KR20220156465A - Novel diagnostic test devices for detecting SARS-CoV-2 antibody - Google Patents
Novel diagnostic test devices for detecting SARS-CoV-2 antibody Download PDFInfo
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- KR20220156465A KR20220156465A KR1020220060648A KR20220060648A KR20220156465A KR 20220156465 A KR20220156465 A KR 20220156465A KR 1020220060648 A KR1020220060648 A KR 1020220060648A KR 20220060648 A KR20220060648 A KR 20220060648A KR 20220156465 A KR20220156465 A KR 20220156465A
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Abstract
Description
본 발명은 사스-코로나바이러스-2 항체를 검출하는 신규한 진단 장치에 관한 것이다.The present invention relates to a novel diagnostic device for detecting SARS-coronavirus-2 antibodies.
전세계적인 펜데믹을 일으키고 있는 중증급성호흡기증후군 코로나바이러스 2 (Severe acute respiratory syndrome coronavirus 2; SARS-CoV-2)는 RNA 바이러스로, 외부 스파이크 (spike) 단백질이 특징적인 크라운 형태를 가지고 있는 구형으로 spike (S), membrane (M), envelope (E), nucleocapsid (N)으로 구성되어 있다. 2020년 3월 11일 세계보건기구 (WHO)에서 SARS-CoV-2에 의한 질병을 코로나바이러스감염증-19 (coronavirus disease 2019, COVID-19)로 명명하였고, 펜데믹을 선언한 코로나바이러스감염증-19는 현재까지 이어지고 있다.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is causing a worldwide pandemic, is an RNA virus that spikes an external spike protein into a globular shape with a characteristic crown shape. It is composed of (S), membrane (M), envelope (E), and nucleocapsid (N). On March 11, 2020, the World Health Organization (WHO) named the disease caused by SARS-CoV-2 as coronavirus disease 2019 (COVID-19), and declared COVID-19 a pandemic. continues to this day.
SARS-CoV-2는 유전적 배열 (DNA sequencing) 상 전도 기능 (positive sense) 단일 가닥 RNA (single-stranded RNA) 코로나 바이러스로서, 인간에게 전염성이 있고 코로나바이러스감염증-19 (coronavirus disease 2019, COVID-19)의 원인이다. COVID-19의 최초 발생지는 중국 후베이성의 우한시이다.SARS-CoV-2 is a DNA sequencing positive sense single-stranded RNA coronavirus that is contagious to humans and causes coronavirus disease 2019 (COVID-19). 19) is the cause. The first outbreak of COVID-19 is Wuhan City, Hubei Province, China.
SARS-CoV-2에 감염된 사람들은 열, 기침, 호흡 곤란, 설사와 같은 경증에서 중증의 증상을 보일 수 있다. 합병증이나 병을 가진 사람들, 노인은 사망할 가능성이 크다. 특히, 심장질환 및 당뇨병 등의 기저질환 보유자가 감염에 더 취약하며, 합병증이나 장기 손상 등을 겪기 때문에 조기 발견과 치료가 매우 중요하다. 현재까지 한국을 포함한 177개국에서 발생하였다.People infected with SARS-CoV-2 may develop mild to severe symptoms such as fever, cough, shortness of breath, and diarrhea. People with complications or illness, the elderly, are more likely to die. In particular, early detection and treatment are very important because those with underlying diseases such as heart disease and diabetes are more vulnerable to infections and suffer from complications or organ damage. So far, it has occurred in 177 countries including Korea.
사스나 메르스와는 다르게 COVID-19의 세계적 유행 (pandemic)에 대하여 추이를 보며 신중히 접근하는 전문가들이 많다. COVID-19의 무증상 감염자가 전세계에 퍼지게 될 경우 풍토병화될 가능성에 대한 우려가 있다. 중국 및 국내에서의 토착화를 통한 국내 COVID-19 재발병 가능성에 대한 대응책 마련이 시급하다.Unlike SARS or MERS, there are many experts who carefully approach the COVID-19 pandemic while watching the trend. There are concerns about the possibility of becoming endemic if asymptomatic carriers of COVID-19 spread around the world. It is urgent to prepare countermeasures against the possibility of domestic COVID-19 recurrence through indigenization in China and Korea.
신속진단검사 (Rapid diagnostic test, RDT)는 면역크로마토그래피 분석, 래피드 키트 분석 등 다양한 명칭으로 불리우며, 주된 구성이 지지체, 검체패드, 콘쥬게이트 패드, 신호검출패드 및 흡수패드를 포함하는 면역크로마토그래피 스트립에 의한 분석방법으로서, 사용자가 생물학적 또는 화학적 샘플로부터 분석 물질을 특별한 기술이나 장비 없이, 1-100 마이크로리터의 샘플로 2-30분 사이에서 간단하게 검출할 수 있다.Rapid diagnostic test (RDT) is called by various names such as immunochromatography analysis and rapid kit analysis. As an analysis method by, a user can simply detect an analyte from a biological or chemical sample in 2-30 minutes with a sample of 1-100 microliters without special skills or equipment.
신속진단검사는 생물학적 물질 또는 화학적 물질이 서로 특이적으로 부착하는 성질을 이용하여 분석 물질을 단시간에 정성 및 정량적으로 검사할 수 있는 방법으로, 신속진단검사는 단순히 면역 크로마토그래피 스트립을 사용하거나, 이와 같은 면역 크로마토그래피 스트립을 플라스틱 하우징 내부에 장착한 형태의 면역 크로마토그래피 키트가 사용된다. 단순히 면역 크로마토그래피 스트립을 사용할 때는 시료를 담은 용기가 별도로 필요하지만, 하우징에 내장된 면역 크로마토그래피 키트는 하우징에 준비된 투입구에 시료를 직접 투입함으로서 별도의 실험용기가 필요없어 사용하기 간편하다.A rapid diagnostic test is a method that can qualitatively and quantitatively test an analyte in a short time by using the property that biological or chemical substances specifically attach to each other. An immunochromatography kit in the form of mounting the same immunochromatography strip inside a plastic housing is used. When simply using an immunochromatography strip, a container containing the sample is required separately, but the immunochromatography kit built into the housing is easy to use because it does not require a separate experiment container by directly injecting the sample into the inlet prepared in the housing.
신속진단검사는 간편성 및 신속성 측면에서 최근까지 개발된 검출 방법 중 가장 진보된 분석 키트 중 하나로서 감염성 병원체의 항원 또는 항체, 암 인자, 심장 마커 등 다양한 질병 원인 물질을 진단하는데 유용하게 사용된다. 이와 같은 면역크로마토그래피 스트립 또는 이를 포함하는 면역크로마토그래피 키트를 이용한 분석을 통해, 사람 또는 동물의 전혈, 혈장, 혈청, 눈물, 침, 소변, 콧물, 체액 등의 검체를 이용하여, 사스, 메르스, 인플루엔자바이러스, 조류독감 바이러스, 로타 바이러스, A형 간염, B형 간염, C형 간염, 에이즈, 매독, 클라미디아, 말라리아, 장티프스, 위궤양 원인균, 결핵, 뎅기열, 나병 등의 원인 병원체 및 항체의 유무 등을 신속하게 검사 및 진단할 수 있다.The rapid diagnostic test is one of the most advanced analysis kits among the detection methods developed to date in terms of simplicity and rapidity, and is useful for diagnosing various disease-causing substances such as antigens or antibodies of infectious pathogens, cancer factors, and cardiac markers. Through analysis using such an immunochromatography strip or an immunochromatography kit including the same, SARS, MERS using specimens such as human or animal whole blood, plasma, serum, tears, saliva, urine, nasal mucus, body fluids, etc. , Influenza virus, avian flu virus, rotavirus, hepatitis A, hepatitis B, hepatitis C, AIDS, syphilis, chlamydia, malaria, typhoid fever, gastric ulcer causative agent, tuberculosis, dengue fever, leprosy, etc. can be quickly examined and diagnosed.
기존의 항체 검사 진단용 키트는 COVID-19에 감염된 환자의 IgM, IgG 항체를 검사하는 제품으로서, COVID-19에 감염된 또는 감염 이력이 있는 환자의 단순 항체 생성 유무만을 확인하였다. 한편, COVID-19에 감염된 또는 감염이력이 있는 환자와 백신 접종자의 항체 생성 유무의 판별이 가능하고, 구분할 수 있는 진단용 키트는 없다.Existing antibody test diagnostic kits are products that test IgM and IgG antibodies of patients infected with COVID-19, and only confirmed the presence or absence of simple antibody production in patients infected with or with a history of infection with COVID-19. On the other hand, there is no diagnostic kit that can determine whether or not antibodies are produced between patients infected with COVID-19 or have a history of infection and those who have been vaccinated.
