WO2024258868A1 - Variants du virus des andes, compositions pharmaceutiques et méthodes de traitement associées - Google Patents

Variants du virus des andes, compositions pharmaceutiques et méthodes de traitement associées Download PDF

Info

Publication number
WO2024258868A1
WO2024258868A1 PCT/US2024/033437 US2024033437W WO2024258868A1 WO 2024258868 A1 WO2024258868 A1 WO 2024258868A1 US 2024033437 W US2024033437 W US 2024033437W WO 2024258868 A1 WO2024258868 A1 WO 2024258868A1
Authority
WO
WIPO (PCT)
Prior art keywords
andv
hamsters
virus
variants
disease
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.)
Ceased
Application number
PCT/US2024/033437
Other languages
English (en)
Inventor
Jay W. Hooper
Rebecca BROCATO
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.)
Geneva Foundation
Original Assignee
Geneva Foundation
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 Geneva Foundation filed Critical Geneva Foundation
Priority to EP24824017.8A priority Critical patent/EP4709419A1/fr
Publication of WO2024258868A1 publication Critical patent/WO2024258868A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61P31/14—Antivirals for RNA 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
    • A61K39/12—Viral antigens
    • 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
    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/12011—Bunyaviridae
    • C12N2760/12111—Hantavirus, e.g. Hantaan virus
    • C12N2760/12121—Viruses as such, e.g. new isolates, mutants or their genomic sequences
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/12011—Bunyaviridae
    • C12N2760/12111—Hantavirus, e.g. Hantaan virus
    • C12N2760/12134—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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/12011—Bunyaviridae
    • C12N2760/12111—Hantavirus, e.g. Hantaan virus
    • C12N2760/12161—Methods of inactivation or attenuation
    • C12N2760/12162—Methods of inactivation or attenuation by genetic engineering

