KR20230157180A - 코로나바이러스의 스파이크 단백질, 뉴클레오캡시드 단백질 및 PgsA 단백질을 동시발현하는 복제불능 아데노바이러스를 이용한 코로나바이러스 백신 - Google Patents
코로나바이러스의 스파이크 단백질, 뉴클레오캡시드 단백질 및 PgsA 단백질을 동시발현하는 복제불능 아데노바이러스를 이용한 코로나바이러스 백신 Download PDFInfo
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Abstract
본 발명은 코로나바이러스의 스파이크(spike) 단백질과 뉴클레오캡시드(nucleocapsid) 단백질 및 PgsA가 복제불능 아데노바이러스 E1영역과 E3영역에 삽입된 형태로 발현되는 재조합 아데노바이러스 및 이를 이용한 코로나바이러스 백신에 관한 발명으로, 본 발명에 의한 백신조성물은 체액성 면역반응 및 세포 매개성 반응을 유도하여 SARS-CoV-2 및 그 변이바이러스에 대한 면역반응을 유도할 수 있다.
Description
본 발명은 코로나바이러스의 스파이크(spike) 단백질과 뉴클레오캡시드(nucleocapsid) 단백질 및 PgsA 단백질이 복제불능 아데노바이러스의 E1영역과 E3영역에 삽입된 형태로 발현되는 재조합 아데노바이러스 및 이를 이용한 코로나바이러스 백신에 관한 발명이다.
코로나바이러스감염증-19(coronavirus disease 2019, 이하 “COVID-19”라 함)는 2019년 12월 중국 우한에서 처음 발생한 이후 중국 전역과 전 세계로 확산된 새로운 유형의 코로나바이러스(이하 “SARS-CoV-2”라 함)에 의한 호흡기 감염질환을 말하는데, 감염자의 비말(침방울)이 호흡기나 눈·코·입의 점막으로 침투될 때 전염되며, 약 2~14일(추정)의 잠복기를 거친 뒤 발열 및 기침이나 호흡곤란 등 호흡기 증상, 폐렴이 주증상으로 나타나지만 무증상 감염 사례 빈도도 높게 나오고 있다.
“SARS-CoV-2”는 외피를 가지며, 유전체로서 약 30kb 길이의 단일 가닥 RNA를 가지는데, 바이러스 유전체인 RNA 자체가 전사체로 작용하는 양성 가닥(positive-strand) RNA 유전자에 해당하고, 코로나바이러스의 유전자는 뉴클레오캡시드(nucleocapsid, N) 단백질, 막(membrane, M) 단백질, 외피(envelope, E) 단백질, 스파이크(spike, S) 당단백질 등의 구조 단백질을 암호화한다(도 1). 인간코로나바이러스(HCoV) 중 일부에서는 hemagglutinin-esterase(HE) 단백질을 생성하며, 바이러스 입자의 세포 표면의 부착 및 유리 과정에서 중요한 역할을 하는 것으로 알려져 있다.
이 중 스파이크 단백질은 숙주세포의 표면에 부착과 관련하여 감염 개시에 있어 중요한 역할을 하는 것으로 알려져 있으며 특히 스파이크 단백질의 S1 도메인은 세포 수용체에 특이적인 결합을 매개하는 수용체 결합 도메인(receptor binding domain: RBD)을 포함하고 있는 것으로 알려져 있으며, 뉴클레오캡티드 단백질은 바이러스 게놈의 패키징 및 복제 과정에 관여하는 단백질로서 연결부위(linkage region)로 연결된 2개의 바이러스 RNA 결합부위로 구성되며, 연결부위는 세린/아르기닌이 풍부하게 존재하며 보존적인 부분으로 알려져 있다(Sebastano et al., 2020).
한편, SARS-CoV-2 연구를 기반으로 영장류 모델에서 SARS-CoV-2 백신을 개발하고 있으며, 개발중인 SARS-CoV-2 백신은 접종을 통해 체액성 및 세포성 면역반응을 증가시키는 것으로 나타났다(도 2). 다만, 최근 일부 제약회사들이 SARS-CoV-2 백신개발을 추진 중인 상태이나, 아직 개발단계로서 전임상, 임상 시험 등을 통한 유효성 검증이 필요한 상황으로, SARS-CoV-2 감염예방을 위한 백신이 절실히 요구되는 상황이며, 나아가 현재 사용되고 있는 SARS-CoV-2 백신은 Wuhan-hu 바이러스 균주 정보를 기반으로 만들어진 것으로서, SARS-CoV-2 변이바이러스를 방어할 수 있도록 특화되어 있지 않은 바, SARS-CoV-2 변이바이러스의 전파까지 유효하게 예방이 가능하고 범용으로 사용될 수 있는 차세대백신의 개발이 시급한 상황이다.
본 발명의 목적은 SARS-CoV-2 감염예방을 위한 백신 조성물을 제공하는 것이다.
상기 목적을 달성하기 위하여 본 발명은 코로나바이러스(SARS-CoV-2)의 스파이크(spike) 단백질이 복제불능 아데노바이러스의 E1영역에 삽입되고, PgsA 및 코로나바이러스(SARS-CoV-2)의 뉴클레오캡시드(nucleocapsid) 단백질이 복제불능 아데노바이러스의 E3영역에 삽입된 형태로 발현되는 재조합 아데노바이러스로서, E1의 bp 350 내지 3328 영역 결실(deletion) 후 서열번호 1의 아미노산서열이 삽입되고, E3의 bp 28139 내지 30995 영역 결실(deletion) 후 서열번호 2의 아미노산서열이 삽입되는 것을 특징으로 하는 재조합 아데노바이러스를 제공한다.
또한 본 발명은 상기 재조합 아데노바이러스에 의하여 제조되는 코로나바이러스(SARS-CoV-2) 백신을 제공한다.
또한 본 발명은 SARS-CoV-2 변이 바이러스에 작용하는 것을 특징으로 하는 코로나바이러스 백신을 제공한다.
또한 본 발명은 D614G 변이 바이러스에 작용하는 것을 특징으로 하는 코로나바이러스 백신을 제공한다.
