4 occurs either on encapsidation of the viral RNA or following empty capsid assembly.
  • the inventors have used a viral vector system to express the optimized Pl- 2A+3C pro cassettes and shown that the expected protein expression occurs within infected cells.
  • rSFVs containing three different FMDV cassettes have been made (see Figure 3) and are here termed rSFV-FMDVs. These cassettes either encode the capsid precursor (P1-2A) alone or with the 3C pro (the level of 3C pro activity is reduced by two separate means in the two cassettes rSFV-FMDV-Pl-2A-3CC142S and rSFV- FMDV-Pl-2A-mIRES-3C) .
  • RNA transcripts from these vectors can be packaged by SFV capsid proteins, if these are co-expressed by helper RNAs, and this generates infectious virus particles that can only initiate a single round of infection .
  • These packaged rSFV- FMDVs have each been tested in cells and shown to express the anticipated FMDV proteins (Figure 4 (top)) and the fully processed capsid proteins (but not the Pl- 2A precursor alone) have been found to self-assemble into empty capsid particles, as expected (see Figure 4 (middle)) .
  • the packaged rSFVs are also infectious for animals but following inoculation into animals, no transmission within the animal or to other animals occurs and they do not cause any disease.
  • the FMDV cDNA cassettes used, that encode the capsid precursor (P1-2A) alone or with 3C pro are shown in Figure 3 and were prepared by standard methods (Sambrook et al ., 1989) .
  • the split-helper RNA system for production of rSFV particles as shown in Figure 1 was based on pSFV3, pSFV- helper-C-S219A and pSFV-helper-S2 vectors (Smerdou and Liljestrom, 1999) .
  • the three plasmids containing the different FMDV cDNA inserts were digested with EcoRI and Xmal to release the FMDV cDNA cassettes, and the pSFV3 vector was digested with Bglll and Xmal or with Bg III and EcoRI (the pSFV3 vector contains three EcoRI sites) .
  • pSFV3-0-Pl-2A, pSFV3-0-Pl-2A-3CC142S and pSFV3-0- Pl-2A-IRESgtta3Cwt (here referred to as pSFV3-0-Pl-2A-mIRES-3C) were made through a single-step three-part ligation (between the different EcoRI/Xmal fragments and two parts of the backbone vector, i.e. a Xmal/Bglll part and a Bglll/EcoRI part). Plasmids were amplified in Escherichia coli (ToplO, Invitrogen), purified (Midiprep kit, Fermentas) and verified by sequencing .
  • the second boosting step of the prime-boost FMDV-vaccination strategy on which the kit-of-parts of the invention relies, has been tested using non-infectious FMDV-empty capsid particles produced using e.g . a vaccinia virus based system .
  • the FMDV-empty capsid consists of 60 copies of 3 different proteins, termed VP1, VP3 and VPO proteins. These proteins can "self-assemble" within cells of animals to make empty capsid particles, which appear very similar to intact virus particles, but lack the RNA genome and hence are completely non- infectious. Cleavage of VPO to VP2 and VP4 can occur and thus the particles may contain both unprocessed VPO, the precursor of VP4 and VP2, as well as the mature products.
  • FMDV vaccine preparations could potentially be used for the boosting step in the process described here and the combination of inactivated FMDV antigen with the primary vaccination using the rSFV-FMDV vector may result in an enhanced immune response.
  • This approach could be a useful "half-way house” between the use of current technology and full adoption of materials generated outside of high containment.
  • it may serve to extend the duration of immunity achieved compared to that obtained with the conventional vaccine alone.
  • Figure 1 shows a schematic representation of the SFV split helper system
  • FIG 2 shows the concept of the prime-boost FMDV-vaccination and challenge strategy on which the present invention is based, i.e. primary vaccination with a single-cycle alphavirus vector system expressing FMDV-antigens within cells of the animal (priming composition), e.g. rSFV-FMDV, followed by a boost vaccination with vaccinia virus expressed, non-infectious, recombinant FMDV-capsid particles.
  • Primary composition e.g. rSFV-FMDV
  • Challenge FMDV O UKG 34/2001.
  • Figure 3 shows a schematic representation of the FMDV genome and the rSFV plasmids used in this study.
