WO2013148335A1 - Host biomarkers for dengue fever (df) and methods thereof - Google Patents
Host biomarkers for dengue fever (df) and methods thereof Download PDFInfo
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- WO2013148335A1 WO2013148335A1 PCT/US2013/032265 US2013032265W WO2013148335A1 WO 2013148335 A1 WO2013148335 A1 WO 2013148335A1 US 2013032265 W US2013032265 W US 2013032265W WO 2013148335 A1 WO2013148335 A1 WO 2013148335A1
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- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
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- G01N2333/18—Togaviridae; Flaviviridae
- G01N2333/183—Flaviviridae, e.g. pestivirus, mucosal disease virus, bovine viral diarrhoea virus, classical swine fever virus (hog cholera virus) or border disease virus
- G01N2333/185—Flaviviruses or Group B arboviruses, e.g. yellow fever virus, japanese encephalitis, tick-borne encephalitis, dengue
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- G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
- G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
- G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
- G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
- G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
- G01N2333/96433—Serine endopeptidases (3.4.21)
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/26—Infectious diseases, e.g. generalised sepsis
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
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- Y—GENERAL 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- Dengue is the most medically important arboviral disease in humans. Its etiological agent, the Dengue virus (DENV), causes a wide range of diseases, ranging from acute febrile Dengue fever (DF) to life-threatening Dengue hemorrhagic fever (DHF) and Dengue shock syndrome (DSS).
- DF acute febrile Dengue fever
- DHF Dengue hemorrhagic fever
- DSS Dengue shock syndrome
- Dengue fever is self- limited though debilitating illness characterized by fever, frontal headache, retro-orbital pain, myalgia, arthralgia, nausea, vomiting, weakness and rash.
- Dengue hemorrhagic fever is marked by increased vascular permeability, thrombocytopenia and hemorrhagic manifestations.
- Common hemorrhagic manifestations include skin hemorrhages such as petechiae, purpuric lesions and ecchymoses. Epistaxis, bleeding gums, gastro-intestinal hemorrhage and hematuria occur less frequently.
- Dengue shock syndrome occurs when fluid leakage into the interstitial spaces results in shock, which without appropriate treatment may lead to death [reviewed from (1-3)].
- DHF/DSS severe Dengue
- DF mild febrile illness
- the present invention provides, in one embodiment, a method of determining whether a subject in need thereof has a Dengue virus infection that is likely to develop into a life-threatening Dengue disease.
- the method of this embodiment comprises (a) detecting in a sample from the subject an expression level of at least two proteins selected from the group consisting of vascular endothelial growth factor protein (SEQ ID NO: l), chymase-l protein (SEQ ID NO:2) and alpha-2 macroglobulin protein (SEQ ID NO:3); (b) comparing the expression level of each protein detected in (a) to a corresponding expression level for each protein in a control; and (c) determining that the patient has a Dengue virus infection that is likely to develop into a life -threatening Dengue disease when the expression level of each protein detected in the sample in (a) is significantly greater than the corresponding expression level for each protein in the control.
- SEQ ID NO: l vascular endothelial growth factor protein
- SEQ ID NO:2 chymase-
- the method comprises detecting an expression level of vascular endothelial growth factor protein (SEQ ID NO: l), chymase-l protein (SEQ ID NO:2) and alpha-2 macroglobulin protein (SEQ ID NO:3) in the sample from the subject.
- SEQ ID NO: l vascular endothelial growth factor protein
- SEQ ID NO:2 chymase-l protein
- SEQ ID NO:3 alpha-2 macroglobulin protein
- the invention relates to a method of determining whether a subject in need thereof has a Dengue virus infection that is likely to develop into a life-threatening Dengue disease comprising (a) detecting in a sample from the subject an expression level of at least two proteins selected from the group consisting of vascular endothelial growth factor protein (SEQ ID NO: l), chymase-1 protein (SEQ ID NO:2) and alpha-2 macroglobulin protein (SEQ ID NO:3); (b) comparing the expression level of each protein detected in (a) to a corresponding expression level for each protein in a control; (c) determining that the patient has a Dengue virus infection that is likely to develop into a life-threatening Dengue disease when the expression level of each protein detected in the sample in (a) is significantly greater than the corresponding expression level for each protein in the control; and (d) administering a treatment regimen for a life-threatening Dengue disease to the subject upon determining that the subject has a Dengue virus infection that is likely to
- the invention relates to a method of selecting a treatment regimen for a subject in need thereof who has been infected with a Dengue virus, comprising (a) detecting in a sample from the subject an expression level of at least two proteins selected from the group consisting of vascular endothelial growth factor protein (SEQ ID NO: l), chymase-1 protein (SEQ ID NO:2), and alpha-2 macroglobulin protein (SEQ ID NO:3); (b) comparing the expression level of each protein detected in (a) to a corresponding expression level for each protein in a control; and (c) selecting either: (1) a regimen for treating a life-threatening Dengue disease when the expression level of each protein detected in the sample in (a) is significantly greater than the corresponding expression level for each protein in the control; or (2) a regimen for treating a mild Dengue disease when the expression level of each protein detected in the sample in (a) is not significantly greater than the corresponding expression level for each protein in the control.
