KR20220086521A - 신규 코로나바이러스 예방 및 치료용 백신 조성물 - Google Patents
신규 코로나바이러스 예방 및 치료용 백신 조성물 Download PDFInfo
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Abstract
본 발명은 신규 CoV 예방 및 치료용 백신 조성물에 관한 것으로서, 보다 구체적으로는 SARS CoV의 S 단백질을 암호화하는 제1폴리뉴클레오타이드 및 SARS CoV의 뉴클레오캡시드 단백질(NP 단백질)을 암호화하는 제2폴리뉴클레오타이드를 유효성분으로 포함하는 SARS CoV 예방 및 치료용 백신 조성물을 제공한다.
Description
본 발명은 백신 조성물에 관한 것으로서, 보다 구체적으로는 신규 코로나바이러스 예방 및 치료용 백신 조성물에 관한 것이다.
최근 코로나바이러스 19의 세계적 대유행(pandemic)으로 인해 인류는 심각한 공중보건학적 위기를 맞고 있다. 코로나바이러스 19는 건강한 사람은 걸리더라도 큰 문제가 없으나, 기저질환을 갖고 있거나 고령자에게는 큰 위협이 될 수 있고, 간혹 건강하고 젊은 사람일지라도 사이토카인 폭풍과 같은 비정상적인 면역반응이 유발될 경우 매우 심각한 상황을 초래할 수 있다. 코로나바이러스(Coronavirus, 이하, "CoV"로 약칭함)는 스파이크 당단백질(spike glycoprotein, S 당단백질, 이하 "S 단백질"로 약칭함), 헤마글루티닌-아세틸트랜스퍼레이즈 당단백질, 막 당단백질 및 작은 외피 당단백질과 같은 몇몇 당단백질로 구성되어 있다(도 1). 상기 S 단백질은 코로나바이러스의 수용체 인식과 막융합을 매개하고 감염 동안 체액성 면역반응의 일차적인 표적이 된다. CoV S 단백질은 두 개의 서브유닛으로 구성되어 있는데, 하나는 수용체 결합 도메인(RBD)을 포함하는 서브유닛(S1)이고 다른 하나는 융합 조직 서브유닛(fusion machinery subunit, S2)이다. 현재까지 오직 S 단백질만 중화 항체를 유도할 수 있을 것으로 알려지고 있으며, 이는 코로나바이러스에 대항할 수 있는 결정적인 효과기이다(도 2).
한편, 코로나바이러스 19의 pandemic은 현 사회에서 유례없는 심각한 팬데믹인만큼 그 어느 때보다 백신 개발이 빠르게 진행되고 있다. 2020년 1월 SARS-CoV-2 바이러스의 유전자 서열이 공개된 이후 많은 제약사 및 연구 기관에서 개발에 박차를 가했으며, 백신 개발 기간을 단축하기 위해 국제적인 연대를 구축하였다. 개발 플랫폼 또한 차세대 바이오 기술을 도입하여 여러 가지 종류의 백신이 개발되었으나, 기존 승인된 코로나 백신(mRNA 백신, Adenovirus 백신 등)의 안전성(아나필락시스, 혈소판 감소성 희귀 혈전증, 심근염 등)에 대한 우려 사례가 계속해서 보고되고 있다.
한편, SARS CoV-2 감염 후 T 세포 면역반응 강도와 질병의 심각성 사이에 상관관계 있음이 보고된 바 있고(Moderbacher, C.R. et al., Cell, 183(4): 996-1012, 2020), 2,826명의 고위험군에 대한 장기 추적결과, 낮은 T 세포 면역반응군에서만 COVID-19 증상이 발생하고, 오히려 항체가 없더라도 높은 T 세포 면역반응군은 COVID-19 발생 방어가 가능하다는 연구결과가 보고된 바 있다(//www.medrxiv.org/content/10.1101/2020.11.02.20222778v1.full-text). 따라서, 이러한 선행연구 결과에 따라 COVID-19 방어에 T 세포 면역반응이 주요한 역할을 할 것이라고 보고 있다.
따라서, 본 발명자들은 항체 뿐만 아니라 T 세포를 유도할 수 있는 안전한 백신을 개발하고자 예의 노력한 결과, 스파이크에 뉴클레오캡시드를 추가하여 강하고 폭 넓은 T 세포 면역을 유도하도록 GX-19N을 디자인하였다. 최근 백신 부작용에 대한 우려에 기반한 백신 접종 기피 현상이 팬데믹 시대의 사회적 문제로 대두되고 있는 상황에서, 안전성이 높고 폭넓은 면역반응 유도가 가능한 GX-19N은 COVID-19로 인한 질환을 차단할 수 있는 훌륭한 예방 백신이 될 것이다.
본 발명은 상기 문제점을 포함한 다양한 문제점을 해결하기 위한 것으로서, COVID-19를 포함한 CoV의 예방 및 치료를 위한 백신 조성물의 제공을 목적으로 한다. 그러나, 상기 목적에 의해 본 발명의 범위가 제한되는 것은 아니다.
본 발명의 일 관점에 따르면, SARS CoV의 S 단백질을 암호화하는 제1폴리뉴클레오타이드 및 SARS CoV의 NP 단백질을 암호화하는 제2폴리뉴클레오타이드를 유효성분으로 포함하는 SARS CoV 예방 및 치료용 백신 조성물이 제공된다.
본 발명의 다른 일 관점에 따르면, 상기 SARS CoV 예방 및 치료용 백신 조성물을 개체에 투여하는 단계를 포함하는 상기 개체의 SARS CoV 감염 증 예방 및 치료방법이 제공된다.
본 발명의 일 실시예에 따른 백신 조성물은 SARS CoV-2를 포함한 SARS 코로라바이러스의 감염에 대항하여 중화 항체의 생성을 촉진할 뿐만 아니라, 항원 특이적 T 세포 면역반응을 유도함으로써 재감염에 대한 저항면역 형성이 도움이 될 수 있기 때문에, 다양한 변종 바이러스에 대한 감염 예방 및 치료용 백신으로 유용하게 사용될 수 있다.
도 1는 CoV의 비리온 구조를 개략적으로 나타낸 개요도이다.
도 2는 CoV의 스파이크 당단백질(S 단백질)의 도메인 구조를 개략적으로 나타낸 개요도이다.
도 3은 본 발명자에 의해 도출된 COVID-19 S 단백질의 대표 아미노산 서열이다.
도 4는 본 발명자에 의해 도출된 COVID-19 S 단백질의 대표 아미노산 서열 내 신호 펩타이드 위치를 예측 프로그램을 통해 확인한 결과이다.
도 5는 본 발명자들에 의해 도출된 COVID-19 S 단백질의 대표 아미노산 서열에서 개별 도메인의 위치를 아미노산 서열에 표시하여 나타낸 결과이다.
도 6은 본 발명의 일 실시예에 따른 CoV 예방 및 감염용 DNA 백신의 다양한 구조를 개략적으로 나타낸 유전자 맵이다.
도 7은 본 발명의 일 실시에에 따른 S 단백질의 삼량체화 유도를 위해 사용되는 삼량체 형성 재조합 단백질인 T4 박테리오파지 fibritin(A), 서펙틴 D 단백질(B) 및 CD40L(C)를 이용한 재조합 단백질 삼량체화 전략을 개략적으로 나타낸 개요도이다.
도 8은 본 발명의 실시예에 따른 COVID-19 DNA 백신 컨스트럭트로부터 단백질의 발현 여부를 확인한 결과이다.
도 9 내지 도 11은 마우스 모델에서 COVID-19 DNA 백신의 효능(항체 반응, T 세포 반응)을 확인한 실험 방법과 결과이다.
도 12a는 본 발명의 일 실시예에 따라 제조된 다양한 SARS CoV-2 항원(pGX27-S: S1S2full, pGX27-SΔTM: S1S2ΔTM/IC)을 발현시키기 위해 제조된 유전자 컨스트럭트의 구조를 나타내는 개요도이고, 도 12b는 상기 유전자 컨스트럭트로 형질전환된 세포에서 생산된 SARS CoV-2 항원의 발현을 웨스턴블랏 분석으로 분석한 결과를 나타내는 사진이다.
도 13은 본 발명의 일 실시예에 따른 DNA 백신 조성물의 투여 정보(상단) 및 마우스에 대한 투여스케쥴(하단)을 나타내는 개요도이다.
도 14는 본 발명의 일 실시예에 따라 제조된 다양한 백신 조성물을 마우스 모델에 투여한 후 면역반응을 측정한 결과를 나타내는 그래프이다.
도 15는 본 발명의 일 실시예에 따른 DNA 컨스트럭트 pGX-21의 구조를 개략적으로 나타낸 개요도이다.
도 16a는 본 발명의 일 실시예에 따른 백신 조성물 GX-19 및 GX-19N을 소동물인 마우스에 접종하여 백신으로서의 효능을 검증하는 동물실험 스케쥴을 나타내는 개요도이고, 도 16b는 백신 접종 후 실험동물에서 중화 항체의 생성 여부를 확인한 surrogate virus neutralization test(SVNT) 결과를 나타내는 그래프이며, 도 16c는 본 발명의 일 실시예에 따른 백신 조성물 투여 후, 항원(스파이크 펩타이드 및 뉴클레오캡시드 펩타이드) 특이적 T 세포 면역반응을 INF-γ ELISPOT으로 분석한 결과를 나타내는 그래프이다.
도 17a는 본 발명의 일 실시예에 따른 백신 조성물 GX-19 및 GX-19N을 대동물인 게잡이 원숭이에 접종하여 백신으로서의 효능을 검증하는 동물실험 스케쥴을 나타내는 개요도이고, 도 17b는 백신 접종 후 실험동물에서 중화 항체의 생성 여부를 확인한 surrogate virus neutralization test(SVNT) 결과를 나타내는 그래프이며, 도 17c는 본 발명의 일 실시예에 따른 백신 조성물 투여 후, 항원(스파이크 펩타이드 및 뉴클레오캡시드 펩타이드) 특이적 T 세포 면역반응을 INF-γ ELISPOT으로 분석한 결과를 나타내는 그래프이다.
도 18a는 본 발명의 일 실시예에 따른 백신 조성물 GX-19 및 GX19N에 대한 1상 임상시험에서의 항체 역가를 측정한 결과를 나타내는 일련의 그래프이고, 도 18b는 본 발명의 일 실시예에 따른 GX-19N 3.0 mg 용량군에서의 중화 항체 역가를 PsVNA 분석을 이용하여 측정한 결과를 나타내는 그래프(좌측) 및 SARS CoV-2 감염후 회복중인 환자에서의 중화 항체 역가를 동일한 방법으로 측정한 결과를 나타내는 그래프(우측)이며, 도 18c는 본 발명의 일 실시예에 따른 DNA 백신 조성물 GX-19N 3.0 mg 용량군에서의 중화 항체 역가를 FRNT 분석으로 측정한 결과를 나타내는 그래프(좌측) 및 SARS CoV-2 감염 후 회복중인 환자에서의 중화 항체 역가를 동일한 방법으로 측정한 결과를 나타내는 그래프(우측)이다.
도 19a는 본 발명의 일 실시예에 따른 DNA 백신 조성물 GX-19 접종 후 시험대상자에서 수득한 말초혈액 단핵구의 S-특이적인 T 세포 반응을 측정한 결과를 나타내는 그래프(좌측: 1.5 mg 용량군, 우측: 3.0 mg 용량군)이고, 도 19b는 본 발명의 일 실시예에 따른 DNA 백신 조성물 GX-19N 3.0 mg 용량군에서 수득한 말초혈액 단핵구의 S-특이적인 T 세포 반응을 측정한 결과를 나타내는 그래프이며, 도 19c는 본 발명의 일 실시예에 따른 DNA 백신 pGX-19N 3.0 mg 용량군에서 수득한 말초혈액 단핵구의 S-특이적 및 N-특이적 T 세포 반응을 각각 측정한 결과를 나타내는 일련의 그래프이다.
