WO2022119896A1 - Procédés de détection de virus en suspension dans l'air dans des échantillons d'air - Google Patents

Procédés de détection de virus en suspension dans l'air dans des échantillons d'air Download PDF

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Publication number
WO2022119896A1
WO2022119896A1 PCT/US2021/061358 US2021061358W WO2022119896A1 WO 2022119896 A1 WO2022119896 A1 WO 2022119896A1 US 2021061358 W US2021061358 W US 2021061358W WO 2022119896 A1 WO2022119896 A1 WO 2022119896A1
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Prior art keywords
virus
complex
protein
capture antibodies
respiratory
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English (en)
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Michael E. Hogan
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PathogenDx Inc
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PathogenDx Inc
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G01N33/54326—Magnetic particles
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
    • G01N2333/08—RNA viruses
    • G01N2333/11—Orthomyxoviridae, e.g. influenza virus
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
    • G01N2333/08—RNA viruses
    • G01N2333/165—Coronaviridae, e.g. avian infectious bronchitis virus

Definitions

  • the invention relates to the fields of microarray technology and virology. More specifically, the present invention is directed to magnetic field enhanced protein microarray technology to analyze a panel of multiple airborne viruses.
  • respiratory virus testing of air samples is performed via ordinary air filter-based collection followed by rinsing of the filters, sample concentration, RNA purification and a nucleic acid based viral test, such as isothermal amplification or q- rtPCR.
  • Air filtration has a low recovery of the viral sample and cannot distinguish intact viral particles from viral debris.
  • the subsequent concentration and purification reactions require multiple steps and thus take several hours and require significant manual processing or mechanical automation.
  • the subsequent terminal nucleic acid tests are sensitive and specific but are difficult to multiplex. Thus, in the aggregate the airborne testing of today requires several hours and cannot support rapid analysis of multiple pathogens.
  • microarray technology provides a quick analysis of a panel of multiple airborne viruses to enable large-scale collection thereof for analysis.
  • the present invention fulfills this longstanding need and desire in the art.
  • the present invention is directed to a method for analyzing the viral complement of an air sample.
  • the air sample is obtained and particulate matter is collected from the air sample.
  • the particulate matter is mixed with a suspension of first fluorescently labeled magnetic beads that bind to intact viruses therein to produce a complex.
  • the complex binds to second fluorescently labeled capture antibodies specific for a viral protein to form a bound virus complex, where the second fluorescently labeled capture antibodies are linked via an oligonucleotide to a surface of a protein microarray comprising a magnet array.
  • the protein microarray is imaged to detect simultaneously signals from the bound virus complex and from the second fluorescently labeled capture antibodies, thereby analyzing the viral complement of the air sample.
  • the present invention is direct to a related method further comprising, prior to the imaging step, removing unbound virus complex via the magnet array.
  • the present invention also is directed to a method for detecting at least one airborne respiratory virus.
  • an air sample is obtained and particles are collected from the air sample.
  • the particles are added to a suspension of magnetic beads labeled with a first detectable label where the magnetic beads bind to intact respiratory viruses therein to produce a respiratory virus complex.
  • the respiratory virus complex binds to capture antibodies labeled with a second detectable label specific for at least one respiratory viral protein to form a bound respiratory virus complex, where the capture antibodies are linked via an oligonucleotide to a surface of a protein microarray comprising a magnet array.
  • the protein microarray is imaged to detect simultaneously signals from the bound respiratory virus complex and from the capture antibodies, thereby detecting the at least one airborne respiratory virus.
  • the present invention is direct to a related method further comprising, prior to the imaging step, removing unbound respiratory virus complex via the magnet array.
  • the present invention is directed further to a method for detecting Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) present in air.
  • SARS-CoV-2 Respiratory Syndrome Coronavirus 2
  • a sample of air is obtained and particulate matter is collected from the sample of air.
  • the particulate matter is mixed with a suspension of magnetic beads labeled with a first fluorophore that bind to intact SARS-CoV-2 viruses therein to form a SARS-CoV-2 complex.
  • the SARS-CoV-2 complex binds to capture antibodies labeled with a second fluorophore or other label specific for a SARS-CoV-2 protein, where the capture antibodies are linked via an oligonucleotide to a surface of a protein microarray comprising a magnet array and the unbound SARS-CoV-2 complex is removed via the magnet array.
