WO1985002862A1 - PRODUCTION D'INTERFERON alpha HUMAIN - Google Patents

PRODUCTION D'INTERFERON alpha HUMAIN Download PDF

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Publication number
WO1985002862A1
WO1985002862A1 PCT/AU1984/000263 AU8400263W WO8502862A1 WO 1985002862 A1 WO1985002862 A1 WO 1985002862A1 AU 8400263 W AU8400263 W AU 8400263W WO 8502862 A1 WO8502862 A1 WO 8502862A1
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WO
WIPO (PCT)
Prior art keywords
ifn
human interferon
nucleotide sequence
polypeptide
sequence
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PCT/AU1984/000263
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English (en)
Inventor
Anthony William Linnane
Phillip Nagley
Sangkot Marzuki
Manfred Werner Beilharz
Ian Thomas Nisbet
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Monash University
Commonwealth Serum Laboratories Commission
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Application filed by Monash University, Commonwealth Serum Laboratories Commission filed Critical Monash University
Publication of WO1985002862A1 publication Critical patent/WO1985002862A1/fr

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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
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/555—Interferons [IFN]
    • C07K14/56—IFN-alpha

Definitions

  • This invention relates to a human . interferon- ⁇ and to the production thereof.
  • the invention relates to a complete nucleotide sequence of a human interferon- ⁇ gene, and recombinant DNA molecules comprising this nucleotide sequence, as well as processes utilising said recombinant DNA molecules for producing the human interferon- ⁇ .
  • the human interferons are a group of proteins possessing potent antiviral, antiproliferative and immune response modulating activities (1) .
  • the potential therapeutic value of the interferons together with their limited availability from natural sources, considerable effort has been directed towards the cloning and expression of interferon genes.
  • Three distinct types of interferon, ⁇ , ⁇ and ⁇ , have been described, based on differences in antigenicity and biological characteristics of the molecules (for review, 2) .
  • IFN- ⁇ interferon- ⁇
  • cDNAs derived from induced leukocytes and DNA from human chromosomal libraries The results obtained indicate that the human genome contains at least thirteen functional, non-allelic IFN- ⁇ genes as well as a number of allelic variants and pseudogenes (3) .
  • Complete nucleotide sequences for some IFN- ⁇ coding regions have been published, eight derived from cDNA clones and seven from clones of genomic DNA (4,5,6,7,8,9, 9a, 9b), and comparison of the nucleotide sequences of different IFN- ⁇ coding regions reveals a high degree of homology (88 to 98%) . Differences in the DNA sequence of flan ⁇ ing regions and the location of IFN- ⁇ genes in tandem array on a single chromosomal fragment have been the basis for suggesting that the genes are non-allelic (3) .
  • the present invention relates to an IFN- ⁇ gene which has been isolated from a human genome library using oligonucleotide probes.
  • the gene designated IFN- ⁇ Ml, has been expressed in E. coli using the Ml3 phage vector, and its nucleotide sequence has been ascertained. This data represents the first complete nucleotide sequence published for this IFN- ⁇ genetic locus.
  • a DNA molecule which on expression codes for a human interferon- ⁇ , comprising a nucleotide sequence substantially as shown in Figure 2.
  • nucleotide sequence of this aspect of the invention may be obtained from natural, synthetic or semi-synthetic sources; furthermore, the nucleotide sequence may be a naturally-occurring sequence, or may be related by mutation, including single or multiple base substitutions, deletions insertions and inversions, to such a naturally-occurring sequence, provided always that the DNA molecule comprising such a sequence is capable of being expressed as the desired amino acid sequence.
  • the nucleotide sequence may have expression control sequences positioned adjacent to it, such control sequences being derived either from homologous or heterologous sources.
  • the nucleotide sequence of IFN- ⁇ Ml according to this invention is further characterised in having a restriction map substantially as shown in Figure lb.
  • IFN- ⁇ Ml coding region sequence most closely resembles that of IFN-C (4) .
  • IFN- ⁇ Ml and IFN-C are 98% homologous at the nucleotide sequence level, however at the level of amino acid homology they differ by seven residues.
  • IFN- ⁇ 4a 153 of 189 amino acids
  • ⁇ 4b a complete amino acid sequence for another IFN- ⁇ denoted ⁇ 4b.
  • the amino acid sequences were derived from unpublished nucleotide sequences of clones isolated from the same human gene library as that used in the present report (12) .