  • the P1-2A, P1-2A-3CC142S and Pl-2A-mIRES-3C FMDV cDNA cassettes have been described elsewhere (Polacek et al., 2013;
  • P1-2A capsid precursor protein
  • 3C 3CP ro wild-type
  • mIRES internal ribosome entry site GTTA mutant
  • SP6 SP6 promotor
  • nsPl-P4 non-structural proteins 1-4
  • PS packaging signal
  • 26S 26S subgenomic promotor
  • C capsid
  • p62, 6K and El spike proteins.
  • Figure 4 (top) It has been demonstrated in cells that the rSFV vector containing the FMDV P1-2A cassette produces the P1-2A capsid precursor as an approx. 90kDa protein.
  • the FMDV-cassette encodes the FMDV-capsid precursor together with the 3C protease then processing of the P1-2A to VPO, VP3 and VP1 (and 2A) occurs.
  • Figure 4 (middle) In order to assess the assembly of the products expressed from the rSFV-FMDVs, infected cell lysates were analysed on sucrose gradients and the presence of FMDV proteins in each fraction was determined by ELISA.
  • FIG. 4 shows the ability of the FMDV capsid proteins to bind specifically to the integrin ⁇ ⁇ ⁇ (a cellular receptor for FMDV), assessed using an ELISA.
  • the protomers, pentamers and empty capsids were each able to bind specifically to this integrin in a divalent cation dependent manner (binding was blocked in the presence of EDTA).
  • Figure 5 shows induction of anti-FMDV antibodies following vaccination (prime on day 0 and boost on day 14) and challenge (on day 28).
  • ODP optical density percentage
  • Anti-FMDV antibody titres, on selected days, are shown on the right hand side. No detectable viral RNA was present within the sera of cattle (group 2) that received this treatment (see Figure 6). In contrast, unvaccinated cattle (group 1) had no anti-FMDV antibodies prior to challenge but did seroconvert after challenge although they generated only a relatively low titre of such antibodies ( Figure 5, right hand panels)); these animals displayed a high level of viremia post challenge (see Figure 6).
  • FIG. 6 shows the assessment of FMDV RNA in serum.
  • FMDV RNA in serum was measured by RT-qPCR.
  • Group 1 were unvaccinated.
  • Group 2 were vaccinated at day 0 with rSFV-FMDV (prime) and then on day 14 with non-infectious FMDV- capsid particles (boost).
  • Group 3 were vaccinated at day 0 with FMDV noninfectious capsid particles and then on day 14 with the rSFV-FMDV. All animals were challenged with FMDV on day 28. Surprisingly, no detectable virus was present within the sera of cattle (group 2) that received this treatment.
  • Figure 7 shows the level of neutralizing anti-FMDV antibodies in serum samples collected on the indicated days from calves 1-9 in experiment 3 (as described for Figure 6).
  • Anti- FMDV antibodies were determined using a virus neutralization assay in porcine IBRS2 cells. Values are given as log 2 of the reciprocal titre values. Values below the horizontal bar are considered negative whereas values above the bar are considered positive. Intermediate values are considered “inconclusive”. It is clear that the prime-boost treatment (given to calves 4-6) generated high levels of neutralizing anti-FMDV antibodies prior to challenge (on PVD 28) with FMDV. The present invention will now be described in more detail in the following.
  • administering into an animal refers to use of an acceptable (according to veterinary practice) and effective amount of the priming and boosting
  • compositions according to the invention wherein the administration may be via various routes including, but not limited to, intramuscular (IM), intradermal (ID) or subcutaneous (SC) injection or via intranasal or oral administration.
  • IM intramuscular
  • ID intradermal
  • SC subcutaneous
  • the therapeutic composition according to the invention can also be administered by a needleless apparatus, electroporation, by gene gun or gold particle bombardment or similar methods well-known in the art.
  • Animal or host includes mammals and human.
  • the animal may be selected from the group consisting of equine (e.g. horse), canine (e.g., dogs, wolves, foxes, coyotes, jackals), feline (e.g., lions, tigers, domestic cats, wild cats, other big cats, and other felines including cheetahs and lynx), ovine (e.g. sheep), bovine (e.g. cattle), porcine (e.g. pig), caprine (e.g. goat), avian (e.g.