  • the protein microarray is imaged to detect simultaneously signals from bound SARS-CoV-2 complex and from the capture antibodies, thereby detecting SARS-CoV-2 virus present in the air.
  • FIG. 1 illustrates the magnetic bead-based viral capture and fluorescent dye based detection on a protein microarray.
  • FIGS. 2A-2C illustrate the magnetic field induced binding, mixing, and imaging of the magnet array.
  • FIG. 2A illustrates binding and shows the binding position A.
  • FIG. 2B illustrates washing to the side and shows the mixing/imaging position B.
  • FIG. 2C is an alternative imaging position C to that in FIG. 2B and illustrates moving the magnet array above the plate and moving the bead complex to the edge of the meniscus.
  • FIG. 3 illustrates the structure of a typical 3-dimensional microarray probe “spot”.
  • the term “about” refers to a numeric value, including, for example, whole numbers, fractions, and percentages, whether or not explicitly indicated.
  • the term “about” generally refers to a range of numerical values (e.g., ⁇ 5- 10% of the recited value) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result).
  • the term “about” may include numerical values that are rounded to the nearest significant figure. For example, a sample of about 1 cubic meter of air encompasses an air sample of 0.9 cubic meters of air to 1 .1 cubic meters of air.
  • first and second are used to describe a common object, merely indicate that different instances of like objects are being referred to, and are not intended to imply that the objects so described must be in a given sequence, either temporally, spatially, in ranking, or in any other manner.
  • a method for analyzing the viral complement of an air sample comprising obtaining the air sample; collecting particulate matter from the air sample; mixing the particulate matter with a suspension of first fluorescently labeled magnetic beads that bind to intact viruses therein to produce a complex; binding the complex to second fluorescently labeled capture antibodies specific for a viral protein to form a bound virus complex, said second fluorescently labeled capture antibodies linked via an oligonucleotide to a surface of a protein microarray comprising a magnet array; and imaging the protein microarray to detect simultaneously signals from bound virus complex and from the second fluorescently labeled capture antibodies, thereby analyzing the viral complement of the air sample.
  • the method comprises, prior to the imaging step, removing unbound virus complex via the magnet array.
  • the first fluorescently labeled magnetic beads may be coated with a hydrogel or with biotin. Also in both embodiments the first fluorescently labeled magnetic beads may be labeled with a green fluorescent dye or a strepavidin-linked fluorescent dye.
  • the second fluorescently labeled capture antibodies may be labeled with a red fluorescent dye. Alternatively, the second fluorescently labeled capture antibodies are labeled with a red fluorescent dye linked to an oligothymidine.
  • the second fluorescently labeled capture antibodies may be specific for different surface proteins on a virus or variants thereof. Alternatively, the second fluorescently labeled capture antibodies may be specific for viral surface proteins from a panel of different viruses or variants thereof.
  • the virus in the complex may be a coronavirus, a respiratory syncytial virus A (RSV A), a respiratory syncytial virus B (RSV B) or a variant of each or a combination thereof.
  • the coronavirus may be a Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) or variant thereof.
  • the second labeled capture antibodies may be specific for a spike protein or a G protein or an F protein on the virus.
  • the virus in the complex may be an influenza A virus or an influenza B virus or a subtype of each or a combination thereof.
  • the second fluorescently labeled capture antibodies may be specific for a surface protein on the virus. Representative examples of the surface protein are neuraminidase or haemagglutinin or a combination thereof.
  • a method for detecting at least one airborne respiratory virus comprising obtaining an air sample; collecting particles from the air sample; adding the particles to a suspension of magnetic beads labeled with a first detectable label, said magnetic beads binding to intact respiratory viruses therein to produce a respiratory virus complex; binding the respiratory virus complex to capture antibodies labeled with a second detectable label specific for at least one respiratory viral protein to form a bound respiratory virus complex, said capture antibodies linked via an oligonucleotide to a surface of a protein microarray comprising a magnet array; and imaging the protein microarray to detect simultaneously signals from the bound respiratory virus complex and from the capture antibodies, thereby detecting the at least one airborne respiratory virus.