이러한 배경 하에, 본 발명자들은 SARS-CoV-2 항체를 검출하는 진단용 키트로서, 백신 (vaccine) 접종 후 생성되는 Spike protein 항체를 검출하여 COVID-19에 감염된 또는 감염 이력이 있는 환자와 구분할 수 있으며, 우수한 민감도, 특이도로 COVID-19에 감염된 또는 감염 이력이 있는 환자를 확인할 수 있는 COVID-19 최적화된 진단 장치를 최초로 개발하여 본 발명을 완성하였다.Under this background, the present inventors are a diagnostic kit for detecting the SARS-CoV-2 antibody, which can be distinguished from patients infected with COVID-19 or with a history of infection by detecting Spike protein antibodies produced after vaccination, The present invention was completed by developing a COVID-19 optimized diagnostic device that can identify patients infected with or with a history of infection with excellent sensitivity and specificity.
본 발명의 목적은 사스-코로나바이러스-2의 스파이크 단백질 (spike protein) 항체를 검출하는 제1 검사선 및 사스-코로나바이러스-2의 뉴클레오캡시드 단백질 (nucleocapsid protein) 항체를 검출하는 제2 검사선을 포함하는 사스-코로나바이러스-2 진단장치를 제공하는 것이다.An object of the present invention is a first test line for detecting a spike protein antibody of SARS-coronavirus-2 and a second test line for detecting a nucleocapsid protein antibody of SARS-coronavirus-2. To provide a SARS-coronavirus-2 diagnostic device comprising a.
본 발명의 다른 목적은 상기 진단장치를 이용하여 사스-코로나바이러스-2 진단에 필요한 정보를 제공하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for providing information necessary for diagnosing SARS-coronavirus-2 using the diagnostic device.
본 발명의 이점 및 특징, 그리고 그것들을 달성하는 방법은 첨부되는 도면과 함께 상세하게 후술되어 있는 실시예들을 참조하면 명확해질 것이다. 그러나, 본 발명은 이하에서 개시되는 실시예들에 제한되는 것이 아니라 서로 다른 다양한 형태로 구현될 수 있으며, 단지 본 실시예들은 본 발명의 개시가 완전하도록 하고, 본 발명이 속하는 기술 분야의 통상의 기술자에게 본 발명의 범주를 완전하게 알려주기 위해 제공되는 것이며, 본 발명은 청구항의 범주에 의해 정의될 뿐이다. Advantages and features of the present invention, and methods of achieving them, will become clear with reference to the detailed description of the following embodiments taken in conjunction with the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below, but may be implemented in various different forms, only these embodiments are intended to complete the disclosure of the present invention, and are common in the art to which the present invention belongs. It is provided to fully inform the person skilled in the art of the scope of the invention, and the invention is only defined by the scope of the claims.
본 명세서에서 사용된 용어는 실시예들을 설명하기 위한 것이며 본 발명을 제한하고자 하는 것은 아니다. 본 명세서에서, 단수형은 문구에서 특별히 언급하지 않는 한 복수형도 포함한다. 명세서에서 사용되는 "포함한다 (comprises)" 및/또는 "포함하는 (comprising)"은 언급된 구성요소 외에 하나 이상의 다른 구성요소의 존재 또는 추가를 배제하지 않는다. 명세서 전체에 걸쳐 동일한 도면 부호는 동일한 구성 요소를 지칭하며, "및/또는"은 언급된 구성요소들의 각각 및 하나 이상의 모든 조합을 포함한다. 비록 "제1", "제2" 등이 다양한 구성요소들을 서술하기 위해서 사용되나, 이들 구성요소들은 이들 용어에 의해 제한되지 않음은 물론이다. 이들 용어들은 단지 하나의 구성요소를 다른 구성요소와 구별하기 위하여 사용하는 것이다. 따라서, 이하에서 언급되는 제1 구성요소는 본 발명의 기술적 사상 내에서 제2 구성요소일 수도 있음은 물론이다.Terminology used herein is for describing the embodiments and is not intended to limit the present invention. In this specification, singular forms also include plural forms unless specifically stated otherwise in a phrase. As used herein, "comprises" and/or "comprising" does not exclude the presence or addition of one or more other elements other than the recited elements. Like reference numerals throughout the specification refer to like elements, and “and/or” includes each and every combination of one or more of the recited elements. Although "first", "second", etc. are used to describe various components, these components are not limited by these terms, of course. These terms are only used to distinguish one component from another. Accordingly, it goes without saying that the first element mentioned below may also be the second element within the technical spirit of the present invention.
다른 정의가 없다면, 본 명세서에서 사용되는 모든 용어(기술 및 과학적 용어를 포함)는 본 발명이 속하는 기술분야의 통상의 기술자에게 공통적으로 이해될 수 있는 의미로 사용될 수 있을 것이다. 또한, 일반적으로 사용되는 사전에 정의되어 있는 용어들은 명백하게 특별히 정의되어 있지 않는 한 이상적으로 또는 과도하게 해석되지 않는다.Unless otherwise defined, all terms (including technical and scientific terms) used in this specification may be used with meanings commonly understood by those skilled in the art to which the present invention belongs. In addition, terms defined in commonly used dictionaries are not interpreted ideally or excessively unless explicitly specifically defined.
본 발명은 사스-코로나바이러스-2의 스파이크 단백질 (spike protein) 항체를 검출하는 제1 검사선 및 사스-코로나바이러스-2의 뉴클레오캡시드 단백질 (nucleocapsid protein) 항체를 검출하는 제2 검사선을 포함하는 사스-코로나바이러스-2 진단장치를 제공한다.The present invention includes a first test line for detecting a spike protein antibody of SARS-coronavirus-2 and a second test line for detecting a nucleocapsid protein antibody of SARS-coronavirus-2. Provides a SARS-coronavirus-2 diagnostic device that does.
본 발명의 사스-코로나바이러스-2 (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2)는 2019년 12월 중국 후베이성 우한시에서 최초 보고된 신규 바이러스로, 외피가 있는 양성가닥 RNA 바이러스 (non-segmented positive-strand RNA virus)이고, 50 내지 200 nm의 직경, 9 내지 12 nm의 스파이크 단백질 (spike protein)을 가진다. 사스-코로나바이러스-2는 외부 스파이크 단백질이 특징적인 크라운 형태를 가지고 있는 구형으로, spike (S), membrane (M), envelope (E), nucleocapsid (N)으로 구성되어 있다.SARS-CoV-2 of the present invention is a novel virus first reported in Wuhan, Hubei Province, China in December 2019, and is an enveloped positive-stranded RNA virus (non- segmented positive-strand RNA virus), and has a diameter of 50 to 200 nm and a spike protein of 9 to 12 nm. SARS-Coronavirus-2 is a spherical shape in which the external spike protein has a characteristic crown shape, and is composed of spike (S), membrane (M), envelope (E), and nucleocapsid (N).
코로나 19 (COVID-19)의 명칭은 감염병을 나타내는 것이고, 사스-코로나바이러스-2는 바이러스 이름을 나타내는 것으로 각각 분리되어 명명되었다. 사스-코로나바이러스-2는 폐 ACE2 수용체를 매개로 진입하여, 기침, 호흡곤란, 폐렴 등의 호흡기 증후군을 일으키며, 전파 경로는 비말 접촉이다.The name Corona 19 (COVID-19) represents an infectious disease, and SARS-Coronavirus-2 represents the virus name, and they were named separately. SARS-coronavirus-2 enters through the pulmonary ACE2 receptor, causing respiratory syndromes such as coughing, dyspnea, and pneumonia, and the transmission route is droplet contact.
본 발명의 사스-코로나바이러스-2의 스파이크 단백질 (spike protein)은 S1 및 S2 서브유닛으로 이루어져 있다. 이 중에서 S1 서브유닛은 스파이크의 머리 부분이며, receptor binding domain (RBD)을 가지고 있다. RBD는 숙주 세포의 ACE2 수용체와 결합하는 핵심 영역이며, 사스-코로나바이러스-2 감염에 대한 강력한 중화 항체를 유도하는 multiple conformational-dependent epitopes을 포함하고 있기 때문에 COVID-19의 치료에 핵심 타깃이 될 수 있다. S2 서브유닛은 스파이크의 기둥 부분이다. 스파이크 단백질은 숙주 세포의 수용체 (receptor)와 결합하는 중요한 부위이며, 세포 내로 viral nucleocapsid를 전달하며 복제 (replication)가 이루어진다.The spike protein of SARS-coronavirus-2 of the present invention consists of S1 and S2 subunits. Among them, the S1 subunit is the head of the spike and has a receptor binding domain (RBD). RBD is a key region that binds to the host cell's ACE2 receptor and contains multiple conformational-dependent epitopes that induce potent neutralizing antibodies against SARS-CoV-2 infection, making it a key target for the treatment of COVID-19. have. The S2 subunit is the pillar part of the spike. The spike protein is an important site that binds to the receptor of the host cell, delivers the viral nucleocapsid into the cell, and replicates.