도 20a는 pGX-19N 백신 임상시험 시험대상자들에 대한 NP-특이적 에피토프를 포함하는 15-mer의 펩타이드의 아미노산 서열과 SARS CoV-2 변이체의 아미노산 서열을 비교하기 위한 IFN-γ ELISPOT 분석에 대한 개요도(상단) 및 실제 IFN-γ ELISPOT 분석을 수행한 결과를 촬영한 일련의 사진들(하단)이고, 도 20b는 상기 도 20a의 결과를 임상시험 시험대상자 개개인별로 정량화하여 나타낸 일련의 그래프이며, 도 20c는 T ELISpot 분석에서 T 세포 반응이 확인되지 않은 시험대상자를 대상으로 항원 유래 일련의 15-mer 펩타이드를 이용한 다양한 SARS CoV-2 바이러스 유래 항원 펩타이드와의 서열 상동성을 조산 결과를 나타내는 것이다.
도 2는 CoV의 스파이크 당단백질(S 단백질)의 도메인 구조를 개략적으로 나타낸 개요도이다.
도 3은 본 발명자에 의해 도출된 COVID-19 S 단백질의 대표 아미노산 서열이다.
도 4는 본 발명자에 의해 도출된 COVID-19 S 단백질의 대표 아미노산 서열 내 신호 펩타이드 위치를 예측 프로그램을 통해 확인한 결과이다.
도 5는 본 발명자들에 의해 도출된 COVID-19 S 단백질의 대표 아미노산 서열에서 개별 도메인의 위치를 아미노산 서열에 표시하여 나타낸 결과이다.
도 6은 본 발명의 일 실시예에 따른 CoV 예방 및 감염용 DNA 백신의 다양한 구조를 개략적으로 나타낸 유전자 맵이다.
도 7은 본 발명의 일 실시에에 따른 S 단백질의 삼량체화 유도를 위해 사용되는 삼량체 형성 재조합 단백질인 T4 박테리오파지 fibritin(A), 서펙틴 D 단백질(B) 및 CD40L(C)를 이용한 재조합 단백질 삼량체화 전략을 개략적으로 나타낸 개요도이다.
도 8은 본 발명의 실시예에 따른 COVID-19 DNA 백신 컨스트럭트로부터 단백질의 발현 여부를 확인한 결과이다.
도 9 내지 도 11은 마우스 모델에서 COVID-19 DNA 백신의 효능(항체 반응, T 세포 반응)을 확인한 실험 방법과 결과이다.
도 12a는 본 발명의 일 실시예에 따라 제조된 다양한 SARS CoV-2 항원(pGX27-S: S1S2full, pGX27-SΔTM: S1S2ΔTM/IC)을 발현시키기 위해 제조된 유전자 컨스트럭트의 구조를 나타내는 개요도이고, 도 12b는 상기 유전자 컨스트럭트로 형질전환된 세포에서 생산된 SARS CoV-2 항원의 발현을 웨스턴블랏 분석으로 분석한 결과를 나타내는 사진이다.
도 13은 본 발명의 일 실시예에 따른 DNA 백신 조성물의 투여 정보(상단) 및 마우스에 대한 투여스케쥴(하단)을 나타내는 개요도이다.
도 14는 본 발명의 일 실시예에 따라 제조된 다양한 백신 조성물을 마우스 모델에 투여한 후 면역반응을 측정한 결과를 나타내는 그래프이다.
도 15는 본 발명의 일 실시예에 따른 DNA 컨스트럭트 pGX-21의 구조를 개략적으로 나타낸 개요도이다.
도 16a는 본 발명의 일 실시예에 따른 백신 조성물 GX-19 및 GX-19N을 소동물인 마우스에 접종하여 백신으로서의 효능을 검증하는 동물실험 스케쥴을 나타내는 개요도이고, 도 16b는 백신 접종 후 실험동물에서 중화 항체의 생성 여부를 확인한 surrogate virus neutralization test(SVNT) 결과를 나타내는 그래프이며, 도 16c는 본 발명의 일 실시예에 따른 백신 조성물 투여 후, 항원(스파이크 펩타이드 및 뉴클레오캡시드 펩타이드) 특이적 T 세포 면역반응을 INF-γ ELISPOT으로 분석한 결과를 나타내는 그래프이다.
도 17a는 본 발명의 일 실시예에 따른 백신 조성물 GX-19 및 GX-19N을 대동물인 게잡이 원숭이에 접종하여 백신으로서의 효능을 검증하는 동물실험 스케쥴을 나타내는 개요도이고, 도 17b는 백신 접종 후 실험동물에서 중화 항체의 생성 여부를 확인한 surrogate virus neutralization test(SVNT) 결과를 나타내는 그래프이며, 도 17c는 본 발명의 일 실시예에 따른 백신 조성물 투여 후, 항원(스파이크 펩타이드 및 뉴클레오캡시드 펩타이드) 특이적 T 세포 면역반응을 INF-γ ELISPOT으로 분석한 결과를 나타내는 그래프이다.
도 18a는 본 발명의 일 실시예에 따른 백신 조성물 GX-19 및 GX19N에 대한 1상 임상시험에서의 항체 역가를 측정한 결과를 나타내는 일련의 그래프이고, 도 18b는 본 발명의 일 실시예에 따른 GX-19N 3.0 mg 용량군에서의 중화 항체 역가를 PsVNA 분석을 이용하여 측정한 결과를 나타내는 그래프(좌측) 및 SARS CoV-2 감염후 회복중인 환자에서의 중화 항체 역가를 동일한 방법으로 측정한 결과를 나타내는 그래프(우측)이며, 도 18c는 본 발명의 일 실시예에 따른 DNA 백신 조성물 GX-19N 3.0 mg 용량군에서의 중화 항체 역가를 FRNT 분석으로 측정한 결과를 나타내는 그래프(좌측) 및 SARS CoV-2 감염 후 회복중인 환자에서의 중화 항체 역가를 동일한 방법으로 측정한 결과를 나타내는 그래프(우측)이다.
도 19a는 본 발명의 일 실시예에 따른 DNA 백신 조성물 GX-19 접종 후 시험대상자에서 수득한 말초혈액 단핵구의 S-특이적인 T 세포 반응을 측정한 결과를 나타내는 그래프(좌측: 1.5 mg 용량군, 우측: 3.0 mg 용량군)이고, 도 19b는 본 발명의 일 실시예에 따른 DNA 백신 조성물 GX-19N 3.0 mg 용량군에서 수득한 말초혈액 단핵구의 S-특이적인 T 세포 반응을 측정한 결과를 나타내는 그래프이며, 도 19c는 본 발명의 일 실시예에 따른 DNA 백신 pGX-19N 3.0 mg 용량군에서 수득한 말초혈액 단핵구의 S-특이적 및 N-특이적 T 세포 반응을 각각 측정한 결과를 나타내는 일련의 그래프이다.
도 20a는 pGX-19N 백신 임상시험 시험대상자들에 대한 NP-특이적 에피토프를 포함하는 15-mer의 펩타이드의 아미노산 서열과 SARS CoV-2 변이체의 아미노산 서열을 비교하기 위한 IFN-γ ELISPOT 분석에 대한 개요도(상단) 및 실제 IFN-γ ELISPOT 분석을 수행한 결과를 촬영한 일련의 사진들(하단)이고, 도 20b는 상기 도 20a의 결과를 임상시험 시험대상자 개개인별로 정량화하여 나타낸 일련의 그래프이며, 도 20c는 T ELISpot 분석에서 T 세포 반응이 확인되지 않은 시험대상자를 대상으로 항원 유래 일련의 15-mer 펩타이드를 이용한 다양한 SARS CoV-2 바이러스 유래 항원 펩타이드와의 서열 상동성을 조산 결과를 나타내는 것이다.
본 발명의 일 관점에 따르면, SARS CoV의 S 단백질을 암호화하는 제1폴리뉴클레오타이드 및 SARS CoV의 뉴클레오캡시드 단백질(NP 단백질)을 암호화하는 제2폴리뉴클레오타이드를 유효성분으로 포함하는 SARS CoV 예방 및 치료용 백신 조성물이 제공된다.
상기 조성물에 있어서, 상기 S 단백질은 i) S1 단백질 또는 그의 수용체 결합 도메인을 포함하는 단편 또는 ii) 상기 S1 단백질 또는 그의 수용체 결합 도메인을 포함하는 단편 및 막통과 도메인이 제거된 S2 단백질을 포함하는 융합 단백질일 수 있다.
상기 조성물에 있어서, 상기 SARS CoV의 S1 수용체 결합 도메인은 SARS CoV-2 S 단백질(서열번호 38) 기준으로 319 내지 541 번째 아미노산 잔기에 상응하는 폴리펩타이드(서열번호 41)를 포함할 수 있고, 상기 막통과 도메인은 SARS CoV-2 S 단백질(서열번호 38) 기준으로 1214 내지 1234번째 아미노산 잔기에 상응하는 폴리펩타이드일 수 있으며, 상기 S1 단백질은 서열번호 1로 기재되는 아미노산 서열을 포함할 수 있다.
상기 조성물에 있어서, 상기 막통과 도메인이 제거된 S2 단백질은 SARS CoV-2 S 단백질(서열번호 38) 기준으로 685 내지 1213 번째 아미노산 잔기에 상응하는 폴리펩타이드일 수 있으며, 상기 S 단백질(S1S2ΔTM/IC)은 SARS CoV-2 S 단백질(서열번호 38) 기준으로 16 내지 1213 번째 아미노산 잔기에 상응하는 폴리펩타이드를 포함할 수 있다.
상기 조성물에 있어서, 상기 S 단백질은 C-말단에 삼량체 형성 도메인이 부가된 융합 단백질일 수 있고, 상기 삼량체 형성 도메인은 CD40L 엑토도메인, T4 박테리오파지 fibritin 또는 그의 C-말단 도메인(foldon 도메인), Fas 리간드, 41BB, OX40L, CD70, TRAIL, 또는 서펙틴일 수 있으며, CD40L 엑토도메인 또는 foldon 도메인인 것이 바람직하다. 상기 CD40L 엑토도메인은 서열번호 5로 기재되는 아미노산 서열을 포함할 수 있고, 상기 foldon 도메인은 서열번호 39로 기재되는 아미노산 서열을 포함할 수 있다.
상기 조성물에 있어서, 상기 NP 단백질은 서열번호 45로 구성되는 아미노산 서열을 포함할 수 있다.
상기 조성물에 있어서, 상기 제1폴리뉴클레오타이드는 서열번호 29 내지 31, 34 내지 37 및 50으로 구성되는 군으로부터 선택되는 핵산서열을 포함할 수 있고, 상기 제2폴리뉴클레오타이드는 서열번호 46으로 기재되는 핵산서열을 포함할 수 있다.
상기 조성물에 있어서, 상기 제1폴리뉴클레오타이드 및 상기 제2폴리뉴클레오타이드는 하나의 벡터 내에 포함되거나 별도의 벡터로 제공될 수 있다.
상기 조성물은 SARS CoV의 S1 수용체 결합 도메인을 포함하는 폴리펩타이드를 암호화하는 제3폴리뉴클레오타이드를 추가적으로 포함할 수 있다.
상기 조성물에 있어서, 상기 SARS CoV의 S1 수용체 결합 도메인은 SARS CoV-2 S 당단백질(서열번호 38) 기준으로 319 내지 541 번째 아미노산 잔기에 상응하는 폴리펩타이드(서열번호 41)를 포함할 수 있다.
상기 조성물에 있어서, 상기 SARS CoV의 S1 수용체 결합 도메인을 포함하는 폴리펩타이드는 C-말단에 삼량체 형성 도메인이 부가된 융합 단백질일 수 있고, 상기 삼량체 형성 도메인은 CD40L 엑토도메인, T4 박테리오파지 fibritin 또는 그의 C-말단 도메인(foldon 도메인), Fas 리간드, 41BB, OX40L, CD70, TRAIL, 또는 서펙틴일 수 있으며, CD40L 엑토도메인 또는 foldon 도메인인 것이 바람직하다. 상기 CD40L 엑토도메인은 서열번호 5로 기재되는 아미노산 서열을 포함할 수 있고, 상기 foldon 도메인은 서열번호 39로 기재되는 아미노산 서열을 포함할 수 있다.
