AU2017222644B2 - Novel vaccines against Zika virus - Google Patents

Novel vaccines against Zika virus Download PDF

Info

Publication number
AU2017222644B2
AU2017222644B2 AU2017222644A AU2017222644A AU2017222644B2 AU 2017222644 B2 AU2017222644 B2 AU 2017222644B2 AU 2017222644 A AU2017222644 A AU 2017222644A AU 2017222644 A AU2017222644 A AU 2017222644A AU 2017222644 B2 AU2017222644 B2 AU 2017222644B2
Authority
AU
Australia
Prior art keywords
zikv
prme
zika
mice
dna
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
AU2017222644A
Other languages
English (en)
Other versions
AU2017222644A1 (en
Inventor
Karuppiah Muthumani
David Weiner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Pennsylvania Penn
Wistar Institute of Anatomy and Biology
Original Assignee
University of Pennsylvania Penn
Wistar Institute of Anatomy and Biology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Pennsylvania Penn, Wistar Institute of Anatomy and Biology filed Critical University of Pennsylvania Penn
Publication of AU2017222644A1 publication Critical patent/AU2017222644A1/en
Application granted granted Critical
Publication of AU2017222644B2 publication Critical patent/AU2017222644B2/en
Priority to AU2021258056A priority Critical patent/AU2021258056B2/en
Priority to AU2024204641A priority patent/AU2024204641A1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/12Viral antigens
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/04Immunostimulants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C07K14/08RNA viruses
    • C07K14/18Togaviridae; Flaviviridae
    • C07K14/1816Flaviviridae, e.g. pestivirus, mucosal disease virus, bovine viral diarrhoea virus, classical swine fever virus (hog cholera virus), border disease virus
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N7/00Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/51Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/53DNA (RNA) vaccination
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52Cytokines; Lymphokines; Interferons
    • C07K14/54Interleukins [IL]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide
    • C07K2319/01Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/02Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011Details
    • C12N2770/24011Flaviviridae
    • C12N2770/24034Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011Details
    • C12N2770/24011Flaviviridae
    • C12N2770/24111Flavivirus, e.g. yellow fever virus, dengue, JEV
    • C12N2770/24122New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011Details
    • C12N2770/24011Flaviviridae
    • C12N2770/24111Flavivirus, e.g. yellow fever virus, dengue, JEV
    • C12N2770/24134Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011Details
    • C12N2770/24011Flaviviridae
    • C12N2770/24111Flavivirus, e.g. yellow fever virus, dengue, JEV
    • C12N2770/24171Demonstrated in vivo effect
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Genetics & Genomics (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Wood Science & Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Biomedical Technology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicinal Preparation (AREA)
AU2017222644A 2016-02-25 2017-02-24 Novel vaccines against Zika virus Active AU2017222644B2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2021258056A AU2021258056B2 (en) 2016-02-25 2021-10-29 Novel vaccines against Zika virus
AU2024204641A AU2024204641A1 (en) 2016-02-25 2024-07-04 Novel vaccines against Zika virus

Applications Claiming Priority (11)

Application Number Priority Date Filing Date Title
US201662300030P 2016-02-25 2016-02-25
US62/300,030 2016-02-25
US201662305183P 2016-03-08 2016-03-08
US62/305,183 2016-03-08
US201662396742P 2016-09-19 2016-09-19
US62/396,742 2016-09-19
US201662417100P 2016-11-03 2016-11-03
US62/417,100 2016-11-03
US201762462249P 2017-02-22 2017-02-22
US62/462,249 2017-02-22
PCT/US2017/019407 WO2017147458A1 (en) 2016-02-25 2017-02-24 Novel vaccines against zika virus

Related Child Applications (1)

Application Number Title Priority Date Filing Date
AU2021258056A Division AU2021258056B2 (en) 2016-02-25 2021-10-29 Novel vaccines against Zika virus

Publications (2)

Publication Number Publication Date
AU2017222644A1 AU2017222644A1 (en) 2018-09-13
AU2017222644B2 true AU2017222644B2 (en) 2021-07-29

Family

ID=59685658

Family Applications (3)

Application Number Title Priority Date Filing Date
AU2017222644A Active AU2017222644B2 (en) 2016-02-25 2017-02-24 Novel vaccines against Zika virus
AU2021258056A Active AU2021258056B2 (en) 2016-02-25 2021-10-29 Novel vaccines against Zika virus
AU2024204641A Pending AU2024204641A1 (en) 2016-02-25 2024-07-04 Novel vaccines against Zika virus

Family Applications After (2)

Application Number Title Priority Date Filing Date
AU2021258056A Active AU2021258056B2 (en) 2016-02-25 2021-10-29 Novel vaccines against Zika virus
AU2024204641A Pending AU2024204641A1 (en) 2016-02-25 2024-07-04 Novel vaccines against Zika virus