  • the method comprises, prior to the imaging step, removing unbound complex via the magnet array.
  • the magnetic beads may be coated with a hydrogel or with biotin.
  • the first detectable label may be a green fluorescent dye or a strepavidin-linked fluorescent dye.
  • the second detectable label may be a red fluorescent dye.
  • the second detectable label may be a red fluorescent dye linked to an oligothymidine.
  • the capture antibodies may be specific for different viral proteins on a single virus or variants or subtypes thereof or may be specific for viral proteins from a panel of respiratory viruses or variants or subtypes thereof. Particularly, the capture antibodies may be specific for a spike protein or a G protein or an F protein or neuraminidase or haemagglutinin or a combination thereof.
  • the respiratory virus may be at least one of a coronavirus, a respiratory syncytial virus A (RSV A), a respiratory syncytial virus B (RSV B) or a variant of each, an influenza A virus or an influenza B virus or a subtype of each or a combination of the viruses.
  • RSV A respiratory syncytial virus A
  • RSV B respiratory syncytial virus B
  • a representative example of a coronavirus is a Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) or variant thereof.
  • a method for detecting Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) present in air comprising obtaining a sample of air; collecting particulate matter from the sample of air; mixing the particulate matter with a suspension of magnetic beads labeled with a first fluorophore that bind to intact SARS-CoV-2 viruses therein to produce a SARS-CoV-2complex; binding the SARS-CoV-2 complex to capture antibodies labeled with a second fluorophore or other label specific for a SARS-CoV- 2protein, said capture antibodies linked via an oligonucleotide to a surface of a protein microarray comprising a magnet array; removing unbound SARS-CoV-2 complex via the magnet array; and imaging the protein microarray to detect simultaneously signals from bound complex and from the capture antibodies, thereby detecting SARS-CoV-2 virus present in the air.
  • SARS-CoV-2 Respiratory Syndrome Coronavirus 2
  • the magnetic beads may be coated with a hydrogel or with biotin.
  • the first fluorophore may be a green fluorescent dye or a strepavidin-linked fluorescent dye.
  • the second fluorophore may be a red fluorescent dye.
  • the second fluorophore may be a red fluorescent dye linked to an oligothymidine.
  • the capture antibodies may be specific for a spike protein on the SARS-CoV-2 virus.
  • the methods analyze respiratory viral pathogens in the air via a vortex based air sample collection, followed by magnetic bead based collection of intact viral particles and the by analysis of their surface protein complement while still an intact particle on a microarray.
  • This enables analysis of about 100 air samples (or less) in parallel. More particularly, the method may comprise the steps of:
  • Magnetic bead capture of fluid phase virus particles e.g. Ceres Nanotrap
  • the magnetic beads may be coated with a hydrogel and labeled with a first fluorescent label or a first detectable label or a first fluorophore, such as a green fluorescent dye, for example, but not limited to, the cyanine dye CY-3.
  • a first fluorescent label or a first detectable label or a first fluorophore such as a green fluorescent dye, for example, but not limited to, the cyanine dye CY-3.
  • the magnetic beads may be coated with biotin and labeled with a strepavidin (SA)- linked fluorophore, such as, but not limited to, SA-phycoerythrin.
  • SA strepavidin
  • the antibodies may be labeled with a second fluorescent label or a second detectable label or second fluorophore, such as a red fluorescent dye, for example, but not limited to, the cyanine dye CY-5.
  • the antibodies also may be labeled with a red fluorescent dye linked to an oligonucleotide such as the oligothymidine Oligo-T.
  • the antibodies may be labeled with strepavidin.
  • the viruses or airborne viruses detectable by the methods described herein may be a coronavirus, for example, but not limited to, Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which causes the respiratory infection coronavirus disease 2019 (COVID-19), a respiratory syncytial virus A (RSV A), a respiratory syncytial virus B (RSV B) or a variant of each, an influenza A virus or an influenza B virus or a subtype of each or any combination of these.
  • SARS-CoV-2 Respiratory Syndrome Coronavirus 2
  • RSV A respiratory syncytial virus A
  • RSV B respiratory syncytial virus B
  • the antibodies comprising the microarray are specific for at least one viral protein on each virus, for example, the spike protein on the coronaviruses or the G or F proteins of RSV viruses or a surface protein on the influenza viruses, for example, neuraminidase or haemagglutinin.