  • IFN- ⁇ 4a and IFN- ⁇ 4b are considered to be allelic as they have similar flanking DNA sequences and, on currently published data, have only two amino acid differences (3) .
  • the amino acid sequence predicted for IFN- ⁇ Ml is identical to the 153 amino acids of IFN- ⁇ 4a that have been published (3). Also IFN- ⁇ Ml differs from IFN- ⁇ 4b at the same two amino acid residues as IFN- ⁇ 4a. However, the IFN- ⁇ Ml coding region contains two restriction enzyme sites (one EcoRII site and one Bspl site ? indicated by asterisks in Fig.lb) which are not present in either IFN- ⁇ 4a or IFN- ⁇ 4b (3) . This suggests the existence of the three separate coding regions, IFN- ⁇ Ml, IFN- ⁇ 4a and IFN- ⁇ 4b, in the one individual and hence the presence of at least two genetic loci.
  • Synthetic oligonucleotides have been used in the screening of cDNA clones (21) but they have not been used extensively in the screening of genome libraries. While the lack of specificity of hybridization presents a problem in the selection of genomic clones with individual oligonucleotides, this can be overcome by using combinations of oligonucleotides.
  • the set of five oligonucleotides used throughout this work (Table 1) was suitable not only for the selection of genomic clones but also for the identification of subclones, for the construction of restriction maps and for priming the chain-termination nucleotide sequencing reactions.
  • an Alul fragment containing the coding region of the IFN- ⁇ Ml gene has been inserted into the Hindi site of the phage Ml3 mp 11, resulting in a fusion of the IFN- ⁇ Ml gene and the ⁇ -galactosidase gene.
  • E. coli infected with the recombinant M13 phage carrying the fused gene has been cultured and extracts have shown antiviral activity in cytopathic effect inhibition assays. This antiviral activity was completely neutralised by IFN- ⁇ antibodies.
  • a recombinant DNA molecule which on expression codes for a human interferon- ⁇ , comprising a nucleotide sequence substantially as shown in Figure 2, operatively linked to an expression control sequence.
  • the expression control sequence may comprise known initiator and terminator sequences with the interferon nucleotide sequence located between them.
  • a recombinant DNA cloning vehicle or vector capable of expressing a human interferon- ⁇ , having inserted therein a nucleotide sequence substantially as shown in Figure 2, operatively linked to an expression control sequence.
  • the cloning vehicle or vector may comprise a known bacteriophage or plasmid.
  • This invention further provides a host cell, such as a known E. coli strain, transformed with a recombinant DNA cloning ' vehicle or a recombinant DNA molecule as described above.
  • the amino acid sequence of IFN- ⁇ Ml expressed by the nucleotide sequence of Figure 2 can be predicted on the basis of the known genetic code. Accordingly, in yet another aspect of this invention, there is provided a polypeptide having human interferon- ⁇ activity, comprising an amino acid sequence substantially as shown in Figure 2.
  • This polypeptide may comprise either the pre-IFN- ⁇ sequence of 189 amino acids and containing a secretion leader of 23 amino acids, as shown in Figure 2, or the mature IFN- ⁇ sequence of 166 amino acids as shown.
  • this invention provides a method of producing a polypeptide having human interferon- ⁇ activity, which comprises the steps of culturing a host cell as described above, and recovering said polypeptide from, the culture.
  • Figure la shows the restriction map of the ⁇ Ml PstI fragment containing the IFN- ⁇ Ml gene. Restriction sites are indicated by the symbols ⁇ Q, Pstl ? - ⁇ , EcoRI; f r Hindlll. The hatched area indicates the IFN- ⁇ Ml coding region. The direction of transcription is from left to right.
  • Figure lb shows the restriction map of the ⁇ Ml Rsal fragment containing the IFN- ⁇ Ml gene and the strategy for sequencing the IFN- ⁇ Ml gene. Restriction sites are indicated by the symbols: ⁇ >, Rsal; ⁇ *, Bspl; ⁇ r, Alul; , Sau3AI; ⁇ , EcoRII; ⁇ , Hindlll. Arrowed segments below the map indicate the extent and direction of nucleotide sequence data obtained from M13 subclones. The asterisks indicate the Bspl and EcoRII sites which are present in IFN- ⁇ Ml but absent from both IFN- ⁇ 4a and IFN- ⁇ 4b (see below) .
  • Figure 2 shows the nucleotide and predicted amino acid sequence of IFN- ⁇ Ml.
  • the initiation codon for pre-interferon, the codon for the N-terminal amino acid of the mature interferon and the termination codon are underlined.
  • the putative 'TATA' box is underlined twice-.
  • Figure 3 shows the nucleotide sequence of the M13 recombinant phage M13- ⁇ Ml-Bl in the region of the fusion between the ⁇ -galactosidase gene of Ml3mpll and the IFN- ⁇ Ml gene.
  • the numbers' and amino acid sequences refer to segments derived from the ⁇ -galactosidase N-terminus, the M13m.pl1 polylinker, the IFN- ⁇ Ml leader and the N-terminus of the mature IFN- ⁇ Ml protein.