- SEQ ID NO: l vascular endo
- the invention relates to a prognostic kit for distinguishing a subject who is likely to develop a mild Dengue disease from a subject who is likely to develop a life-threatening Dengue disease.
- the kit comprises at least two of: (a) one or more reagents for detecting an expression level of: (1) a vascular endothelial growth factor protein, (2) an antibody to a vascular endothelial growth factor protein, or (3) a combination thereof; (b) one or more reagents for detecting an expression level of: (1) a chymase- 1 protein, (2) an antibody to a chymase- 1 protein, or (3) a combination thereof; or (c) one or more reagents for detecting an expression level of: (1) an alpha-2 macroglobulin protein, (2) an antibody to an alpha-2 macroglobulin protein, or (3) a combination thereof.
- the methods and kits of the invention can be used to differentiate DHF from DF and severe and non-severe forms of Dengue with high sensitivity and specificity.
- Figure 1A is a graph depicting levels of VEGF protein in serum samples obtained from Dengue patients with different degrees of severity. VEGF is significantly increased in DHF samples compared to that of DF at the early time points.
- Figure IB is a graph depicting levels of chymase- 1 protein in serum samples obtained from Dengue patients with different degrees of severity. Chymase levels are significantly increased in DHF samples compared to that of DF at the early time points.
- Figure 2 A is a graph depicting levels of alpha-2 macroglobulin protein in serum samples from Dengue patients with different degrees of severity obtained from a prospective study (first batch of sera). Significantly higher levels of macroglobulin are observed in DHF samples compared to that of DF samples at both early and late time points.
- Figure 2B is a graph depicting levels of chymase- 1 protein in serum samples from Dengue patients with different degrees of severity obtained from a prospective study (first batch of sera). Chymase levels are significantly increased in DHF sera samples only at the early time point.
- Figure 2C is a graph depicting levels of VEGF protein in serum samples from Dengue patients with different degrees of severity obtained from a prospective study (first batch of sera). No significant differences in the levels of VEGF between DF and DHF serum samples are obtained.
- Figure 3 A is a graph depicting levels of chymase-1 protein in Dengue patient samples obtained for further validation (second batch of sera).
- Figure 3B is a graph depicting levels of alpha-2 macroglobulin protein in Dengue patient samples obtained for further validation (second batch of sera).
- Figure 3C is a graph depicting levels of VEGF protein in Dengue patient samples obtained for further validation (second batch of sera).
- Figure 4A is a workflow diagram depicting screening of protein microarrays to identify novel autoantibodies in serum samples of Dengue patients.
- Figure 4B is a graph depicting the number of candidate biomarkers identified by cross-reactive antibodies that were significantly more prevalent in serum of Dengue patients than in healthy controls with Z-score values between 1 and 15.
- Figure 5 is a graph depicting the distribution according to cellular compartment of 67 autoantigens (Z-score above 3) identified by cross-reactive antibodies that were significantly more prevalent in Dengue patients than in healthy controls.
- Figure 6 A is a graph depicting higher levels of VEGF in DF samples from Dengue Clinic (DC) with warning signs (WS) compared to those without warning signs (NWS).
- Figure 6B is a graph depicting levels of chymase-1 in DF samples from Dengue Clinic (DC) with warning signs (WS) compared to those without warning signs (NWS).
- Figure 6C is a graph depicting levels of alpha-2 macroglobulin in DF samples from Dengue Clinic (DC) with warning signs (WS) compared to those without warning signs (NWS).
- Figure 7A is a graph depicting levels of alpha-2 macroglobulin in severe Dengue samples compared to non-severe Dengue samples from Dengue Clinic (DC).
- Figure 7B is a graph depicting higher levels of VEGF in severe Dengue samples compared to non-severe Dengue samples from Dengue Clinic (DC).
- Figure 7C is a graph depicting levels of chymase- 1 in severe Dengue samples compared to non-severe Dengue samples from Dengue Clinic (DC).
- Dengue is a re-emerging arboviral disease with over half of the world's population living in areas of risk. Its etiological agent, the Dengue virus (DENV), causes a wide range of diseases, ranging from acute febrile Dengue fever (DF) to life-threatening Dengue hemorrhagic fever (DHF) and Dengue shock syndrome (DSS). No effective therapeutic option is currently available. Physicians can only rely on early recognition and prompt supportive treatment to lower the risk of patients developing DHF/DSS. However, there is a clear lack of relevant technology to accurately identify patients who will develop DHF/DSS.