상기 백신 조성물에 있어서, SARS CoV의 S1 수용체 결합 도메인을 포함하는 폴리펩타이드는 서열번호 41로 기재되는 아미노산 서열을 포함할 수 있고, 서열번호 39로 기재되는 아미노산 서열을 갖는 foldon 도메인이 부가된 것일 수 있으며, 이 경우 상기 폴리펩타이드는 서열번호 43으로 기재되는 아미노산 서열을 포함할 수 있고, 상기 폴리펩타이드는 서열번호 44로 기재되는 핵산서열을 갖는 폴리뉴클레오타이드(제3폴리뉴클레오타이드)에 의해 암호화될 수 있다.
상기 조성물에 있어서, 상기 제1폴리뉴클레오타이드는 29 내지 31, 34 내지 37 및 50으로 구성되는 군으로부터 선택되는 핵산서열을 포함할 수 있고, 상기 제2폴리뉴클레오타이드는 서열번호 46으로 기재되는 핵산서열을 포함할 수 있으며, 상기 제3폴리뉴클레오타이드는 서열번호 42 또는 44로 기재되는 핵산서열을 포함할 수 있다.
상기 조성물에 있어서, 상기 제1폴리뉴클레오타이드 내지 제3폴리뉴클레오타이드는 단일 벡터 내에 포함되거나, 두 개의 벡터에 나눠 삽입이 되거나, 또는 3개의 발현벡터 내에 하나씩 삽입될 수 있다.
상기 백신 조성물에 있어서, 상기 SARS CoV는 SARS CoV-1 또는 SARS CoV-2일 수 있으나, SARS CoV-2인 것이 바람직하다.
상기 백신 조성물은 상기 폴리뉴클레오타이드들 중 하나 또는 둘 이상이 해당 폴리뉴클레오타이드에 의해 발현되는 폴리펩타이드로 대체될 수도 있다.
본 문서에서 사용되는 용어 "융합단백질"은 둘 이상의 단백질 또는 단백질 내 특정 기능을 담당하는 도메인이 연결된 재조합 단백질(recombinant protein)을 의미한다. 상기 둘 이상의 단백질 또는 도메인 사이에는 통상적으로 유연한 구조를 갖는 링커(linker) 펩타이드가 삽입될 수 있는데, 연결되는 폴리펩타이드의 본래의 기능을 제한하지 않고, 융합단백질의 발현을 저해하지 않는 유연성 펩타이드 링커라면 어느 것이라도 사용이 가능하며, 구체적인 예시는 상술한 바와 같다.
상기 백신 조성물이 융합단백질을 암호화하는 폴리뉴클레오타이드를 포함할 경우 상기 융합 단백질은 융합파트너 사이에 하나 이상의 링커 펩타이드를 포함할 수 있으며, 상기 링커 펩타이드는 공지된 그 어떠한 것이라도 사용하는 것이 가능하다. 이러한 링커의 예로는 (GS)5(서열번호 6), (G4S, 서열번호 7)n, (GSSGGS, 서열번호 8)n, KESGSVSSEQLAQFRSLD(서열번호 9), EGKSSGSGSESKST(서열번호 10), GSAGSAAGSGEF(서열번호 11), (EAAAK, 서열번호 12)n, CRRRRRREAEAC(서열번호 13), A(EAAAK)4ALEA(EAAAK)4A(서열번호 14), GGGGGGGG(서열번호 15), GGGGGG(서열번호 16), AEAAAKEAAAAKA(서열번호 17), PAPAP(서열번호 18), (Ala-Pro)n, VSQTSKLTRAETVFPDV(서열번호 19), PLGLWA(서열번호 20), TRHRQPRGWE(서열번호 21), AGNRVRRSVG(서열번호 22), RRRRRRRR(서열번호 23), GFLG(서열번호 24), 및 GSSGGSGSSGGSGGGDEADGSRGSQKAGVDE(서열번호 25) 등이 사용될 수 있다.
아울러, 상기 CoVS 단백질, SARS CoV NP 단백질, 및 SARS CoV의 S1 수용체 결합 도메인을 포함하는 폴리펩타이드는 분비 신호서열을 포함할 수 있다. 상기 분비 신호서열은 공지된 그 어떠한 것이든 사용할 수 있는데 예컨대, tPA(tissue plasminogen activator) 신호서열(서열번호 26 또는 47), HSV gDs(단순포진 바이러스 당단백질 Ds) 신호서열 또는 성장호르몬 신호서열일 수 있다.
본 문서에서 사용되는 용어 "작동 가능하게 연결된(operably linked to)"이란 목적으로 하는 핵산서열(예컨대, 시험관내 전사/번역 시스템에서 또는 숙주세포에서)이 그의 발현이 이루어질 수 있도록 하는 방식으로 상기 조절서열에 연결되어 있다는 것을 의미한다. 상기 "조절서열"이란 용어는 프로모터, 인핸서 및 다른 조절 요소(예, 폴리아데닐화 신호)를 포함하는 의미이다. 조절서열에는 많은 숙주세포에서 목적으로 하는 핵산이 항상적으로 발현될 수 있도록 지시하는 것, 특정한 조직세포에서만 목적으로 하는 핵산이 발현될 수 있도록 지시하는 것(예, 조직특이적 조절서열), 그리고 특정 신호에 의해 발현이 유도되도록 지시하는 것(예, 유도성 조절서열)이 포함된다. 발현벡터의 설계는 형질전환될 숙주세포의 선택 및 원하는 단백질 발현의 수준 등과 같은 인자에 따라 달라질 수 있다는 것은 당업자라면 이해할 수 있다. 본 발명의 발현벡터는 숙주 세포에 도입되어 상기 융합 단백질을 발현할 수 있다. 상기 진핵세포 및 원핵세포에서 발현을 가능하게 하는 조절서열들은 당업자에게 잘 알려져 있다. 상술한 바와 같이, 이들은 보통 전사개시를 담당하는 조절서열들 및, 선택적으로 전사물의 전사종결 및 안정화를 담당하는 폴리-A 신호를 포함한다. 추가적인 조절서열들은 전사조절인자 외에도 번역 증진인자 및/또는 천연-조합 또는 이종성 프로모터 영역을 포함할 수 있다. 예를 들어 포유류 숙주 세포에서 발현을 가능하게 하는 가능한 조절서열들은 CMV-HSV 티미딘 키나아제 프로모터, SV40, RSV-프로모터(로우스 육종 바이러스), 인간 신장 요소 1α-프로모터, 글루코코르티코이드-유도성 MMTV-프로모터(몰로니 마우스 종양 바이러스), 메탈로티오네인-유도성 또는 테트라사이클린-유도성 프로모터 또는, CMV 프로모터 또는 SV40 프로모터와 같은 프로모터를 포함한다. 신경 세포 내 발현을 위해, 신경미세섬유-프로모터(neurofilament-promoter), PGDF-프로모터, NSE-프로모터, PrP-프로모터 또는 thy-1-프로모터들이 사용될 수 있다는 것이 고려되고 있다. 상기 프로모터들은 당 분야에 알려져 있으며, 문헌(Charron, J. Biol. Chem. 270: 25739-25745, 1995)에 기술되어 있다. 원핵세포 내 발현을 위해, lac-프로모터, tac-프로모터 또는 trp 프로모터를 포함하는 다수의 프로모터들이 개시되어 있다. 전사를 개시할 수 있는 인자들 외에, 상기 조절서열들은 본 발명의 일 실시예에 따른 폴리뉴클레오타이드의 하류(downstream)에 SV40-폴리-A 부위 또는 TK-폴리-A 부위와 같은 전사 종결 신호를 포함할 수도 있다. 본 문서에서, 적당한 발현 벡터들은 당 분야에 알려져 있으며, 그 예로는 오카야마-베르그(Okayama-Berg) cDNA 발현 벡터 pcDV1(Parmacia), pRc/CMV, pcDNA1, pcDNA3(In-vitrogene), pSPORT1(GIBCO BRL), pGX27(특허 제1442254호), pX(Pagano (1992) Science 255, 1144-1147), 효모 2-혼성(two-hybrid) 벡터, 가령 pEG202 및 dpJG4-5(Gyuris (1995) Cell 75, 791-803) 또는 원핵 발현 벡터, 가령 람다 gt11 또는 pGEX(Amersham-Pharmacia)가 있다. 본 발명의 핵산 분자들 외에, 벡터는 분비신호를 암호화하는 폴리뉴클레오타이드를 추가로 포함할 수 있다. 상기 분비신호들은 당업자에게 잘 알려져 있다. 그리고, 사용된 발현 시스템에 따라, 융합 단백질을 세포 구획으로 이끌 수 있는 리더서열(leader sequence)이 본 발명의 일 실시예에 따른 폴리뉴클레오타이드의 코딩 서열에 조합되며, 바람직하게는 해독된 단백질 또는 이의 단백질을 세포질 주변 또는 세포외 매질로 직접 분비할 수 있는 리더서열이다.
상기 백신 조성물은 하나 또는 둘 이상의 면역증진 펩타이드를 암호화하는 폴리뉴클레오타이드를 추가로 포함할 수 있고, 이 경우 상기 면역증진 펩타이드는 상기 S1 단백질 또는 융합 단백질에 연결된 융합 단백질의 형태로 발현될 수 있는데, 이 경우 상기 면역증진 펩타이드는 상기 S1 단백질 또는 융합 단백질의 N-말단 또는 C-말단에 부가되거나 중간에 삽입될 수 있으며, 상기 면역증진 펩타이드는 CD28, ICOS(inducible costimulator), CTLA4(cytotoxic T lymphocyte associated protein 4), PD1(programmed cell death protein 1), BTLA(B and T lymphocyte associated protein), DR3(death receptor 3), 4-1BB, CD2, CD40, CD40L, CD30, CD27, SLAM(signaling lymphocyte activation molecule), 2B4(CD244), NKG2D(natural-killer group 2, member D)/DAP12(DNAX-activating protein 12), TIM1(T-Cell immunoglobulin and mucin domain containing protein 1), TIM2, TIM3, TIGIT, CD226, CD160, LAG3(lymphocyte activation gene 3), B7-1, B7-H1, GITR(glucocorticoid-induced TNFR family related protein), Flt3 리간드(fms-like tyrosine kinase 3 ligand), 플라젤린(flagellin), HVEM(herpesvirus entry mediator) 또는 OX40L[ligand for CD134(OX40), CD252]의 세포질 도메인 또는 이들 중 둘 이상의 연결체일 수 있다.
상기 조성물에 있어서, 상기 Flt3 리간드는 서열번호 27로 구성되는 폴리펩타이드일 수 있다.
아울러, 상기 유전자 컨스트럭트는 제조 및 조작의 편의를 위해 플라스미드 벡터와 같은 발현벡터의 형태로 제공될 수 있다.
또한, 본 발명에서 사용되는 벡터는 예를 들면, 표준 재조합 DNA 기술에 의하여 제조될 수 있으며, 표준 재조합 DNA 기술에는 예를 들면, 평활말단 및 접착말단 라이게이션, 적절한 말단을 제공하기 위한 제한 효소 처리, 부적합한 결합을 방지하기 위하여 알칼리 포스파테이즈 처리에 의한 인산기 제거 및 T4 DNA 라이게이즈에 의한 효소적 연결 등이 포함된다. 화학적 합성 또는 유전자 재조합 기술에 의하여 얻어진 신호 펩타이드를 코딩하는 DNA, 본 발명의 일 실시예에 따른 융합단백질을 암호화하는 DNA를 적절한 조절서열이 포함되어 있는 벡터에 재조합함으로써 본 발명의 벡터가 제조될 수 있다. 상기 조절 서열이 포함되어 있는 벡터는 상업적으로 구입 또는 제조할 수 있으며, 본 발명의 일 실시예에서는 DNA 백신 제조용 벡터인 pGX27(한국 등록특허 제1442254호)을 사용하였다.