또한 본 발명은 어주번트(adjuvant)를 추가로 포함하는 것을 특징으로 하는 코로나바이러스 백신을 제공한다.
본 발명에 의한 백신조성물은 체액성 면역반응 및 세포 매개성 반응을 유도하여 SARS-CoV-2에 대한 면역반응을 유도할 수 있다.
도 1은 SARS-CoV-2 구조 및 이를 암호화하는 유전자를 나타낸 것이다.
도 2는 백신접종을 통한 체액성 및 세포성 면역반응을 나타낸 것이다.
도 3은 아데노바이러스에 SARS-CoV-2 스파이크 단백질(S protein), PgsA 및 SARS-CoV-2 뉴클레오캡시드 단백질(N protein)을 코딩하는 유전자를 삽입한 모식도를 나타낸 것이다.
도 4는 본 발명에 의하여 재조합된 아데노바이러스를 감염시킨 세포의 스파이크 단백질 및 뉴클레오캡시드 단백질 발현여부를 나타낸 것이다.
도 5는 본 발명에 의하여 재조합된 아데노바이러스에 의한 CD80, CD86 및 MHCII 발현정도를 나타낸 것이다.
도 6은 본 발명에 의한 백신의 스파이크 항원에 대한 항체가를 나타낸 그래프이다.
도 7은 본 발명에 의한 백신 접종 후 항체형성 기간을 나타낸 것이다.
도 8은 스파이크 항원에 대한 세포독성 T세포(cytotoxic T cell)의 기억능에 관한 그래프이다.
도 9는 스파이크 항원에 대한 도움 T세포(helper T cell)의 기억능에 관한 그래프이다.
도 10은 스파이크 항원에 의하여 세포특이적 면역반응이 유도되었음을 나타내는 그래프이다.
도 11은 본 발명에 의한 백신의 뉴클레오캡시드 항원에 대한 항체가를 나타낸 그래프이다.
도 12는 뉴클레오캡시드 항원에 대한 세포독성 T세포(cytotoxic T cell)의 기억능에 관한 그래프이다.
도 13은 뉴클레오캡시드 항원에 대한 도움 T세포(helper T cell)의 기억능에 관한 그래프이다.
도 14는 뉴클레오캡시드 항원에 의하여 세포특이적 면역반응이 유도되었음을 나타내는 그래프이다.
도 15, 16은 본 발명에 의하여 재조합된 아데노바이러스를 감염시킨 세포에서 발현되는 항원과 완치환자의 항체 사이에 일어나는 항원항체 반응을 확인한 것이다.
도 17, 도 18은 본 발명에 의한 백신의 이중항원에 대한 중화항체가 검증을 나타낸 것이다.
도 19는 본 발명에 의한 백신의 SARS-CoV-2 D614G 변이바이러스에 대한 체액성 면역을 나타내는 그래프이다.
도 2는 백신접종을 통한 체액성 및 세포성 면역반응을 나타낸 것이다.
도 3은 아데노바이러스에 SARS-CoV-2 스파이크 단백질(S protein), PgsA 및 SARS-CoV-2 뉴클레오캡시드 단백질(N protein)을 코딩하는 유전자를 삽입한 모식도를 나타낸 것이다.
도 4는 본 발명에 의하여 재조합된 아데노바이러스를 감염시킨 세포의 스파이크 단백질 및 뉴클레오캡시드 단백질 발현여부를 나타낸 것이다.
도 5는 본 발명에 의하여 재조합된 아데노바이러스에 의한 CD80, CD86 및 MHCII 발현정도를 나타낸 것이다.
도 6은 본 발명에 의한 백신의 스파이크 항원에 대한 항체가를 나타낸 그래프이다.
도 7은 본 발명에 의한 백신 접종 후 항체형성 기간을 나타낸 것이다.
도 8은 스파이크 항원에 대한 세포독성 T세포(cytotoxic T cell)의 기억능에 관한 그래프이다.
도 9는 스파이크 항원에 대한 도움 T세포(helper T cell)의 기억능에 관한 그래프이다.
도 10은 스파이크 항원에 의하여 세포특이적 면역반응이 유도되었음을 나타내는 그래프이다.
도 11은 본 발명에 의한 백신의 뉴클레오캡시드 항원에 대한 항체가를 나타낸 그래프이다.
도 12는 뉴클레오캡시드 항원에 대한 세포독성 T세포(cytotoxic T cell)의 기억능에 관한 그래프이다.
도 13은 뉴클레오캡시드 항원에 대한 도움 T세포(helper T cell)의 기억능에 관한 그래프이다.
도 14는 뉴클레오캡시드 항원에 의하여 세포특이적 면역반응이 유도되었음을 나타내는 그래프이다.
도 15, 16은 본 발명에 의하여 재조합된 아데노바이러스를 감염시킨 세포에서 발현되는 항원과 완치환자의 항체 사이에 일어나는 항원항체 반응을 확인한 것이다.
도 17, 도 18은 본 발명에 의한 백신의 이중항원에 대한 중화항체가 검증을 나타낸 것이다.
도 19는 본 발명에 의한 백신의 SARS-CoV-2 D614G 변이바이러스에 대한 체액성 면역을 나타내는 그래프이다.
본 발명의 구체적인 일 실시예로서, 본 발명은 코로나바이러스(SARS-CoV-2)의 스파이크(spike) 단백질이 복제불능 아데노바이러스의 E1영역에 삽입되고, PgsA 및 코로나바이러스(SARS-CoV-2)의 뉴클레오캡시드(nucleocapsid) 단백질이 복제불능 아데노바이러스의 E3영역에 삽입된 형태로 발현되는 재조합 아데노바이러스로서 E1영역의 bp 350 내지 3328 부분 결실(deletion) 후 서열번호 1의 아미노산서열이 삽입되고, E3영역의 bp 28139 내지 30995 부분 결실(deletion) 후 서열번호 2의 아미노산서열이 삽입되는 것을 특징으로 하는 재조합 아데노바이러스를 제공한다.