  • Oligonucleotides were synthesized by the solid-phase phosphotriester method (10) and purified by HPLC on a Partisil 10 SAX column operated at ambient temperature and eluted with a gradient of potassium phosphate, pH 6.5, from ImM in 5% acetonitrile to 0.2M in 30% acetonitrile.
  • the nucleotide sequences of these oligonucleotides and the positions at which they are complementary to IFN- ⁇ sequences are presented in Table 1.
  • Oligonucleotide probes were 5'-end labelled using T4 polynucleotide kinase (Boehringer-Mannheim) and [ ⁇ - P ]ATP (Amersham) (11) . Unincorporated label was separated from the probes by polyacrylamide gel electrophoresis.
  • Hybridization was carried out using the synthetic oligonucleotide probes (Table 1) . Restriction maps were constructed using standard methods, including-
  • Single-stranded DNA was prepared from M13 subclones and sequenced by the dideoxy chain-termination method of Sanger et al. (19) . Priming was carried out using synthesized oligonucleotides, either the Ml3 'universal primer* (5'-GTAAAACGACGGCCAGT-3*) or an IFN- ⁇ gene-specific oligonucleotide (Table 1) .
  • CPE cytopathic effect
  • a human genome library in phage ⁇ Charon 4A (12) was screened for the presence of IFN- ⁇ genes with synthetic oligonucleotides.
  • the sequences of the oligonucleotide probes correspond to a number of different, highly conserved segments within published IFN- ⁇ coding regions (Table 1) .
  • Using the individual probes approximately 300,000 recombinant phage were screened, resulting in the isolation of 297 putative IFN- ⁇ clones. The number of putative positive clones was reduced to twenty-eight by using combinations of the oligonucleotide probes.
  • One clone, designated ⁇ Ml, which hybridized to all five oligonucleotide probes (Table 1) was selected for detailed analysis.
  • a PstI fragment of the- ⁇ Ml DNA to which the oligonucleotide probes hybridized was subcloned into p ⁇ C9 by standard methods. Following amplification in E. coli the purified PstI fragment was digested with selected restriction enzymes and the resulting fragments were separated by electrophoresis on an agarose gel. The fragments were transferred to nitrocellulose paper, hybridized to specific oligonucleotide probes and a restriction map of the PstI fragment was derived (Fig.la) .
  • the identification of recombinant clones of interest and the determination of the orientation of the inserted fragments was achieved by screening the M13 recombinant clones with the appropriate oligonucleotides. Utilizing either the M13 'universal primer' or an IFN- ⁇ -specific oligonucleotide as the primer, the nucleotide sequence of these M13 recombinant subclones was obtained by the dideoxy chain-termination method. The sequence determined is shown in Fig.2 and a detailed restriction map derived both from this sequence and restriction enzyme analysis is shown in Fig.lb. Comparison with previously reported IFN- ⁇ sequences reveals that the nucleotide sequence of the Rsal fragment contains an entire IFN- ⁇ coding region. This coding region specifies a pre-IFN- ⁇ of 189 amino acids, consisting of a 23 amino acid leader and a 166 amino acid mature IFN- ⁇ protein (Fig.2) .
  • the gene was expressed in E. coli.
  • An Alul-fragment of 669 bp (Fig.lb) was cloned into the Hindi site of Ml3mpll and clones with the correct orientation of the Alul fragment were selected by hybridization with oligonucleotides 4 and 5 (Table 1) .
  • Ml3- ⁇ Ml-Bl contained the ⁇ -galactosidase promoter and the N-terminal 15 nu ⁇ leotides of the ⁇ -galactosidase gene coding region, 20 nucleotides of the M13mpll polylinker sequence, and 25 nu ⁇ leotides of the IFN- ⁇ Ml leader sequence followed by the mature IFN- ⁇ Ml coding region (Fig.3) .
  • the 23 amino acid interferon leader would be replaced by a 19 amino acid leader (11 residues of which are non-interferon) , assuming the N-terminal methionine is removed from the ⁇ -galactosidase N-terminus.
  • the interferon activity in both the culture supernatant and in the cell pellet extracts' was completely neutralized by both a polyclonal antiserum against human IFN- ⁇ (Cantell) and a monoclonal anti-human IFN- ⁇ antibody. It may be noted that the level of interferon expression obtained was lower than that previously reported with a M13 vector (20) .
  • Factors which may account for this difference include the intrinsic specific activities of the particular interferons, the specific activity of the product of the particular fused gene constructed here
  • Nucleotide posi tion 1 of the IFN gene is taken as being the 'A' of the ⁇ TG coding for translation ini tiation in the IFN- ⁇ l gene (9) .
  • the temperature gi ven indicates the empirical ly determined temperature of hybridi zation and washing for the ol igonucleotide probes .