  • equine e.g. horse
  • canine e.g., dogs, wolves, foxes, coyotes, jackals
  • feline e.g., lions, tigers, domestic cats, wild cats, other big cats, and other felines including cheetahs and lynx
  • ovine e.g. sheep
  • bovine e.g.
  • animal also includes an individual animal in all stages of development, including embryonic and fetal stages.
  • Antigen refers to a substance that induces a specific immune response in a host animal.
  • the antigen may comprise a whole organism, killed, attenuated or live; a subunit or portion of an organism; a recombinant vector containing an insert with immunogenic properties; a piece or fragment of DNA capable of inducing an immune response upon presentation to a host animal; a polypeptide, an epitope, a hapten, or any combination thereof.
  • substitutions will generally be conservative in nature, i.e., those substitutions that take place within a family of amino acids.
  • - CI, C2, C3 etc. refers to host animal (calf) subject numbers.
  • FMDV-antigen variants refers to FMDV polypeptides, particularly ovine, bovine, caprine or porcine polypeptides and variants or fragments thereof, having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 96%, 97%, 98% or 99% sequence identity to an antigenic polypeptide of the invention .
  • Heterologous means derived from a genetically distinct entity from the rest of the entity to which it is being compared.
  • a polynucleotide may be placed by genetic engineering techniques into a plasmid or vector derived from a different source, and is a heterologous polynucleotide.
  • a promoter removed from its native coding sequence and operatively linked to a coding sequence other than the native sequence is a heterologous promoter.
  • immunological response to a composition or vaccine refers to the development in the host of a cellular and/or antibody-mediated immune response to a composition or vaccine of interest.
  • an "immunological response” includes but is not limited to one or more of the following effects: the production of antibodies, B cells, helper T cells, and/or cytotoxic T cells, directed specifically to an antigen or antigens included in the composition or vaccine of interest.
  • - ODP values Optical Density Percentage (compared to negative control serum) .
  • -"Plasmid covers any DNA transcription unit comprising a polynucleotide according to the invention and the elements necessary for its in vivo expression in a cell or cells of the desired host or target; and, in this regard, it is noted that a supercoiled or non-supercoiled, circular plasmid, as well as a linear form, are intended to be within the scope of the invention.
  • Each plasmid comprises or contains or consists essentially of, in addition to the polynucleotide encoding an FMDV antigen, epitope or immunogen, optionally fused with a heterologous peptide sequence, variant, analog or fragment, operably linked to a promoter or under the control of a promoter or dependent upon a promoter.
  • a purified polypeptide preparation is one in which the polypeptide is more enriched than the polypeptide is in its natural environment. That is the polypeptide is separated from cellular components.
  • substantially purified it is intended that such that the polypeptide represents several embodiments at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98%, or more of the cellular components or materials have been removed.
  • the polypeptide may be partially purified.
  • partially purified is intended that less than 60% of the cellular components or material is removed. The same applies to polynucleotides.
  • the polypeptides disclosed herein can be purified by any of the means known in the art - PVD: for example "PVD 0" refers to Post Vaccination Day 0 etc.
  • Recombinant refers to a polynucleotide semisynthetic, or synthetic origin which either does not occur in nature or is linked to another polynucleotide in an arrangement not found in nature.
  • rSFV refers to recombinant Semliki Forest Virus (SFV).
  • Vector refers to a recombinant DNA plasmid or a DNA or RNA virus that comprises a heterologous polynucleotide to be delivered to a target cell, either in vitro or in vivo.
  • the heterologous polynucleotide may comprise a sequence of interest for purposes of prevention or therapy, and may optionally be in the form of an expression cassette.
  • a vector needs not necessarily be capable of replication in the ultimate target cell or subject. The term includes cloning vectors and viral vectors.
  • “Vessel” in the context of the present invention, “vessel” refers to any pharmaceutically and/or acceptable (according to veterinary practice) containers suitable for storing and preserving medication as liquids, powders or capsules, such as vials, multi-dose vials, single-dose vials, phials, flacons, small glass or plastic vessel or bottle, vacutainer, ampoule or similar small sealed vials, etc.