사스-코로나바이러스-2의 막 (M)과 외피 (E) 단백질은 바이러스의 겉부분을 형성하고 형태를 유지하는데 중요한 역할을 한다. 외피 내부에는 뉴클레오캡시드 (N) 단백질이 있다.The membrane (M) and envelope (E) proteins of SARS-coronavirus-2 play an important role in forming the outer shell of the virus and maintaining its shape. Inside the envelope is a nucleocapsid (N) protein.
본 발명의 사스-코로나바이러스-2의 뉴클레오캡시드 단백질 (nucleocapsid protein)은 사스-코로나바이러스-2의 9번째 ORF에 의해 인코딩 (encoding)되며, 422개의 아미노산으로 이루어진 분자량이 약 46 kDa인 단백질이다. 뉴클레오캡시드 단백질의 주요 기능은 genomic RNA를 encapsidation하는 것으로서, 이를 위해 뉴클레오캡시드 단백질은 genomic RNA를 인식하고 결합하는 기능과 캡시드를 형성하기 위해 self-association을 통해 올리고머 (oligomer)를 형성하는 기능을 가진다. 이외에도 뉴클레오캡시드 단백질은 host cellular machinery를 조절하는 역할을 한다. 뉴클레오캡시드 단백질은 사스-코로나바이러스-2 감염 초기 상태에서 우선적으로 발현되는 단백질로서, 숙주세포는 뉴클레오캡시드 단백질을 대항하여 강한 항체반응을 시작한다.The nucleocapsid protein of SARS-Coronavirus-2 of the present invention is encoded by the 9th ORF of SARS-Coronavirus-2 and is a protein composed of 422 amino acids and having a molecular weight of about 46 kDa. . The main function of nucleocapsid protein is to encapsidate genomic RNA. To this end, nucleocapsid protein recognizes and binds genomic RNA and forms oligomers through self-association to form capsid. have In addition, nucleocapsid proteins play a role in regulating the host cellular machinery. The nucleocapsid protein is a protein that is preferentially expressed in the early stage of SARS-coronavirus-2 infection, and the host cell initiates a strong antibody response against the nucleocapsid protein.
본 발명의 진단은 병리 상태의 존재 또는 특징을 확인하는 것을 의미한다. 본 발명의 목적상, 진단은 사스-코로나바이러스-2의 감염 여부 또는 상기 바이러스의 감염에 따른 COVID-19 발병 가능성 여부를 확인하는 것일 수 있다. 또한, 동시에 백신 접종 후 항체 생성 유무를 확인하는 것일 수 있다.Diagnosis of the present invention means confirming the presence or character of a pathological condition. For the purposes of the present invention, diagnosis may be to determine whether or not there is infection with SARS-coronavirus-2 or whether there is a possibility of developing COVID-19 due to infection with the virus. In addition, it may be to check the presence or absence of antibody production after vaccination at the same time.
본 발명의 진단장치는 진단키트와 혼용되어 사용될 수 있다. 상기 진단장치는 면역학적 분석에 사용되는 당 분야에서 일반적으로 사용되는 도구, 시약 등이 포함될 수 있다. 상기 도구 및 시약은 적합한 담체, 검출 가능한 신호를 생성할 수 있는 표지 물질, 용해제, 세정제, 완충제, 안정화제 등이 포함될 수 있으나, 이에 제한되지 않는다. The diagnostic device of the present invention may be used in combination with a diagnostic kit. The diagnostic device may include tools and reagents commonly used in the art for immunological analysis. The tools and reagents may include, but are not limited to, a suitable carrier, a labeling material capable of generating a detectable signal, a solubilizer, a detergent, a buffer, and a stabilizer.
상기 적합한 담체는 가용성 담체, 예를 들어 당 분야에 공지된 생리학적으로 허용되는 완충액, 예를 들어 PBS, 불용성 담체, 예를 들어 폴리스티렌, 폴리에틸렌, 폴리프로필렌, 폴리에스테르, 폴리아크릴로니트릴, 불소 수지, 가교 덱스트란, 폴라사카라이드, 라텍스에 금속을 도금한 자성 미립자와 같은 고분자, 기타 종이, 유리, 금속, 아가로오스 및 이들의 조합일 수 있으나, 이에 제한되지 않는다.Such suitable carriers include soluble carriers such as physiologically acceptable buffers known in the art such as PBS, insoluble carriers such as polystyrene, polyethylene, polypropylene, polyesters, polyacrylonitrile, fluororesins. , cross-linked dextran, polysaccharide, polymers such as magnetic microparticles plated with metal on latex, other paper, glass, metal, agarose, and combinations thereof, but are not limited thereto.
본 발명의 진단장치는 피검 시료를 수용하는 검체 영역; 검체 영역과 연동되어 있고 탐침물질이 축합된 콘쥬게이트 영역; 상기 콘쥬게이트 영역과 연동되어 있는 제1 검사선, 제2 검사선 또는 제1 검사선 및 제2 검사선을 포함하는 신호검출 영역; 및 신호검출 반응이 종료된 피검 시료를 흡수하는 흡수 영역을 포함할 수 있다.The diagnostic device of the present invention includes a sample area accommodating a test sample; a conjugate region interlocked with the sample region and condensed with a probe; a signal detection region including a first test line, a second test line, or a first test line and a second test line linked to the conjugate region; and an absorption region that absorbs the test sample after the signal detection reaction has been completed.
본 발명의 피검 시료는 사스-코로나바이러스-2의 뉴클레오캡시드 단백질 또는 스파이크 단백질에 대한 특이 항체가 존재할 수 있는 시료로서 혈액, 혈청, 혈장, 타액, 눈물, 점액, 콧물, 질 분비물 등을 포함할 수 있고, 바람직하게는 혈청 또는 혈장이다. 이는 항체가 혈청이나 혈장 중에 높은 농도로 존재하기 때문이다.The test sample of the present invention is a sample in which specific antibodies to the nucleocapsid protein or spike protein of SARS-coronavirus-2 may be present, and may include blood, serum, plasma, saliva, tears, mucus, nasal mucus, vaginal secretions, etc. It may be, preferably serum or plasma. This is because the antibody is present in high concentrations in serum or plasma.
본 발명의 탐침물질은 금 나노입자, 은 나노입자, 퀀텀닷 (quantum dot) 나노입자, 카본 나오입자, 라텍스 비드/형광 나노입자, 셀룰로오스 나노입자, 자기 나노입자, 실리카 나노입자, 폴리머 비드 (polymer bead), 형광물질 (fluorescein), 발광물질 (luminescent substances), 색소 (dye), 단백질로 구성된 군으로부터 선택된 어느 하나 이상일 수 있으나, 이에 제한되지 않는다.The probe material of the present invention is gold nanoparticles, silver nanoparticles, quantum dot nanoparticles, carbon nanoparticles, latex beads/fluorescent nanoparticles, cellulose nanoparticles, magnetic nanoparticles, silica nanoparticles, polymer beads bead), fluorescein, luminescent substances, dyes, and proteins, but is not limited thereto.
본 발명의 신호검출 영역은 제1 검사선 및 제2 검사선을 함께 포함하거나, 둘 이상의 신호검출 영역에서 각각 제1 검사선 및 제2 검사선을 포함할 수 있다.The signal detection area of the present invention may include both the first inspection line and the second inspection line, or may include the first inspection line and the second inspection line in two or more signal detection areas, respectively.
본 발명의 진단장치는 듀오타입 (duo type) 또는 싱글타입 (single type)일 수 있다. 상기 듀오타입은 둘 이상의 신호검출 영역을 포함하며, 제1 검사선 및 제2 검사선에는 각각 제1 검출라인 및 제2 검출라인을 포함할 수 있다. 상기 싱글타입은 제1 검사선 및 제2 검사선을 함께 포함할 수 있다.The diagnosis device of the present invention may be of a duo type or a single type. The duotype may include two or more signal detection regions, and the first detection line and the second detection line may include a first detection line and a second detection line, respectively. The single type may include both the first inspection line and the second inspection line.
상기 제1 검사선은 스파이크 단백질에 대한 항체를 검출하며, 상기 제2 검사선은 뉴클레오캡시드 단백질에 대한 항체를 검출할 수 있다.The first test line may detect an antibody against spike protein, and the second test line may detect an antibody against nucleocapsid protein.