Definitions

  • the present disclosure relates to Andes virus variants comprising one or more attenuating amino acid modifications, pharmaceutical compositions and vaccines comprising Andes virus variants, and methods of treating diseases and conditions via administration of Andes virus variants.
  • ANDV Andes virus belongs to the family Hantaviridae, of the order Bunyavirales (Walker PJ et al. Changes to virus taxonomy and the International Code of Virus Classification and Nomenclature ratified by the International Committee on Taxonomy of Viruses. Arch Virol. 2019; 164(9):24i 7-29).
  • ANDV is an etiological agent of hantavirus pulmonary syndrome (HPS) or hantavirus cardiopulmonary syndrome (HCPS) that is characterized by respiratory distress, pulmonary edema, and cardiogenic shock (Jonsson CB et al. A global perspective on hantavirus ecology, epidemiology, and disease. Clin Microbiol Rev.
  • the three segments are denoted as small (S), medium (M), and large (L) encoding for the nucleoprotein (N), glycoproteins (Gn and Gc), and the RNA-dependent RNA polymerase, respectively (Elliot RM & Schmaljohn CS. Bunyaviridae. In: Knipe D, Howley P, editors. Fields Virology. 1. Sixth Edition ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2013. p. 1244).
  • Hantaviruses infect microvascular endothelial cells altering the barrier properties of these cells resulting in a vascular leakage disease in the target organ, the lung in the case of ANDV infection (G192ovskaya I et al.
  • the attenuated ANDV may be utilized to form the bases of an attenuated virus hantavirus vaccine.
  • a vaccine may be further attenuated by producing reassortants with Sin Nombre virus, which would not require reverse genetics.
  • the E265K mutation may be incorporated along with other attenuating mutations.
  • FIGS. 1A-E relate to serial passaging of ANDV in Vero E6 cells leading to an accumulation of mutations and attenuation in hamsters; ANDV p2 was passaged 18 times in Vero E6 cells.
  • FIG. 1A shows images of morphology changes between ANDV p2 and ANDV p20 by immunostaining.
  • FIG. IB is a table showing ANDV p2 and ANDV p20 variants were sequenced and percentages of variants with detected mutations are shown.
  • FIG 1C is a graph relating to hamsters that were exposed to either 1,000 PFU of ANDV p2 or ANDV p20 by the intramuscular route; the lone hamster fatality from the ANDV p20 group is shown as a lone square at day 14 post-infection. ****, PO.OOOl by log-rank test.
  • FIG ID is a graph showing RT-PCR of ANDV S-segment in hamster lungs. The lone square at 14 days and the upper three squares at 28 days for ANDV p20 indicate lung samples collected for viral sequencing. ***, P ⁇ 0.001 by unpaired t- test.
  • FIG IE is a table wherein, from select ANDV p20 hamster lungs, the percentage of variants with detected mutations are shown.
  • FIG. 3A-J relate to pathogenic ANDV (p2 and p20ppl) replicate to higher titers in Syrian hamsters compared to nonpathogenic ANDV (p20ppI5 and p20ppI7); hamsters were exposed to 1 ,000 PFU of the indicated ANDV variant by the intramuscular route.
  • FIG. 3 A is a table relating to whole blood collected from 3 hamsters/group every other day being analyzed for S-segment viral RNA by RT-PCR; the numbers above the 12 dpi indicate the number of hamsters remaining from each group.
  • FIG. 3 A is a table relating to whole blood collected from 3 hamsters/group every other day being analyzed for S-segment viral RNA by RT-PCR; the numbers above the 12 dpi indicate the number of hamsters remaining from each group.
  • 3B is a graph showing 8 dpi (open symbols) and 10 dpi (closed symbols) were combined for the pathogenic ANDV (p2 and p20ppl) and nonpathogenic ANDV (p20pp!5 and p20pp!7). ****, F ⁇ 0.0001, unpaired t- test. H&E staining of FFPE lung tissue from hamsters exposed to ANDV p2 (FIG. 3C), ANDV p20pp 1 (FIG. 3D), ANDV p20ppl5 (FIG. 3E), and ANDV p20ppl7 (FIG. 3F): asterisks indicate mild to moderate perivascular edema and hemorrhage.
  • FIGS. 4A-E relate to attenuated ANDV (p20ppl5 and p20ppl7) protecting against lethal ANDV challenge; hamsters were exposed to 1,000 PFU or ANDV p20pp!5 or p20ppl7 on either Day -14, -3, or 0; and then on Day 0 they were challenged with wild type ANDV p2.
  • Panels A and B show the antibody responses on Day 0.
  • FIG. 4A is a graph showing N-ELISA reporting anti-N binding antibody.
  • FIG. 4B is a graph showing. ANDV PsVNA data reporting neutralizing antibody activity.
  • FIG. 4C is a graph showing Survival data. Approximately one month after challenge, sera was collected from survivors and the antibody responses were evaluated, with FIG. 4D being a graph showing N-ELISA.
  • FIG. 4E is a graph showing ANDV and PsVNA.
  • an Andes virus (ANDV) variant may c ompri se an amino acid sequence that is about 90% to about 99% identical to the sequence of the wild type ANDV.
  • the ANDV variant may comprise an amino acid sequence that is about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of the wild type ANDV.
  • the ANDV variant may comprise one or more attenuating amino acid modification(s).
  • the amino acid modification(s) may comprise a substitution at position 265.
  • the amino acid modification may comprise E265K.
  • a pharmaceutical composition comprising the above ANDV variants or viral particles thereof are envisioned.
  • the pharmaceutical composition may be for use in the treatment and/or prevention of an infection or disease in a subject in need thereof.
  • the infection or disease may be characterized by respiratory' distress, pulmonary' edema, and/or cardiogenic shock.
  • the infection or disease may be hantavirus pulmonary syndrome (HPS) or hantavirus cardiopulmonary' syndrome (HCPS).
  • a vaccine comprising the above ANDV variants or viral particles, or above pharmaceutical composition, is envisioned.