Country Status (10)

Country Link
US (2) US11648303B2 (enExample)
EP (1) EP3419660A4 (enExample)
JP (3) JP7012365B2 (enExample)
KR (1) KR20190003471A (enExample)
CN (2) CN115927399A (enExample)
AU (3) AU2017222644B2 (enExample)
BR (1) BR112018017307A2 (enExample)
CA (1) CA3015792A1 (enExample)
MX (2) MX2018010291A (enExample)
WO (1) WO2017147458A1 (enExample)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4218805A1 (en) 2015-07-21 2023-08-02 ModernaTX, Inc. Infectious disease vaccines
US11364292B2 (en) 2015-07-21 2022-06-21 Modernatx, Inc. CHIKV RNA vaccines
WO2017070624A1 (en) 2015-10-22 2017-04-27 Modernatx, Inc. Tropical disease vaccines
BR112018017307A2 (pt) * 2016-02-25 2019-01-08 Univ Pennsylvania molécula de ácido nucleico isolada, composição, e, métodos para indução de uma resposta imune contra um zika vírus, para tratamento de um indivíduo e para prevenção de uma infecção por zika vírus
US11666649B2 (en) * 2016-10-11 2023-06-06 University Of Miami Vectors and vaccine cells for immunity against Zika virus
US11806393B2 (en) * 2017-02-10 2023-11-07 La Jolla Institute For Allergy And Immunology Flavivirus peptide sequences, epitopes, and methods and uses thereof
EP3582790A4 (en) 2017-02-16 2020-11-25 ModernaTX, Inc. VERY POWERFUL IMMUNOGENIC COMPOSITIONS
WO2019055807A1 (en) 2017-09-14 2019-03-21 Modernatx, Inc. RNA VACCINES AGAINST ZIKA VIRUS
CN111526885A (zh) 2017-11-03 2020-08-11 武田疫苗股份有限公司 寨卡疫苗和免疫原性组合物及其使用方法
CA3084605A1 (en) 2017-11-30 2019-06-06 Takeda Vaccines, Inc. Method for inactivating zika virus and related methods
WO2019113285A2 (en) * 2017-12-06 2019-06-13 Emory University Zika vaccines and methods of use
AU2019310347A1 (en) * 2018-07-23 2021-03-04 The University Of Adelaide Zika virus vaccine
WO2020092564A1 (en) * 2018-10-31 2020-05-07 Icahn School Of Medicine At Mount Sinai Human antibodies targeting zika virus ns1, ns1 polypeptides and uses thereof
WO2020190750A1 (en) 2019-03-15 2020-09-24 Modernatx, Inc. Hiv rna vaccines
KR102553857B1 (ko) * 2021-02-05 2023-07-17 에스티팜 주식회사 신규 핵산 분자

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070292453A1 (en) * 2005-12-14 2007-12-20 Floyd Robert A RNA virus vaccines and methods
US8691961B1 (en) * 2009-11-09 2014-04-08 Integral Molecular, Inc. Flavivirus reporter virus and methods of making and using the same
WO2017015463A2 (en) * 2015-07-21 2017-01-26 Modernatx, Inc. Infectious disease vaccines

