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WO2016114669A1 - Vaccin combiné pour camélidés - Google Patents

Vaccin combiné pour camélidés Download PDF

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Publication number
WO2016114669A1
WO2016114669A1 PCT/NL2016/050040 NL2016050040W WO2016114669A1 WO 2016114669 A1 WO2016114669 A1 WO 2016114669A1 NL 2016050040 W NL2016050040 W NL 2016050040W WO 2016114669 A1 WO2016114669 A1 WO 2016114669A1
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Prior art keywords
mers
mva
virus
camelids
immunogenic
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Ceased
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PCT/NL2016/050040
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English (en)
Inventor
Albertus Dominicus Marcellinus Erasmus Osterhaus
Bartholomeus Leonardus Haagmans
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Erasmus University Medical Center
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Erasmus University Medical Center
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Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C07K14/08—RNA viruses
    • C07K14/165—Coronaviridae, e.g. avian infectious bronchitis virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/543—Mucosal route intranasal
    • 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
    • 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
    • C12N2710/24041—Use of virus, viral particle or viral elements as a vector
    • C12N2710/24043—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
    • C12N2770/20011—Coronaviridae
    • C12N2770/20034—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
    • C12N2770/20011—Coronaviridae
    • C12N2770/20071—Demonstrated in vivo effect