- DEV Dengue virus
- Dengue patients are hospitalized on a first-come-first-serve basis and this led to a great shortage of hospital beds and significant burden on the healthcare infrastructure during major Dengue epidemics.
- described herein is the identification of a panel of prognostic biomarkers that were identified using protoarray technology.
- the study described herein highlights a set of autoantigens to which Dengue- specific cross-reactive antibodies in Dengue patients' sera can bind more specifically and these novel autoantigens can be used as biomarkers in Dengue prognosis.
- the presence of identified autoantigens were also examined in Dengue patients' sera obtained from Early Dengue Infection and Outcome Study (EDEN study) and Adult Dengue Study (Dengue Clinic) at TTSH.
- alpha-2 macroglobulin and chymase levels were significantly higher in DHF patients' sera.
- the application of the prognostic biomarkers identified herein will increase the ability of hospitals and doctors to prioritize and allocate valuable healthcare resources to the correct group of Dengue patients. Moreover this technology would bring about tremendous socioeconomic impacts in Dengue-affected countries by reducing hospitalization cost, improving the quality of hospital care, reducing patient suffering and saving lives.
- the present invention provides, in one embodiment, a method of determining whether a subject in need thereof has a Dengue virus infection that is likely to develop into a life-threatening Dengue disease.
- the method of this embodiment comprises the steps of (a) detecting in a sample from the subject an expression level of at least two proteins selected from the group consisting of vascular endothelial growth factor protein (SEQ ID NO: l), chymase-l protein (SEQ ID NO:2) and alpha-2 macroglobulin protein (SEQ ID NO:3); (b) comparing the expression level of each protein detected in (a) to a corresponding expression level for each protein in a control; and (c) determining that the patient has a Dengue virus infection that is likely to develop into a life -threatening Dengue disease when the expression level of each protein detected in the sample in (a) is significantly greater than the corresponding expression level for each protein in the control.
- SEQ ID NO: l vascular endothelial growth factor protein
- SEQ ID NO:2 chy
- the method comprises detecting in a sample an expression level of vascular endothelial growth factor protein (SEQ ID NO: l), chymase-l protein (SEQ ID NO:2) and alpha-2 macroglobulin protein (SEQ ID NO:3), or any combination of two of these proteins, including an expression level of vascular endothelial growth factor protein (SEQ ID NO: l) and alpha-2
- SEQ ID NO:3 or a combination of chymase-l protein (SEQ ID NO:2) and alpha-2 macroglobulin protein (SEQ ID NO:3).
- vascular endothelial growth factor or "VEGF” refers to a human vascular endothelial growth factor A (VEGF A) protein having the
- Chymase-1 or "chymase” refers to a human chymase-1 protein having the Accession Number EAW66007.1 and the amino acid sequence indicated below:
- Alpha-2 macroglobulin or “macroglobulin” or “A2M” refers to a human alpha-2 macroglobulin protein having the Accession Number NM 000014.3 and the amino acid sequence indicated below:
- vascular endothelial growth factor protein SEQ ID NO: l
- chymase-1 protein SEQ ID NO:2
- alpha-2 macroglobulin protein SEQ ID NO:3
- a "subject in need thereof encompasses vertebrates (e.g., mammals) who have a Dengue virus infection as well as vertebrates who are at risk for developing a Dengue virus infection.
- the subject in need thereof is a human.
- a subject in need thereof can be a subject having one or more symptoms of a Dengue disease (e.g., a mild Dengue disease, a life-threatening Dengue disease) or a subject who is asymptomatic.
- the methods of the invention can be performed on a subject who is known to have a Dengue virus infection or a subject who is suspected of having a Dengue virus infection, but whose infection status is uncertain.
- the methods of the invention can be performed on a subject in need thereof before the onset of symptoms of a life- threatening Dengue disease or after the onset of symptoms of a life-threatening Dengue disease.
- the sample obtained from the subject can be any suitable biological sample, including, but not limited to, whole blood, serum, plasma, urine, lymph fluid, cerebrospinal fluid, saliva, tissue biopsy, or a combination thereof.
- the sample to be tested is a serum sample or plasma sample.
- the expression level of a vascular endothelial growth factor protein (SEQ ID NO: l), chymase-l protein (SEQ ID NO:2) or alpha-2 macroglobulin protein (SEQ ID NO:3) in a sample can be determined by detecting the protein itself in the sample from the subject, or by detecting antibodies (e.g., cross-reactive antibodies) to the protein in the sample from the subject.
- SEQ ID NO: l vascular endothelial growth factor protein
- SEQ ID NO:2 chymase-l protein
- alpha-2 macroglobulin protein SEQ ID NO:3
- Suitable techniques and assays for measuring the expression level of a protein (or antibodies thereto) in a sample are well known in the art and include, for example, Western blotting techniques and various immunoassays.