  • kit-of-parts for use in immunizing an animal against FMDV infections, wherein the kit-of-parts comprises:
  • a vessel containing a priming composition which comprises a single-cycle alphavirus vector system expressing FMDV-antigens in vivo within cells of the animal;
  • kits-of- parts for use in immunizing an animal against FMDV infections derived from serotype 0, wherein the kit-of-parts comprises :
  • a vessel containing a priming composition which comprises a SFV system expressing a FMDV-antigen encoded by SEQ ID NOs: 8 (Pl-2A-mIRES-3C) in vivo within cells of the animal;
  • the priming composition is administered into the animal prior to the administration into said animal of the boosting composition.
  • the subject matter disclosed herein is directed to the use of the kit-of-parts of the invention wherein the dose of the infectious single cycle viral vector of the priming composition per 100 kg animal is between : lxlO 6 and 1.5xl0 9 infectious units, 5xl0 6 and 1.5xl0 9 infectious units, lxlO 7 and 1.5xl0 9 infectious units, 5xl0 7 and 1.5xl0 9 infectious units, lxlO 8 and 1.5xl0 9 infectious units, preferably 2xl0 8 and 1.3xl0 9 , more preferably 3xl0 8 and l .
  • the dose of the non-infectious FMDV-capsid particles of the boosting composition is between 1 -20 Mg/per 100 kg animal, preferably 2- 19 Mg/per 100 kg animal, more preferably 3- 18 Mg/per 100 kg animal, more preferably 4- 17 Mg/per 100 kg animal, more preferably 5- 16 [ig/per 100 kg animal, more preferably 4- 15 [ig/per 100 kg animal, more preferably 5-14 [ig/per 100 kg animal, more preferably 6-13 Mg/per 100 kg animal, more preferably 7- 12 [ig/per 100 kg animal, more preferably 6- 11 [ig/per 100 kg animal, most preferably ca .
  • 10 [ig/per 100 kg animal and/or the duration between the successive administration of priming composition and boosting com position into the animal is between 10-20 days, preferably 11- 19 days, 12- 18 days, 13- 17 days, 14- 16, 14- 15 days, most preferably 14 days. and/or the route of successive administration into the animal of priming and boosting compositions of the kit-in parts is by intramuscular and/or intradermal and/or subcutaneous injection or via intranasal or oral administration, preferably by subcutaneous injection .
  • a priming composition which comprises a single-cycle alphavirus vector system expressing FMDV- antigens in vivo within cells of the animal, is ad ministered to the animal prior to a subsequent administration to said animal of a boosting composition, which comprises non-infectious FMDV-capsid particles.
  • Kit-of-parts for use in immunizing an animal against FMDV infections, wherein the kit-of-parts comprises : (i) a vessel containing a priming composition which comprises a single-cycle alphavirus vector system expressing FMDV-antigens in vivo within cells of the animal;
  • kits-of-parts according to items 1 or 2, wherein the FMDV-antigens of the priming composition are encoded by one or more nucleotide sequence/sequences selected the group consisting of SEQ ID NO : 4 (P1-2A) and/or SEQ ID NO : 6 (Pl- 2A-3CC142S) and/or SEQ ID NO : 8 (Pl-2A-mIRES-3C) and/or SEQ ID NO : 9 (Pl- 2A+ 3CP ro ) and/or SEQ ID NO : 11 (VPO (VP4 and VP2)) and/or SEQ ID NO : 13 (VP1) and/or SEQ ID NO : 15 (VP2) and/or SEQ ID NO : 17 (VP3) and/or SEQ ID NO : 19 (VP4) and/or SEQ ID NO : 21 (2A) and/or SEQ ID NO : 24 (3Cwt) and/or SEQ ID NO : 26 (pSFV3-0-Pl-2A-IRES
  • Kit-of-parts according to any of items 1-4, wherein the animal to be immunized is a cloven-footed animal such as bovine, ovine, porcine or caprine.
  • kits-of-parts according to any of items 1-5, wherein the FMDV is derived from serotypes selected from the group consisting of serotype O, A, C, SATl, SAT2 ,
  • SAT3 and Asia-1 preferably serotype O.