Definitions

  • the invention relates to an immunogenic composition that is able to protect camelids, in particular camels and dromedary camels against both camelpox virus and Middle East Respiratory Syndrome (MERS)
  • camelids in particular camels and dromedary camels against both camelpox virus and Middle East Respiratory Syndrome (MERS)
  • MERS Middle East Respiratory Syndrome
  • Camelpox is caused by the Orthopoxvirus camelii, which belongs to the genus of Orthopoxviruses within the family Poxviridae. Clinical manifestations range from inapparent and mild local infections, confined to the skin, to moderate and severe systemic infections, which can ultimately lead to the death of the animal. The mortality rate in adult animals is between 5% and 28% and higher in young animals Mayer, A, Czerny C.-P., 1990. Chpater 4; camelpox virus. In: Virus infections of Vertebrates, Vol. 3: Virus Infections of Ruminants, Dinter Z., Morein, B. (eds). Elsevier Science Publ., Amsterdam, The Netherlands, page 19-22).
  • camelpox virus like the human pox variant, is closely related to Vaccinia virus, which often is used in vaccines. It has especially been described that the attenuated modified Vaccinia virus Ankara (MVA) can be used as an effective vaccine (Mahy, B.W.J., 2008, The Dictionary of Virology, Elsevier/Academic Press, Amsterdam, The Netherlands, page 74). However, in this reference no data at all are shown nor is it clear how the vaccine has been produced.
  • VVA attenuated modified Vaccinia virus Ankara
  • MERS Middle East Respiratory Syndrome
  • an immunogenic composition comprising the MVA virus as a vector and which also comprises an immunogenic element of the MERS coronavirus is able to prevent infection with both camelpox and MERS virus in camelids.
  • the immunogenic composition comprises both parts of the MVA and the MERS coronavirus.
  • the AMV as a vector for an immunogenic element of the MERS coronavirus.
  • immunogenic element includes reference to any art of a MERS CoV protein especially the spike protein, or a functional variant or functional fragment thereof, which is capable of eliciting an immune response in a mammal. Said immunogenic element preferably corresponds to an antigenic determinant of said pathogen.
  • the term “functional fragment” refers to a shortened version of the protein, which is a functional variant or functional derivative.
  • “functional derivative” of a protein is a protein the amino acid sequence of which can be derived from the amino acid sequence of the original protein by the substitution, deletion and/or addition of one or more amino acid residues in a way that, in spite of the change in the amino acid sequence, the functional variant retains at least a part of at least one of the biological activities of the original protein that is detectable for a person skilled in the art.
  • a functional variant is generally at least 60% homologous (preferably the amino acid sequence is at least 60% identical), advantageously at least 70% homologous and even more
  • a functional variant may also be any functional part of a protein; the function in the present case being particularly but not exclusively essential activity for respiratory illness .
  • “Functional” as used herein means functional in MERS-Cov and capable of eliciting antibodies which give protection against disease caused by said virus.
  • substitutions relate to the substitution of a given amino acid by an amino acid having physicochemical characteristics in the same class.
  • an amino acid of the SP1298 and/or SP2205 proteins has a hydrophobic characterising group
  • a conservative substitution replaces it by another amino acid also having a hydrophobic characterising group; other such classes are those where the characterising group is hydrophilic, cationic, anionic or contains a thiol or thioether.
  • substitutions are well known to those of ordinary skill in the art, i.e. see US 5,380,712.
  • Conservative amino acid substitutions may be made, for example within the group of aliphatic non-polar amino acids (Gly, Ala, Pro, He, Leu, Val), the group of polar uncharged amino acids (Cys, Ser, Thr, Met, Asn, Gin), the group of polar charged amino acids (Asp, Glu, Lys, Arg) or the group of aromatic amino acids (His, Phe, Tyr, Trp).
  • prophylactic or therapeutic treatment of an infection by MERS or “prophylactic or therapeutic treatment of a MERS infection” refers to both prophylactic or therapeutic treatments wherein virulence of the pathogen is blocked or diminished, but also to treatments wherein antibodies against the MERS protein(s) recognize the virus and will protect the host against infection, either directly through immune clearance, or indirectly by blocking the activity of the protein or virus, thereby inhibiting the constitution and/or replication of the virus. Also, the term refers to blocking the function of the MERS protein(s) in vivo thereby reducing the replication abilities of the pathogen with a concomitant reduction in invasion capabilities. The term thus includes inducing immune responses in subjects using methods of the invention, as well as inhibiting replication of the pathogen in vivo by using antibodies generated by methods of the present invention as an active compound in a pharmaceutical composition administered to the subject.
  • MVA can be used as a production platform for vaccines against respiratory diseases, as has been described in Altenburg, A.F. et al. (2014, Viruses 6(7):2735-2761).
  • MVA is a replication deficient viral vector that can be used to encode one or more foreign antigens, thereby functioning as a multivalent vaccine.
  • the MVA vectors can be prepared as follows.
  • a foreign polypeptide e.g., any of the MERS antigenic proteins or fragments or functional variants thereof
  • the recombinant vaccinia virus can be isolated by methods known in the art (isolation can be facilitated by use of a detectable marker).