본 발명의 일 실시예에 따른 상기 발현벡터는 숙주세포에서 상기 융합단백질을 발현하도록 할 수 있는 발현벡터일 수 있으며, 상기 발현벡터는 플라스미드 벡터, 바이러스 벡터, 코스미드 벡터, 파지미드 벡터, 인공 인간 염색체 등 그 어떠한 형태를 나타내더라도 무방하다.
본 발명의 다른 일 관점에 따르면, 상기 벡터로 숙주세포를 형질전환시킨 형질전환 숙주세포가 제공된다. 상기 숙주세포는 세균, 진균, 식물 세포 또는 동물 세포일 수 있고, 상기 세균은 그람음성균, 그람양성균일 수 있으며, 상기 동물 세포는 곤충세포 또는 포유동물 세포일 수 있다. 상기 포유동물 세포는 쥐, 생쥐, 원숭이, 햄스터, 개, 말, 소, 고양이, 돼지, 코끼리, 원숭이, 영장류 또는 인간으로부터 분리된 초도배양 세포 또는 확립된 세포주일 수 있다. 이러한 숙주세포는 본 발명의 일 실시예에 따른 유전자 컨스트럭트의 형질전환에 의해 백신에 사용될 수 있는 항원 단백질의 생산에 사용될 수 있다.
상기 백신 조성물은 하나 이상의 약학적으로 허용 가능한 백신 면역보조제를 포함할 수 있다. 상기 백신 면역보조제로는 알루미늄 하이드록사이드, 알루미늄 포스페이트, 알룸(포타슘 알루미늄 설페이트), MF59, virosome, AS04[알루미늄 하이드록사이드 및 모노포스포릴 리피드 A(MPL)의 혼합물], AS03(DL-α-tocopherol, squalene 및 유화제인 polysorbate 80의 혼합물), CpG, Flagellin, Poly I:C, AS01, AS02, ISCOMs 및 ISCOMMATRIX 등이 사용될 수 있다.
본 문서에서 사용되는 용어 "보조제(adjuvant)" 또는 "백신 면역보조제(vaccine adjuvant)"는 백신의 면역반응을 향상시킬 목적으로 투여되는 약학적 또는 면역학적 제제를 의미한다.
선택적으로 상기 백신 조성물은 상술한 백신 면역보조제와 함께 또는 대신에 IL-12 단백질 및 IL-21 단백질을 유효성분으로 포함하거나 상기 IL-12 단백질을 암호화하는 폴리뉴클레오타이드 및 상기 IL-21 단백질을 암호화하는 폴리뉴클레오타이드를 유효성분으로 포함하는 T 림프구 특이적 면역반응 촉진용 백신 면역보조제를 포함할 수 있다.
상기 조성물은 상기 담체 외에 약학적으로 허용가능한 보조제, 부형제 또는 희석제를 추가적으로 포함할 수 있다.
본 문서에서 사용되는 용어 "약학적으로 허용가능한"이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다. 상기 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다.
또한, 본 발명에 일 실시예에 따른 백신 조성물은 포유동물에 투여시, 활성 성분의 신속한 방출, 또는 지속 또는 지연된 방출이 가능하도록 당업계에 공지된 방법을 사용하여 제형화될 수 있다. 제형은 분말, 과립, 정제, 에멀젼, 시럽, 에어로졸, 연질 또는 경질 젤라틴 캅셀, 멸균 주사용액, 멸균 분말 형태를 포함한다.
본 발명의 일 실시예에 따른 백신 조성물은 다양한 경로로 투여될 수 있으며, 예를 들면, 경구, 비경구, 예를 들면 좌제, 경피, 정맥, 복강, 근육내, 병변내, 비강, 척추관내 투여로 투여될 수 있으며, 또한 서방형 또는 연속적 또는 반복적 방출을 위한 이식장치를 사용하여 투여될 수 있다. 투여횟수는 원하는 범위 내에서 하루에 1회, 또는 수회로 나누어 투여할 수 있으며, 투여 기간도 특별히 한정되지 않는다.
본 발명의 일 실시예에 따른 백신 조성물은 일반적인 전신성 투여 또는 국소성 투여, 예컨대, 근육내 주사 또는 정맥 주사 방식으로 투여될 수 있으나, DNA 백신 조성물로 제공되는 경우, 가장 바람직하게는 전기천공기(electroporator)를 이용하여 주입될 수 있다. 상기 전기천공기는 시판 중인 DNA 약물 체내 주입용 전기천공기, 예컨대, 이탈리아의 IGEA 사의 GlinporatorTM, 한국의 JCBIO사의 CUY21EDIT, 스위스의 Supertech사의 SP-4a, 에스엘백시젠 사(대한민국)의 OrbiJectorㄾ 등이 사용될 수 있다.
본 발명의 일 실시예에 따른 백신 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 이와 같은 투여경로는 비경구 투여, 예를 들어, 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 활막강 내 투여될 수 있으나, 이에 제한되지는 않는다.
본 발명의 일 실시예에 따른 백신 조성물은 일반적으로 사용되는 약학적으로 허용가능한 담체와 함께 적합한 형태로 제형화될 수 있다. 약학적으로 허용되는 담체로는 예를 들면, 물, 적합한 오일, 식염수, 수성 글루코스 및 글리콜 등과 같은 비경구 투여용 담체 등이 있으며 안정화제 및 보존제를 추가로 포함할 수 있다. 적합한 안정화제로는 아황산수소나트륨, 아황산나트륨 또는 아스코르브산과 같은 항산화제가 있다. 적합한 보존제로는 벤즈알코늄 클로라이드, 메틸- 또는 프로필-파라벤 및 클로로부탄올이 있다. 또한 본 발명에 따른 조성물은 그 투여방법이나 제형에 따라 필요한 경우, 현탁제, 용해보조제, 안정화제, 등장화제, 보존제, 흡착방지제, 계면활성화제, 희석제, 부형제, pH 조정제, 무통화제, 완충제, 산화방지제 등을 적절히 포함할 수 있다. 상기에 예시된 것들을 비롯하여 본 발명에 적합한 약학적으로 허용되는 담체 및 제제는 문헌[Remington's Pharmaceutical Sciences, 최신판]에 상세히 기재되어 있다.
아울러 본 발명의 백신 조성물은 예방을 위해 필요한 양 또는 치료적으로 유효한 양으로 투여된다.
본 문서에서 사용되는 용어 "치료적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 백신 조성물 또는 약학적 조성물은 0.05 mg/dose 내지 100 mg/dose의 용량으로 투여될 수 있으며, 더 바람직하게는 0.05 mg/dose 내지 10 mg/dose의 투여량으로 투여된다. 한편, 상기 투여량은 환자의 나이, 성별 및 상태에 따라 적절히 조절될 수 있다.
본 발명의 다른 일 관점에 따르면, 상기 중 어느 하나 또는 그 이상의 SARS CoV 예방 및 치료용 백신 조성물을 개체에 투여하는 단계를 포함하는 상기 개체의 SARS CoV 감염증 예방 및 치료방법이 제공된다.
상기 치료방법에 있어서, 상기 SARS CoV는 중증급성호흡기증후군(SARS) CoV-1, 또는 SARS CoV-2일 수 있으며, 특히 SARS CoV-2는 최근 전세계적으로 유행하는 신종코로나 바이러스 질환(COVID-19; 30 January 2020 the World Health Organization declared Coronavirus Disease 2019)을 유발하는 병원성 바이러스이다.
상기 방법에 있어서, 상기 백신 조성물은 생체 내 전기천공법에 의해 투여될 수 있다.
이하, 실시예 및 실험예를 통하여 본 발명을 더 상세히 설명한다. 그러나 본 발명은 이하에서 개시되는 실시예 및 실험예에 한정되는 것이 아니라 서로 다른 다양한 형태로 구현될 수 있는 것으로, 이하의 실시예 및 실험예는 본 발명의 개시가 완전하도록 하며, 본 발명이 속한 기술분야의 통상의 지식을 가진 자에게 발명의 범주를 완전하게 알려주기 위해 제공되는 것이다.
실시예: CoV DNA 백신의 고안
1-1: pGX-19의 제조
CoV S 단백질을 항원으로 하여 효과적인 면역 반응을 유도할 수 있는 백신 조성물의 제조를 위해서는 CoV S 단백질의 항원 유전자 컨스트럭트의 고안이 필요하다.
이에, 본 발명자들은 항원 유전자 컨스트럭트를 고안함에 있어 그 서열과 도메인의 위치를 토대로 어느 위치까지 항원으로 디자인할 지 결정하는 것이 효과적인 백신을 개발하는 데 가장 중요한 포인트임을 고려하여, 우선적으로 미국 국립보건원(NIH)의 유전자 서열 데이터베이스인 GenBank(//www.ncbi.nlm.nih.gov/genbank/sars-cov-2-seqs)에서 확인된 45종의 SARS-CoV-2 뉴클레오티드 서열을 기반으로 Jalview 소프트웨어(//www.jalview.org/)를 이용하여 CoV의 S 단백질의 대표 아미노산 서열을 도출하였다(도 3). 본 발명자들이 규명한 상기 CoV의 S 단백질의 대표 아미노산 서열은 추후 공개된 NCBI 등재 대표 서열(NCBI Reference Sequence: YP_009724390.1)과 100% 동일한 것으로 확인하였으며, 이에, 본 발명자들은 본 문서에서 사용된 CoV S 단백질의 도메인들의 아미노산 위치를 상기 대표서열과 동일한 서열번호 38을 기준으로 정하였다.
이후, S1 서브유닛, S2 서브유닛, 막통과 도메인(TM)의 위치에 대한 S 단백질 도메인 구조가 이미 규명되어 있는 다른 CoV 속(CoV genus; Middle East respiratory syndrome-related coronavirus (isolate United Kingdom/H123990006/2012) (Betacoronavirus England 1) (Human coronavirus EMC), Human SARS coronavirus (SARS-CoV) (Severe acute respiratory syndrome coronavirus), Human coronavirus OC43 (HCoV-OC43), Human coronavirus HKU1 (isolate N5) (HCoV-HKU1), Human coronavirus 229E (HCoV-229E), Human coronavirus NL63 (HCoV-NL63))들의 도메인 서열을 비교 분석함과 동시에 문헌(Kleine-Weber H et al., Sci. Rep. 8(1): 16597, 2018)을 통해 밝혀진 보존된 아미노산 서열 정보와 SignalP-5.0 소프트웨어를 토대로 한 신호서열 절단 부위 예측 정보(도 4)를 모두 종합함으로써 상기 도출된 S 단백질의 대표 아미노산 서열을 기준으로 각 도메인의 위치를 결정하였다(도 5).
그런 다음, 도 5에 기재된 결정된 도메인 정보를 바탕으로 네 가지 형태의 유전자 컨스트럭트를 고안하였다(표 1 및 도 6). 구체적으로, S1 서브유닛 단독만 포함한 형태(도 6a, 실시예 1) 또는 S1/S2 서브유닛 모두 포함한 형태(도 6b, 실시예 2)로 구분하여 고안하였다. S2 서브유닛의 경우 세포 내에서 발현된 항원이 효과적으로 세포 밖으로 노출될 수 있도록 막통과 도메인 및 세포질 내 꼬리(intracellular tail, IC) 부분은 제거하도록 고안하였다(S2ΔTM/IC).