  • the adjuvant is a mineral oil adjuvant such as Montanide ISA 201 VG (Seppic) mineral oil adjuvant.
  • kits-of-parts according to any of items 1-9, wherein the priming composition and/or the boosting composition comprise one or more acceptable (according to veterinary practice) carrier(s), excipient(s), and/or vehicle(s) such as water-in-oil emulsion or oil-in-water emulsion .
  • kit-of-parts according to any of items 1- 10, wherein said kit-of-parts further comprises instructions for the successive administration to the animal wherein the priming composition is administered into the animal prior to the administration into said animal of the boosting composition .
  • Kit-of-parts according to any of items 1-2 or 5- 11 , wherein the antigen of the infectious single cycle viral vector of the priming composition is one or more of
  • SEQ ID NO : 5 P1-2A
  • SEQ ID NO : 7 P1-2A-3CC142S
  • SEQ ID NO : 10 Pl- 2A+ 3CP ro
  • SEQ ID NO : 12 VP0
  • SEQ ID NO : 14 VP1
  • SEQ ID NO : 16 VP2
  • SEQ ID NO : 18 VP3
  • SEQ ID NO : 20 VP4
  • SEQ ID NO : 22 (2A) or SEQ ID NO : 25 (3Cwt) or any fragments and/or combinations thereof.
  • kit-of-parts according to any of items 1- 16 for immunizing animals against FMDV-infections, wherein the dose of the infectious single cycle viral vector of the priming composition to be administered to the animal is between lxlO 6 and 1.5xl0 9 infectious units/per 100 kg animal .
  • kit-of-parts according to any of items 1 - 16, wherein the dose of the infectious single cycle viral vector of the priming composition per 100 kg animal is between lxlO 6 and 1.5xl0 9 infectious units, 5xl0 6 and 1.5xl0 9 infectious units, lxlO 7 and 1.5xl0 9 infectious units, 5xl0 7 and 1.5xl0 9 infectious units, lxlO 8 and 1.5xl0 9 infectious units, preferably 2xl0 8 and 1.3xl0 9 , more preferably 3xl0 8 and l .
  • lxlO 9 more preferably 4xl0 8 and lxlO 9 , more preferably 5xl0 8 and 9xl0 8 , more preferably 5xl0 8 and 8xl0 8 , more preferably 5xl0 8 and 7.5xl0 8 , most preferably 7.5xl0 8 .
  • kit-of-parts for immunizing animals against FMDV-infections, wherein the dose of the non-infectious FMDV-capsid particles of the boosting composition to be administered to the animal is between 1-20 Mg/per 100 kg animal.
  • kit-of-parts according to any of items 1-16, wherein the dose of the non-infectious FMDV-capsid particles of the boosting composition per 100 kg animal is between 1-20 Mg, preferably 2-19 Mg, more preferably 3-18 Mg, more preferably 4-17 [ig, more preferably 5-16 Mg, more preferably 4-15 Mg, more preferably 5-14 [ig, more preferably 6-13 Mg, more preferably 7-12 [ig, more preferably 6-11 Mg, most preferably approx. 10 [ig .
  • kit-of-parts of any of items 1-16 for immunizing animals against FMDV-infections, wherein the priming composition is administered into the animal prior to the administration into said animal of the boosting composition.
  • kit-of-parts of any of items 1-16 for immunizing animals against FMDV-infections, wherein the duration between the successive administration of priming composition and boosting composition into the animal is between 10-20 days, preferably 14 days.
  • kit-of-parts of any of items 1-16 for immunizing animals against FMDV-infections, wherein the duration between the successive administration of priming composition and boosting composition into the animal is between 10-20 days, preferably 11-19 days, 12-18 days, 13-17 days, 14-16, 14-15 days, most preferably 14 days.
  • kit-of-parts of any of items 1-16 for immunizing animals against FMDV-infections, wherein the route of successive administration into the animal of priming and boosting compositions of the kit-in parts is by intramuscular and/or intradermal and/or subcutaneous injection or via intranasal or oral administration, preferably by subcutaneous injection.