  • the DNA constructed to be inserted can be linear or circular (e.g., a plasmid, linearized plasmid, gene, gene fragment, or modified MERS-CoV genome).
  • the foreign DNA sequence is inserted between the sequences flanking the naturally occurring deletion.
  • the sequence can include regulatory sequences (e.g., a promoter, such as the promoter of the vaccinia 11 kDa gene or the 7.5 kDa gene).
  • the DNA construct can be introduced into MVA-infected cells by a variety of methods, including calcium phosphate-assisted transfection (Graham et al., Virol. 52:456-467, 1973 and Wigler et al., Cell 16:777-785, 1979), electroporation (Neumann et al., EMBO J. 1:841-845, 1982) microinjection
  • MERS-CoV For MERS-CoV this has been shown in Song et al. (2013) where an insert has been introduced into deletion site III of the MVA genome (see Fig. 1 in Song et al.). In this deletion site the coding sequence for the MERS CoV spike protein was inserted and placed under transcriptional control of a vaccinia virus promoter. As is shown in this paper, the S protein is expressed by the recombinant virus particles when administered to mice. This was demonstrated by detection of titers of MERS CoV neutralizing antibodies.
  • the recombinant MVA-MERS virus as described by Song et al. may be used. It is, however, also possible to use
  • MVA-MERS viruses that are produced in another way. It would, e.g. be feasible to insert an immunogenic element of the MERS CoV in any spot of the MVA viral particle that is not critical for the immunogenicity of the MVA.
  • inserts may be provided at the site of deletions I, II, II, IV, V and VI (as depicted in Fig. 1A of Song et al.), but also, for instance, in intergenic region III (Manuel, E. et al., 2010, Virology 403(2): 155-162) and in a site located between the essential I8R and GIL genes in the central conserved region of MVA (Wyatt, l.S. et al., 2009, J. Virol. 83(14):7176-7184).
  • the complete sequence coding for the MERS CoV spike protein was inserted.
  • other genes that are deemed to yield immunogenic products may be inserted. As such these sequences do not necessarily need to encode the full protein, but it may be sufficient to encode an antigenic protein from the MERS CoV.
  • Any viral vector that can be used in methods according to the invention can be tested for expression by transfecting cells, such as chicken embryo fibroblasts (CEF) cells and assessing the level of viral particle formation and
  • viral vectors that express immunogens at a level comparable to, or higher than, the viral vectors described herein are strong therapeutic candidates and are within the scope of the invention (of course, any construct that elicits an effective immune response (e.g., any desirable degree of protection from infection or other therapeutic benefit) is usable in methods according to the invention, regardless of the level of antigen expression it generates).
  • assessing expression and viral particle formation in cell culture one can assess candidate vectors in vivo. For example, one can assess immunogenicity in animal models.
  • Plasmids that have substantially the same sequence as the MVA-MERS-S vector described in the experimental part and that express one or more of the antigenic proteins described herein are within the scope of the invention so long as they are immunogenic enough to induce or enhance a therapeutically beneficial response in a camelid. In tests in animals for
  • immunogenicity one can perform an intracellular cytokine assay or an ELISPOT assay for IFN- [gamma] production in response to stimulation with an antigenic peptide to evaluate the frequency of responding T cells to that peptide.
  • Proliferation assays can also be carried out. Antigens produced by transient transfection can be used for stimulation, and supernatants from mock-transfected cultures can serve as controls. If desired, the data can be presented as a
  • stimulation index the growth of cultures in the presence of pathogenic (e.g., viral) antigens divided by the growth of cultures in the presence of mock antigen.
  • the viral vectors of this invention are administered at a concentration that is therapeutically effective to prevent or treat infections by both camelpox and MERS-CoV.
  • the vaccines may be formulated using a variety of acceptable excipients known in the art.
  • the vaccines are administered by injection, either intramuscularly, subcutaneously, intredermally, intravenously, intraperitoneally or mucosally (e.g. intranasally). Methods to accomplish this administration are known to those of ordinary skill in the art.
  • the vaccine contains at least 10 6 PFU viral vectors per dose.
  • Any physiologically acceptable medium can be used to introduce a vector comprising a vaccine insert into a subject.
  • suitable pharmaceutically acceptable carriers known in the art include, but are not limited to, sterile water, saline, glucose, dextrose, or buffered solutions.
  • the media may include auxiliary agents such as diluents, stabilizers (i.e., sugars (e.g. glucose and dextrose) and amino acids), preservatives, wetting agents, emulsifying agents, pH buffering agents, additives that enhance viscosity or syringability, colorants, and the like.
  • the medium or carrier will not produce adverse effects, or will only produce adverse effects that are far outweighed by the benefit conveyed.
  • Preferably used EVERY the MVA viral vector are water, saline or PBS buffer.
  • a vaccine according to the invention may contain a (partially) purified recombinant viral vector, wherein said recombinant viral vector is preferably produced by passaging on chicken embryo fibroblast (CEF) cells.
  • CEF chicken embryo fibroblast
  • An immunogenic composition that can be used in a method according to the invention may further comprise a suitable adjuvant.