본 발명의 탐침물질은 스파이크 단백질 항체와 특이적으로 결합하는 펩타이드 및 뉴클레오캡시드 단백질 항체와 특이적으로 결합하는 펩타이드와 축합된 것일 수 있다.The probe material of the present invention may be condensed with a peptide specifically binding to a spike protein antibody and a peptide specifically binding to a nucleocapsid protein antibody.
상기 탐침물질은 스파이크 단백질 항체와 특이적으로 결합하는 서열번호 1의 펩타이드 또는 뉴클레오캡시드 단백질 항체와 특이적으로 결합하는 서열번호 2의 펩타이드와 축합된 것일 수 있다.The probe material may be condensed with the peptide of SEQ ID NO: 1 that specifically binds to the spike protein antibody or the peptide of SEQ ID NO: 2 that specifically binds to the nucleocapsid protein antibody.
본 발명의 싱글타입 진단장치는 1) 분석하고자 하는 피검 시료를 수용하는 검체 영역; 2) 상기 검체 영역과 연동되어 있고, 금 나노입자가 축합된 콘쥬게이트 영역; 3) 상기 콘쥬게이트 영역과 연동되어 있고, 스파이크 단백질 (spike protein) 항체를 검출하는 제1 검사선, 뉴클레오캡시드 단백질 (nucleocapsid protein) 항체를 검출하는 제2 검사선 및 대조선을 포함하는 신호검출 영역; 및 4) 신호검출 반응이 종료된 피검 시료를 흡수하는 흡수 영역을 포함할 수 있다.The single-type diagnostic device of the present invention includes: 1) a sample area accommodating a test sample to be analyzed; 2) a conjugate region interlocked with the sample region and condensed with gold nanoparticles; 3) A signal detection region interlocked with the conjugate region and including a first test line for detecting a spike protein antibody, a second test line for detecting a nucleocapsid protein antibody, and a control line ; and 4) an absorption region that absorbs the test sample upon completion of the signal detection reaction.
본 발명의 신호검출 영역은 검사선에 항-사람 IgG 단클론 항체, 항-사람 IgM 단클론 항체 또는 이들의 조합이 고정화되어 있을 수 있다. 상기 신호검출 영역은 니트로셀룰로오스, 셀룰로오스, 폴리에틸렌, 폴리에테르설폰, 폴리스틸렌, 폴리카보네이트, 폴리메틸메타크릴레이트 및 나일론으로 구성된 군으로부터 선택된 어느 하나일 수 있으나, 이에 제한되지 않는다.In the signal detection region of the present invention, an anti-human IgG monoclonal antibody, an anti-human IgM monoclonal antibody, or a combination thereof may be immobilized on the test line. The signal detection region may be any one selected from the group consisting of nitrocellulose, cellulose, polyethylene, polyethersulfone, polystyrene, polycarbonate, polymethyl methacrylate, and nylon, but is not limited thereto.
본 발명의 흡수 영역은 다공성 지지체의 공동 (pore)에 분산되거나 다공성 지지체의 섬유사에 흡착 또는 코팅되어 있는 흡수제를 포함할 수 있다.The absorbent region of the present invention may include an absorbent dispersed in the pores of the porous support or adsorbed or coated on the fiber yarns of the porous support.
본 발명의 진단장치는 사스-코로나바이러스-2 감염 유무 및 백신 접종 후 항체 생성 유무를 동시에 구별하여 진단할 수 있다. 상기 진단장치는 면역 크로마토그래피법을 이용한 스트립 형태일 수 있다.The diagnostic device of the present invention can diagnose the presence or absence of SARS-coronavirus-2 infection and the presence or absence of antibodies after vaccination by simultaneously distinguishing and diagnosing. The diagnostic device may be in the form of a strip using immunochromatography.
본 발명의 진단장치에서, 대조선 및 제1 검사선에 발색선이 나타나고, 제2 검사선에 발색선이 나타나지 않는 경우 사스-코로나바이러스-2 백신 접종자로 판단할 수 있으며, 제1 검사선 및 제2 검사선에 발색선이 나타나는 경우 사스-코로나바이러스-2 감염자로 판단할 수 있다.In the diagnostic device of the present invention, when a color line appears on the control line and the first test line and no color line appears on the second test line, it can be determined that the SARS-coronavirus-2 vaccine has been vaccinated, and the first test line and the second test line do not show a color line. 2 If a color line appears on the test line, it can be judged as a SARS-CoV-2 infection.
상기한 바와 같이, 사스-코로나바이러스-2 백신 접종자와 COVID-19 감염된 또는 감염 이력이 있는 환자를 구별하는 것은 항체 생성을 구분하여 측정함으로써 감염이력이 있는 환자의 추가 백신 접종과 같은 맞춤형 진단이 가능한 이점이 있다.As described above, distinguishing patients infected with or with a history of COVID-19 from those vaccinated with SARS-CoV-2 can measure antibody production separately, enabling customized diagnosis such as additional vaccination of patients with a history of infection. There is an advantage.
또한, 본 발명의 진단장치는 스파이크 단백질 및 뉴클레오캡시드 단백질의 항체를 각각 검출함으로써, COVID-19에 감염된 환자 또는 최근에 감염 이력이 있는 환자 또는 감염 이력에 관계없이 백신 접종에 대한 항체 생성 유무를 확인할 수 있다. 본 발명의 구체적인 일 실시예에서, 비교예로서 기재된 타사 (S사) 제품은 스파이크 단백질에 대한 항체만을 검출 가능하며, 뉴클레오캡시드 단백질에 대한 항체를 검출하지 않는다는 점에서 본 발명과 차이가 있다.In addition, the diagnostic device of the present invention detects antibodies to spike protein and nucleocapsid protein, respectively, to determine whether or not antibodies to vaccination are generated regardless of patients infected with COVID-19 or patients with a recent history of infection or infection history. You can check. In a specific embodiment of the present invention, the product of another company (Company S) described as a comparative example is different from the present invention in that it can detect only antibodies to spike proteins and does not detect antibodies to nucleocapsid proteins.
따라서, 본 발명의 진단장치는 스파이크 단백질 및 뉴클레오캡시드 단백질에 대한 항체를 각각 구분지어서 검출할 수 있는 것이 타사 제품과 상이한 점이라 할 수 있다. 즉, 본 발명의 진단장치는 스파이크 단백질에 대한 항체 및 뉴클레오캡시드 단백질에 대한 항체의 검출을 동시에 구별할 수 있으며, 백신 접종으로 인하여 생성된 항체인지 사스-코로나바이러스-2 감염에 의해 생성된 항체인지 구분이 가능하다.Therefore, it can be said that the diagnosis device of the present invention is different from other products in that it can separately detect antibodies against spike protein and nucleocapsid protein. That is, the diagnostic device of the present invention can simultaneously distinguish the detection of antibodies against spike protein and antibodies against nucleocapsid protein, and whether antibodies produced due to vaccination or antibodies produced by SARS-coronavirus-2 infection can be distinguished. cognition can be distinguished.
또한, 본 발명의 구체적인 일 실시예에서, 본 발명의 진단장치는 백신 접종 후 생성되는 항체에 대한 검출율이 100%인 반면에, 타사 제품은 75% 였고, COVID-19 확진 판정을 받은 양성 검체에서 농도별로 반응시킨 결과, 타사 제품보다 민감도가 높음을 확인하였다.In addition, in a specific embodiment of the present invention, the diagnostic device of the present invention has a detection rate of 100% for antibodies generated after vaccination, while the other company's product was 75%, and a positive sample confirmed as COVID-19 As a result of reacting by concentration in , it was confirmed that the sensitivity was higher than that of other companies' products.
또한, 본 발명은 상기 진단장치를 이용하여 사스-코로나바이러스-2 진단에 필요한 정보를 제공하는 방법을 제공한다.In addition, the present invention provides a method for providing information necessary for diagnosing SARS-coronavirus-2 using the diagnostic device.
본 발명의 용어, 진단장치, 사스-코로나바이러스-2 및 진단에 관하여는 상기 기재된 바와 같다.The terms of the present invention, diagnosis device, SARS-coronavirus-2 and diagnosis are as described above.