- an immunoassay is used to detect the expression level of vascular endothelial growth factor protein (SEQ ID NO: l), chymase-l protein (SEQ ID NO:2) or alpha-2 macroglobulin protein (SEQ ID NO:3) in a sample from a subject.
- Immunoassays that are useful in the present invention include, but are not limited to, enzyme-linked immunosorbent assays (ELISAs), lateral flow
- immunoassays radioimmunoassays, sandwich immunoassays, protein microarrays, magnetic immunoassays and surround optical fiber immunoassays.
- an ELISA is used to detect the expression level of vascular endothelial growth factor protein (SEQ ID NO: l), chymase-l protein (SEQ ID NO:2) or alpha-2 macroglobulin protein (SEQ ID NO:3) in a sample from a subject.
- a lateral flow immunoassay is used to detect the expression level of vascular endothelial growth factor protein (SEQ ID NO: l), chymase-l protein (SEQ ID NO:2) or alpha-2 macroglobulin protein (SEQ ID NO:3) in a sample from a subject.
- a protein microarray is used to detect antibodies to a vascular endothelial growth factor protein (SEQ ID NO: l), chymase- 1 protein (SEQ ID NO:2) or alpha-2 macroglobulin protein (SEQ ID NO:3) in a sample from a subject.
- vascular endothelial growth factor protein SEQ ID NO: l
- chymase- 1 protein SEQ ID NO:2
- alpha-2 macroglobulin protein SEQ ID NO:3
- Useful protein microarrays are available commercially and include, for example, ProtoArray ® Human Protein Microarrays (Life Technologies, Grand Island, New York).
- the methods of the invention further comprise the step of comparing the expression level of each protein detected in the sample from the subject to a corresponding expression level for each protein in a control.
- a "corresponding expression level" can be an actual expression level of a protein in a sample obtained from a control (e.g., a healthy human subject) or a standard reference protein level that is indicative of the typical or average level of the protein in a healthy human subject.
- the methods of the invention further comprise the step of determining that the patient has a Dengue virus infection that is likely to develop into a life- threatening Dengue disease when the expression level of each protein detected in the sample from the subject is significantly greater than the corresponding expression level for each protein in the control.
- the expression level of vascular endothelial growth factor protein (SEQ ID NO: l), chymase-l protein (SEQ ID NO:2) or alpha-2 macroglobulin protein (SEQ ID NO:3) in the sample from the subject is significantly greater than the corresponding expression level for the relevant protein in the control when there is a statistically greater expression level of the protein in the sample compared to the control.
- the statistically greater expression level in the sample compared to the control is at a level of about 5% significance (95% confidence interval).
- Suitable statistical tests for evaluating whether a protein expression level in a sample is significantly greater than a protein level in a control are well known in the art and include, for example, the statistical tests employed in the Examples described herein.
- the method of determining whether a subject in need thereof has a Dengue virus infection that is likely to develop into a life- threatening Dengue disease further comprises the step of administering a treatment regimen for a life-threatening Dengue disease to the subject upon determining that the patient has a Dengue virus infection that is likely to develop into a life- threatening Dengue disease.
- a "life-threatening Dengue disease” includes, for example, Dengue hemorrhagic fever (DHF), Dengue shock syndrome (DSS), severe Dengue and Dengue with warning signs.
- DHF is characterized by increased vascular permeability, thrombocytopenia and hemorrhagic manifestations. Common hemorrhagic manifestations include skin hemorrhages such as petechiae, purpuric lesions and ecchymoses. Epistaxis, bleeding gums, gastro -intestinal hemorrhage and hematuria occur less frequently.
- DSS occurs when fluid leakage into the interstitial spaces results in shock, which without appropriate treatment may lead to death. Both DHF and DSS can be diagnosed clinically according to World Health
- Severe Dengue and Dengue with warnings signs can be classified according to WHO criteria published in "Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control", Geneva (2009), the relevant contents of which are incorporated herein by reference.
- characteristics of severe Dengue include severe plasma leakage, severe bleeding/haemorrhage, or severe organ impairment/failure
- characteristics of Dengue with warning signs include abdominal pain or tenderness, persistent vomiting, fluid accumulation, mucosal bleeding, lethargy, restlessness, liver enlargement, increasing haematocrit with rapid decrease in platelet count.
- a treatment regimen for a life-threatening Dengue disease can include one or more of the following: hospitalization, administration of antipyretics (e.g., paracetamol), intake of fluid (e.g., water, electrolyte replacement solution, fruit juice) by mouth, platelet transfusion, sedative therapy, and oxygen therapy.