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Abstract

Une molécule d'ADN qui, lors de sa sécrétion, code pour un interféron alpha humain appelé IFN-alphaM1, comporte une séquence de nucléotides essentiellement semblable à celle montrée dans la figure 2. Sont également décrits une molécule d'ADN recombinant, un vecteur ou véhicule de clonage et une cellule hôte, contenant chacun cette séquence de nucléotide. Est également décrit un polypeptide possédant une activité d'interféron alpha humain, comportant une séquence d'acides aminés essentiellement semblable à celle montrée dans la figure 2.
PCT/AU1984/000263 1983-12-23 1984-12-20 PRODUCTION D'INTERFERON alpha HUMAIN WO1985002862A1 (fr)

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AU298283 1983-12-23
AUPG2982 1983-12-23

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0154186A3 (en) * 1984-02-10 1987-12-09 J.K. And Susie L. Wadley Research Institute And Blood Bank Isolation of a novel interferon gene and expression thereof
US5413908A (en) * 1984-11-12 1995-05-09 Lister Institute Of Preventive Medicine Method of characterizing genomic DNA by reference to a genetic variable
US5480956A (en) * 1989-06-29 1996-01-02 Toray Industries, Inc. Feline interferon and process for production thereof
EP1997900A2 (fr) 1996-04-05 2008-12-03 Novartis Vaccines and Diagnostics, Inc. Vecteurs à base d'alpha virus recombinants avec inhibition réduite de synthèse macromoléculaire cellulaire
EP2206785A1 (fr) 1998-12-31 2010-07-14 Novartis Vaccines and Diagnostics, Inc. Expression améliorée de polypeptides HIV et production de particules de type virus
EP2266602A2 (fr) 2004-11-01 2010-12-29 Novartis Vaccines and Diagnostics, Inc. Approches combinatoires destinées à produire des réponses immunitaires
EP2281832A2 (fr) 2000-07-05 2011-02-09 Novartis Vaccines and Diagnostics, Inc. Polynucléotides codant pour des polypeptides antigéniques du type C du VIH, de tels polypeptides et leurs utilisations
EP2292772A1 (fr) 2001-07-05 2011-03-09 Novartis Vaccines and Diagnostics, Inc. Vaccination VIH avec un ADN codant un polypeptide VIH et un polypeptide VIH
EP2298900A1 (fr) 1996-09-17 2011-03-23 Novartis Vaccines and Diagnostics, Inc. Compositions et procédés de traitement de maladies intracellulaires
EP2339010A2 (fr) 2002-05-01 2011-06-29 Gbp Ip, Llc Particules de vecteur de lentivirus pour l'inactivation de complément
EP2412242A2 (fr) 2001-07-05 2012-02-01 Novartis Vaccines and Diagnostics, Inc. Polynucléotides codant pour des polypeptides antigènes de type C du VIH, polypeptides et leurs utilisations
US8486693B2 (en) 2006-05-23 2013-07-16 Bellicum Pharmaceuticals, Inc. Modified dendritic cells having enhanced survival and immunogenicity and related compositions and methods
WO2017040387A2 (fr) 2015-08-31 2017-03-09 Technovax, Inc. Vaccin à base de pseudoparticules virales (vlp) contre le virus syncytial respiratoire humain (hrsv)
WO2017180770A1 (fr) 2016-04-13 2017-10-19 Synthetic Genomics, Inc. Systèmes de réplicon d'artérivirus recombinant et utilisations correspondantes
EP3608401A1 (fr) 2012-07-05 2020-02-12 Ohio State Innovation Foundation Compositions et procédés liés aux vaccins viraux
US11020476B2 (en) 2017-12-19 2021-06-01 Janssen Sciences Ireland Unlimited Company Methods and compositions for inducing an immune response against Hepatitis B Virus (HBV)
US11021692B2 (en) 2017-12-19 2021-06-01 Janssen Sciences Ireland Unlimited Company Hepatitis B virus (HBV) vaccines and uses thereof
US11083786B2 (en) 2018-01-19 2021-08-10 Janssen Pharmaceuticals, Inc. Induce and enhance immune responses using recombinant replicon systems
US11364310B2 (en) 2016-10-17 2022-06-21 Janssen Pharmaceuticals, Inc. Recombinant virus replicon systems and uses thereof
US11389531B2 (en) 2017-12-19 2022-07-19 Janssen Sciences Ireland Unlimited Company Methods and apparatus for the delivery of hepatitis B virus (HBV) vaccines
US11845939B2 (en) 2016-12-05 2023-12-19 Janssen Pharmaceuticals, Inc. Compositions and methods for enhancing gene expression