아울러, 효과적인 중화 항체 반응을 유도하기 위해서는 온전한 형태(intact form)의 항원이 체내에 형성 및 노출되도록 하는 것이 매우 중요하다. CoV S 단백질은 삼량체 사전-융합 형태(trimer pre-fusion form)으로 존재하기 때문에 백신에서 만들어지는 CoV S 단백질은 삼량체 사전-융합 형태이어야 한다. 표적 단백질을 삼량체화할 수 있는 여러 방법이 있을 수 있는데, 가령, T4 박테리오파지 피프리틴 삼량체화 모티프(bacteriophage fibritin trimerization motif(FT) 또는 계면활성 단백질 D(surfactant protein D, SPD)를 연결하는 방법이 있다(도 7).
본 발명자들은 CoV DNA 백신의 S 단백질이 삼량체 사전-융합 형태로 생성될 뿐 아니라, 동시에 면역반응을 증가시킬 수 있는 구조가 될 수 있는 방안을 고안하였다. 구체적으로, 종양 괴사 인자 수용체 슈퍼패밀리(TNFRSF)의 리간드 중 하나인 CD40 리간드(CD40L)는 삼량체 형태로 CD40에 신호 전달을 주는 것으로 알려져 있고, 항체 면역 반응뿐만 아니라 세포성 면역반응까지 증가시키는 것으로 알려져 있다. 따라서 본 발명자들은 CoV S 단백질과 가용성 CD40L을 연결한 형태의 융합단백질을 암호화하는 폴리뉴클레오타이드를 포함하는 백신을 고안하여 CoV S 단백질이 효율적으로 삼량체 사전-융합 형태로 발현될 뿐만 아니라, 백신의 면역반응을 증가시킬 수 있도록 고안하였다(도 6c 및 6d, 실시예 3 및 4).
| 백신후보 | 분비 신호서열 (상응 핵산서열) |
항원 (상응 핵산서열) |
링커 펩타이드 (상응 핵산서열) |
삼량체화 도메인 (상응 핵산서열) |
아미노산서열 (핵산서열) |
| #1 | tPA(28) | S1(29) | - | - | 1 (29) |
| #2 | tPA(28) | S1/S2△TM/IC(34) | - | - | 2 (34) |
| #3 | tPA(28) | S1(50) | (GS)5(51) | sCD40L113-261(52) | 3 (36) |
| #4 | tPA(28) | S1/S2△TMIC35) | (GS)5(32) | sCD40L113-261(33) | 4 (37) |
상기 백신후보 #1 내지 #4와 같이 고안한 CoV DNA 백신 유전자 컨스트럭트를 합성한 후 pGX27 벡터(Genexine, Inc., 대한민국)에 삽입함으로써 DNA 백신용 발현벡터를 제조하였고(도 6), 이 중 백신후보 #2의 백신 컨스트럭트를 'pGX-19'로 명명하였고 이를 포함하는 백신 조성물을 "GX-19"로 명명하였다.
1-2: pGX-21의 제조
본 발명자들은 SARS CoV에 대한 방어 면역에 있어서 중화 항체의 생산보다는 T 세포 면역반응이 더욱 중요하다는 최신 연구결과를 바탕으로 SARS CoV의 항원 단백질 투여 시 T 세포 면역반응을 향상시킬 수 있는 백신 조성물을 개발하고자 하였다.
이를 위해 구체적으로, tPA 신호서열 뒤에 S1의 수용체 결합 도메인(서열번호 41)과 foldon(서열번호 39)을 연결한 융합단백질(서열번호 43)을 암호화하는 폴리뉴클레오타이드(서열번호 44)를 합성한 후 pGX27 벡터의 CMV 프로모터 뒤에 연결한 후 마찬가지로 tPA 신호서열 뒤에 NP 단백질(서열번호 45)을 암호화하는 폴리뉴클레오타이드(서열번호 46)를 합성하여 상기 pGX27 벡터의 pRSV 프로모터의 뒤에 연결하여 하나의 발현벡터로 상기 융합단백질과 NP 단백질이 발현되도록 고안하였으며, 이렇게 제조된 벡터를 pGX-21로 명명하였다(도 15).
1-3: GX-19N의 제조
상기 실시예 1-1에서 제조된 pGX-19와 상기 실시예 1-2에서 제조된 pGX-21을 1:1 또는 1:2로 혼합한 백신 조성물을 'GX-19N'으로 명명하였다.
실험예 1: COVID-19 DNA 백신에 의한 단백질 발현 확인
1-1: 스파이크 단백질 검출
본 발명자들은 GX-19N의 유전자 발현을 조사하기 위해 형질감염 후 웨스턴 블랏 분석을 수행하였다. 구체적으로 COS-7 세포 1 x 107 cells(전체 부피 15 mL)을 100 mm culture dish에 접종하여 16시간 배양 후 4종의 DNA 컨스트럭트(pGX27-COVID-19 S1, pGX27-COVID-19 S1-sCD40L, pGX-27-COVID-19 S1S2ΔTM/IC-sCD40L 및 pGX27) 24 μg과 lipofectamine 2000 60 μL를 혼합하여 세포에 첨가한 뒤 37℃ CO2 incubator에서 4 ~ 5시간 반응시켜 유전자를 도입하고 배양 배지를 교환하였다. 배지 교환 후 48시간 동안 배양한 뒤, 배양세포를 용해시켜 단백질을 추출하였다. 이후 추출한 단백질에 4x SDS 시료 완충액을 첨가하고 72 ℃에서 10분간 끓여주었다. 이 후 SDS gel을 이용하여 전기영동을 실시하였고, Gel 상의 단백질을 iBlot Gel transfer stacks nitrocellulose(Invitrogen)을 이용하여 이동시킨 후 SARS CoV-2 spike에 특이적인 항체(Genetex, GTX135356)를 1 차 항체로 이용하여 4 ℃ overnight 반응하고, HRP conjugated 2차 항체를 1:5000으로 희석하여 상온에서 1 시간 반응 시켰다. 위 항체와 반응성이 있는 밴드를 ECL(Enhanced chemiluminencence solution) 용액으로 발색시켜 COVID-19 DNA 백신(pGX-19N)에 도입된 유전자에 의해 발현되는 단백질 생성물을 검출하였다. 그 결과, COVID-19 DNA 백신이 도입된 COS-7 검체에서 SARS CoV-2 전장 S 단백질 또는 S1 서브유닛 단백질을 CMV 프로모터에서 발현하여 예측한 위치에 특이적 밴드를 확인하였으며, 음성대조군 에서는 특이적인 단백질이 검출되지 않으며(도 8a), 이를 통해 본 발명의 항원 유전자 컨스트럭트의 발현 시스템이 정상적으로 작동함을 확인할 수 있었다.
1-2: 스파이크 RBD 발현 분석
이어 본 발명자들은 세포 내 pGX-21의 유전자 생성물 확인을 위해 pGX-19와 pGX-21이 혼합된 GX-19N을 상기 실시예 1-1과 유사하게 COS-7 세포에 형질감염시킨 후 SARS CoV-2(COVID-19) 스파이크 수용체 결합 도메인(RBD)에 특이적인 항체를 이용하여 웨스턴 블랏 분석을 수행하였다. 구체적으로, 6% lipofectamine 2000 희석액 2 mL과 pGX-19와 pGX-21이 1:1로 혼합된 GX-19N 50 μg을 2 mL 무혈청 배지에 혼합한 DNA 희석액을 1:1로 혼합한 후 상온에서 5분간 반응을 시켰다. 이어, 상기 혼합액 4 mL을 2.0 x 106 cells COS-7 세포가 파종되어 95%의 표면 포화도를 달성한 100 mm 배양접시에 도포하고 6시간 동안 37℃의 CO2 배양기에서 배양함으로써 형질감염을 수행하였다. 형질감염 완료 후, 배양배지를 제거하고 각 배양욕기에 15 mL 배양배지를 첨가하고 37℃ 5% CO2 조건에서 72시간 동안 추가배양을 하였다. 배양 완료후 배양배지를 제거하고 5 mL PBS를 이용하여 세척을 하였다. 세포를 스크래퍼로 회수한 후 수차례 원심분리 및 세척을 한 후, 용해 완충액으로 세포를 용해시킨 후 PierceTM BCA Protein Assay Kit(Thermoscientific, 23225)의 방법서에 따라 총 단백 함량을 정량한 후, 항-RBD 항체(Genetex, GTX135385)를 1:1,000 비율로 희석하여 가한 후, HRP-결합 2차 항체를 이용하여 ECL 방식으로 검출하였다.
그 결과, pGX-21의 유전자 생성물의 예측 분자량인 약 31 kDa 보다 높은 위치에서 밴드가 관찰되었다(도 8b). 이에, NetNGly 1.0 서버를 이용하여 SRBD-Foldon 아미노산 서열 내의 N-당화 부위가 존재함을 확인하였다. 따라서, 본 연구에서 SRBD-Foldon의 밴드가 예측 분자량보다 높은 위치에서 관찰되는 현상은 세포 내 SRBD-Foldon 단백질 발현시 당쇄화 현상에 의한 것이라고 판단된다. 음성 대조군(NC)에서는 특이적인 밴드가 관찰되지 않았고, 내재적 편재 단백질인 베타-액틴(43 kDa)의 발현 수준을 비교할 때, 겔에 적재된 각 검채의 단백질 양은 동등함을 확인할 수 있었다.
1-3: 뉴클레오캡시드 단백질의 검출
pGX-21 컨스트럭트 내에는 SRBD-foldon 외에도 뉴클레오캡시드(NP) 단백질을 암호화하는 폴리뉴클레오타이드가 존재하므로, 본 발명자들은 pGX-21을 포함하는 GX-19N으로 세포를 형질감염시 정상적으로 NP 단백질이 발현되는지 여부를 조사하였다.
이를 위해, 항체만 항-SARS COVID-19 NP 항체(Sinobiological, 40143-MM05) 를 사용한 점을 제외하고는 상기 실시예 1-2와 동일한 방식으로 웨스턴 블랏 분석을 수행하였으며, 그 결과, 유전자 생성물의 예상 분자량인 약 49 kDa보다 큰 위치에서 밴드가 관찰되었다. 이에, NetNGly 1.0 서버를 이용하여 NP 단백질의 아미노산 서열 내 N-당쇄화 부위가 존재함을 확인하였다(도 8c). 따라서, 본 연구에서 NP단백질의 밴드가 예측 분자량보다 높은 위치에서 관찰되는 현상은 동물세포 내 뉴클레오캡시드 단백질 발현시 당쇄화 현상에 의한 것이라고 판단된다. 한편, 내재적 편재 단백질인 베타-액틴(43 kDa)의 발현 수준을 비교할 때, 겔에 적재된 각 검채의 단백질 양은 동등함을 확인할 수 있었다.
실험예 2: 마우스 모델에서 본 발명의 COVID-19 DNA 백신 효능 평가
본 발명의 COVID-19 DNA 백신(백신 후보 #1 내지 #4)의 마우스 모델에서의 면역반응을 확인하기 위하여 도 9에 기재된 용량군과 스케줄을 토대로 마우스 실험을 수행하였다.
항체 반응
BALB/c 마우스의 대퇴근육에 투여물을 25 μL/head씩 투여하고, 2주 간격으로 2회 반복 투여하였다. 모든 용량군에는 전기천공(EP) 카트리지 주사 바늘을 삽입한 채 전기천공 장치를 이용하여 전기천공(200 V/cm, (3 pulses at 10 ms/pulse and 10 ms between pulses) x 4 cycles)을 실시하였다. 백신 첫 투여시점을 기준으로 2주, 4주차에 혈청 내 항원 특이적 IgG 항체 역가 ELISA를 수행하여 COVID-19 DNA 백신의 면역원성을 평가하였다.
실험 결과는 (1) CD40L(CD40 ligand)의 결합에 의한 백신 면역반응증가 여부, (2) S 항원 구성요소(S1 서브유닛 또는 S1/S2 서브유닛) 사용 범위, 그리고 (3) 투여 횟수에 따른 면역원성 증가여부 등 총 4 가지의 비교항목으로 나누어 분석하였다. CD40L의 결합에 의한 백신 면역반응증가 여부를 분석한 결과, 전반적으로 S 항원에 CD40L를 결합함에 따른 항체반응이 차이가 없거나 오히려 약간 감소하는 경향을 나타냈다{S1 (25 μg) vs. S1-sCD40Lm (25 μg), p=0.075 (2 weeks), p=0.69 (4 weeks); S1/S2 (25 μg) vs. S1/S2-sCD40Lm (25 μg), p=0.042 (2 weeks), p=0.548 (4 weeks)}.