스파이크 단백질은 막-원위 S1 서브유닛과 막-근위 S2 서브유닛으로 구성되며 바이러스 외피에 동종 삼량체로 존재하는데, S1 서브유닛은 수용체결합 도메인을 통해 수용체를 인식하고, S2 서브유닛은 바이러스 진입에 필요한 막 융합을 담당하는 바, 이러한 스파이크 단백질은 숙주세포 수용체와 결합시 필수적으로 작용하며, 감염시키는 숙주의 범위를 결정하는 요소로 알려져 있다. 뉴클레오캡시드는 바이러스 RNA와 결합된 뉴클레오캡시드 단백질로 구성되며, 뉴클레오캡시드 단백질은 바이러스 RNA 유전체에 결합하여 바이러스 입자 조립, 외피 형성, RNA합성 과정에서 유전체를 안정화하고 포장하는데 중요한 역할을 수행하는데, 뉴클레오캡시드 단백질은 돌연변이율이 낮다는 점에서 뉴클레오캡시드 단백질을 항원으로 사용시 SARS-CoV-2 변이바이러스에도 효과적으로 작용될 수 있다.
또한 본 발명의 또 다른 일 실시예로서 재조합 아데노바이러스에 의하여 제조되는 SARS-CoV-2 백신을 제공한다.
본 발명에서 단백질은 서열번호 1, 2의 아미노산 서열을 갖는 폴리펩타이드일 수 있다. 상기 단백질은 서열번호 1, 2와 동일한 폴리펩타이드 뿐만 아니라 이의 아미노산이 보존적 치환에 의하여 치환된 폴리펩타이드, 이와 80 내지 99%, 85 내지 99%, 바람직하게는 90 내지 99%의 서열 상동성을 갖는 폴리펩타이드를 모두 포함할 수 있다.
또한 본 발명의 또 다른 일 실시예로서 본 발명은 SARS-CoV-2 변이 바이러스에 작용하는 것을 특징으로 하는 코로나바이러스 백신을 제공하며, 상기 SARS-CoV-2 변이 바이러스는 D614G 변이 바이러스일 수 있다.
본 발명에서 사용한 용어 "백신 조성물"은 동물에서 면역학적 반응을 유도하는 적어도 하나 이상의 면역학적으로 활성인 성분을 함유하는 조성물을 의미한다.
본 발명에서 사용한 용어 "항원"은 바이러스의 구성성분 중 면역반응을 유도할 수 있는 성분으로서 바이러스가 발현하는 단백질을 의미한다.
본 발명에서 사용한 용어 "항체"는 면역계 내에서 항원의 자극에 의하여 만들어지는 성분으로서 특정한 항원과 특이적으로 결합하여 림프와 혈액을 떠돌며 항원-항체반응을 일으키는 단백질이다. 항원-항체 반응은 각 항원에 대하여 높은 특이성을 갖으며, 림프구의 B세포에서 항체가 만들어질 때 특정항원에 의해 생성된 항체는 원칙적으로 다른 항원과 반응하지 않는다. 이러한 높은 특이성은 면역, 알레르기, 각종 병 및 감염의 종류·형의 결정 등의 검사에 사용된다.
상기 백신 조성물은 당업계에 알려진 임의의 형태, 예를 들면, 액제 및 주사제의 형태 또는 현탁액에 적합한 고체 형태일 수 있으나, 이에 한정되는 것은 아니다. 이러한 제제는 또한 리포좀이나 가용 유리 내로 유화 또는 캡슐화되거나 에어로졸이나 스프레이 형태로도 제조될 수 있다. 이들은 경피(transdermal) 패치에 함유시킬 수도 있다. 액제 또는 주사제의 경우, 필요시 프로필렌글리콜 및 용혈 현상을 방지하는데 충분한 양의 염화나트륨을 함유할 수 있다.
본 발명의 백신 조성물은 약제학적으로 허용가능한 담체 또는 희석제를 포함할 수 있다. 백신에 적합한 담체는 기술분야의 당업자에게 공지되어 있으며, 단백질, 당 등을 포함할 수 있지만, 이에 한정되는 것은 아니다. 상기의 담체는 수용액 또는 비-수용액, 현탁액, 및 에멀전일 수 있다. 비-수용액 담체의 예는 프로필렌글리콜, 폴리에틸렌 글리콜, 식용유 예컨대 올리브 오일, 및 주사 가능한 유기 에스테르 예컨대 에틸 올리에이트일 수 있다.
또한, 상기 백신 조성물은 어주번트(adjuvant, 면역조성제, 면역증강제)를 추가로 포함할 수 있다. 상기 어주번트는 면역반응의 향상 및/또는 접종 후 흡수 속도를 촉진하는 화합물 또는 혼합물을 칭하는 것으로 임의의 흡수-촉진제를 포함할 수 있다. 허용 가능한 어주번트로는 프로인트 완전 어주번트, 프로인트 불완전 어주번트, 사포닌, 미네랄 젤 예컨대 수산화 알루미늄, 계면활성제 예컨대 리소레시틴, 플루론 폴리올, 다중음이온, 펩타이드, 오일 또는 탄화수소 에멀전, 키홀림펫 헤모시아닌, 디니트로페놀 등을 포함할 수 있으나, 이에 한정되는 것은 아니다.
본 발명의 백신 조성물은 경구, 경피, 근육내, 복막내, 정맥내, 피하내 또는 비강으로 이루어진 군으로부터 선택되는 어느 하나의 투여경로를 통해 투여될 수 있으며, 바람직하게는 주사로 투여되는 것이 바람직하다.
본 발명에서 용어 "SARS-CoV-2 감염 질환"이란 SARS-CoV-2 바이러스의 감염으로 유발되는 질환으로서, 부비강염, 발작적 천식, 중이염, 낭성 섬유종, 기관지염, 폐렴, 설사 등을 유발할 수 있으나, 이에 한정되지 않는다.