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU7246281A (en) * 1980-07-01 1982-01-07 F. Hoffmann-La Roche Ag Interferons and process for their preparation
WO1983002460A1 (fr) * 1982-01-15 1983-07-21 Cetus Corp INTERFERON 'alpha' 74
WO1983002457A1 (fr) * 1982-01-15 1983-07-21 Cetus Corp Interferon alpha 76
WO1984000776A1 (fr) * 1982-08-18 1984-03-01 Cetus Corp Interferon-alpha 6l
WO1984003300A1 (fr) * 1983-02-24 1984-08-30 Inst Organicheskogo Sinteza Ak Interferon n humain leucocytaire et son procede d'obtention dans des cellules bacteriennes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU7246281A (en) * 1980-07-01 1982-01-07 F. Hoffmann-La Roche Ag Interferons and process for their preparation
WO1983002460A1 (fr) * 1982-01-15 1983-07-21 Cetus Corp INTERFERON 'alpha' 74
WO1983002457A1 (fr) * 1982-01-15 1983-07-21 Cetus Corp Interferon alpha 76
WO1984000776A1 (fr) * 1982-08-18 1984-03-01 Cetus Corp Interferon-alpha 6l
WO1984003300A1 (fr) * 1983-02-24 1984-08-30 Inst Organicheskogo Sinteza Ak Interferon n humain leucocytaire et son procede d'obtention dans des cellules bacteriennes