  • a method of treating a disease or condition in need thereof is envisioned, wherein the method may comprise administering a therapeutically' effective amount of the above pharmaceutical composition, or, alternatively, may' comprise administering the above vaccine.
  • ANDV Andes virus
  • Cells were maintained in complete Eagle minimum essential medium with Earle’s salts (cEMEM) supplemented with 10% FBS, lOnM HEPES (pH 7.4), 200 U ml-1 penicillin, 200 pg ml-1 streptomycin, lx non-essential amino acids (NEAA), 1.5 pg ml-1 amphotericin B, and 50 pg ml-1 gentamicin sulfate at 37°C in a 5% CO2 incubator. All cell culture reagents were procured from Life Technologies (Gibco, Grand Island, NY).
  • Plaque Assay Serial dilutions of neat virus were performed beginning at the 1:10 dilution as described (Hooper JW et al. A lethal disease model for hantavirus pulmonary syndrome. Virology. 200i;289(l):6-14; Wahl-Jensen V et al. Temporal analysis of Andes virus and Sin Nombre virus infections of Syrian hamsters. J Virol. 2007;81(14):7449-62).
  • RNA sequencing libraries were prepared using the KAPA RNA HyperPrep kit (KAPA Biosystems, Wilmington, MA, USA) following manufacturers’ guidelines. Following library preparation, libraries were enriched for ANDV specific reads using the Illumina TruSeq RNA Exome enrichment reagents (using one-quarter quantities to enable singleplex enrichment) with a custom ANDV biotinylated probe set.
  • the ANDV probe set included 201 unique probes of 120-nt in length that were designed against ANDV strain Chile-9717869 (AF291702, AF291703, and AF291704) and manufactured by Twist Biosciences (San Francisco, CA, USA). Pooled libraries were sequenced on the Illumina Miseq or NextSeq500sequencing platforms using 2 x 151 bp paired-end sequencing.
  • RNA and real-time RT-PCR Isolation of RNA and real-time RT-PCR. Approximately 200 mg of organ tissue w T as homogenized in 1.0 ml of TRIzol (ThermoFisher, Waltham, MA) reagent using M tubes on the gentleMACS (Miltenyi Biotec, Auburn, CA) dissociation system on the RNA setting. RNA was extracted from TRIzol per manufacturers protocol. A NanoDrop 8000 was used to determine RNA concentration, which was then raised to 100 ng ul-1 in UltraPure distilled water. Real-time PCR was conducted on a BioRad CFX thermal cycler using an Agilent Brilliant II QRT-PCR one-step master mix.
  • ANDV primer/probe sequences are described in (Khaiboullina SF et al. Andes-virus-induced cytokine storm is partially suppressed by ribavirin. Antivir Ther. 2013; 18(4):575-84). Cycling conditions were 30 min at 48 °C, 10 min at 95 °C, followed by 40 cycles of 15 s at 95 °C and 1 min at 60 °C. Data acquisition occurs following the annealing step.
  • N-ELISA Recombinant N protein ELISA w T ere performed on serum samples as previously described (Hooper JW et al. DNA vaccination with hantavirus M segment elicits neutralizing antibodies and protects against Seoul virus infection. Virology. 1999;255(2):269- 78). Samples were gamma-irradiated (on dry ice) with 3 x 106 rads from a 60C source.
  • ANDV PsVNA The PsVNA using a non-replicating VSVAG-luciferase pseudovirion system was performed as previously described (Kwilas S et al. A hantavirus pulmonary syndrome (HPS) DNA vaccine delivered using a spring-powered jet injector elicits a potent neutralizing antibody response in rabbits and nonhuman primates. Curr Gene Ther.
  • ISH in situ hybridization
  • ISH probes targeting ANDV genomic RNA fragment were designed and synthesized by Advanced Cell Diagnostics. Tissue sections were deparaffinized with xylene, underwent a series of ethanol washes and peroxidase blocking, and were then heated in kit-provided antigen retrieval buffer and digested by kit-provided proteinase. Sections were exposed to ISH target probe pairs and incubated at 40°C in a hybridization oven for 2 h. After rinsing, ISH signal was amplified using kit-provided Pre-amplifier and Amplifier conjugated to alkaline phosphatase and incubated with a Fast Red substrate solution for 10 min at room temperature. Sections were then stained with hematoxylin, air-dried, and cover slipped.
  • ANDV p20 is attenuated in hamsters
  • Lung tissue was collected during peak viremia indicating mild to moderate perivascular edema and hemorrhage admixed with lymphocytes, heterophils, and macrophages extending into adjacent alveolar lumen and expanding alveolar septa from hamsters exposed to pathogenic ANDV variants and minimal edema and reduced numbers of infiltrating macrophages and heterophils from hamsters exposed to nonpathogenic ANDV variants (FIGS. 3C-3F).
  • ISH in situ hybridization
  • Adaptation of Puumala hantavirus to cell culture is associated with point mutations in the coding region of the L segment and in the noncoding regions of the S segment. J Virol. 2003:77(16):8793-800) and pathogenicity in animal models (Safronetz D et al. Pathophysiology of hantavirus pubnonary syndrome in rhesus macaques. Proc Natl Acad Sci U S A. 2014:111(19):7114-9).
  • ANDV p2 which is typically uniformly lethal was passaged through 18 additional cell culture passages, resulted in a virus stock that was highly attenuated with significant reduced lethality in Syrian hamsters.
  • these attenuated ANDV form the bases of a future attenuated virus hantavirus vaccine.
  • Such a vaccine would need to be further attenuated by producing reassortants with Sin Nombre virus, which would not require reverse genetics. If a reverse genetics system is discovered, then the E265K mutation could be incorporated along with other attenuating mutations that remain to-be-discovered.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Microbiology (AREA)
  • Immunology (AREA)
  • Veterinary Medicine (AREA)
  • Genetics & Genomics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