- antipyretics e.g., paracetamol
- fluid e.g., water, electrolyte replacement solution, fruit juice
- a skilled physician can readily determine and administer an appropriate treatment regimen, including suitable dosages of therapeutic agents, based on relevant patient characteristics (e.g., age, weight, severity of symptoms, existing or prior medical conditions).
- the invention relates to a method of selecting a treatment regimen for a subject in need thereof who has been infected with a Dengue virus.
- the method of selecting comprises (a) detecting in a sample from the subject an expression level of at least two proteins selected from the group consisting of vascular endothelial growth factor protein (SEQ ID NO: l), chymase-1 protein (SEQ ID NO:2), and alpha-2 macroglobulin protein (SEQ ID NO:3); (b) comparing the expression level of each protein detected in (a) to a corresponding expression level for each protein in a control; and (c) selecting either: (1) a regimen for treating a life-threatening Dengue disease when the expression level of each protein detected in the sample in (a) is significantly greater than the corresponding expression level for each protein in the control; or (2) a regimen for treating a mild Dengue disease when the expression level of each protein detected in the sample in (a) is not significantly greater than the corresponding expression level for each protein in the control.
- the method of selecting a treatment regimen further comprises administering the selected regimen to the subject.
- the selected regimen can be administered to the subject before the onset of symptoms of a life- threatening Dengue disease or after the onset of symptoms of a life-threatening Dengue disease.
- a regimen for treating a life-threatening Dengue disease is selected for the subject when the expression level of each protein detected in the sample is significantly greater than the corresponding expression level for each protein in the control.
- a suitable regimen for treating a life-threatening Dengue disease can be readily determined by a skilled physician and can include, for example, one or more of the treatments for a life-threatening Dengue disease disclosed above.
- a regimen for treating a mild Dengue disease is selected.
- a "mild Dengue disease” includes, for example, Dengue fever (DF), as defined by WHO criteria published in “Dengue haemorrhagic fever: Diagnosis, treatment, prevention and control", 2 nd Ed., Geneva (1997), and Dengue without warning signs, as defined by WHO criteria published in “Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control", Geneva (2009).
- DF is characterized by such symptoms as undifferentiated febrile disease, mild febrile syndrome, high fever with abrupt onset, severe headache, aches and pains, nausea, vomiting and rash.
- Dengue without warnings signs is characterized by fever and at least 2 symptoms selected from nausea/vomiting, rash, aches and pains, positive tourniquest test, and leukopenia without exhibiting any of the symptoms of Dengue with warning signs.
- a treatment regimen for a mild Dengue disease can include, for example, increasing fluid intake and monitoring (e.g., daily monitoring) of the patient by healthcare providers for signs of disease progression and/or warning signs. In some cases, no treatment will be administered to a subject having a mild Dengue disease and the subject will be sent home without further monitoring.
- the present invention also provides a prognostic kit for distinguishing a subject who is likely to develop a mild Dengue disease from a subject who is likely to develop a life-threatening Dengue disease.
- the kit comprises at least two of: (a) one or more reagents for detecting an expression level of: (1) a vascular endothelial growth factor protein, (2) an antibody to a vascular endothelial growth factor protein, or (3) a combination thereof; (b) one or more reagents for detecting an expression level of: (1) a chymase-1 protein, (2) an antibody to a chymase-1 protein, or (3) a combination thereof; or (c) one or more reagents for detecting an expression level of: (1) an alpha-2 macroglobulin protein, (2) an antibody to an alpha-2 macroglobulin protein, or (3) a combination thereof.
- the kit comprises reagents (e.g., antibodies, aptamers) for detecting the expression level of vascular endothelial growth factor protein (SEQ ID NO: l), chymase-1 protein (SEQ ID NO:2), and alpha-2
- reagents e.g., antibodies, aptamers
- SEQ ID NO: l vascular endothelial growth factor protein
- SEQ ID NO:2 chymase-1 protein
- alpha-2 alpha-2
- the reagents are antibodies.
- antibody is intended to encompass both whole antibodies and antibody fragments (e.g. , antigen-binding fragments of antibodies, for example, Fv, Fc, Fd, Fab, Fab', F(ab'), and dAb fragments).
- Antibody refers to both polyclonal and monoclonal antibodies and includes naturally-occurring and engineered antibodies.
- the term “antibody” includes, for example, human, chimeric, humanized, primatized, veneered, single chain, and domain antibodies (dAbs). (See e.g., Harlow et ah, Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory, 1988).
- the antibodies in the kit are immobilized on a solid support. Suitable solid supports for immobilization of proteins, including antibodies, are well known in the art.
- the kit comprises reagents for detecting the expression level of antibodies to a vascular endothelial growth factor protein (SEQ ID NO: l), antibodies to a chymase-1 protein (SEQ ID NO:2), and antibodies to an alpha-2 macroglobulin protein (SEQ ID NO:3).