본 발명에 따르면, 상기 정보제공 방법은 1) 시료를 상기 진단장치에 적용하여 시료 내 스파이크 단백질 항체 및/또는 뉴클레오캡시드 단백질 항체가 탐침물질과 반응하는 단계; 2) 제1 검사선 및 제2 검사선에 의해 시료 내 스파이크 단백질 항체 및/또는 뉴클레오캡시드 단백질 항체의 반응을 확인하는 단계로서, 스파이크 단백질 항체 및/또는 뉴클레오캡시드 단백질 항체는 각각의 검사선에서 샌드위치 복합체의 존재에 의해 발생하는 신호에 의해 감지되는 단계; 및 3) 대조선 및 제1 검사선에 발색선이 나타나고, 제2 검사선에 발색선이 나타나지 않은 경우 사스-코로나바이러스-2 백신 접종자로 판단하고, 대조선, 제1 검사선 및 제2 검사선에 발색선이 나타나는 경우 사스-코로나바이러스-2 감염자로 판단하는 단계를 포함할 수 있다.According to the present invention, the information providing method includes: 1) applying the sample to the diagnostic device so that the spike protein antibody and/or the nucleocapsid protein antibody in the sample reacts with the probe; 2) A step of confirming the reaction of the spike protein antibody and/or the nucleocapsid protein antibody in the sample by the first test line and the second test line, wherein the spike protein antibody and/or the nucleocapsid protein antibody are tested for each test line detected by a signal generated by the presence of a sandwich complex in; and 3) If a color line appears on the control line and the first inspection line and no color line appears on the second inspection line, it is determined that the SARS-coronavirus-2 vaccine was inoculated, and the control line, the first inspection line, and the second inspection line A step of determining that a person is infected with SARS-coronavirus-2 may be included if a color line appears.
본 발명은 사스-코로나바이러스-2 항체를 검출하는 신규한 진단 장치를 제공하고, 상기 진단 장치는 사스-코로나바이러스-2의 스파이크 단백질 (spike protein)에 대한 항체와 뉴클레오캡시드 단백질 (nucleocapsid protein)에 대한 항체를 구별하여, 백신 접종으로 인해 생성된 항체와 사스-코로나바이러스-2 감염에 의해 생성된 항체를 높은 민감도 및 특이도로 구분할 수 있고, 사스-코로나바이러스-2에 감염된 또는 감염된 이력이 있는 환자 또한 향상된 민감도 및 특이도로 검출할 수 있다.The present invention provides a novel diagnostic device for detecting a SARS-coronavirus-2 antibody, the diagnostic device comprising an antibody against the spike protein of SARS-coronavirus-2 and a nucleocapsid protein It is possible to distinguish between antibodies produced by vaccination and antibodies produced by SARS-coronavirus-2 infection with high sensitivity and specificity by distinguishing antibodies against SARS-coronavirus-2, and those who are infected with or have a history of infection with SARS-coronavirus-2. Patients can also be detected with improved sensitivity and specificity.
도 1은 사스-코로나바이러스-2 항체 신규 진단장치 구조를 나타낸 것으로, spike protein 항체를 검출하는 카세트 및 nucleocapsid protein 항체를 검출하는 카세트 2개로 구성되는 Duo type 진단장치를 나타낸 도이다.
도 2는 사스-코로나바이러스-2 항체 신규 진단장치 구조를 나타낸 것으로, 제1 검사선에는 spike protein 항체를 검출하고, 제2 검사선에는 nucleocapsid protein 항체를 한번에 검출하도록 구성되는 Single type 진단장치를 나타낸 도이다.
도 3은 사스-코로나바이러스-2 항체 진단장치 (Single type 진단장치) 제조 후 검체 발색을 통해 COVID-19 감염 유무 및 Vaccine 접종 후 항체 생성 유무를 확인한 도이다.
도 4는 백신 접종 후 생성되는 항체의 검출 여부를 확인한 결과를 나타낸 도이다 (A: N-protein 항체 검출 키트, B: S-protein 항체 검출 키트, C: S사 제품인 COVID-19 IgM/IgG RAPID KIT/ ++: highly positive, +: positive, w+: weak positive, -: negative).
도 5는 COVID-19 확진 판정을 받은 검체를 농도별로 반응시킨 결과를 나타낸 것으로, 진단키트의 민감도를 비교한 결과를 나타낸 도이다 (A: N-protein 항체 검출 키트, B: S-protein 항체 검출 키트, C: S사 제품인 COVID-19 IgM/IgG RAPID KIT/ ++: highly positive, +: positive, w+: weak positive, -: negative).
도 6은 본 발명에 따라 제조된 면역크로마토그래피 스트립의 구현예를 보여주는 개요도이다 (1: 검체패드부, 2: 콘쥬게이트패드부, 3: 니트로셀룰로오스 멤브레인, 4: 흡수패드, 5: 제1 검사선, 6: 제2 검사선, 7: 대조선).1 shows the structure of a new diagnostic device for SARS-coronavirus-2 antibody, and is a diagram showing a Duo type diagnostic device consisting of two cassettes, a cassette for detecting spike protein antibodies and a cassette for detecting nucleocapsid protein antibodies.
Figure 2 shows the structure of a new diagnostic device for SARS-coronavirus-2 antibody, a single type diagnostic device configured to detect a spike protein antibody on a first test line and detect a nucleocapsid protein antibody on a second test line at once. It is also
Figure 3 is a diagram confirming the presence or absence of COVID-19 infection and the presence or absence of antibody generation after vaccine inoculation through sample color development after manufacturing a SARS-coronavirus-2 antibody diagnostic device (Single type diagnostic device).
4 is a diagram showing the results of confirming whether antibodies produced after vaccination are detected (A: N-protein antibody detection kit, B: S-protein antibody detection kit, C: COVID-19 IgM/IgG RAPID manufactured by S company) KIT/ ++: highly positive, +: positive, w+: weak positive, -: negative).
Figure 5 shows the results of reacting samples confirmed with COVID-19 by concentration, and is a diagram showing the results of comparing the sensitivity of diagnostic kits (A: N-protein antibody detection kit, B: S-protein antibody detection) Kit, C: COVID-19 IgM/IgG RAPID KIT/ ++: highly positive, +: positive, w+: weak positive, -: negative).
6 is a schematic diagram showing an embodiment of an immunochromatography strip manufactured according to the present invention (1: sample pad part, 2: conjugate pad part, 3: nitrocellulose membrane, 4: absorbent pad, 5: first test line, 6: second inspection line, 7: control line).
이하, 본 발명의 내용을 하기의 실시예 및 실험예를 통해 더욱 상세히 설명하고자 한다. 다만, 본 발명의 권리범위가 하기 실시예 및 실험예에만 한정되는 것은 아니고, 이와 등가의 기술적 사상의 변형까지를 포함한다.Hereinafter, the contents of the present invention will be described in more detail through the following examples and experimental examples. However, the scope of the present invention is not limited only to the following examples and experimental examples, and includes modifications of equivalent technical ideas.
실시예 1. 사스-코로나바이러스-2 항체 진단용 신속 면역크로마토그래피 진단키트의 제조Example 1. Preparation of rapid immunochromatography diagnostic kit for diagnosis of SARS-coronavirus-2 antibody
1-1. 스트립 제조 및 진단키트의 구성1-1. Composition of strip manufacturing and diagnostic kit
스트립의 아래 쪽부터 완충용액이 처리된 버퍼패드; 사스-코로나바이러스-2 재조합 항원과 금축합체가 축합된 콘쥬게이트 패드; 검체를 주입하는 검체패드; 및 제1 검사선과 제2 검사선 및 대조선이 순서대로 부착/분주되어 있는 멤브레인을 순차적으로 부착시키고, 상단에는 흡수패드를 부착시켰다.A buffer pad treated with a buffer solution from the bottom of the strip; A conjugate pad in which SARS-coronavirus-2 recombinant antigen and gold condensate are condensed; a sample pad for injecting a sample; And membranes to which the first test line, the second test line, and the control line are attached/dispensed in order are sequentially attached, and an absorbent pad is attached to the top.
상기에서 준비된 스트립을 플라스틱 카세트에 장착하고, 조립을 하여 진단키트를 완성하였다.The strip prepared above was mounted on a plastic cassette and assembled to complete a diagnostic kit.
상기 제1 검사선은 백신 접종 후 생성되는 스파이크 단백질 (spike protein) 항체를 검출하고, 상기 제2 검사선은 뉴클레오캡시드 단백질 (nucleocapsid protein) 항체를 검출하여, 동시에 상기 2가지 항체를 구별하여 검출할 수 있다. 즉, 항체에 대한 정확도 높은 진단이 가능하다.The first test line detects a spike protein antibody generated after vaccination, and the second test line detects a nucleocapsid protein antibody, and simultaneously distinguishes and detects the two antibodies. can do. That is, it is possible to diagnose the antibody with high accuracy.