S 항원 서브유닛 사용범위에 따른 항원 (S1+S2) 특이적 항체반응을 분석한 결과, S1 서브유닛 용량군과 S1/S2 서브유닛 용량군간의 S 항원에 대한 항체 반응에 유의한 차이가 나타내지 않았다{S1 (25 μg) vs. S1/S2 (25 μg), p=0.089 (2 weeks), p=0.841 (4 weeks); S1-sCD40Lm (25 μg) vs. S1/S2-sCD40Lm (25 μg), p=0.28 (2 weeks), p=0.421 (4 weeks)}.
투여 횟수(1회 또는 2회)에 따른 면역원성 증가여부를 관찰한 결과, 단회 투여만으로도 유의미한 항체 역가가 유도되었다. 부스팅 시 약간 증가하는 경향은 있으나 통계적으로 유의한 차이를 보이지는 않았다{Prime-boost: S1 (25 μg), p=0.310; S1-sCD40Lm (25 μg), p=0.222; S1/S2 (25 μg), p=0.056; S1/S2-sCD40Lm (25 μg), p=0.032}. 다만 프라이밍 시 항체 역가가 낮았던 개체가 부스팅 후 항체반응이 증가하는 현상은 동일하게 나타났다. 이는 본 발명의 COVID-19 DNA 백신이 항체 반응을 증가시켜 바이러스 감염에 대한 예방 및 치료 효능을 나타낼 수 있는 효율적인 백신임을 입증하는 결과이다(도 10).
T 세포 반응
BALB/c 마우스의 대퇴근육에 투여물을 25 μL/head씩 투여하고, 2주 간격으로 2회 반복 투여하였다. 모든 용량군에는 전기천공(EP) 카트리지 주사 바늘을 삽입한 채 전기천공 장치를 이용하여 전기천공{200 V/cm, (3 pulses at 10 ms/pulse and 10 ms between pulses) x 4 cycles}을 실시하였다. 마지막 투여 후 2주일 뒤(4주 차)에 비장을 얻어 스파이크 항원 특이적 T 세포 반응은 ELISPOT법을 이용해서 분석하였다.
COVID-19 DNA 백신의 효능은 SARS CoV-2 스파이크 항원 특이적 T 세포 반응을 IFN-γ ELISPOT 방법으로 평가함으로써 확인하였고, 실험 결과는 (1) CD40L (CD40 ligand)의 결합에 의한 백신 면역반응증가 효능 평가, (2) 스파이크 단백질 서브유닛(S1 서브유닛 또는 S1/S2 서브유닛) 사용 범위 결정으로 나누어 분석하였다.
CD40L 유무에 따른 백신-특이적 T 세포 면역반응 유도능을 분석한 결과, S 항원에 CD40L의 결합에 따른 차이가 없었고(S1 vs. S1-sCD40Lm, p=0.151; S1/S2 vs. S1S2- sCD40Lm, p=0.841), S 항원 subunit 사용범위에 따른 백신 특이적 T 세포 면역반응을 분석한 결과, S1 서브유닛에 비해 S1/S2 서브유닛 용량군이 스파이크 단백질 전체 pool에 대한 T세포 반응에 증가하는 경향을 보였다(S1 vs. S1/S2, p=0.548; S1-sCD40Lm vs. S1/S2-sCD40Lm, p=0.056, 도 11).
SARS CoV-2가 속해 있는 코로나바이러스는 숙주세포의 안지오텐신-변환 효소 2(angiotension-converting enzyme 2, ACE2)를 통해 감염을 하며, 수용체 결합 도메인(RBD)는 S1 서브유닛에 있는 것으로 알려져 있다. 따라서 항체 반응은 S1 서브유닛에 대해 잘 유도하는 것이 중요한 것으로 이해되고 있다. 본 발명자들이 고안한 COVID-19 DNA 백신 4종(pGX27-COVID-19/S1, pGX27-COVID-19/S1S2, pGX27-COVID-19/S1-CD40L 및 pGX27-COVID-19/S1S2-CD40L)의 항체 반응은 유사한 수준이었고, 이를 통해 백신에 대한 항체 반응은 주로 S1 서브유닛에 대한 것임을 알 수 있었다. 이때, 항체 반응뿐 아니라 T 세포 반응을 통해서 바이러스에 감염된 세포의 효율적인 제거를 통해 감염 이후의 빠른 회복을 돕는 것 또한 매우 중요한데, 도 11의 T 세포 반응 결과를 보면 S1/S2 서브유닛에 대한 반응이 모두 잘 유도됨을 확인할 수 있었고, 이를 통해 S2 서브유닛 에는 치료면역 반응과 연관이 있는 T cell 에피토프가 많이 분포할 수 있음을 알 수 있었다.
따라서, 유사한 항체반응을 유도함과 동시에 S1-, S2- 서브유닛에 대한 효율적인 T 세포를 유도할 수 있는 컨스트럭트가 백신으로서 적용되는 데 더욱 적절할 것으로 생각되며, 결론적으로, 본 실험을 통해 S1, S2 서브유닛을 모두 포함하는 항원에 대해 CD40L 연결하는 구조적 변경이 없는 pGX27-COVID-19/S1S2가 COVID-19에 대한 최적의 DNA 백신 컨스트럭트 형태임을 확인하였다.
실험예 3: COVID-19 S 당단백질 항원 형태에 따른 면역원성 비교
상기 실험예 2 및 3을 통해 COVID-19 DNA 백신으로 상기 실시예 1-1에서 제조된 pGX-19가 COVID-19 감염의 예방 및 치료를 위한 최적의 백신 컨스트럭트임을 확인하였다. 이때, S2 서브유닛에는 삼량체화에 관여하는 hepted 반복 지역과 표면 막을 관통하는 막통과 도메인(transmembrane domain)을 포함하게 되는데, SARS CoV-2 항원 DNA 컨스트럭트에 있어 이러한 막통과 도메인의 존재 여부가 면역원성에 어떤 영향을 주는 지 확인하기 위하여, 도 12a에 기재된 바와 같이 S1 단백질 항원에 S2 서브유닛을 전장 형태로 포함한 유전자 컨스트럭트를 추가로 고안하였다.
상기 유전자 컨스트럭트가 정상적으로 발현되는지 여부를 확인하기 위해 상기 유전자 컨스트럭트들을 COS-7에 형질감염시킨 후 단백질 발현양상을 항-S 단백질 항체를 이용한 웨스턴 블랏 분석으로 분석하였다. 그 결과 도 12b에서 확인되는 바와 같이, S1S2full 유전자 컨스트럭트 및 S1S2ΔTM/IC 유전자 컨스트럭트 모두 S 단백질을 정상적으로 발현하는 것으로 확인되었다. 그러나, 막통과 도메인이 제거된 형태의 S 단백질의 발현 정도가 현저하게 증가하였다. 이는 막결합 형태가 아닌 수용성 단백질 형태로 S 단백질이 생산이 되기 때문인 것으로 해석이 된다.
이후, S1 서브유닛의 형태에 따른 COVID-19 DNA 백신의 마우스 모델에서의 면역반응을 확인하기 위하여 도 13에 기재된 용량군과 스케줄을 토대로 실험을 수행하였다.
구체적으로, BALB/c 마우스의 대퇴 근육에 pGX-19를 12 μL/head씩 투여하고, 2주 간격으로 2회 반복 투여하였다. 모든 용량군에는 전기천공 카트리지 주사 바늘을 삽입한 채 전기천공 장치를 이용하여 전기천공(200 V/cm, (3 pulses at 10 ms/pulse and 10 ms between pulses) x 4 cycles)을 실시하였다. 백신 첫 투여시점을 기준으로 2주, 4주차에 혈청 내 항원 특이적 IgG 항체역가 ELISA를 수행하여 COVID-19 DNA 백신 후보물질의 면역원성을 평가하였다.
그 결과, 1회 투여 후 항체 반응은 항원의 형태에 따라 유의미하게 차이가 나지 않았으나 S1S2ΔTM 형태의 백신에서 가장 높은 항체 역가를 나타냈고, 2회 투여 후 항체 반응에서는 S1S2ΔTM 형태의 백신 용량군이 다른 두 가지 형태의 백신 용량군에 비해 통계적으로 유의미하게 높은 항체 역가를 나타냄을 확인하였다(도 14).
실험예 4: GX-19N의 효능 평가
4-1: 마우스 실험
본 발명자들은 도 16a에 기재된 실험 스케쥴대로 본 발명의 일 실시예에 따른 GX-19(12 μg/동물) 및 GX-19N(pGX-19:pGX-21 = 1:1, 12 μg/ml)을 BALB/c 마우스에 2주간의 간격으로 2차례 투여하고, surrogate virus neutralization test(SVNT)를 수행하였다.
구체적으로, 테스트 혈청(10 μl), 양성 및 음성 대조군을 1:10으로 희석하고 SARS-CoV-2 스파이크 수용체 결합 도메인(RBD)에 접합된 동량의 서양고추냉이 과산화 효소(HRP) 6 ng과 혼합하고 37℃에서 30분간 반응시켰다. 그런 다음 100 μL의 각 혼합물을 ACE-2 수용체로 코팅된 마이크로타이터 플레이트의 각 웰에 첨가하였다. 플레이트를 밀봉하고 15분 동안 실온에서 반응시켰다. 그런 다음 플레이트를 세척용액으로 세척하고 건조시키고 100 μL의 3,3',5,5'-Tetramethylbenzidine (TMB) 용액을 각 웰에 첨가하고 암실에서 15분 동안 실온에서 반응시켰다.
50 μL의 정지용액을 각 웰에 첨가하여 반응을 중지시킨 후 450 nm에서의 흡광도를 ELISA 마이크로 플레이트 판독기로 측정하였다. 양성 및 음성 대조군이 권장 OD450 값을 제공했다고 가정하면, 각 혈청의 억제율(%)는 하기 공식으로 계산되었다:
억제율(%) = (1- 샘플 OD 값/음성 대조군 OD 값)x100.
그 결과, 도 16b에서 확인되는 바와 같이, 음성대조군(PBS)과 pGX-19의 경우 중화 항체 반응이 큰 차이를 두고 관찰되지는 않았으나, pGX-21을 동시에 투여한 GX-19N의 경우에는 높은 중화 항체 반응이 관찰되었다.
아울러, 본 발명자들은 상기 실험동물을 최초 백신 접종 4주 경과시에 희생시킨 후, 비장을 적출하여 다양한 스파이크 펩타이드들 및 뉴클레오캡시드 펩타이드들을 이용한, 항원 특이적 T 세포 반응은 ELISPOT법을 이용해서 분석하였다.
그 결과, 도 16c에서 확인되는 바와 같이, GX-19 접종시 다양한 스파이크 펩타이드에 의한 T 세포 특이적 면역반응이 유도되었으며, 특히 pGX-21과 함께 접종시(GX-19N) 스파이크 펩타이드에 의한 T 세포 특이적 면역반응이 강화되었다. 아울러, 뉴클레오캡시드 펩타이드에 대한 T 세포 특이적 면역반응을 측정한 결과, GX-19 접종군에서는 예상한 바와 같이 T 세포 특이적 면역반응이 유발되지 않았으나, GX-19N 접종군에서는 뉴클레오캡시드 펩타이드에 대한 T 세포 특이적 면역반응이 유도되었다.
상기 결과를 검토하건대, 본 발명의 일 실시예에 따른 GX-19N은 스파이크 단백질과 뉴클레오캡시드 단백질을 모두 항원으로 사용함으로써, 중화 항체 생성 반응 및 항원 단백질에 대한 T 세포 특이적 면역반응 모두를 현저하게 증가시키는 매우 효율적인 백신 후보물질임을 알 수 있다.