La présente invention concerne des variants du virus des Andes (ANDV) comprenant une ou plusieurs modifications d'acides aminés d'atténuation, des compositions pharmaceutiques et des vaccins comprenant des variants du virus des Andes, et des méthodes de traitement de maladies et d'états par administration de variants du virus des Andes.
PCT/US2024/033437 2023-06-12 2024-06-11 Variants du virus des andes, compositions pharmaceutiques et méthodes de traitement associées Ceased WO2024258868A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP24824017.8A EP4709419A1 (fr) 2023-06-12 2024-06-11 Variants du virus des andes, compositions pharmaceutiques et méthodes de traitement associées

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363507569P 2023-06-12 2023-06-12
US63/507,569 2023-06-12

Publications (1)

Publication Number Publication Date
WO2024258868A1 true WO2024258868A1 (fr) 2024-12-19

Family

ID=93852629

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/033437 Ceased WO2024258868A1 (fr) 2023-06-12 2024-06-11 Variants du virus des andes, compositions pharmaceutiques et méthodes de traitement associées

Country Status (2)

Country Link
EP (1) EP4709419A1 (fr)
WO (1) WO2024258868A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022073144A1 (fr) * 2020-10-05 2022-04-14 Pontificia Universidad Catolica De Chile Formulation immunogène contenant une souche bcg modifiée qui exprime une protéine de virus andes (andv) utile pour prévenir et traiter des infections provoquées par hanta-andv

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022073144A1 (fr) * 2020-10-05 2022-04-14 Pontificia Universidad Catolica De Chile Formulation immunogène contenant une souche bcg modifiée qui exprime une protéine de virus andes (andv) utile pour prévenir et traiter des infections provoquées par hanta-andv

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BELLOMO CARLA M., ALONSO DANIEL O., PÉREZ-SAUTU UNAI, PRIETO KARLA, KEHL SEBASTIAN, COELHO ROCIO M., PERIOLO NATALIA, DI PAOLA NIC: "Andes Virus Genome Mutations That Are Likely Associated with Animal Model Attenuation and Human Person-to-Person Transmission", MSPHERE, vol. 8, no. 3, 22 June 2023 (2023-06-22), Washington , pages 1 - 14, XP093259941, ISSN: 2379-5042, DOI: 10.1128/msphere.00018-23 *
WARNER BRYCE M., SLOAN ANGELA, DESCHAMBAULT YVON, DOWHANIK SEBASTIAN, TIERNEY KEVIN, AUDET JONATHAN, LIU GUODONG, STEIN DEREK R., : "Differential Pathogenesis between Andes Virus Strains CHI-7913 and Chile-9717869 in Syrian Hamsters", JOURNAL OF VIROLOGY, vol. 95, no. 10, 26 April 2021 (2021-04-26), US , pages 1 - 15, XP093259943, ISSN: 0022-538X, DOI: 10.1128/JVI.00108-21 *