본 발명의 백신 조성물은 약제학적으로 유효한 양으로 투여한다. 본 발명의 용어 "약제학적으로 유효한 양"이란, 백신효과를 나타낼 수 있을 정도의 충분한 양으로, 부작용 또는 심각하거나 과도한 면역반응을 일으키지 않을 정도의 양을 의미하며, 유효 용량의 수준은 치료하려는 장애, 장애의 중증도, 특정 화합물의 활성, 투여 경로, 단백질의 제거 속도, 치료 지속 기간, 단백질과 조합되거나 동시에 사용되는 약물, 개체의 연령,체중, 성별, 식습관, 일반적인 건강 상태 및 의학 분야에 공지된 인자를 비롯한 다양한 인자들에 따라 달라질 수 있다.
이하, 구체적인 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.
실시예 1. 재조합 아데노바이러스 벡터를 이용한 SARS-CoV-2 백신 제조
본 실시예에서는 SARS-CoV-2 바이러스에 대한 백신 후보군으로서 당단백질인 스파이크 단백질과 뉴클레오캡시드 단백질을 동시 발현하는 백신을 제조하기 위하여, 복제불능 아데노바이러스의 E1영역에 SARS-CoV-2 스파이크(spike, S) 단백질을 코딩하는 유전자를 삽입하고, 복제불능 아데노바이러스의 E3영역에 세포막 고정 능력이 있는 단백질(membrane anchoring protein)인 PgsA 및 SARS-CoV-2 뉴클레오캡시드(nucleocapsid, N) 단백질을 코딩하는 유전자를 삽입하였는 바(도 3), PgsA는 뉴클레오캡시드 단백질을 세포막에 발현시킬 수 있도록 하는 역할을 하며, 삽입된 유전자들은 포유류 세포 발현에 대하여 최적화된 코돈으로서, 이에 의하여 발현되는 단백질은 체액성면역반응 및 세포매개성 반응을 유도하여 SARS-CoV-2 바이러스 감염 억제능을 가지게 된다.
실시예 2. 스파이크 단백질 및 뉴클레오캡시드 단백질 발현확인
Western blot을 통하여 스파이크 단백질 및 뉴클레오캡시드 단백질의 발현여부를 확인한 결과를 도 4에 나타내었다. 구체적으로, 각 단백질(항원)들의 발현 여부를 관찰하기 위해 제작된 SARS-CoV-2 백신후보군 1 내지 4(#1, #2, #3, #4)를 6well에 5x105 cells로 시딩(seeding)한 HEK293에 감염시킨 후 48시간 뒤에 스파이크 항체(anti spike) 및 PgsA 항체(anti PgsA)를 이용하여 western blot을 통해 발현 여부를 관찰하였고(도 4), 그 중 발현양이 가장 우수한 후보군 3(#3)을 이용하여 후속 실험을 진행하였으며, 후보군 3의 서열은 다음과 같다.
먼저, 아데노바이러스 E1 영역의 bp 350 부터 3328 부분을 결실(deletion)하고, SARS-CoV-2 스파이크 단백질 중 항원으로 작용가능한 부분을 코딩하는 유전자를 최적화하여 삽입하였는 바, 삽입된 아미노산 서열은 하기 서열번호 1과 같다.
서열번호 1
5`MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYRYRLFRKSNLKPFERDISTEIYQAGSKPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQGVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPSRAGSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT 3`
다음으로, 아데노바이러스 E3 영역의 bp 28139 부터 30995 부분을 결실(deletion)하고, PgsA 및 SARS-CoV-2 뉴클레오캡시드(nucleocapsid) 단백질 중 항원으로 작용가능한 부분을 코딩하는 유전자를 최적화하여 삽입하였는 바, 삽입된 아미노산 서열은 하기 서열번호 2와 같다.
서열번호 2
5`MKKELSFHEKLLKLTKQQKKKTNKHVFIAIPIVFVLMFAFMWAGKAETPKVKTYSDDVLSASFVGDIMMGRYVEKVTEQKGADSIFQYVEPIFRASDYVAGNFENPVTYQKNYKQADKEIHLQTNKESVKVLKDMNFTVLNSANNHAMDYGVQGMKDTLGEFAKQNLDIVGAGYSLSDAKKKISYQKVNGVTIATLGFTDVSGKGFAAKKNTPGVLPADPEIFIPMISEAKKHADIVVVQSHWGQEYDNDPNDRQRQLARAMSDAGADIIVGHHPHVLEPIEVYNGTVIFYSLGNFVFDQGWTRTRDSALVQYHLKKNGTGRFEVTPIDIHEATPAPVKKDSLKQKTIIRELTKDSNFAWKVEDGKLTFDIDHSDKLKSKGGSGGSGGSGGSGGSIGYYRRATRRIRGGPAPAPIIWVATEGAPAPAPLLLLDRLNQLPAPAPRTATKAYNVPAPAPFAPSASAFFGMSRIGMEVPAPAPTWLTYTGAIKLDDKDPNFKDQVILLPAPAPKHIDAYKTFPPTEPKK 3`
상기 후보군 3의 스파이크 단백질 및 뉴클레오캡시드 단백질에 대한 면역원성을 확인하기 위하여, 본 발명에 의한 바이러스를 면역 세포인 Raw264.7 세포에 처리하였을 때 Co-자극성 분자 (CD80, CD86) 및 II군 주요 조직 적합 유전자 복합체(Major histocompatibility complex II, MHCII) 발현정도를 각각 확인하여 도 5에 나타내었다.
B7 단백질은 활성화된 면역세포에서 나타나는 주변부 막 단백질로, T 세포의 표면 단백질인 CD28이나 CD152(CTLA-4)와의 상호작용으로 면역 세포와 T 세포 사이의 MHC-TCR 신호전달을 증가시키거나 감소시키는 공동자극 신호를 만들 수 있는데, B7 단백질에는 B7-1(CD80)와 B7-2(CD86) 두 가지 주요 타입이 있고, CD28과 CTLA-4는 각각 CD80과 CD86 모두와 상호작용한다. 또한, II 군 주요 조직 적합 유전자 복합체(Major histocompatibility complex II; MHCII) 분자들은 외부 항원이 면역 세포에 도입되었을때 세포내에서 단편으로 분해 후 외부에 항원 노출 및 발현을 시키는 역할을 하는 바, 이러한 CD80, CD86 및 MHCII는 항원 전달능의 평가 지표가 될 수 있다.