4-2: 원숭이 실험
상기 소동물을 이용한 실험결과로부터, 본 발명의 일 실시예에 따른 GX-19N이 인간과 가까운 대동물에서도 유효한 성능을 나타내는지 확인하기 위해 게잡이 원숭이(Cynomolgus monkey)를 대상으로 한 동물실험을 수행하였다.
실험 스케쥴은 도 17a에 기재된 바와 같이, 최초 백신 투여 후(GX-19: 3 mg/동물, GX-19N: 3 mg/동물) 3주 후에 2차 접종을 하였으며, 2차 접종 2주 후에 실험동물로부터 혈액을 채취하여 중화 항체 생성여부를 surrogate virus neutralization test(SVNT)로 분석하였고 항원 특이적 T 세포 면역반응 유무를 IFN-γ ELISPOT으로 분석하였다.
그 결과, 도 17b 및 17c에서 확인되는 바와 같이, 본 발명의 일 실시예에 따른 GX-19N은 pGX-19 단독에 비해 중화 항체 생성을 현저하게 증가시켰고, 스파이크 펩타이드에 대한 T 세포 특이적 면역반응 역시 현저하게 증가시켰다. 아울러, NP 펩타이드에 특이적인 T 세포 면역반응 역시 pGX-19와는 달리 성공적으로 유도하였다. 따라서, 본 발명의 일 실시예에 따른 GX-19N은 소동물 뿐만 아니라 인간과 밀접하게 가까운 영장류를 이용한 실험에서도 동등한 결과를 보여주어, 인간을 대상으로 한 임상시험에 있어서도 긍정적인 결과를 예상케 하였다.
실험예 5: 임상 1상 시험
5-1: 시험대상자 인구통계학적 특성
발명자들은 본 발명에서 제조된 백신 후보물질인 GX-19와 GX-19N 에 대한 임상 1상 시험을 수행하였다(각각 NCT04445389 및 NCT04715997).
구체적으로, 본 발명자들은 19-54 세의 건강한 성인을 대상으로 임상시험을 수행하였으며, 전체 인원은 61명으로 이중 40명은 2020년 6월 17일 및 7월 30일 사이에 모집되었고, 이들은 GX-19 임상시험의 경우 GX-19를 1:1 비율로 1.5 mg 용량군(n=20)과 3.0 mg 용량군(n=20)으로 나뉘었고, GX-19N 임상시험의 경우 pGX-19 임상 시험 결과를 바탕으로 3.0 mg 단일 용량군(n=21)으로 2020년 12월 28일과 2020년 12월 31일 사이에 모집되었다.
61명의 시험대상자 모두 두 번의 백신을 접종하였고, 모두 57일째까지 예정된 일정대로 병원에 내방하여 안전성 및 면역원성 평가를 위한 다양한 분석을 수행하였다. 임상 시험대상자의 인구통계학적 특성은 표 2에 제시된 바와 같다. 평균 연령은 37.4세(범위 20-52세) 로 52.5% 는 남성이었고, 모든 시험대상자는 한국인이었으며, 용량군 사이에 유사한 인구통계학적 특징을 나타냈다.
| 통계 |
GX-19 1.5 mg
용량군 (N=20) |
GX-19 3.0 mg
용량군 (N=20) |
GX-19N 3.0 mg
용량군 (N=21) |
|
| 성별 남성 여성 |
n (%) n (%) |
10 (50.00) 10 (50.00) |
13 (65.00) 7 (35.00) |
9 (42.86) 12 (57.14) |
| 인종 아시아인 |
n (%) |
20 (100.00) |
20 (100.00) |
21 (100.00) |
| 연령 | n 평균 (표준편차) 최소값, 최대값 |
20 35.50 (7.69) 20.00, 46.00 |
20 37.30 (8.83) 20.00, 49.00 |
21 39.29 (8.30) 21.00, 52.00 |
| 기저 신장 (cm) | n 평균 (표준편차) 최소값, 최대값 |
20 165.50 (7.03) 154.30, 176.50 |
20 169.30 (8.15) 156.00, 185,00 |
21 169.62 (6.97) 155.90, 183.50 |
| 기저 체중 (kg) | n 평균 (표준편차) 최소값, 최대값 |
20 66.85 (7.77) 55.00, 83.30 |
20 70.62 (11.58) 50.10, 89.50 |
21 67.80 (10.70) 51.10, 89.10 |
| 기저 BMI (kg/m 2 ) | n 평균 (표준편차) 최소값, 최대값 |
20 24.38 (1.99) 21.20, 27.80 |
20 24.48 (2.31) 20.30, 27.70 |
21 23.62 (2.52) 18.70, 27.60 |
| 임신 가능성 예 |
n (%) |
10 (50.00) |
6 (30.00) |
12 (57.14) |
| 흡연 이력 무 유 |
n (%) n (%) |
14 (17.00) 6 (30.00) |
15 (75.00) 5 (25.00) |
11 (52.38) 10 (47.62) |
| 음주 이력 무 유 |
n (%) n (%) |
11 (55.00) 9 (45.00) |
11 (55.00) 9 (45.00) |
3 (14.29) 18 (85.71 |
| 약물 남용 이력 무 |
n (%) |
20 (100.00) |
20 (100.00) |
21 (100.00) |
GX-19와 GX-19N 백신은 위탁생산업체인 한국 (주)바이넥스에서 cGMPs 및 EU-GMP 기준에 따라 엄격한 관리하에 생산ㅇ공급되었다. 약물 주입과 동시에 고전압 펄스를 발생시켜 근육 세포 내로 DNA 전달을 극대화하기 위해 전기천공기(Elimtek Co., Ltd., Korea)를 사용하여 접종하였다.
GX-19 임상시험에서 자의적으로 서면 동의한 시험대상자들은 최대 안전성을 확보하기 위해 1.5 mg 용량군부터 최초 3명의 시험대상자를 1일 이상의 간격으로 순차적으로 접종하였다. 첫 접종일로부터 7일 동안 안전성 및 내약성 자료를 취합하여 독립적인 데이터 안전성 모니터링 위원회(DSMC)에서 안전성을 평가한 후 3.0 mg 용량군을 등록하였다. 시험대상자는 임상시험 1일차와 29일차에 삼각근에 GX-19를 1.5 mg(0.38 ml) 또는 3.0 mg(0.75 ml)으로 근육주사하고 1차 백신 접종 후 52주 동안 추적 관찰하였다. GX-19N 임상시험에서 시험대상자들은 동일하게 임상시험 1일차 및 29일차에 삼각근에 GX-19N 3.0 mg(0.75 ml)을 근육주사하고 1차 접종 후 52주 동안 추적하였다. 시험대상자의 안전을 보장하기 위해 모든 시험대상자는 1차 백신 접종 후 최대 7일 동안 매일 부작용(AE) 여부에 대하여 전화통화를 통해 추적 관찰하였으며 백신 접종 8일차에는 병원에 내방하여 안전성 평가를 받도록 하였다.
1차 백신 접종 후 8일차, 29일차, 43일차, 57일차, 24주차 및 52주차에 추적관찰 일정을 잡고 안전성 및 면역원성 관련 자료를 수집하였다. 백신 투여 후 약 4주 동안 경험한 모든 부작용을 개별적으로 수집하기 위해 1차 및 2차 백신 접종 시 시험대상자에게 시험대상자 일지를 배포하였다. 아울러 백신의 면역원성을 평가하기 위해 기저시점 및 1차 백신 접종 후 29일차, 43일차 및 57일차에 혈액 시료를 채취하였다.
5-2: SARS CoV-2 결합 항체 반응 분석
SARS CoV-2 S 단백질에 대한 결합 항체 반응은 본 발명자들이 자체개발한 SARS CoV-2 Spike protein Ab ELISA 분석법을 이용하여 평가하였고, SARS CoV-2 RBD 단백질에 대한 항체는 ELISA 키트(Bionote Inc, Korea)를 이용하여 평가하였다. 결합항체 반응은 백신 접종 전, 그리고 1차 백신 접종 후 43일차 및 57일차에 분석하였다.
그 결과, S 단백질에 대한 결합 항체의 기하평균항체가(GMT)는 GX-19 1.5 mg 및 3.0 mg 용량군 모두에서 57일까지 1차 백신 접종 후 증가하였다. GX-19N 용량군에서 S 및 RBD 단백질에 대한 항체 반응은 백신 접종 후 43일차까지 증가했으나 57일차의 결과는 43일차 항체 반응에 비해 다소 감소하였다(표 3, 도 18a). 각 용량군에서 기저시점 대비 43일과 57일에 GMT가 통계적으로 유의하게 증가하였다. 백신 접종 후 57일 경과시 S-결합 항체의 GMT는 GX-19 1.5 mg 용량군에서 85.74(95% CI 구간 49.67-148.00) 및 3.0 mg 용량군에서 144.20(95% CI 구간 80.81-257.32), 그리고 GX-19N 3.0 mg 용량군에서 201.59(95% CI 구간 105.32-385.83)인 것으로 나타났다. 백신 접종 후 S 또는 RBD 단백질에 특이적인 항체가가 4배 이상 증가한 시험대상자 의 비율은 GX-19 1.5 mg 용량군에서 55% 및 3.0 mg 용량군에서 65%이었고, 그리고 GX-19N 3.0 mg 용량군에서는 80.95%로 나타났다.
| 통계 | pGX-19 1.5 mg 용량군 (N=20) | pGX-19 3.0 mg 용량군 (N=20) | pGX-19N 3.0 mg 용량군 (N=21) |
|
| 스파이크 | 스파이크 | 스파이크/RBD | ||
| 1일차 | N GMT (SD) 95% CI Mean Median Min-Max |
20 25.49 (2.6) 16.25, 39.98 42.50 20.00 1.00-160.00 |
20 33.4 (3.00) 20.11, 56.25 61.00 30.00 1.00-320.00 |
21 24.38 (3.67) / 1.14 (1.83) 13.49, 44.05 / 0.87, 1.50 97.14 / 1.71 20.00 / 1.00 10.00-1280.00 / 1.00-16.00 |
| 43 일차 |
N GMT (SD) 95% CI ≥4배 증가 (%) Mean Median Min-Max p-value* |
20 60.63 (3.11) 35.67, 103.05 35.00 107.50 80.00 10.00-640.00 0.0010 |
20 129.96 (3.58) 71.59, 235.93 65.00 255.00 160.0 20.00-1280.00 <0.0001 |
21 320.00 (4.78) / 8.55 (7.18) 156.93, 652.53 / 3.48, 20.97 80.95 703.33 / 114.90 640.00/8.00 10.00-2560.00 / 1.00-2048.00 <0.0001 / <0.0001 |
| 57 일차 |
N GMT (SD) 95% CI ≥4배 증가 (%) Mean Median Min-Max p-value* |
20 85.74 (3.21) 49.67, 148.00 55.00 166.00 120.00 10.00-1280.00 0.0002 |
21 144.20 (3.45) 80.81, 257.32 65.00 286.00 160.00 20.00-1280.00 <0.0001 |
21 201.59 (4.16) / 5.38 (6.31) 105.32, 385.83 / 2.33, 12.45 80.95 433.33 /62.00 160.00 / 4.00 10.00-2560.00 / 1.00-1024.00 0.0004 / 0.0001 |
*: p-값은 Wilcoxon Matched-Pairs 사인 랭크 테스트로 계산하였음
5-3: SARS-CoV-2 중화 항체 반응 분석
백신-유도 중화 활성은 live wild-type SARS-CoV-2를 이용한 focus reduction neutralization testing(FRNT) 및 SARS-CoV-2 spike (S)-pseudotype murine leukemia (MLV) retrovirus-based single-infection neutralization assay(PsVNA)를 이용하여 수행하였다. 50% 중화 항체 역가(nAb ID50 titer)는 시험관 내, ACE-2를 발현하는 세포에 연속적으로 희석된 혈청과 바이러스를 처리한 후, 바이러스에 감염된 세포가 50% 감소되는 시점에서의 혈청 희석 배수로 산출하였다. FRNT 분석은 백신 접종 전과 1차 백신 접종 후 43일차 및 57일차에 수집된 검체에 대해 수행되었다.