- the reagents are immobilized vascular endothelial growth factor (SEQ ID NO: l), chymase-1 (SEQ ID NO:2), and alpha-2 macroglobulin (SEQ ID NO:3) proteins.
- the immobilized proteins can be full-length proteins, partial proteins or peptides.
- the protein reagents in the kits of the invention are provided on a protein microarray.
- the reagents (e.g., antibodies, proteins, peptides) in the kits of the invention comprise one or more detectable labels.
- Labels suitable for use according to the present invention are known in the art and generally include any molecule that, by its chemical nature, and whether by direct or indirect means, provides an identifiable signal allowing detection of the probe.
- reagents may be labeled in a conventional manner, such as with specific reporter molecules, fluorophores, radioactive materials, or enzymes (e.g., peroxidases, phosphatases).
- Detectable labels suitable for attachment to reagents can be indirect labels or direct labels.
- Exemplary indirect labels include, e.g., haptens, biotin, or other specifically bindable ligands.
- the ligand-binding partner typically has a direct label, or, alternatively, is also labeled indirectly.
- Examples of indirect labels that are haptens include dinitrophenol (DNP), digoxigenin, biotin, and various fluorophores or dyes (e.g., fluorescein, DY490, DY590, Alexa 405/Cascade blue, Alexa 488, Bodiby FL, Dansyl, Oregon Green, Lucifer Yellow,
- a hapten is typically detected using an anti-hapten antibody as the ligand-binding partner.
- a hapten can also be detected using an alternative ligand-binding partner (e.g., in the case of biotin, anti -biotin antibodies or streptavidin, for example, can be used as the ligand-binding partner).
- a hapten can also be detected directly (e.g. , in the case of fluorescein, an anti- fluorescein antibody or direct detection of fluorescence can be used).
- Exemplary "direct labels” include, but are not limited to, fluorophores (e.g., fluorescein, rhodamine, Texas Red, phycoerythrin, Cy3, Cy5, DY f uors (Dyomics GmbH, Jena, Germany) Alexa 532, Alexa 546, Alexa 568, or Alexa 594).
- fluorophores e.g., fluorescein, rhodamine, Texas Red, phycoerythrin, Cy3, Cy5, DY f uors (Dyomics GmbH, Jena, Germany) Alexa 532, Alexa 546, Alexa 568, or Alexa 594).
- radionuclides e.g., 3H, 35S, 32P, 1251, and 14C
- enzymes such as, e.g., alkaline phosphatase, horseradish peroxidase, or ⁇ - galactosidase
- chromophores e.g., phycobiliproteins
- luminescers e.g.,
- fluorophores are not to be limited to single species organic molecules, but include inorganic molecules, multi- molecular mixtures of organic and/or inorganic molecules, crystals, heteropolymers, and the like.
- CdSe-CdS core-shell nanocrystals enclosed in a silica shell can be easily derivatized for coupling to a biological molecule (Bruchez et al. , Science, 281 :2013-2016, 1998).
- highly fluorescent quantum dots (zinc sulfide-capped cadmium selenide) have been covalently coupled to biomolecules for use in ultrasensitive biological detection (Warren and Nie, Science, 281 : 2016-2018, 1998).
- kits of the invention further comprise components for performing an immunoassay.
- the immunoassay is a rapid test assay which can be completed in less than 45 minutes.
- the kit comprises reagents and components for performing an ELISA.
- Reagents and components for performing an ELISA are well known in the art and include, for example, an antibody-coated plate (e.g., microwell plate), a detection antibody, standards, detection reagents, diluents, wash buffer, stop solution, and plate sealers.
- the kit comprises reagents and components for performing a lateral flow assay.
- the kit can include one or more test strips for a lateral flow assay.
- a test strip comprises a sample pad to which the test sample is applied, a conjugate or reagent pad containing detectably labeled antibodies specific to the target, a reaction membrane (e.g., nitrocellulose, cellulose acetate) to which antibodies are immobilized, and a wick or waste reservoir to draw the sample across the reaction membrane and collect it.
- a reaction membrane e.g., nitrocellulose, cellulose acetate
- kits of the invention can also include, for example, instructions for the kit user.
- Example 1 Identification of Host Biomarkers Differentiating Dengue Fever (DF) and Dengue Hemorrhagic Fever (DHF)
- Dengue virus (DENV) infection is a re-emerging infectious disease that accounts for a hundred million cases annually.
- DHF/DSS Dengue Hemorrhagic Fever/Dengue Shock Syndrome
- DF Dengue fever
- Microarrays that consisted of 9000 host proteins were utilized. This array provides absolute identification of auto-antibodies/proteins (biomarkers) present in the patient serum/plasma. The identity of every antigen printed on the array is known and addressable. The array includes specific controls to monitor assay quality and normalize data and this leads to the accurate detection of biomarkers.