  • the kit-of-parts of any of items 1-16 for immunizing animals against FMDV-infections, wherein the period between the prime-boost vaccination with the kit-of-parts according to items 1-15, and a subsequent prime-boost
  • vaccination is 0.5 - 10 years, preferably 0.6 - 8 years, preferably 0.7 - 7 years, preferably 0.8 - 6 years, preferably 0.9 - 5 years, preferably 1 - 4 years, preferably 1.1 - 3 years, preferably 1.2 - 2 years, most preferably ca. 2 years .
  • kit-of-parts of any of items 1-16 for immunizing animals against FMDV-infections, and using the periods of item 24, wherein the subsequent prime- boost vaccination is according to any of items 1-15.
  • a priming composition which comprises a single-cycle alphavirus vector system expressing FMDV-antigens in vivo within cells of the animal, is administered to the animal prior to a subsequent administration to said animal of a boosting
  • composition which comprises non-infectious FMDV-capsid particles.
  • Method of prime-boost vaccination against FMDV in an animal according to item 27, comprising the kit-of-parts according to items 1-16, which can be used for serological differentiation between animals infected with FMDV and animals vaccinated against FMDV.
  • Method of prime-boost vaccination against FMDV in an animal according to item 27, comprising the kit-of-parts according to items 1-16, which can be used to readily differentiate between FMDV- infected animals by the presence and/or amounts of antibodies to the FMDV non-structural protein (NSP 3B, FMDV 3ABC or 3D-specific ELISA) using a commercial ELISA kit (e.g . Prionics) .
  • kit-of-parts according to items 1-16 which can be used to readily differentiate between FMDV- infected animals by the presence and/or amounts of antibodies to the FMDV non-structural protein (NSP 3B, FMDV 3ABC or 3D-specific ELISA) using a commercial ELISA kit (e.g . Prionics) .
  • Both the rSFV vector and the recombinant non-infectious FMDV-capsid particles can be generated outside of high-containment facilities, in contrast to
  • the inventors have focused recent efforts on the processing of the capsid precursor (P1-2A) by the 3C protease (3C pro ) (Polacek et al., 2013). This processing yields the capsid proteins VPO, VP3 and VP1 plus the 2A peptide.
  • Optimal protein expression is achieved when the level of 3C pro is reduced relative to the capsid precursor (Polacek et al., 2013).
  • "Self-assembly" of the processed capsid proteins occurs to generate "empty" capsid particles (60 copies of each protein, Gullberg et al., 2013a)).
  • the inventors have demonstrated that the cleavage of the VP1-2A junction is not essential for the formation of empty capsid particles (Gullberg et al., 2013b) and indeed infectious "self-tagged" viruses with uncleaved VP1-2A can be made (see e.g. Gullberg et al., 2013b).
  • the three serotype O FMDV cDNA cassettes indicated in Figure 3 have previously been described in Polacek et al., 2013; Gullberg et al., 2013a.
  • One cassette encodes the capsid precursor P1-2A (from 01 Manisa) alone while the P1-2A- 3CC142S cassette encodes P1-2A linked directly (within a single open reading (ORF) to a mutant form of 3C pro with much reduced catalytic activity.
  • the third FMDV cDNA cassette, Pl-2A-mIRES-3C includes two separate ORFs for P1-2A and the wt 3C pro ; the expression of the 3C ro is dependent on a mutant form of the FMDV IRES element (termed GTTA) that is highly defective (ca.
  • FMDV capsid proteins The ability of the FMDV capsid proteins to bind specifically to the integrin ⁇ ⁇ ⁇ (a cellular receptor for FMDV) was also assessed using an ELISA.
  • the protomers, pentamers and empty capsids were each able to bind specifically to this integrin in a divalent cation dependent manner (binding was blocked in the presence of EDTA) (see figure 4).
  • the recombinant, non-infectious, FMDV empty capsid particles were produced using a vaccinia virus vector system that is only suitable for use in cell culture, see e.g . Abrams et al., 1995; Porta et al., 2013.