상기 진단키트는 Duo type과 Single type으로 구분지을 수 있다. Duo type은 스파이크 단백질 항체를 검출하는 카세트 및 뉴클레오캡시드 단백질 항체를 검출하는 카세트 2개로 구성된다 (도 1 참조). Single type은 제1 검사선에서는 스파이크 단백질 항체를 검출하고, 제2 검사선에서는 뉴클레오캡시드 단백질 항체를 한번에 검출하도록 구성된다 (도 2 참조).The diagnostic kit can be classified into a Duo type and a Single type. The Duo type consists of two cassettes: a cassette for detecting spike protein antibodies and a cassette for detecting nucleocapsid protein antibodies (see FIG. 1). The single type is configured to detect the spike protein antibody in the first test line and detect the nucleocapsid protein antibody in the second test line at once (see FIG. 2 ).
각 라인에 대한 발색 여부에 따라 COVID-19 감염 유무 및 백신 (Vaccine) 접종 후 항체 생성 유무를 판정할 수 있다.Depending on the color development of each line, the presence or absence of COVID-19 infection and the formation of antibodies after vaccination can be determined.
1-2. 사스-코로나바이러스-2 진단용 검사선 및 대조선에 원료 분주1-2. Dispensing raw materials to the test line and control line for diagnosis of SARS-Coronavirus-2
본 발명의 사스-코로나바이러스-2 Duo type 진단장치에서는, 항-사람 IgG-단클론 항체와 항-사람 IgM-단클론 항체를 준비하여, 니트로셀룰로오스 멤브레인에 0.5 내지 4.0 mg/ml의 농도로 제1 검사선과 제2 검사선 부위에 분주를 하였다. 본 발명의 사스-코로나바이러스-2 Single type 진단장치에서는, 사스-코로나바이러스-2 스파이크 재조합 항원과 뉴클레오캡시드 재조합 항원을 검사선 부위에 분주하였다. 또한, 멤브레인의 대조선 위치에는 산양 항-생쥐 IgG 다클론 항체를 1.0 mg/ml의 농도로 PBS로 희석하여 분주하였다.In the SARS-coronavirus-2 Duo type diagnosis device of the present invention, anti-human IgG-monoclonal antibody and anti-human IgM-monoclonal antibody are prepared, and the first test is performed at a concentration of 0.5 to 4.0 mg/ml on a nitrocellulose membrane. The line and the second inspection line were dispensed. In the SARS-coronavirus-2 Single type diagnostic device of the present invention, the SARS-coronavirus-2 spike recombinant antigen and the nucleocapsid recombinant antigen were dispensed at the test line site. In addition, goat anti-mouse IgG polyclonal antibody diluted with PBS at a concentration of 1.0 mg/ml was dispensed on the control line of the membrane.
1-3. 사스-코로나바이러스-2 진단용 금축합체 및 콘쥬게이트 패드의 제조1-3. Preparation of gold condensate and conjugate pad for diagnosis of SARS-CoV-2
상기 제작된 금 입자에 사스-코로나바이러스-2 스파이크 단백질 항체에 특이적인 서열번호 1의 펩타이드, 사스-코로나바이러스-2 뉴클레오캡시드 단백질에 특이적인 서열번호 2의 펩타이드를 각각 금 입자용액에 축합하였으며, 원심분리 후 안정액을 처리한 후 건조시켜 콘쥬게이트 패드를 제조하였다. To the prepared gold particles, the peptide of SEQ ID NO: 1 specific to the SARS-coronavirus-2 spike protein antibody and the peptide of SEQ ID NO: 2 specific to the SARS-coronavirus-2 nucleocapsid protein were condensed into the gold particle solution, respectively. , After centrifugation, the stabilizer was treated and dried to prepare a conjugate pad.
1-4. 샘플패드 및 흡수패드1-4. Sample pad and absorbent pad
유리 섬유 (glass fiber), 코튼 (cotton) 또는 셀룰로오스 재질의 패드에 전처리 후, 건조하여 샘플패드로 사용하였다. 흡수패드는 코튼 재질의 패드를 별도의 처리없이 잘라서 사용하였다.After pretreatment on a pad made of glass fiber, cotton, or cellulose, it was dried and used as a sample pad. As the absorbent pad, a cotton pad was cut and used without any additional treatment.
실시예 2. 사스-코로나바이러스-2 신속 면역크로마토그래피 진단키트의 검사 방법Example 2. Test method for SARS-coronavirus-2 rapid immunochromatography diagnostic kit
바이러스 항체가 존재하는 사람의 혈청/혈장, 전혈을 검체주입구에 넣고, 샘플패드에 반응 용액을 떨어뜨린다. 이후, 검액이 분리되고, 멤브레인으로 이동하여 반응하게 된다.Serum/plasma and whole blood of a person with virus antibodies are put into the sample inlet, and the reaction solution is dropped on the sample pad. Thereafter, the sample solution is separated and moved to the membrane to react.
진단용 키트는 반응용액이 콘쥬게이트 패드로 이동하여, 펩타이드-금 축합체를 용해시킨 후, 멤브레인으로 이동하여 “펩타이드-금 축합체-COVID-19 항체-항 사람 IgG, IgM”과 같은 형태 또는 “펩타이드-금 축합체-COVID-19 항체-펩타이드”와 같은 형태로 반응하게 되어 색 띠를 형성하게 된다. In the diagnostic kit, the reaction solution moves to the conjugate pad, dissolves the peptide-gold condensate, and then moves to the membrane to produce a form such as “peptide-gold condensate-COVID-19 antibody-anti-human IgG, IgM” or “ It reacts in the form of “peptide-gold condensate-COVID-19 antibody-peptide” to form a color band.
진단키트의 제1 검사선은 백신 접종 후 생성되는 스파이크 단백질 (spike protein) 항체를 검출하여 색 띠를 형성하고, 제2 검사선은 뉴클레오캡시드 단백질 (nucleocapsid protein) 항체를 검출하여 색 띠를 형성한다. 즉, 본 발명의 진단키트는 백신 접종 후 생성되는 스파이크 단백질 항체와 COVID-19 환자의 뉴클레오캡시드 단백질 항체를 동시에 구별하여 검출할 수 있다.The first test line of the diagnostic kit detects the spike protein antibody produced after vaccination to form a color band, and the second test line detects the nucleocapsid protein antibody to form a color band. do. That is, the diagnostic kit of the present invention can detect spike protein antibodies generated after vaccination and nucleocapsid protein antibodies of COVID-19 patients at the same time.
한편, 반응하지 않은 펩타이드-금 축합체는 대조선 부위에 부착되어 있는 항 생쥐 면역글로불린 G와 반응하여 색 띠를 나타내게 된다.On the other hand, the unreacted peptide-gold condensate reacts with the anti-mouse immunoglobulin G attached to the control line to show a color band.
실험예 1. 백신 접종 후 생성되는 항체의 검출 여부 확인Experimental Example 1. Confirmation of detection of antibodies produced after vaccination
백신 접종자 8명의 검체를 수집하였다. 백신 접종 후 생성되는 항체의 검출 여부를 확인한 결과, 본 발명의 진단키트는 백신 접종 후 생성되는 항체에 대한 검출율이 100%를 나타냄을 확인하였다 (도 4 참조). 상기 결과는 하기 표 1에 기재된 바와 같다.Specimens were collected from 8 vaccinated persons. As a result of checking whether antibodies produced after vaccination were detected, it was confirmed that the diagnostic kit of the present invention showed a detection rate of 100% for antibodies produced after vaccination (see FIG. 4). The results are as shown in Table 1 below.
A는 뉴클레오캡시드 단백질 항체를 검출하는 것이고, B는 스파이크 단백질 항체를 검출하는 것이며, C는 타사 (S사) 키트 제품 결과이다. 본 발명의 키트와 타사 제품을 비교하여 시험한 결과를 살펴보면, 본 발명의 경우 백신 접종 후에 생성되는 항체에 대한 검출율이 100% 였고, 타사 제품의 경우에는 75% 임을 확인하였다.A is to detect the nucleocapsid protein antibody, B is to detect the spike protein antibody, and C is the result of a kit product from another company (S company). Looking at the results of testing by comparing the kit of the present invention with products of other companies, in the case of the present invention, it was confirmed that the detection rate for antibodies generated after vaccination was 100%, and in the case of products of other companies, it was 75%.
또한, 본 발명의 진단키트는 뉴클레오캡시드 단백질에 대한 항체를 검출하는 검사선과 스파이크 단백질 항체를 검출하는 검사선을 구별하여 백신 접종으로 인하여 생성된 항체인지, SARS-CoV-2 감염에 의해 생성된 항체인지 구별이 가능하다 (도 4 참조).In addition, the diagnostic kit of the present invention distinguishes between a test line that detects antibodies against nucleocapsid protein and a test line that detects spike protein antibodies, and determines whether the antibody is produced by vaccination or SARS-CoV-2 infection. It is possible to distinguish whether it is an antibody (see FIG. 4).