- the sera collected from Dengue patients with varying degrees of disease severity were used to probe the protoarray chips.
- the samples were collected at three different time points from each of patients DKI, DK2 and DK3 (DKI: 1-3 days after the onset of fever; DK2: 4-7 days after the onset of fever; DK3: 21-28 days after the onset of fever) in EDEN study (retrospective).
- DKI 1-3 days after the onset of fever
- DK2 4-7 days after the onset of fever
- DK3 21-28 days after the onset of fever
- 46 different proteins involved in signal transduction, membrane permeability, intracellular trafficking, enzymatic activity, transcription, muscle functions, immune response and apoptosis were found to be stimulated during Dengue infections.
- VEGF Vascular endothelial growth factor
- Chymase-1 Functions in the degradation of the extracellular matrix, regulation of submucosal gland secretion, and generation of vasoactive peptides.
- proteinases inhibitor of fibrinolysis, acts as a carrier protein by binding to numerous growth factors and cytokines, such as platelet- derived growth factor, basic fibroblast growth factor, TGF- ⁇ , insulin, and IL- ⁇ .
- cytokines such as platelet- derived growth factor, basic fibroblast growth factor, TGF- ⁇ , insulin, and IL- ⁇ .
- VEGF was significantly increased (p ⁇ 0.05) in DHF samples compared to that of DF samples ( Figure 1A). The increase was predominantly higher at the early stages of the disease (DK1 and DK2) and decreased subsequently (DK3). Although some DF samples showed a moderate increase, the increased levels in DHF patients were found to be significantly higher. Chymase
- Chymase levels were significantly increased (p ⁇ 0.05) in DK1 samples of DHF sera compared to that of DF sera samples ( Figure IB). The increase was predominant at the early stage of the disease and decreased subsequently in DK3 samples.
- Table 2 The statistics generated from 2nd batch of patient sera from Prospective
- the diagnostic kits can be developed utilizing these panel of three biomarkers which will be of commercial value.
- the unique thing about the biomarkers identified herein is that, as a panel of biomarkers, they can differentiate between DF and DHF, between severe and non-severe dengue and between DF with and without warning signs.
- Dengue patients were recruited in 2 cohorts.
- the first cohort of patients and controls consisted of 130 Dengue patients, 10 Dengue-negative (febrile) patients and 10 healthy controls. These subjects were enrolled for the Early Dengue Infection and Outcome Study (EDEN study) and were retrospectively included in this study following Institutional Review Board's approval.
- the enrolled Dengue cases consisted of all 4 serotypes of Dengue (Dl to D4). Out of 130 Dengue cases, 16 were DHF cases and the rest were DF cases. DF and DHF patients were
- the second cohort of patients and controls consisted of 100 Dengue patients, 10 Dengue-negative (febrile) patients and 10 healthy controls. These subjects were prospectively recruited from Adult Dengue Study (Dengue Clinic) at TTSH. Out of 100 Dengue cases, 41 subjects were diagnosed as DHF cases and the rest were DF cases. The enrolled Dengue cases consisted of all 4 serotypes of Dengue (Dl to D4). DF and DHF patients were characterized based on WHO 1997 classification. The sera samples were collected at two time points from each patient (acute 1-3 days; Convalescent 21 days). The mean fever for DF patients was 37.5 °C (range 36-39.3) and that of DHF patients was 37.61 °C (range 36.5-39). The mean age of DF patients was 33.84 years (range 20-63) and that of DHF patients was 41.95 years (range (21-74). The patient characteristics are summarized in Table 5. Protein Microarray to Screen for Cross-reactive Autoantibodies
- Protoarray® Human Protein Microarrays (v5) for Immune Response Biomarker Profiling (Invitrogen) consisted of over 9,000 unique human proteins individually purified and arrayed under native conditions to maximize functionality. This array included control ProtoArray® Human Protein Microarray proteins in each sub-array for normalization purposes. The experiment was performed following manufacturer's instructions. In brief, all the manipulations were performed at 4 °C. Protoarray slides were treated with blocking buffer (PBS, pH 7.4, containing 1% BSA and 0.1% Tween 20).
- PBS blocking buffer
- Serum samples were diluted (1 :500) in a probe buffer (PBS, pH 7.4, 5 mM MgCl 2 , 0.05% Triton X-100, 1% glycerol, and 1% BSA) and used to probe the protoarray slides.
- the arrays were washed three times with probe buffer and Alexa Fluor 647-conjugated anti -human IgG antibody (1 ⁇ g/ml buffer) was added.
- the arrays were washed and dried by centrifugation at 200g for 2 min at room temperature.