Also Published As

Publication number Publication date
EP4709419A1 (fr) 2026-03-18

Similar Documents

Publication Publication Date Title
Susta et al. Expression of interferon gamma by a highly virulent strain of Newcastle disease virus decreases its pathogenicity in chickens
CN107815441A (zh) 一种ⅱ型伪狂犬病毒减毒株及其制备方法和应用
Su et al. Chicken infectious anemia virus helps fowl adenovirus break the protection of maternal antibody and cause inclusion body hepatitis-hydropericardium syndrome in layers after using co-contaminated Newcastle disease virus-attenuated vaccine
Yuen et al. An interferon-integrated mucosal vaccine provides pan-sarbecovirus protection in small animal models
Xu et al. A genotype VII Newcastle disease virus-like particles confer full protection with reduced virus load and decreased virus shedding
Vatter et al. A simian hemorrhagic fever virus isolate from persistently infected baboons efficiently induces hemorrhagic fever disease in Japanese macaques
Dong et al. Studies on the pathogenesis of a Chinese strain of bovine parainfluenza virus type 3 infection in Balb/c mice
US10329584B2 (en) Modified Sendai virus vaccine and imaging vector
Zhao et al. A novel oral rabies vaccine enhances the immunogenicity through increasing dendritic cells activation and germinal center formation by expressing U-OMP19 in a mouse model
Park et al. Intranasal immunization with avian paramyxovirus type 3 expressing SARS-CoV-2 spike protein protects hamsters against SARS-CoV-2
CN104059889B (zh) 伪狂犬病病毒变异株双基因缺失毒株及其构建方法和应用
Warner et al. Oral vaccination with recombinant vesicular stomatitis virus expressing sin nombre virus glycoprotein prevents sin nombre virus transmission in deer mice
Umeshappa et al. A comparison of intradermal and intravenous inoculation of bluetongue virus serotype 23 in sheep for clinico-pathology, and viral and immune responses
Wu et al. Development and evaluation of Newcastle disease-avian influenza bivalent vector vaccines in commercial chickens
Risalde et al. Comparison of pathological changes and viral antigen distribution in tissues of calves with and without preexisting bovine viral diarrhea virus infection following challenge with bovine herpesvirus-1
CN109563491B (zh) 新颖的副粘病毒及其用途
Kumar et al. Lumpy skin disease virus suppresses the antiviral response of bovine peripheral blood mononuclear cells that support viral dissemination
EP4709419A1 (fr) Variants du virus des andes, compositions pharmaceutiques et méthodes de traitement associées
CN119351472A (zh) 一种可用于bsl-2下模拟人类马尔堡病毒病症状的替代病毒感染模型及其建立方法与应用
Kim et al. Intramuscular administration of recombinant Newcastle disease virus expressing SARS-CoV-2 spike protein protects hACE-2 TG mice against SARS-CoV-2 infection
CN116410991B (zh) 水泡性口炎病毒和新型冠状病毒的重组核酸分子、重组载体和重组病毒及其应用
Iwata-Yoshikawa et al. Non susceptibility of neonatal and adult rats against the middle east respiratory syndrome Coronavirus
US20250127878A1 (en) Rapid Acting Vaccine Against Nipah Virus
Xu et al. Evaluation of the safety and protection efficacy of an attenuated genotype vii newcastle disease virus strain as a candidate vaccine
Fathy et al. Evaluation of bivalent inactivated infectious bronchitis viral vaccine prepared from local isolates

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24824017

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2024824017

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2024824017

Country of ref document: EP

Effective date: 20251212

ENP Entry into the national phase

Ref document number: 2024824017

Country of ref document: EP

Effective date: 20251212

ENP Entry into the national phase

Ref document number: 2024824017

Country of ref document: EP

Effective date: 20251212

ENP Entry into the national phase

Ref document number: 2024824017

Country of ref document: EP

Effective date: 20251212

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2024824017

Country of ref document: EP

Effective date: 20251212

ENP Entry into the national phase

Ref document number: 2024824017

Country of ref document: EP

Effective date: 20251212

ENP Entry into the national phase

Ref document number: 2024824017

Country of ref document: EP

Effective date: 20251212

ENP Entry into the national phase

Ref document number: 2024824017

Country of ref document: EP

Effective date: 20251212

WWP Wipo information: published in national office

Ref document number: 2024824017

Country of ref document: EP