구체적으로 Raw264.7 세포에 본 발명에 의한 바이러스를 20moi로 감염시킨 후 48시간 뒤 세포를 각각 Co-자극성 분자 (CD80, CD86), MHCII를 이용하여 염색하고, navios flow cytometer(Beckman Coulter사)를 이용하여 발현도를 검출하였으며, 데이터는 MFI (평균 형광강도; mean fluorescence intensity)로 표현하였는 바, 항원이 도입되지 않은 Mock과 비교하여 스파이크 단백질 및 뉴틀레오캡티드 단백질이 도입된 백신에서 CD80, CD86, MHCII 분자들의 발현양이 현저하게 증가하였음을 확인할 수 있다(도 5).
실시예 3. 스파이크 항원에 대한 면역원성 확인
실시예 3-1. 체액성 면역 확인
먼저 본 발명에 의한 백신의 면역원성을 평가하기 위해 스파이크 단백질(항원)에 대한 항체가(antibody titer) 검증을 실시하였다. 여기서 항체가는 특정 항원에 대해서 대응하는 항체의 역가로서 항체의 양을 나타내는 단위이고 항체를 포함한 용액을 희석해 동일량의 항원을 가한 경우에 반응이 생기는 최대희석 농도의 역수로 표시한다.
본 실시예에서는 그룹당 다섯 마리의 암컷 BALB/c 마우스(Orient, Korea) 6 내지 8주령 마우스를 이용하여, 0 및 14일 째에 5x108, 5x109, 1x1010, 5x1010VP(viral particles)로 mock 및 SARS-CoV-2 백신을 근육 접종을 통해 각각 면역화시킨 후 28일째에 마우스의 혈청을 분리하였다. 이 후, 효소 면역 측정법(enzyme-linked immunosorbent assay; ELISA)을 통하여 SARS-CoV-2 스파이크 단백질 특이적 항체반응을 측정하였다. 마이크로타이터플레이트(Microtiter plate, Nunc, Denmark)에 50mM 중탄산나트륨 완충액(pH 9.6)중에서 100ng/well로 스파이크 단백질 100μL를 코팅하고, 4℃에서 밤새 배양하였다. 그 후 플레이트를 PBST(PBS+0.05% tween20)로 세척하고, 실온에서 1시간 동안 1% BSA(Bovine Serum Albumin, 우태아혈청알부민)가 포함된 PBS로 블록킹시킨 후, 혈청을 상기 블록킹완충액을 이용하여 1/800, 1/3200, 1/12800, 1/51200으로 희석하였다. 그 후, 시료 100μL를 각 웰에 도말한 후 상온에서 1시간 동안 배양하고, PBST 400 μL로 4회 세척 후 mouse IgG-HRP를 1:1000 비율로 희석 후 플레이트에 100 μL로 도말하고 상온에서 1시간 동안 배양하였다. 그 후 PBST 400 μL로 4회 세척 후 TMB기질 용액100 μL로 암중에서 20분 동안 색상을 발현시켰다. 그 후 2N 황산 용액으로 반응을 정지시킨 후 마이크로플레이트 리더기(Thermoscientific사의 multiskansky)에서 450nm에서의 흡수능을 측정하였는 바, 항체가는 Cutoff value: the mean optical density values at 450nm (OD450)+3×standard derivations (SD) from the sera of non-vaccinated animals (Nat Commun. 2020; 11: 4207) 문헌을 참조하여 결정하였고, 1x1010VP 이상에서 안정적인 항체가를 나타내는 것을 확인할 수 있었다(도 6).
본 발명에 의한 SARS-CoV-2 백신 접종 후 항체형성 기간을 확인하기 위하여, 그룹당 다섯 마리의 암컷BALB/c 마우스(Orient, Korea) 6 내지 8주령을 이용하였다. 마우스를 0 및 14일째에 1x1010VP로 mock 및 SARS-CoV-2 백신을 근육 접종을 통해 면역화시켰으며, 2주, 4주, 6주째에 마우스에서 혈청을 분리한 후, 효소 면역 측정법(enzyme-linked immunosorbent assay; ELISA)으로 SARS-CoV-2 스파이크 특이적 항체반응을 측정하였다. 마이크로타이터플레이트(Microtiter plate, Nunc, Denmark)에 50mM 중탄산나트륨 완충액(pH 9.6)중에서 100ng/well로 스파이크 단백질100 μL를 코팅하고, 4℃에서 밤새 배양하였다. 그 후 플레이트를 PBST(PBS+0.05% tween20)로 세척하고, 실온에서 1시간 동안 1% BSA(우태아혈청알부민)가 포함된 PBS로 블록킹시켰다. 상기 블록킹완충액으로 혈청을 1/800, 1/3200, 1/12800, 1/51200로 희석한 후, 시료100μL를 각 웰에 도말하고 상온에서 1시간 동안 배양하였다. 다음으로 PBST 400μL로 4회 세척 후 mouse IgG-HRP를 1:1000 비율로 희석 후 플레이트에 100μL로 도말하고 상온에서 1시간 동안 배양하였고, PBST 400μL로 4회 세척 후 TMB기질 용액100 μL로 암중에서 20분 동안 색상을 발현시켰다. 그 후 2N 황산 용액으로 반응을 정지시킨 후 마이크로플레이트 리더기(Thermoscientific사의 multiskansky)에서 450nm에서의 흡수능을 측정하였다. 항체가는 Cutoff value: the mean optical density values at 450nm (OD450)+3×standard derivations (SD) from the sera of non-vaccinated animals (Nat Commun. 2020; 11: 4207) 문헌을 참조하여 결정하였는 바(도 7), 접종 후 2주 시점부터 안정적으로 SARS-CoV-2 스파이크 단백질 특이적 항체가 형성되는 것을 확인할 수 있다.