  • the antibodies may be specific for or directed to different proteins on a single virus or may be specific for at least one protein on each of multiple viruses thereby enabling detection of one or more viruses.
  • the microarray comprises a substrate to which the antibodies are surface- linked by UV crosslinking of a polymer, such as an oligonucleotide comprising about 60 nucleotides, for example, but not limited to, an oligothymidine (Oligo-T).
  • the microarray comprises a magnet array disposed over or under the microarray plate for removal of unbound [Virus+Bead+Dye] complexes.
  • a representative example of a magnetic array is an 8x12 array of neodymium magnets. When disposed under the microarray plate the magnet array is effective to wash the unbound complexes to the side of each well. When disposed over the microarray plate the magnet array is effective to move the unbound complexes to the top of each well
  • the method entails the following eight steps requiring about 10 min. These method steps may be performed by any adult operator and requires minimal training and no fluid handling other than with a disposable eye dropper.
  • a 1 cubic meter air sample is collected via a representative air sample collector (Bertin Coriolis Micro-Microbial Air Sampler (1 )).
  • the particulate complement of a 1 m 3 air sample can be collected into 2mls of an aqueous collection buffer.
  • a representative buffer of that type is phosphate buffered saline (PBS) with 0.1 % added TWEEN 20 as a wetting agent, but other neutral saline buffers, e.g.150 mM NaCI or NaCitrate, with a small amount of a non-ionic wetting agent, e.g., TWEEN 20 or NP40 or an equivalent, may be substituted.
  • PBS phosphate buffered saline
  • other neutral saline buffers e.g.150 mM NaCI or NaCitrate
  • a non-ionic wetting agent e.g., TWEEN 20 or NP40 or an equivalent
  • a magnetic bead suspension that comprises in this example a suspension of ferrite magnetic beads (about 2nm) coated by the manufacturer with a hydrogel, i.e., Nanotrap particles, that is designed to bind to enveloped respiratory viruses (Ceres Nanotrap (2)).
  • Nanotrap particles also stably bind partially hydrophobic dyes such as, but not limited to, CY-3. In that way, upon adding about 100 dye equivalents per Ceres particle, a fluorescently labeled [Bead+nDye] complex is generated on mixing and is then ready to serve as the magnetic bead suspension (FIG. 1 ).
  • the magnetic bead suspension is diluted with PBS to about 10,000 magnetic beads/ml, so that, upon addition of 4 drops of that suspension to 2 ml of collection buffer, the resulting [Bead+nDye] complex has been diluted to about 1 ,000 Beads/ml.
  • the enveloped virus e.g. SARS-CoV-2
  • the enveloped virus e.g. SARS-CoV-2
  • the microarray substrate comprises a protein microarray fabricated such that each spot in the microarray is about 100pM in diameter and spaced about 250pm on center.
  • Each spot of the microarray contains a capture antibody specific for the spike protein of SARS-CoV2 or for another representative respiratory virus such as influenza an antibody specific for an influenza surface protein such as neuraminidase or haemagglutinin.
  • a representative spike protein specific antibody is represented by Recombinant SARS- CoV-2 Spike RBD Protein with His tag (RP01258) from Abclonal.
  • Representative printing conditions include formulation of the anti-spike antibody at 1 mg/ml in a print solution containing PBS, 1 mg/ml of bovine serum albumin and 0.1 mg/ml Oligo-dT (60 bases long) and 0.01 mg/ml Oligo-dT (25 bases long modified at its 5’ terminus with CY5, to confer a red fluorescent marker signal to the microarray spot containing the antibody.
  • Microarray fabrication printing of the above mentioned antibody print solution is performed by contact or ink jet methods to deliver about 0.3 nL (300 pL) per spot onto a glass or plastic substrate.
  • the resulting air-dried spots are crosslinked at about 300 mJ to induce thymidine crosslinking, thereby entrapping the antibody in the microarray spot, linking the antibody to the red fluorescent marker and in turn fixing the spot onto the underlying glass or plastic surface to be made available for binding to a cognate solution state [Virus+ Bead+nDye] complex (FIG. 3).
  • a binding buffer is added to raise the ionic strength and the complex binds to surface bound antibody.