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2341354C (en) * 1998-09-02 2009-10-20 The Government Of The United States Of America Dengue viruses that are replication defective in mosquitos for use as vaccines
WO2009099716A1 (en) 2008-01-11 2009-08-13 Vgx Pharmaceuticals, Inc. Novel vaccines against multiple subtypes of dengue virus
CA3001374A1 (en) * 2008-11-17 2010-05-20 Vgx Pharmaceuticals, Llc Antigens that elicit immune response against flavivirus and methods of using same
KR20120093163A (ko) * 2009-09-14 2012-08-22 더 트러스티스 오브 더 유니버시티 오브 펜실바니아 Il-15 수용체 알파 및/또는 이를 인코딩하는 핵산 분자를 포함하는 백신 및 면역 치료제, 및 이를 이용하는 방법
EP2498814B1 (en) 2009-11-02 2015-09-09 The Trustees of the University of Pennsylvania Foot and mouth disease virus (fmdv) consensus proteins, coding sequences therefor and vaccines made therefrom
WO2011115583A1 (en) * 2010-03-19 2011-09-22 National University Of Singapore A novel platform for retrovirus-like particle (vlp)-display of vaccine antigens
US10081795B2 (en) 2010-03-24 2018-09-25 Research Development Foundation Flavivirus host range mutations and uses thereof
CN105821078A (zh) * 2010-12-09 2016-08-03 巴斯德研究所 用于获得高产量重组蛋白表达的基于mgmt的方法
MX352974B (es) 2011-01-31 2017-12-15 Univ Pennsylvania Moleculas de acido nucleico que codifican novedosos antigenos de herpes, vacunas que las comprenden y metodos para su uso.
JP6215223B2 (ja) * 2011-12-09 2017-10-18 アンスティテュ・パストゥール マルチプレックス免疫スクリーニングアッセイ
US9987347B2 (en) * 2013-03-15 2018-06-05 The Trustees Of The University Of Pennsylvania Vaccines against multiple subtypes of dengue virus
EA035921B1 (ru) 2015-07-16 2020-08-31 Бхарат Байотек Интернэшнл Лимитед Вакцинные композиции для профилактики арбовирусных инфекций
WO2017070624A1 (en) * 2015-10-22 2017-04-27 Modernatx, Inc. Tropical disease vaccines
WO2017140905A1 (en) * 2016-02-17 2017-08-24 Curevac Ag Zika virus vaccine
BR112018017307A2 (pt) * 2016-02-25 2019-01-08 Univ Pennsylvania molécula de ácido nucleico isolada, composição, e, métodos para indução de uma resposta imune contra um zika vírus, para tratamento de um indivíduo e para prevenção de uma infecção por zika vírus
WO2018014113A1 (en) * 2016-07-18 2018-01-25 Variation Biotechnologies Inc. Vaccine compositions for treatment of zika virus
KR102668318B1 (ko) * 2016-09-19 2024-05-22 더 트러스티스 오브 더 유니버시티 오브 펜실바니아 지카바이러스에 대항하는 신규한 백신 및 지카바이러스에 대해 사용하기 위한 dna 항체 작제물의 조합
MX2019008303A (es) * 2017-01-11 2019-12-02 Univ Pennsylvania Ácido ribonucleico modificado con nucleósidos para inducir una respuesta inmune contra el virus zika.
EP3412307A1 (en) * 2017-06-07 2018-12-12 Institut Pasteur Recombinant measles virus expressing zika virus proteins and their applications

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070292453A1 (en) * 2005-12-14 2007-12-20 Floyd Robert A RNA virus vaccines and methods
US8691961B1 (en) * 2009-11-09 2014-04-08 Integral Molecular, Inc. Flavivirus reporter virus and methods of making and using the same
WO2017015463A2 (en) * 2015-07-21 2017-01-26 Modernatx, Inc. Infectious disease vaccines

Also Published As

Publication number Publication date
AU2021258056A1 (en) 2021-11-25
CN109152826B (zh) 2022-11-04
CN115927399A (zh) 2023-04-07
CN109152826A (zh) 2019-01-04
WO2017147458A1 (en) 2017-08-31
AU2017222644A1 (en) 2018-09-13
BR112018017307A2 (pt) 2019-01-08
US12419945B2 (en) 2025-09-23
JP2019506175A (ja) 2019-03-07
CA3015792A1 (en) 2017-08-31
KR20190003471A (ko) 2019-01-09
JP7555325B2 (ja) 2024-09-24
US20210315987A1 (en) 2021-10-14
AU2024204641A1 (en) 2024-07-25
AU2021258056B2 (en) 2024-04-04
JP2024096281A (ja) 2024-07-12
US11648303B2 (en) 2023-05-16
MX2018010291A (es) 2019-06-06
EP3419660A4 (en) 2019-11-06
US20240115689A1 (en) 2024-04-11
JP2022023241A (ja) 2022-02-07
MX2023006203A (es) 2023-06-12
JP7012365B2 (ja) 2022-03-04
EP3419660A1 (en) 2019-01-02

Similar Documents

Publication Publication Date Title
AU2021258056B2 (en) Novel vaccines against Zika virus
JP5744719B2 (ja) チクングニヤウィルスタンパク質の共通配列、これをコードする核酸分子、並びにこれを使用する組成物および方法
US8961994B2 (en) DNA constructs eliciting immune response against flavivirus and effective adjuvants
US20240226291A9 (en) Combination of novel vaccines against zika virus and dna antibody constructs for use against zika virus
US20190091322A1 (en) Dna antibody constructs and method of using same
KR20110082566A (ko) 개량된 hcv 백신 및 이를 이용하는 방법
US20180326037A1 (en) Novel Vaccines Against Multiple Subtypes Of Dengue Virus
HK40091502A (zh) 新抗寨卡病毒疫苗
EP2968394A1 (en) Novel vaccines against multiple subtypes of dengue virus

Legal Events

Date Code Title Description
DA3 Amendments made section 104

Free format text: THE NATURE OF THE AMENDMENT IS: TO ADD CO-APPLICANT THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY

FGA Letters patent sealed or granted (standard patent)