실험예 2. 진단적 효능 평가Experimental Example 2. Evaluation of diagnostic efficacy
본 발명의 진단키트의 진단적 효능을 시험하기 위해서 민감도 및 특이도를 확인하였다. COVID-19 확진 판정을 받은 3명의 양성 검체 (A, B 및 C 검체)를 농도별로 반응시킨 결과, 본 발명의 키트가 타사 (S사) 제품보다 민감도가 높은 것을 확인하였다 (도 5 참조).In order to test the diagnostic efficacy of the diagnostic kit of the present invention, sensitivity and specificity were confirmed. As a result of reacting three positive samples (sample A, B, and C) who were confirmed for COVID-19 by concentration, it was confirmed that the kit of the present invention is more sensitive than the product of another company (Company S) (see Fig. 5).
구체적으로, A 검체는 본 발명의 키트의 경우 1/100x까지 검출이 가능하지만, 타사 제품의 경우에는 1/10x까지 검출이 가능하였다. B 검체는 본 발명의 키트의 경우 1/100x까지 검출이 가능하지만, 타사 제품의 경우에는 1/10x까지 검출이 가능하였다. C 검체는 상기 2개의 진단키트 모두 1/10x까지 검출되지만, 본 발명의 진단키트의 발색 세기가 타사 제품보다 강함을 확인하였다.Specifically, sample A could be detected up to 1/100x in the case of the kit of the present invention, but up to 1/10x in the case of another company's product. Sample B can be detected up to 1/100x in the case of the kit of the present invention, but up to 1/10x in the case of another company's product. Sample C was detected up to 1/10x in both diagnostic kits, but it was confirmed that the color development intensity of the diagnostic kit of the present invention was stronger than that of other companies' products.
상기 결과를 통해, 본 발명의 진단키트는 사스-코로나바이러스-2를 특이적으로 높은 민감도로 검출할 수 있음을 나타내고, 각 검사선에 대한 발색 여부에 따라 COVID-19 감염 유무 및 Vaccine 접종 후 항체 생성 유무를 동시에 정확히 구별하여 진단할 수 있음을 시사한다.Through the above results, it is shown that the diagnostic kit of the present invention can specifically detect SARS-coronavirus-2 with high sensitivity, and according to the color development of each test line, the presence or absence of COVID-19 infection and antibody after vaccination with Vaccine This suggests that it is possible to diagnose by accurately distinguishing whether or not it is produced at the same time.
이상, 본 발명의 실시예를 설명하였지만, 본 발명이 속하는 기술분야의 통상의 기술자는 본 발명이 그 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 그러므로, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며, 제한적이 아닌 것으로 이해해야만 한다. Although the embodiments of the present invention have been described above, those skilled in the art to which the present invention pertains will understand that the present invention can be implemented in other specific forms without changing the technical spirit or essential features. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.
<110> ADTech Co.,LTD <120> Novel diagnostic test devices for detecting SARS-CoV-2 antibody <130> APP2022-0152KRC1 <150> KR 10-2021-0064015 <151> 2021-05-18 <160> 2 <170> KoPatentIn 3.0 <210> 1 <211> 223 <212> PRT <213> Artificial Sequence <220> <223> Spike glycoprotein precursor of Severe Acute Respiratory Syndrome Coronavirus 2 <400> 1 Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn 1 5 10 15 Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val 20 25 30 Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser 35 40 45 Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val 50 55 60 Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp 65 70 75 80 Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln 85 90 95 Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr 100 105 110 Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly 115 120 125 Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys 130 135 140 Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr 145 150 155 160 Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser 165 170 175 Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val 180 185 190 Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly 195 200 205 Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe 210 215 220 <210> 2 <211> 419 <212> PRT <213> Artificial Sequence <220> <223> Nucleocapsid protein of Severe Acute Respiratory Syndrome Coronavirus 2 <400> 2 Met Ser Asp Asn Gly Pro Gln Asn Gln Arg Asn Ala Pro Arg Ile Thr 1 5 10 15 Phe Gly Gly Pro Ser Asp Ser Thr Gly Ser Asn Gln Asn Gly Glu Arg 20 25 30 Ser Gly Ala Arg Ser Lys Gln Arg Arg Pro Gln Gly Leu Pro Asn Asn 35 40 45 Thr Ala Ser Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Asp Leu 50 55 60 Lys Phe Pro Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser Ser Pro 65 70 75 80 Asp Asp Gln Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg Ile Arg Gly 85 90 95 Gly Asp Gly Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr Phe Tyr Tyr 100 105 110 Leu Gly Thr Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala Asn Lys Asp 115 120 125 Gly Ile Ile Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys Asp 130 135 140 His Ile Gly Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu Gln 145 150 155 160 Leu Pro Gln Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly Ser 165 170 175 Arg Gly Gly Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser Arg Asn 180 185 190 Ser Ser Arg Asn Ser Thr Pro Gly Ser Ser Arg Gly Thr Ser Pro Ala 195 200 205 Arg Met Ala Gly Asn Gly Gly Asp Ala Ala Leu Ala Leu Leu Leu Leu 210 215 220 Asp Arg Leu Asn Gln Leu Glu Ser Lys Met Ser Gly Lys Gly Gln Gln 225 230 235 240 Gln Gln Gly Gln Thr Val Thr Lys Lys Ser Ala Ala Glu Ala Ser Lys 245 250 255 Lys Pro Arg Gln Lys Arg Thr Ala Thr Lys Ala Tyr Asn Val Thr Gln 260 265 270 Ala Phe Gly Arg Arg Gly Pro Glu Gln Thr Gln Gly Asn Phe Gly Asp 275 280 285 Gln Glu Leu Ile Arg Gln Gly Thr Asp Tyr Lys His Trp Pro Gln Ile 290 295 300 Ala Gln Phe Ala Pro Ser Ala Ser Ala Phe Phe Gly Met Ser Arg Ile 305 310 315 320 Gly Met Glu Val Thr Pro Ser Gly Thr Trp Leu Thr Tyr Thr Gly Ala 325 330 335 Ile Lys Leu Asp Asp Lys Asp Pro Asn Phe Lys Asp Gln Val Ile Leu 340 345 350 Leu Asn Lys His Ile Asp Ala Tyr Lys Thr Phe Pro Pro Thr Glu Pro 355 360 365 Lys Lys Asp Lys Lys Lys Lys Ala Asp Glu Thr Gln Ala Leu Pro Gln 370 375 380 Arg Gln Lys Lys Gln Gln Thr Val Thr Leu Leu Pro Ala Ala Asp Leu 385 390 395 400 Asp Asp Phe Ser Lys Gln Leu Gln Gln Ser Met Ser Ser Ala Asp Ser 405 410 415 Thr Gln Ala <110> ADTech Co.,LTD <120> Novel diagnostic test devices for detecting SARS-CoV-2 antibody <130> APP2022-0152KRC1 <150> KR 10-2021-0064015 <151> 2021-05-18 <160> 2 <170> KoPatentIn 3.0 <210> 1 <211> 223 <212> PRT <213> artificial sequence <220> <223> Spike glycoprotein precursor of Severe Acute Respiratory Syndrome Coronavirus 2 <400> 1 Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn 1 5 10 15 Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val 20 25 30 Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser 35 40 45 Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val 50 55 60 Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp 65 70 75 80 Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln 85 90 95 Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr 100 105 110 Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly 115 120 125 Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys 130 135 140 Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr 145 150 155 160 Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser 165 170 175 Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val 180 185 190 Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly 195 200 205 Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe 210 215 220 <210> 2 <211> 419 <212> PRT <213> artificial sequence <220> <223> Nucleocapsid protein of Severe Acute Respiratory Syndrome Coronavirus 2 <400> 2 Met Ser Asp Asn Gly Pro Gln Asn Gln Arg Asn Ala Pro Arg Ile Thr 1 5 10 15 Phe Gly Gly Pro Ser Asp Ser Thr Gly Ser Asn Gln Asn Gly Glu Arg 20 25 30 Ser Gly Ala Arg Ser Lys Gln Arg Arg Pro Gln Gly Leu Pro Asn Asn 35 40 45 Thr Ala Ser Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Asp Leu 50 55 60 Lys Phe Pro Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser Ser Pro 65 70 75 80 Asp Asp Gln Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg Ile Arg Gly 85 90 95 Gly Asp Gly Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr Phe Tyr Tyr 100 105 110 Leu Gly Thr Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala Asn Lys Asp 115 120 125 Gly Ile Ile Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys Asp 130 135 140 His Ile Gly Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu Gln 145 150 155 160 Leu Pro Gln Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly Ser 165 170 175 Arg Gly Gly Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser Arg Asn 180 185 190 Ser Ser Arg Asn Ser Thr Pro Gly Ser Ser Arg Gly Thr Ser Pro Ala 195 200 205 Arg Met Ala Gly Asn Gly Gly Asp Ala Ala Leu Ala Leu Leu Leu Leu 210 215 220 Asp Arg Leu Asn Gln Leu Glu Ser Lys Met Ser Gly Lys Gly Gln Gln 225 230 235 240 Gln Gln Gly Gln Thr Val Thr Lys Lys Ser Ala Ala Glu Ala Ser Lys 245 250 255 Lys Pro Arg Gln Lys Arg Thr Ala Thr Lys Ala Tyr Asn Val Thr Gln 260 265 270 Ala Phe Gly Arg Arg Gly Pro Glu Gln Thr Gln Gly Asn Phe Gly Asp 275 280 285 Gln Glu Leu Ile Arg Gln Gly Thr Asp Tyr Lys His Trp Pro Gln Ile 290 295 300 Ala Gln Phe Ala Pro Ser Ala Ser Ala Phe Phe Gly Met Ser Arg Ile 305 310 315 320 Gly Met Glu Val Thr Pro Ser Gly Thr Trp Leu Thr Tyr Thr Gly Ala 325 330 335 Ile Lys Leu Asp Asp Lys Asp Pro Asn Phe Lys Asp Gln Val Ile Leu 340 345 350 Leu Asn Lys His Ile Asp Ala Tyr Lys Thr Phe Pro Pro Thr Glu Pro 355 360 365 Lys Lys Asp Lys Lys Lys Lys Ala Asp Glu Thr Gln Ala Leu Pro Gln 370 375 380 Arg Gln Lys Lys Gln Gln Thr Val Thr Leu Leu Pro Ala Ala Asp Leu 385 390 395 400 Asp Asp Phe Ser Lys Gln Leu Gln Gln Ser Met Ser Ser Ala Asp Ser 405 410 415 Thr Gln Ala
Claims (13)
SARS-coronavirus-2 comprising a first test line for detecting a spike protein antibody and a second test line for detecting a nucleocapsid protein antibody for SARS-coronavirus-2 Coronavirus-2 diagnostic device.