  • a suitable adjuvant Many adjuvant systems are known in the art, for example commonly used oil in water adjuvant systems. Any suitable oil may be used, for example a mineral oil known in the art for use in adjuvants.
  • the oil phase may also contain a suitable mixture of different oils, either mineral or non-mineral. Suitable adjuvants may also comprise vitamin E, optionally mixed with one or more oils.
  • the water phase of an oil in water adjuvated vaccine will contain the antigenic material. Suitable formulations will usually comprise from about 25-60% oil phase (40-75% water phase). Examples of suitable formulations may comprise 30% water phase and 70% oil phase or 50% of each.
  • the adjuvant used in connection with the vectors described here can be one that slowly releases antigen (e.g., the adjuvant can be a liposome), or it can be an adjuvant that is strongly immunogenic in its own right (these adjuvants are believed to function synergistically).
  • the vaccine compositions described here can include known adjuvants or other substances that promote DNA uptake, recruit immune system cells to the site of the inoculation, or facilitate the immune activation of responding lymphoid cells.
  • adjuvants or substances include, next to oil and water emulsions, Corynebacterium parvum, Bacillus Calmette Guerin, aluminum hydroxide, glucan, dextran sulfate, iron oxide, sodium alginate, Bacto-Adjuvant, certain synthetic polymers such as poly amino acids and co-polymers of amino acids, saponin, REGRESSIN (Vetrepharm, Athens, GA),
  • AVRIDINE N, N-dioctadecyl-N',N'-bis(2-hydroxyethyl)-propanediamine
  • paraffin oil paraffin oil
  • muramyl dipeptide genetic adjuvants, which encode immunomodulatory molecules on the same or a co-inoculated vector, can also be used.
  • GM-CSF, IL-15, IL-2, interferon response factors, and mutated caspase genes can be included on a vector that encodes a pathogenic immunogen (such as a MERS- CoV antigen) or on a separate vector that is administered at or around the same time as the immunogen is administered.
  • the vaccine formulations of the present invention may be used in prophylactic or therapeutic methods of the invention by immunizing a camelid subject by introducing said formulations into said subject subcutaneously, intramuscularly, intranasally, intradermally, intravenously, transdermally, transmucosally, intranasally, orally, or directly into a lymph node.
  • the composition may be applied locally, near a local pathogen reservoir against which one would like to vaccinate.
  • the present invention further discloses a method for the manufacture of a vaccine intended for the protection of a subject against MERS and camelpox infection, wherein said vaccine is combined with a pharmaceutically acceptable diluent, carrier, excipient or adjuvant therefore, such that a formulation is provided which can provide a prophylactically or therapeutically effective dose in a single administration event.
  • a vaccine (prepared by a method) according to the invention can be used in a method to protect a subject against both camelpox and MERS infection.
  • the vaccine is preferably administered in a 2 shot vaccination regimen, whereby the first shot (priming vaccination) and second shot (boosting vaccination) are given to the subject with an interval of at least 2 weeks. In this way the subject will have obtained full protection against the viral infections.
  • first shot primary vaccination
  • second shot boosting vaccination
  • the viral vector was constructed as essentially described in Song et al., 2013, J. Virol. 87(21): 11950- 11954.
  • flanking sequences were inserted in the major deletion site III of the Modified Vaccinia virus Ankara strain. These sequences were originally prepared by PCR and cloned into MVA transfer plasmids targeting the deletion III site.
  • MVA vector plasmids pIIIH5red recombinant sequences coding for the MERS coV spike protein under control of the vaccine virus promoter pmGH5 and a sequence coding for the fluorescent marker mCherry under transcriptional control of the vaccinia virus late promoter Pll and placed between repetitive sequences were inserted.
  • the MVA-MERS-S was isolated in plaque passages by screening for transient coexpression of the fluorescent marker.
  • the fluorescent marker was excised through intragenomic homologous recombination using the repetitive sequences.
  • PCR analysis was performed on genomic viral DNA using oligonucleotide primers to confirm the identity and proper insertion of the spike protein gene sequence.
  • the recombinant MVA-MERS-S can be efficiently amplified in chicken embryo fibroblasts.
  • the MVA-MERS-S virus particles were solved in PBS at a concentration of 5.10e7 PFU/ml.
  • MVA 1.5 ml doses of Ixl0e8 pfu in each nostril and 3 ml (2xl0e8 pfu) i.m. in the neck, nearby the head.
  • the "in” application is performed with a LMA, MADgic catheter device to ensure spray of the vaccine in the entire nasal mucosa.
  • the boost vaccination is performed in the same schedule. Body temperatures are followed weekly and on the days of inoculations.
  • all animals were challenged with MERS-CoV and at 4 days (half animals of each group) and 14 days after challenge, animals (remaining four) were euthanized to determine viral replication in tissues using different techniques (titration, RT-PCR, immunohistochemistry and in situ hybridization).
  • the challenge was performed with MERS-CoV EMC isolate 5 x 10 6 TCID50 per animal via the intranasal route. From the challenge to day 5, body temperatures were taken daily and then every 2 days.
  • Swabs are from now collected in Transport Media, for virus preservation.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
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  • Molecular Biology (AREA)
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  • Biotechnology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
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Abstract