- Arrays were then scanned using GenePix 4000B fluorescent microarray scanner (Molecular Devices Corporation, USA) within 24 h.
- Raw pixel counts were generated by scanning arrays at 635 nm using a photomultiplier tube gain setting of 500 and a power setting of 100%.
- GenePix Pro 6.0 software (Molecular Devices Corporation, USA) was used to align the scanned image to the lot- specific 'GAL' file downloaded from ProtoArray Central (Invitrogen) and to determine the pixel intensities for each spot on the array. Acquired data were analyzed using ProtoArray Prospector software (Invitrogen) in Immune Response Profiling mode. This software performs background subtraction, normalization of the signals, and analysis of the differences between two groups of patients. Data were analyzed by calculation of Z score, Chebyshev's inequality precision value (CIP) and the co-efficient of variation (CV). A positive spot is defined by a Z score of > 3, a CIP value of ⁇ 0.05 and a CV of ⁇ 0.5.
- CIP Chebyshev's inequality precision value
- CV co-efficient of variation
- Biomarker Profiling was used to identify novel autoantibodies in the serum samples of Dengue patients.
- the DK1 samples from 14 Dengue patients and 10 healthy controls (EDEN study) were used.
- the workflow of the experiment was illustrated in Figure 4A.
- ProtoArray Prospector software was used to reveal differences between Dengue patients and healthy subjects.
- Antibodies to 196 antigens were detected in Dengue patients than in healthy controls and these antibodies showed a Z-score value of above 1 ( Figure 4B).
- the selection stringency was increased by setting the cut-off at the Z-score value above 3 and this eliminated the potential false positives.
- Z-score indicates how far and in what direction the sample's value deviates from the distribution's mean. After filtering some of the proteins without known functions, 67 exclusive autoantibodies were identified in the serum samples of Dengue patients.
- VEGF vascular endothelial growth factor-A
- alpha-2 macroglobulin a protein that influences vascular permeability and blood coagulation.
- chymase vascular endothelial growth factor-A
- VEGF Vascular endothelial growth factor
- Chymase- 1 is a chymotryptic serine proteinase and is expressed in mast cells and thought to function in the degradation of the
- angiotensin II has been implicated in blood pressure control and in the pathogenesis of hypertension, cardiac hypertrophy, and heart failure.
- Alpha 2 macroglobulin acts as an
- VEGF was significantly increased (P ⁇ 0.05) in DHF samples compared to that of DF samples. The increase was predominantly higher at the early stages of the disease (DK1 and DK2) and decreased subsequently (DK3). Although some DF samples showed a moderate increase, the increased levels in DHF patients were found to be significantly higher.
- DF samples reached the value similar to that of DHF samples; this was likely due to the following reasons: These DF cases could have been clinically diagnosed as DF but physiologically experiencing DHF symptoms, or, in other words, they could have been borderline cases between DF and DHF. Nevertheless, these results confirmed that VEGF can serve as a biomarker to differentiate DF and DHF (although the specificity was low).
- Chymase levels were significantly increased (P ⁇ 0.05) in DK1 samples of DHF sera ( Figure IB) compared to that of DF sera samples. The increase was predominant at the early stage of the disease and decreased subsequently in DK3 samples.
- Table 5 Patient characteristics [Prospective Adult Dengue Study (Dengue Clinic)]
- Table 6 Summary of median, range and standard deviation obtained for various biomarkers (DF/DHF classification)
- Table 7 Summary of median, range and standard deviation obtained for various biomarkers (WS/NWS classification)
- Table 8 Summary of median, range and standard deviation obtained for biomarkers (Severe/Non-severe) classification
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FR3017713A1 (en) * | 2014-02-18 | 2015-08-21 | Biomerieux Sa | METHOD AND KIT FOR DETERMINING THE PROBABILITY FOR A PATIENT TO EVOLVE TO A SEVERE DENGUE |
FR3017714A1 (en) * | 2014-02-18 | 2015-08-21 | Biomerieux Sa | METHOD AND KIT FOR DETERMINING THE PROBABILITY FOR A PATIENT TO EVOLVE TO A SEVERE DENGUE |
CN106290838A (en) * | 2015-05-13 | 2017-01-04 | 上海凯创生物技术有限公司 | A kind of dengue virus IgG/IgM antibody emulsion technique detection kit |
CN110741099A (en) * | 2017-06-09 | 2020-01-31 | 何宗宪 | Method, detection device and detection kit for evaluating severity of dengue fever virus infection of individual |
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CN110741099A (en) * | 2017-06-09 | 2020-01-31 | 何宗宪 | Method, detection device and detection kit for evaluating severity of dengue fever virus infection of individual |
CN110741099B (en) * | 2017-06-09 | 2023-10-17 | 何宗宪 | Method for assessing severity of dengue virus infection in individual, detection device and detection kit |
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