실시예 3-2. 세포성 면역 확인
본 발명에 의한 백신의 스파이크 단백질에 대한 세포 매개성 면역반응을 확인하기 위하여 6 내지 8주령 암컷BALB/c 마우스(Orient, Korea)의 비장에서 단일 세포를 분리한 후 유세포분석기를 통해 T세포에서 면역반응을 유도하는데 있어서 중요한 여러 가지 사이토카인의 분비 정도를 측정하였다.
본 실시예에서는 그룹 당 다섯 마리의 마우스를 0 및 14일 째에 1x1010VP로 mock 및 SARS-CoV-2 백신을 근육 접종을 통해 면역화시킨 후 3주 뒤 마우스의 비장을 적출하여 비장세포(splenocyte)를 분리한 후 24웰플레이트에 웰당 1 x 106세포로 시딩(seeding)하고, SARS-CoV-2 스파이크 20 μg/mL로 24시간 동안 재자극하였다. 그 후 단백질 운반 저해제인 GolgiPlug(BD Biosciences)를 가하여 세포질에 사이토카인을 집적시키고, 6시간 동안 배양하였다. 이 후 PBS로 세척한 후, 세포를 BD Cytofix/cytoperm키트(BD Biosciences)에 통과시키고, 항-CD4, CD8, CD45, IFN-gamma 및 GranzymeB(BD Biosciences)로 염색하였다. CD4는 항-CD4, CD45로 gating한 후 gating안에 있는 세포에서 IFN-gamma, 및 GranzymeB를 동시 발현하는 세포를 Beckman Coulter사의 naviosflow cytometer를 이용하여 세포 관련 형광도의 수준을 측정하였다. CD8은 항-CD8, CD45로 gating한 후 gating안에 있는 세포에서 IFN-gamma, 및 GranzymeB를 동시 발현하는 세포를 Beckman Coulter사의 naviosflow cytometer를 이용하여 세포 관련 형광도의 수준을 측정하였다(도 8, 9). 도 8, 도 9에 따르면, 대조군에 비해 본 발명에 의한 백신으로 면역화시킨 마우스에서 IFN-gamma, 및 GranzymeB 사이토카인을 분비하는 세포가 유의적으로 증가된 것을 확인할 수 있다. 이는 백신이 접종된 마우스에 SARS-CoV-2 바이러스로 감염되었을 때 체내의 T-cell들이 활성화되어 외래 인자를 사멸 시킬 수 있는 IFN-gamma, 및 GranzymeB를 분비하는 것을 의미한다.
또 다른 실시예에서는 본 발명에 의한 SARS-CoV-2 백신이 유도하는 스파이크 항원에 특이적인 IFN-gamma ELISPOT 반응을 도 10에 나타내었으며, SARS-CoV-2 백신의 면역화만으로도 특이적 세포성 면역반응이 유도되었음을 확인할 수 있다. 구체적으로, 그룹 당 다섯 마리의 마우스를 0 및 14일째에 1x1010VP로 mock 및 SARS-CoV-2 백신을 근육 접종을 통해 면역화시킨 후 3주 뒤 마우의 비장을 적출하여 비장세포(splenocyte)를 분리하여 24웰플레이트에 웰당 1 x 106세포로 시딩(seeding)하고, SARS-CoV-2 스파이크 20μg/mL로 48 시간 동안 재자극하였다. 그 후 IFN-gamma ELISPOT assay 키트를 이용하여 스파이크 특이적 IFN-gamma ELISPOT 반응을 확인하였다. 도 10에 따르면, Mock으로 면역화된 마우스보다 백신 접종된 마우스의 비장에서 항원 특이적으로 IFN gamma를 생성하는 세포수(spot number)가 유의적으로 증가하는 것을 관찰할 수 있는데, 이는 본 발명에 의한 백신을 접종한 마우스에서는 백신 항원에 대한 기억능에 의하여 T-cell이 생성되어, 이차적 자극에 대해서도 항원 특이적 세포성 면역반응을 한다고 해석될 수 있다.
실시예 4. 뉴클레오캡시드 항원에 대한 면역원성 확인
실시예 4-1. 체액성 면역 확인
본 발명에 의한 백신의 면역원성을 평가하기 위해 뉴클레오캡시드(항원)에 대한 항체가 검증을 실시하였다. 구체적으로, 그룹당 다섯 마리의 암컷 BALB/c 마우스(Orient, Korea) 6 내지 8주령 마우스를 이용하여, 0 및 14일째에 1x1010VP로 mock 및 SARS-CoV-2 백신을 근육 접종을 통해 면역화시킨 후 28일째에 마우스의 혈청을 분리하여 효소 면역 측정법(enzyme-linked immunosorbent assay; ELISA)으로 뉴클레오캡시드 특이적 항체 반응을 측정하였다. 마이크로타이터플레이트(Microtiter plate, Nunc, Denmark)에 50mM 중탄산나트륨 완충액(pH 9.6)중에서 100ng/well로 뉴클레오캡시드 단백질 100 μL를 코팅하고, 4℃에서 밤새 배양하였다. 플레이트를 PBST(PBS+0.05% tween20)로 세척하고, 실온에서 1시간 동안 1% BSA(우태아혈청알부민)가 포함된 PBS로 블록킹시키고, 혈청 1/800, 1/3200, 1/12800, 1/51200를 상기 블록킹완충액으로 희석한 후, 시료 100μL를 각 웰에 도말하고 상온에서 1시간 동안 배양하였다. 이 후 PBST 400μL로 4회 세척 후 mouse IgG-HRP를 1:1000 비율로 희석 후 플레이트에 100μL로 도말하고 상온에서 1시간 동안 배양하였고, PBST 400μL로 4회 세척 후 TMB기질 용액100 μL로 암중에서 20분 동안 색상을 발현시켰다. 그 후 2N 황산 용액으로 반응을 정지시킨 후 450nm에서의 흡수능을 마이크로플레이트 리더기(Thermoscientific사의 multiskansky)에서 측정하였다. 항체가는 Cutoff value: the mean optical density values at 450nm (OD450)+3×standard derivations (SD) from the sera of non-vaccinated animals (Nat Commun. 2020; 11: 4207) 문헌을 참조하여 결정하였는 바, 1x1010VP에서 안정적인 항체가를 나타내는 것을 확인할 수 있었다(도 11).