L'invention concerne un procédé de prévention d'une infection par la variole du chameau et le coronavirus MERS chez les camélidés, une composition immunogène comprenant le virus MVA en tant que vecteur comprenant un élément immunogène du coronavirus MERS étant administrée aux camélidés. L'invention concerne également l'utilisation de cette composition immunogène à cet effet. De préférence ledit élément immunogène est la protéine de spicule ou un fragment immunogène ou un variant de celle-ci.
PCT/NL2016/050040 2015-01-16 2016-01-18 Vaccin combiné pour camélidés Ceased WO2016114669A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NL2014148A NL2014148B1 (en) 2015-01-16 2015-01-16 Combination vaccine for camelids.
NL2014148 2015-01-16

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WO2016114669A1 true WO2016114669A1 (fr) 2016-07-21

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Citations (4)

* Cited by examiner, † Cited by third party
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WO2001068820A1 (fr) 2000-03-14 2001-09-20 Anton Mayr Souche d'un virus modifie de vaccine ankara (mva)
WO2014045254A2 (fr) 2012-09-23 2014-03-27 Erasmus University Medical Center Rotterdam Lignée c de coronavirus bêta humains et identification de la peptidase dipeptidylique n-terminale en tant que récepteur viral
WO2014134439A1 (fr) * 2013-03-01 2014-09-04 New York Blood Center, Inc. Composition immunogène pour infection de coronavirus de syndrome respiratoire du moyen orient (mers-cov)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5380712A (en) 1987-10-30 1995-01-10 Delta Biotechnology Limited Truncated human serum albumin polypeptides as plasma expanding agents
WO2001068820A1 (fr) 2000-03-14 2001-09-20 Anton Mayr Souche d'un virus modifie de vaccine ankara (mva)
WO2014045254A2 (fr) 2012-09-23 2014-03-27 Erasmus University Medical Center Rotterdam Lignée c de coronavirus bêta humains et identification de la peptidase dipeptidylique n-terminale en tant que récepteur viral
WO2014134439A1 (fr) * 2013-03-01 2014-09-04 New York Blood Center, Inc. Composition immunogène pour infection de coronavirus de syndrome respiratoire du moyen orient (mers-cov)

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ABDELLATIF, M.M. ET AL., REV. SCI. TECH. OFF. INT. EPIZ., vol. 33, no. 3, 2014, pages 1 - 19
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ARWEN ALTENBURG ET AL: "Modified Vaccinia Virus Ankara (MVA) as Production Platform for Vaccines against Influenza and Other Viral Respiratory Diseases", VIRUSES, vol. 6, no. 7, 17 July 2014 (2014-07-17), pages 2735 - 2761, XP055200206, DOI: 10.3390/v6072735 *
F. SONG ET AL: "Middle East Respiratory Syndrome Coronavirus Spike Protein Delivered by Modified Vaccinia Virus Ankara Efficiently Induces Virus-Neutralizing Antibodies", JOURNAL OF VIROLOGY, vol. 87, no. 21, 1 November 2013 (2013-11-01), pages 11950 - 11954, XP055157123, ISSN: 0022-538X, DOI: 10.1128/JVI.01672-13 *
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NL2014148B1 (en) 2017-01-05

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