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Archives of Biochemistry and Biophysics, Volume 221, No. 1, issued 1983, February 15 (New York, U.S.A.), S. PESTKA, "Human Interferons - from Protein Purification and Sequence to Cloning and Expression in Bacteria: Before, Between, and Beyond", see page 16 figure 17, page 18 figure 18, and page 26 figure 26. *
Nature, Volume 290, issued 1981, March 5 (London, U.K.) D.V. GOEDDEL, "The Structure of Eight Distinct Cloned Human Leukocyte Interferon cDNAs", see pages 20-26. *
Philosophical Transactions of the Royal Society London, Series B, Volume 299, No. 1094, issued 1982, September 24, (London, U.K.), C. WEISSMANN et al, "Structure and Expression of Human IFN/OC Genes, see pages 7-28, particularly page 12. *
Science, Volume 212, issued 1981, June 5 (Washington, D.C. U.S.A.), R.M. LAWN et al, "DNA Sequences of Two Closely Linked Human Leukocyte Interferon Genes", see pages 1159-1162. *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0154186A3 (en) * 1984-02-10 1987-12-09 J.K. And Susie L. Wadley Research Institute And Blood Bank Isolation of a novel interferon gene and expression thereof
US5413908A (en) * 1984-11-12 1995-05-09 Lister Institute Of Preventive Medicine Method of characterizing genomic DNA by reference to a genetic variable
US5480956A (en) * 1989-06-29 1996-01-02 Toray Industries, Inc. Feline interferon and process for production thereof
EP1997900A2 (fr) 1996-04-05 2008-12-03 Novartis Vaccines and Diagnostics, Inc. Vecteurs à base d'alpha virus recombinants avec inhibition réduite de synthèse macromoléculaire cellulaire
EP2298900A1 (fr) 1996-09-17 2011-03-23 Novartis Vaccines and Diagnostics, Inc. Compositions et procédés de traitement de maladies intracellulaires
EP2206785A1 (fr) 1998-12-31 2010-07-14 Novartis Vaccines and Diagnostics, Inc. Expression améliorée de polypeptides HIV et production de particules de type virus
EP2281832A2 (fr) 2000-07-05 2011-02-09 Novartis Vaccines and Diagnostics, Inc. Polynucléotides codant pour des polypeptides antigéniques du type C du VIH, de tels polypeptides et leurs utilisations
EP2311958A2 (fr) 2000-07-05 2011-04-20 Novartis Vaccines and Diagnostics, Inc. Polynucléotides codant pour des polypeptides antigéniques du type C du VIH, de tels polypeptides et leurs utilisations
EP2292772A1 (fr) 2001-07-05 2011-03-09 Novartis Vaccines and Diagnostics, Inc. Vaccination VIH avec un ADN codant un polypeptide VIH et un polypeptide VIH
EP2412242A2 (fr) 2001-07-05 2012-02-01 Novartis Vaccines and Diagnostics, Inc. Polynucléotides codant pour des polypeptides antigènes de type C du VIH, polypeptides et leurs utilisations
EP2339010A2 (fr) 2002-05-01 2011-06-29 Gbp Ip, Llc Particules de vecteur de lentivirus pour l'inactivation de complément
EP2266602A2 (fr) 2004-11-01 2010-12-29 Novartis Vaccines and Diagnostics, Inc. Approches combinatoires destinées à produire des réponses immunitaires
US8486693B2 (en) 2006-05-23 2013-07-16 Bellicum Pharmaceuticals, Inc. Modified dendritic cells having enhanced survival and immunogenicity and related compositions and methods
EP3608401A1 (fr) 2012-07-05 2020-02-12 Ohio State Innovation Foundation Compositions et procédés liés aux vaccins viraux
WO2017040387A2 (fr) 2015-08-31 2017-03-09 Technovax, Inc. Vaccin à base de pseudoparticules virales (vlp) contre le virus syncytial respiratoire humain (hrsv)
US11555205B2 (en) 2016-04-13 2023-01-17 Janssen Pharmaceuticals, Inc. Recombinant arterivirus replicon systems and uses thereof
US10538786B2 (en) 2016-04-13 2020-01-21 Janssen Pharmaceuticals, Inc. Recombinant arterivirus replicon systems and uses thereof
WO2017180770A1 (fr) 2016-04-13 2017-10-19 Synthetic Genomics, Inc. Systèmes de réplicon d'artérivirus recombinant et utilisations correspondantes
US11364310B2 (en) 2016-10-17 2022-06-21 Janssen Pharmaceuticals, Inc. Recombinant virus replicon systems and uses thereof
US11845939B2 (en) 2016-12-05 2023-12-19 Janssen Pharmaceuticals, Inc. Compositions and methods for enhancing gene expression
US11020476B2 (en) 2017-12-19 2021-06-01 Janssen Sciences Ireland Unlimited Company Methods and compositions for inducing an immune response against Hepatitis B Virus (HBV)
US11021692B2 (en) 2017-12-19 2021-06-01 Janssen Sciences Ireland Unlimited Company Hepatitis B virus (HBV) vaccines and uses thereof
US11389531B2 (en) 2017-12-19 2022-07-19 Janssen Sciences Ireland Unlimited Company Methods and apparatus for the delivery of hepatitis B virus (HBV) vaccines
US11725194B2 (en) 2017-12-19 2023-08-15 Janssen Sciences Ireland Unlimited Company Hepatitis B virus (HBV) vaccines and uses thereof
US11083786B2 (en) 2018-01-19 2021-08-10 Janssen Pharmaceuticals, Inc. Induce and enhance immune responses using recombinant replicon systems
US11826416B2 (en) 2018-01-19 2023-11-28 Janssen Pharmaceuticals, Inc. Induce and enhance immune responses using recombinant replicon systems

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