상기 진단장치는 피검 시료를 수용하는 검체 영역;
검체 영역과 연동되어 있고 탐칠물질이 축합된 콘쥬게이트 영역;
상기 콘쥬게이트 영역과 연동되어 있는 제1 검사선, 제2 검사선 또는 제1 검사선 및 제2 검사선을 포함하는 신호검출 영역; 및
신호검출반응이 종료된 피검 시료를 흡수하는 흡수 영역을 포함하는 진단장치.
According to claim 1,
The diagnosis device may include a sample area accommodating a test sample;
a conjugate region interlocked with the sample region and condensed with a probe substance;
a signal detection region including a first test line, a second test line, or a first test line and a second test line linked to the conjugate region; and
A diagnostic device including an absorption region for absorbing a test sample in which a signal detection reaction is completed.
상기 탐침물질은 금 나노입자, 은 나노입자, 퀀텀닷 (quantum dot) 나노입자, 카본 나노입자, 라텍스 비드/형광 나노입자, 셀룰로오스 나노입자, 자기 나노입자, 실리카 나노입자, 폴리머 비드 (polymer bead), 형광물질 (fluorescein), 발광물질 (luminescent substances), 색소 (dye), 단백질로 구성된 군으로부터 선택된 어느 하나 이상인 것을 특징으로 하는, 진단장치.
According to claim 2,
The probe material is gold nanoparticles, silver nanoparticles, quantum dot nanoparticles, carbon nanoparticles, latex beads/fluorescent nanoparticles, cellulose nanoparticles, magnetic nanoparticles, silica nanoparticles, polymer beads A diagnostic device, characterized in that it is at least one selected from the group consisting of fluorescein, luminescent substances, dye, and protein.
상기 신호검출 영역은 제1 검사선 및 제2 검사선을 함께 포함하거나, 둘 이상의 신호검출 영역에서 각각 제1 검사선 및 제2 검사선을 포함하는 것을 특징으로 하는, 진단장치.
According to claim 2,
The diagnosis apparatus, characterized in that the signal detection area includes a first inspection line and a second inspection line together, or includes a first inspection line and a second inspection line, respectively, in two or more signal detection areas.
상기 진단장치는 제1 검사선과 제2 검사선의 발색 여부를 동시에 확인할 수 있는 것을 특징으로 하는, 진단장치.
According to claim 1,
The diagnosis device is characterized in that it can simultaneously check whether the first test line and the second test line are colored.
상기 신호검출 영역은 검사선에 항-사람 IgG 단클론 항체, 항-사람 IgM 단클론 항체 또는 이들의 조합이 고정화되어 있는 것을 특징으로 하는, 진단장치.
According to claim 2,
The signal detection region is characterized in that anti-human IgG monoclonal antibody, anti-human IgM monoclonal antibody or a combination thereof is immobilized on the test line.
상기 신호검출 영역은 사스-코로나바이러스-2 스파이크 재조합 단백질 및 사스-코로나바이러스-2 뉴클레오캡시드 재조합 단백질이 고정화되어 있는 것을 특징으로 하는, 진단장치.
According to claim 2,
The signal detection region is a diagnostic device, characterized in that the SARS-coronavirus-2 spike recombinant protein and the SARS-coronavirus-2 nucleocapsid recombinant protein are immobilized.
상기 진단장치는 사스-코로나바이러스-2 감염 유무 및 백신 접종 후 항체 생성 유무를 동시에 구별하여 진단하는 것을 특징으로 하는, 진단장치.
According to claim 1,
The diagnostic device is characterized in that the diagnostic device simultaneously distinguishes and diagnoses the presence or absence of SARS-coronavirus-2 infection and the presence or absence of antibody production after vaccination.
상기 진단장치는 면역크로마토그래피법을 이용한 스트립 형태인 것을 특징으로 하는, 진단장치.
According to claim 1,
The diagnostic device is characterized in that the diagnostic device is in the form of a strip using an immunochromatography method.
상기 신호검출 영역은 니트로셀룰로오스, 셀룰로오스, 폴리에틸렌, 폴리에테르설폰, 폴리스틸렌, 폴리카보네이트, 폴리메틸메타크릴레이트 및 나일론으로 구성된 군으로부터 선택된 어느 하나인 것을 특징으로 하는, 진단장치.
According to claim 2,
The signal detection area is characterized in that any one selected from the group consisting of nitrocellulose, cellulose, polyethylene, polyethersulfone, polystyrene, polycarbonate, polymethyl methacrylate and nylon, diagnostic device.
상기 흡수 영역은 다공성지지체의 공동 (pore)에 분산되거나 다공성지지체의 섬유사에 흡착 또는 코팅되어 있는 흡수제를 포함하는 것을 특징으로 하는, 진단장치.
According to claim 1,
The absorbent region comprises an absorbent dispersed in the pores of the porous support or adsorbed or coated on the fibers of the porous support.
A method of providing information necessary for diagnosing SARS-coronavirus-2 using the diagnostic device of claim 1.
1) 시료를 상기 진단장치에 적용하여 시료 내 스파이크 단백질 항체 또는 뉴클레오캡시드 단백질 항체가 탐침물질에 반응하는 단계;
2) 제1 검사선 및 제2 검사선에 의해 시료 내 스파이크 단백질 항체 또는 뉴클레오캡시드 단백질 항체의 반응을 확인하는 단계; 및
3) 대조선 및 제1 검사선에 발색선이 나타나고, 제2 검사선에 발색선이 나타나지 않는 경우 사스-코로나바이러스-2 백신 접종자로 판정하고, 대조선, 제1 검사선 및 제2 검사선에 발색선이 나타나는 경우 사스-코로나바이러스-2 감염자로 판정하는 단계를 포함하는, 정보를 제공하는 방법.According to claim 12,
1) applying the sample to the diagnostic device so that the spike protein antibody or the nucleocapsid protein antibody in the sample reacts to the probe;
2) confirming the reaction of the spike protein antibody or the nucleocapsid protein antibody in the sample by the first test line and the second test line; and
3) If a color line appears on the control line and the first inspection line and no color line appears on the second inspection line, it is determined that the SARS-coronavirus-2 vaccine has been vaccinated, and color development on the control line, first inspection line, and second inspection line A method for providing information, comprising determining that a person is infected with SARS-coronavirus-2 if a line appears.
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