  • the empty capsid particles were produced by dual infection of RK13 cells with vaccinia virus vTF7-3 (Fuerst et al., 1986) and another containing a T7-P1-2A- 3C pro 01 Manisa cDNA cassette and then purified by sucrose gradient
  • Animal experiment 1 demonstrated that the rSFV-FMDV vectors used were capable of inducing an anti-FMDV antibody response in cattle, however this response was not strong enough to achieve protection against challenge with FMDV. Similarly, simply boosting with a second dose of the rSFV-FMDV (see animal experiment 2, Example 4) also failed to confer protection.
  • Animal experiment 1 (results) : rSFV-FMDV alone followed by challenge gave rise to antibodies against FMDV pre-challenge but did not protect against FMDV.
  • animal experiment 1 eight calves of 2-6 months of age (Danish Jersey calves, approx. 100 kg) were divided into three groups, one group with two animals (control group 1, animals CI and C2) and the other two groups with three animals in each (group 2, animals C3, C4 and C5 and group 3, animals C6, C7 and C8).
  • Group 2 (C3-C5) and 3 (C6-C8) were vaccinated subcutaneously with 5xl0 8 infectious units of each rSFV expressing FMDV P1-2A or FMDV Pl-2A-mIRES-3C, respectively.
  • the control g roup received injections of PBS .
  • the procedure used to challenge the cattle has previously been described in Stenfeldt et al ., 2011.
  • Example 4 (Animal experiment 2 - rSFV-FMDV followed by rSFV-FMDV followed by challenge) .
  • Animal experiment 2 (results) : rSFV-FMDV + rSFV-FMDV also gave rise to antibod ies against FMDV but d id still not fully protect against FMDV. However, as in the animal experiment 1 (example 3), it was apparent that following challenge a large increase in antibody titres against FMDV occurred . These reached a level much hig her than in the unvaccinated calves. In animal experiment 2, thirteen calves of 2-6 months of age (Danish Jersey calves, approx. 100 kg) were divided into 5 groups.
  • Animals in groups 1 and 3 were inoculated into the tongue with FMDV O U KG 34/2001 (ca . 10 6 TCIDso) on PVD 28.
  • mice in group 2 (C3- C4, unvaccinated) and g roup 5 (C11-C13, twice vaccinated) were kept in close contact with those from group 1 (C1 -C2) from one day after challenge (PVD 29) in one stable while cattle in group 4 (C8-C10) were kept in contact with the vaccinated and inoculated cattle (C5-C7) in group 3 within another stable. All animals were monitored daily and blood samples were collected at pre-determined times until day 42 when the experiment was terminated .
  • Group 1-2 control groups, two animals/group (no vaccination)
  • Group 3-5 vaccination groups with 3 animals/group : rSFV-Pl-2A-mIRES-3C dissolved in PBS (dose: 5xl0 8 particles/ml, in total 1,5ml subcutaneous injection in neck, in total 3 animals per group) Week 3 (booster vaccination)
  • Group 1-2 control groups (no vaccination)
  • Group 3-5 vaccination groups: rSFV-Pl-2A-mIRES-3C dissolved in PBS (dose: 5xl0 8 particles/ml, in total 1,5ml subcutaneous injection in neck, in total 3 animals per group)
  • Group 3-5 vaccination groups: Inoculation with FMDV 0 UKG 34/2001. Dose: 10 6 TCID5o/animal, in total 1 ml for intra-/subdermal injection in the tongue. The animals are anesthetized (with a combination of Zoletil 50 Vet and Rompun Vet) before inoculation. The day following the inoculation, the animals are moved such that inoculated animals and contact-animals are intermingled.
  • Blood samples are taken on days: 0, 1, 2, 3, 4, 7, 14, 15, 16, 17, 18, 21, 28, 29, 30, 31, 32, 34, 35, 39 and 42. In total : 22 samples per animal.
  • Swab samples are taken on days: 0, 28, 29, 30, 31, 32, 34, 35, 37, 39 and 42. In total 11 samples per animal.
  • Example 5 (Animal experiment 3 - rSFV-FMDV followed by non-infectious, empty FMDV-capsids followed by challenge)
  • the level of anti-FMDV antibodies elicited by the prime-boost strategy is better than that generated by a single challenge of naive animals with infectious FMD virus. Furthermore, the complete absence of FMDV in serum, post-challenge, in the vaccinated animals is a marked improvement on the outcome observed in animals given two doses of the recombinant empty capsids (Porta et al., 2013). In that study, all animals given the unmodified empty capsid particles showed viremia post-challenge.