실시예 4-2. 세포성 면역 확인
본 발명에 의한 백신의 뉴클레오캡시드 단백질에 대한 세포 매개성 면역반응을 확인하기 위하여 6 내지 8주령 암컷BALB/c 마우스(Orient, Korea)의 비장에서 단일 세포를 분리한 후 유세포분석기를 통해 T세포에서 면역반응을 유도하는데 있어서 중요한 여러 가지 사이토카인의 분비 정도를 측정하였다. 그룹 당 다섯 마리의 마우스를 0 및 14일째에 1x1010VP로 mock 및 SARS-CoV-2 백신을 근육 접종을 통해 면역화시킨 후 3주 뒤 마우스의 비장을 적출하여 비장세포(splenocyte)를 분리한 후 24웰플레이트에 웰당 1 x 106세포로 시딩(seeding)하고, 뉴클레오캡시드 단백질 20μg/mL로 24 시간 동안 재자극하였다. 그 후 단백질 운반 저해제인 GolgiPlug(BD Biosciences)를 가하여 세포질에 사이토카인을 집적시키고, 6 시간 동안 배양하였다. 이 후 PBS로 세척한 후, 세포를 BD Cytofix/cytoperm키트(BD Biosciences)에 통과시시키고, 항-CD4, CD8, CD45, IFN-gamma, 및 GranzymeB(BD Biosciences)로 염색하였다. CD4는 항-CD4, CD45로 gating한 후 gating안에 있는 세포에서 IFN-gamma, 및 GranzymeB를 동시 발현하는 세포를 Beckman Coulter사의 naviosflow cytometer를 이용하여 세포 관련 형광도의 수준을 측정하였다. CD8는 항-CD8, CD45로 gating한 후 gating안에 있는 세포에서 IFN-gamma, 및 GranzymeB를 동시 발현하는 세포를 Beckman Coulter사의 naviosflow cytometer를 이용하여 세포 관련 형광도의 수준을 측정하였다 도 12, 13에 나타낸 바와 같이, 대조군과 비교하여 본 발명에 의한 SARS-CoV-2백신으로 면역화시킨 마우스에서 IFN-gamma, 및 GranzymeB 사이토카인을 분비하는 세포가 유의적으로 증가된 것을 확인할 수 있다. 이는 백신이 접종된 마우스에 SARS-CoV-2 바이러스로 감염되었을 때 체내의 T-cell들이 활성화되어 외래 인자를 사멸 시킬 수 있는 IFN-gamma, 및 GranzymeB를 분비하는 것을 의미한다.
또 다른 실시예에서는 본 발명에 의한 SARS-CoV-2 백신이 유도하는 뉴클레오캡시드 항원에 특이적인 IFN-gamma ELISPOT 반응을 도 14에 나타내었으며, SARS-CoV-2 백신의 면역화만으로도 특이적 세포성 면역반응이 유도되었음을 확인할 수 있다. 구체적으로, 그룹 당 다섯 마리의 마우스를 0 및 14일째에 1x1010VP로 mock 및 SARS-CoV-2 백신을 근육 접종을 통해 면역화시킨 후 3주 뒤 마우의 비장을 적출하여 비장세포(splenocyte)를 분리하여 24웰플레이트에 웰당 1 x 106세포로 시딩(seeding)하고, SARS-CoV-2 뉴클레오캡시드 20μg/mL로 48 시간 동안 재자극하였다. 그 후 IFN-gamma ELISPOT assay 키트를 이용하여 뉴클레오캡시드 특이적 IFN-gamma ELISPOT 반응을 확인하였다. 도 14에 따르면, Mock으로 면역화된 마우스보다 백신 접종된 마우스의 비장에서 항원 특이적으로 IFN gamma를 생성하는 세포수(spot number)가 유의적으로 증가하는 것을 관찰할 수 있는데, 이는 본 발명에 의한 백신을 접종한 마우스에서는 백신 항원에 대한 기억능에 의하여 T-cell이 생성되어, 이차적 자극에 대해서도 항원 특이적 세포성 면역반응을 한다고 해석될 수 있다(도 14).
실시예 5. SARS-CoV-2 완치환자의 혈청을 이용한 항원항체반응 확인
A549 세포에 Ad/spike(Ad/S), Ad/spike+nucleocapsid(Ad/S+N)를 100moi 처리 후 total protein lysate를 추출하여 5ug/ml 농도로 plate에 코팅하고 SARS-CoV-2 감염 후 완치된 환자의 혈청(1/100, 1/1000, 1/10000 희석)과 ELISA기법을 이용하여 반응을 확인한 결과 S+N 항원을 발현하는 단백질이 SARS-CoV-2에 대한 항체를 보유한 환자혈청과 강하게 반응하는 것을 확인할 수 있다(도 15, 도 16).
실시예 6. 이중항원에 대한 중화항체가 검증
본 발명에 의한 백신의 면역원성을 평가하기 위해 스파이크 단백질 및 뉴클레오캡시드 이중항원에 대한 중화항체가 검증을 실시하였다. 여기서 중화항체는 항체가 병원체의 표면 구조에 결합하여 이들이 세포에 결합하는 것을 억제함으로써 감염 차단, 확산 억제, 독소의 병적인 효과를 제거하는 이른바 중화작용(neutralization)을 통해 면역을 매개하는 것을 의미한다. 구체적으로, 먼저 96웰플레이트에 Vero cell을 각 웰당 1.5x104 cells/well 농도로 시딩(seeding)한 후 24시간 경과시켰다. 그 후 상기 시험물질(마우스로부터 채취한 혈청)을 1/10, 1/20, 1/40, 1/80, 1/160, 1/320, 1/640, 1/1280, 1/2560, 1/5120 농도로 희석하여 준비하고, 코로나바이러스 델타변이종(hCoV-19/Korea/KDCA119861/2021;NCCP43390)) 100 TCID50(90㎕/well)을 준비하였다. 다음으로 상기 항체 샘플과 코로나바이러스를 1:1 비율로 혼합한 후 37℃에서 30분 동안 인큐베이션하였고, 미리 준비된 상기 Vero cell에 각 웰당 40㎕씩 분주한 후 37℃ 5% CO2 인큐베이터에서 3일 동안 인큐베이션을 하였으며, 각 희석배수에 해당하는 중화능(%)을 확인하여 그 결과를 도 17, 도 18에 나타내었다. 도 17, 도 18은 본 발명에 의한 코로나바이러스 이중 항원 중화항체의 ID50값을 비교하여 나타낸 것으로 모두 active한 것을 확인할 수 있다.