  • Unbound [Virus+ Bead+nDye] is removed from the center of the microarray by the action of a cognate array of permanent magnets as described in FIG. 2B or, alternatively, FIG. 2C. Having been pulled to the edge of the microarray via the action of the permanent magnets, the remaining dye-labelled [Virus+ Bead+nDye] complex is imaged via two color fluorescence detection using an imager, such as the Sensovation Sensospot imager.
  • the imager detects the location of the protein spots by analysis of CY-5 fluorescence in each microarray spot and detection of the bound [Virus+ Bead+nDye] complex being obtained via simultaneous imaging herein of the CY-3 dye, or equivalent dye to the Ceres Magnetic bead carrier.
  • such protein microarrays may be fabricated to possess a number of different antibodies specific for SARS-CoV2 variants (a different antibody per microarray spot) or to resolve mixtures of respiratory pathogens, with each spot containing antibodies specific for a panel of respiratory viruses, for example, antibodies against SARS-CoV2 and/or SARS-CoV2 variants in some spots, antibodies against Influenza A and/or Influenza A variants in some spots, antibodies against Influenza B and/or Influenza B variants in some spots, and antibodies against RSV A and/or RSV B variants in some spots.
  • the resulting protein microarray resolves a mixture of SARS-CoV2, Influenza A, Influenza B, RSV A, RSV B and subtypes of each for which well-defined surface protein specific antibodies may be obtained in a pure form.

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Abstract

La présente invention concerne des procédés d'analyse ou de détection de virus en suspension dans l'air, par exemple des virus respiratoires en suspension dans l'air, par l'obtention d'un échantillon d'air, l'isolement de la matière particulaire de celui-ci et le mélange de la matière particulaire avec une suspension de billes magnétiques marquées pour produire un complexe viral. Le complexe viral est lié à un ou plusieurs anticorps marqués spécifiques des protéines virales où les anticorps sont liés à un microréseau de protéines contenant un réseau d'aimants. Le microréseau est imagé pour détecter des signaux provenant du complexe de virus lié et à partir des anticorps marqués à partir desquels les signaux en suspension dans l'air peuvent être identifiés.
PCT/US2021/061358 2020-12-01 2021-12-01 Procédés de détection de virus en suspension dans l'air dans des échantillons d'air Ceased WO2022119896A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6627748B1 (en) * 2000-09-11 2003-09-30 The Trustees Of Columbia University In The City Of New York Combinatorial fluorescence energy transfer tags and their applications for multiplex genetic analyses
WO2005085849A2 (fr) * 2003-10-24 2005-09-15 U S. Genomics, Inc Identification de risque biologique par dosage immunologique par fluorescence et par detection de molecule simple
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Publication number Priority date Publication date Assignee Title
US6627748B1 (en) * 2000-09-11 2003-09-30 The Trustees Of Columbia University In The City Of New York Combinatorial fluorescence energy transfer tags and their applications for multiplex genetic analyses
WO2005085849A2 (fr) * 2003-10-24 2005-09-15 U S. Genomics, Inc Identification de risque biologique par dosage immunologique par fluorescence et par detection de molecule simple
US8007999B2 (en) * 2006-05-10 2011-08-30 Theranos, Inc. Real-time detection of influenza virus

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Title
FABIANI L. ET AL.: "Magnetic beads combined with carbon black-based screen-printed electrodes for COVID-19: A reliable and miniaturized electrochemical immunosensor for SARS-CoV-2 detection in saliva", BIOSENSORS & BIOELECTRONICS, vol. 171, no. 112686, 3 October 2020 (2020-10-03), pages 1 - 9, XP086320205, DOI: 10.1016/j.bios.2020.112686 *
OTIENO BRUNAH A., KRAUSE COLLEEN E., JONES ABBY L., KREMER RICHARD B., RUSLING JAMES F.: "Cancer Diagnostics via Ultrasensitive Multiplexed Detection of Parathyroid Hormone-Related Peptides with a Microfluidic Immunoarray", ANALYTICAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 88, no. 18, 20 September 2016 (2016-09-20), US , pages 9269 - 9275, XP055941682, ISSN: 0003-2700, DOI: 10.1021/acs.analchem.6b02637 *
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