  • Group 3 received the same inoculations but in the opposite order, thus the animals were inoculated with the 01 Manisa empty capsid particles in adjuvant on PVD 0 and then with the rSFV-Pl-2A-mIRES-3C on PVD 14.
  • the empty capsid particles were produced by dual infection of RK13 cells with vaccinia virus vTF7-3 (Fuerst et al., 1986) and another containing a T7-Pl-2A-3CP ro 01 Manisa cDNA cassette and then purified by sucrose gradient centrifugation essentially as described by Porta et al., (2013b). All animals were challenged on PVD 28 by needle inoculation into the tongue (as in animal experiment 1, see above).
  • FMDV RNA and anti-FMDV antibodies in the cattle serum samples were determined by RT-qPCR (targeting the 5'-UTR) and a blocking ELISA, respectively.
  • the level of viral RNA detected in serum samples was converted to the number of genome copies by reference to a standard curve of reference RNA samples, assayed in parallel, as described previously (B0tner et al., 2011).
  • Group 1 3 animals, C1-C3 (control, no vaccine and challenge)
  • Group 2 3 animals, C4-C6 (rSFV-FMDV vaccine followed by vaccinia virus expressed FMDV non-infectious capsids and challenge)
  • Group 3 3 animals, C7-C9 (vaccinia virus expressed FMDV non-infectious capsids followed by rSFV-FMDV vaccine and challenge)
  • Blood samples are taken on days : 0, 1, 2, 3, 4, 7, 14, 15, 16, 17, 18, 21, 28, 29, 30, 31, 32, 34, 35, 39 and 42. In total : 22 samples per animal .
  • Swab samples are taken on days : 0, 28, 29, 30, 31, 32, 34, 35, 37, 39 and 42. In total 11 samples per animal .
  • serotype 0 cassettes have been used in the present invention, but this is the serotype that is responsible for about 75% of the global FMDV- outbreaks.
  • the technology should be applicable to other strains of serotype 0 and also to other serotypes if the sequence corresponding to the P1-2A capsid precursor is used in the rSFV vector.
  • the 01 Manisa sequence (field virus) sequence is available in GenBank with an Accession no. AY593823.1 (Foot-and-mouth disease virus 0 isolate olmanisa iso87, complete genome) and the sequences SEQ ID NOs: 4-25 listed below are derived from that)
  • SEQ ID NO: 1 pSFV3 (SFV3) (nucleotide)
  • SEQ ID NO: 2 pSFV-helper-C-S219A (nucleotide)
  • SEQ ID NO: 3 pSFV-helper-S2 (nucleotide)
  • SEQ ID NO: 4 (P1-2A) (OlManisa, with an ATG codon added at the start)
  • SEQ ID NO: 8 Pl-2A-mIRES-3C (nucleotide)
  • VPO VP4 and VP2 (nucleotide)
  • SEQ ID NO: 17 (VP3 (nucleotide)
  • SEQ ID NO: 24 (3Cwt (nucleotide))
  • SEQ ID NO: 25 (3Cwt (amino acid))
  • SEQ ID NO: 26 (pSFV3-0-Pl-2A-IRESgtta-3Cwt (nucleotide))

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Abstract

La présente invention concerne un kit d'éléments pour utilisation dans l'immunisation d'un animal contre une infection par le virus de la fièvre aphteuse. En particulier, la présente invention concerne un kit d'éléments contenant une composition de primo-vaccination et une composition de rappel pour utilisation dans le cadre d'une stratégie de primo-vaccination/rappel contre une infection par le virus de la fièvre aphteuse.
PCT/EP2016/080185 2015-12-08 2016-12-08 Kit d'éléments pour utilisation dans le cadre d'une stratégie de primo-vaccination/rappel visant à protéger des animaux biongulés contre une infection par le virus de la fièvre aphteuse WO2017097875A1 (fr)

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CN109655612A (zh) * 2019-01-31 2019-04-19 中国农业科学院兰州兽医研究所 一种Asia1型口蹄疫病毒的检测试剂盒及检测方法
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