실시예 7. SARS-CoV-2 변이바이러스에 대한 면역원성 확인
본 발명에 의한 백신의 SARS-CoV-2 변이바이러스에 대한 면역원성을 평가하기 위하여 6 내지 8주령 암컷 BALB/c 마우스(Orient, Korea)를 이용하였다. 그룹 당 다섯 마리의 마우스를 0 및 14일째에 1x1010VP로 mock 및 SARS-CoV-2 백신을 근육 접종을 통해 면역화시킨 후 28일째에 마우스의 혈청을 분리하였고, 효소 면역 측정법(enzyme-linked immunosorbent assay; ELISA)으로 스파이크 D614G 특이적 항체 반응을 측정하였다. 마이크로타이터플레이트(Microtiter plate, Nunc, Denmark)에 50mM 중탄산나트륨 완충액(pH 9.6)중에서 100ng/well로 스파이크 단백질100 μL를 코팅하고, 4℃에서 밤새 배양하였다. 플레이트를 PBST(PBS+0.05% tween20)로 세척하고, 실온에서 1시간 동안 1% BSA(우태아혈청알부민)가 포함된 PBS로 블록킹시키고, 혈청 1/800, 1/3200, 1/12800, 1/51200를 상기 블록킹완충액으로 희석한 후, 시료 100μL를 각 웰에 도말하고 상온에서 1시간 동안 배양하였다. 이 후 PBST 400μL로 4회 세척 후 mouse IgG-HRP를 1:1000 비율로 희석 후 플레이트에 100μL로 도말하고 상온에서 1시간 동안 배양하였고, PBST 400μL로 4회 세척 후 TMB기질 용액100 μL로 암중에서 20분 동안 색상을 발현시켰다. 그 후 2N 황산 용액으로 반응을 정지 시킨 후 450 nm에서의 흡수능을 마이크로플레이트 리더기 (Thermoscientific사의 multiskansky)에서 측정 하였다. 항체가는 Cutoff value: the mean optical density values at 450nm (OD450)+3×standard derivations (SD) from the sera of non-vaccinated animals (Nat Commun. 2020; 11: 4207) 문헌을 참조하여 결정하였으며 그 결과를 도 19에 나타내었는 바, 본 발명에 의한 백신은 스파이크 D614G 변이바이러스에도 안정적인 항체가를 나타내는 것을 확인할 수 있었다.
<110> Bioleaders Corporation
<120> Coronavirus vaccine using replication-deficient adenovirus that
simultaneously expresses coronavirus spike protein and
nucleocapsid protein
<130> O/PAPCT-QQ0293
<150> KR 10-2020-0149492
<151> 2020-11-10
<150> KR 10-2021-0136107
<151> 2021-10-13
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Claims (6)
- 코로나바이러스(SARS-CoV-2)의 스파이크(spike) 단백질이 복제불능 아데노바이러스의 E1영역에 삽입되고, PgsA 및 코로나바이러스(SARS-CoV-2)의 뉴클레오캡시드(nucleocapsid) 단백질이 복제불능 아데노바이러스의 E3영역에 삽입된 형태로 발현되는 재조합 아데노바이러스로서,
상기 E1의 bp 350 내지 3328 영역 결실(deletion) 후 서열번호 1의 아미노산서열이 삽입되고,
상기 E3의 bp 28139 내지 30995 영역 결실(deletion) 후 서열번호 2의 아미노산서열이 삽입되는 것을 특징으로 하는 재조합 아데노바이러스. - 제1항의 재조합 아데노바이러스에 의하여 제조되는 코로나바이러스(SARS-CoV-2) 백신.
- 제2항에 있어서, 상기 코로나바이러스 백신은 SARS-CoV-2 변이 바이러스에 작용하는 것을 특징으로 하는 코로나바이러스(SARS-CoV-2) 백신.
- 제3항에 있어서, 상기 SARS-CoV-2 변이 바이러스는 D614G 변이 바이러스인 것을 특징으로 하는 코로나바이러스(SARS-CoV-2) 백신.
- 제2항에 있어서, 어주번트(adjuvant)를 추가로 포함하는 것을 특징으로 하는 코로나바이러스(SARS-CoV-2) 백신.
- 제2항에 있어서, 상기 코로나바이러스 백신은 경구, 경피, 근육내, 복막내, 피하내 또는 비강으로 이루어진 군으로부터 선택되는 어느 하나의 투여경로를 통해 투여되는 것을 특징으로 하는 코로나바이러스(SARS-CoV-2) 백신.
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KR1020220056863A KR20230157180A (ko) | 2022-05-09 | 2022-05-09 | 코로나바이러스의 스파이크 단백질, 뉴클레오캡시드 단백질 및 PgsA 단백질을 동시발현하는 복제불능 아데노바이러스를 이용한 코로나바이러스 백신 |
PCT/KR2022/007208 WO2023219198A1 (ko) | 2022-05-09 | 2022-05-20 | 코로나바이러스의 스파이크 단백질, 뉴클레오캡시드 단백질 및 pgsa 단백질을 동시발현하는 복제불능 아데노바이러스를 이용한 코로나바이러스 백신 |
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KR1020220056863A KR20230157180A (ko) | 2022-05-09 | 2022-05-09 | 코로나바이러스의 스파이크 단백질, 뉴클레오캡시드 단백질 및 PgsA 단백질을 동시발현하는 복제불능 아데노바이러스를 이용한 코로나바이러스 백신 |
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