상기 SARS CoV-2 결합 항체 반응 분석을 토대로 중화 항체 반응은 GX-19N 3.0 mg 용량군에서만 분석하였다. GX-19N 유도 항체의 중화 활성을 입증하기 위해 PsVNA 및 FRNT 방법을 사용하여 시험관 내 중화능을 조사한 결과(도 18b 및 18c), 본 연구에 참여한 시험대상자들은 백신 접종 전에 검출 가능한 중화 항체 반응이 없었으나 백신 접종 후에 중화 항체 반응은 통계적으로 유의하게 증가되었다(p<0.0001). PsVNA에서의 중화 항체 역가(ID50)의 기하평균항체가는 1차 백신 접종 전 1.00(95% CI 구간 1.00-1.00)이었으나, 백신 접종 후 43일차에는 21.87(95% CI 구간 15.30-31.07)이었다. PsVNA 분석결과, 모든 시험대상자에서 50% 중화 역가의 4배 이상 증가가 관찰되었다. 그러나 43차의 50% 중화 항체 기하평균항체가는 20명의 SARS-CoV-2 감염 환자의 회복기 혈청의 GMT보다 낮았다(GMT=222.20, 도 18b). 또한, FRNT 분석 결과는 1차 백신 접종 후 43일차 및 57일차에 GX-19N 3.0 mg 용량군에서 기하평균항체가에서 통계적으로 유의한 증가가 관찰되었다(p=0.0422 및 p=0.0197). 중화 항체의 기하평균항체가는 43일차에 32.47(95% CI 구간 22.71-46.41) 및 57일차에 37.26(95% CI 구간 25.29-54.90)로 57일차까지 항체 수준이 4배 이상 증가한 시험대상자의 비율은 23.81%로 나타났다. 아울러, 57일차까지의 중화 항체의 기하평균항체가(GMT)는 아울러 28명의 회복기 환자 혈청 시료의 중화 항체 기하평균항체가(GMT=487.5) 보다 훨씬 낮았다(도 18C).
5-4: SARS-CoV-2-특이 T 세포 반응
GX-19 또는 GX-19N으로 백신을 접종한 시험대상자의 T 세포 반응은 시험대상자의 혈액에서 분리된 말초혈액 단핵구(PBMC)를 가지고 IFN-γ 효소결합면역반점(ELISpot) 측정법으로 1차 백신 접종 후 43일차에 평가하였다. 이러한 분석에서, 말초혈액 단핵구를 S(GX-19의 경우) 및 S/NP(GX-19N의 경우) 서열을 갖는 중첩 펩타이드(OLP)로 밤새 자극한 후, GX-19 또는 GX-19N 백신에 의해 유도된 SARS CoV-2에 특이적인 T 세포 반응을 보다 특이적으로 평가하기 위해 T-SPOT assay(Oxford Immunotec, UK)를 수행하였다. 이 분석을 위해 시험대상자로부터 수득한 말초혈액 단핵구를 SARS CoV-2가 아닌 코로나바이러스와 높은 상동성을 가진 특정 서열이 제거된 S 및 NP에 걸친 중첩 펩타이드로 자극하였다.
그 결과, GX-19 임상시험에서 GX-19 3.0 mg 용량군에서 백신 접종 후 S-특이적 T 세포 반응이 유의하게 향상되었다(p=0.0027). 구체적으로, GX-19 1.5 mg 용량군 중 10명(50%)의 대상자와 3.0 mg 용량군 중 10명(50%)의 대상자에서 각각 1차 백신 접종 후 43일차에 증강된 S-특이적 T 세포 반응을 나타냈다(도 19a). GX-19N 용량군에서 대상자들은 1차 백신 접종 후 43일차에 S- 및 NP-특이 T 세포 반응이 통계적으로 유의하게 향상되는 것으로 확인되었다(p=0.0005 및 p=0.0003, 도 19b 및 19c). 그 결과 15명(71.42%) 의 대상자가 백신 접종 후 백신-유도 T 세포 반응을 나타냈으며, GX-19N-유도 T 세포 반응의 크기는 6명의 회복기 환자의 PBMC에서 관찰된 것과 유사하였다(도 19b). 더 나아가, 본 발명자들은 전장의 S 및 NP를 포함하는 중첩 펩타이드를 사용한 IFN-γ ELIspot 분석 결과를 기반으로 향상된 T 세포 반응을 나타내지 않은 5명의 시험대상자(01SN001, 01SN004, 01SN006, 02SN008, 및 02SN011)가 백신-유도 SARS CoV-2-특이적 T 세포 반응을 유도하는지 여부를 조사하였다. 이를 위해 본 발명자들은 SARS CoV-2가 아닌 코로나바이러스와 높은 상동성을 갖는 특정 서열을 포함하지 않는 중첩 펩타이드와 4명의 시험대상자(19Na, 19Nd, 19Nf 및 19Nq)의 말초혈액 단핵구를 사용하여 T-SPOT 분석을 수행하였다. 그 결과, 대상자 4명 중 3명이 GX-19N-유도 SARS CoV-2 S- 및/또는 NP-특이적 T 세포 반응을 증가시켰으며, 이는 무반응자로 분류된 시험대상자의 상당 부분이 백신-유도 T 세포 반응을 형성하였음을 시사하는 것이다.
이어, 본 발명자들은 GX-19N에 의해 유도된 NP-특이적 T 세포 반응이 B.1.1.7(Alpha), B.1.351(Beta), P.1(Gamma), B.1.617.2(Delta),및 C.37(Lamda)와 같은 SARS CoV-2 변이체의 NP에 특이적인 것인지 여부를 조사하였다. GX-19N 백신을 접종한 대상자에서 NP-특이적 최소 에피토프를 포함하는 15-mer 펩타이드에 대한 반응성을 확인하기 위해, 본 발명자들은 GX-19N 면역화 이후 강력한 NP-특이적 T 세포 반응을 나타낸 네 명의 대상자자로부터 수득한 말초혈액 단핵구와 전체 NP를 포함하는 중첩 펩타이드의 매트릭스 및 15-mer의 개별 펩타이드들을 이용하여 INF-γ ELISpot 분석을 수행하였다. 이어서, GX-19N의 아미노산 서열과 SARS-CoV-2 변이체의 아미노산 서열을 비교하였다. 이들 4명의 시험대상자들로부터 수득한 말초혈액 단핵구는 여러 15-mer 펩티드에 대한 T 세포 반응을 유도하였는데, 이는 광범위한 NP-특이적 T 세포 반응의 유도를 나타내는 것이다(도 20a 내지 20c). 중요하게, 본 발명자들은 GX-19N 백신 접종 대상자에서 확인된 T 세포 에피토프를 포함하는 15-mer 펩타이드의 아미노산 서열이 SARS CoV-2 변이체(즉, B.1.1.7(Alpha), N.1.351(Beta) 및 P.1(Gamma), B.1.617.2(Delta), C.37(Lamda))의 아미노산 서열과 동일하다는 것을 확인하였다(15-mer 펩타이드 1개 제외, 도 20a 내지 20c). 이러한 결과는 GX-19N에 의해 유도된 NP-특이적 T 세포 반응이 SARS CoV-2 변이체와 교차반응할 수 있음을 시사한다.
결론적으로, 본 발명자들은 SARS CoV-2 백신 항원으로서 수용성 S 단백질과 뉴클레오캡시드 단백질을 각각 암호화하는 폴리뉴클레오타이드를 DNA 백신 형태로 투여할 경우, 중화 항체의 생성은 물론 SARS CoV-2 방어와 밀접하게 관련된 것으로 판단되는 항원-특이적 T 세포 면역반응이 현저하게 증가됨을 확인하였으며, 심각한 부작용 사례도 관찰되지 않은 바, 이를 통해, SARS CoV-2의 수용성 S 단백질을 암호화하는 폴리뉴클레오타이드와 뉴클레오캡시드 단백질을 암호화하는 폴리뉴클레오타이드가 SARS CoV-2 예방 및 치료를 위한 안전하고 유용한 백신 후보물질임을 규명함으로써 본 발명을 완성하였다.
본 발명은 상술한 실시예 및 실험예를 참고로 설명되었으나 이는 예시적인 것에 불과하며, 당해 기술분야에서 통상의 지식을 가진 자라면 이로부터 다양한 변형 및 균등한 다른 실시예가 가능하다는 점을 이해할 것이다. 따라서 본 발명의 진정한 기술적 보호 범위는 첨부된 특허청구범위의 기술적 사상에 의하여 정해져야 할 것이다.
<110> SLVaxigen, Inc.
Genexine, Inc.
<120> A novel vaccine composition for preventing and treating corona
virus
<130> PD21-6130
<150> KR 10-2020-0176874
<151> 2020-12-16
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Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val
100 105 110
Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val
115 120 125
Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val
130 135 140
Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe
145 150 155 160
Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu
165 170 175
Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His
180 185 190
Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu
195 200 205
Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln
210 215 220
Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser
225 230 235 240
Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln
245 250 255
Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp
260 265 270
Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu
275 280 285
Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg
290 295 300
Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu
305 310 315 320
Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr
325 330 335
Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val
340 345 350
Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser
355 360 365
Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser
370 375 380
Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr
385 390 395 400
Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly
405 410 415
Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly
420 425 430
Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro
435 440 445
Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro
450 455 460
Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr
465 470 475 480
Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val
485 490 495
Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro
500 505 510
Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe
515 520 525
Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe
530 535 540
Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala
545 550 555 560
Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser
565 570 575
Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln
580 585 590
Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala
595 600 605
Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly
610 615 620
Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His
625 630 635 640
Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys
645 650 655
Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val
660 665 670
Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn
675 680 685
Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr
690 695 700
Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser
705 710 715 720
Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn
725 730 735
Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu
740 745 750
Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala
755 760 765
Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly
770 775 780
Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg
785 790 795 800
Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala
805 810 815
Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg
820 825 830
Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro
835 840 845
Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala
850 855 860
Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln
865 870 875 880
Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val
885 890 895
Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe
900 905 910
Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser
915 920 925
Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu
930 935 940
Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser
945 950 955 960
Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val
965 970 975
Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr
980 985 990
Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
995 1000 1005
Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg
1010 1015 1020
Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser
1025 1030 1035 1040
Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln
1045 1050 1055
Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala
1060 1065 1070
His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe
1075 1080 1085
Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn
1090 1095 1100
Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn
1105 1110 1115 1120
Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu
1125 1130 1135
Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly
1140 1145 1150
Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile
1155 1160 1165
Asp Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp
1170 1175 1180
Leu Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro
1185 1190 1195
<210> 3
<211> 828
<212> PRT
<213> Artificial Sequence
<220>
<223> SARS CoV-2 S1-sCD40L
<400> 3
Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser
1 5 10 15
Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val
20 25 30
Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr
35 40 45
Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe
50 55 60
Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr
65 70 75 80
Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp
85 90 95
Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val
100 105 110
Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val
115 120 125
Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val
130 135 140
Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe
145 150 155 160
Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu
165 170 175
Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His
180 185 190
Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu
195 200 205
Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln
210 215 220
Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser
225 230 235 240
Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln
245 250 255
Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp
260 265 270
Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu
275 280 285
Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg
290 295 300
Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu
305 310 315 320
Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr
325 330 335
Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val
340 345 350
Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser
355 360 365
Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser
370 375 380
Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr
385 390 395 400
Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly
405 410 415
Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly
420 425 430
Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro
435 440 445
Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro
450 455 460
Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr
465 470 475 480
Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val
485 490 495
Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro
500 505 510
Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe
515 520 525
Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe
530 535 540
Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala
545 550 555 560
Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser
565 570 575
Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln
580 585 590
Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala
595 600 605
Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly
610 615 620
Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His
625 630 635 640
Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys
645 650 655
Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Gly Ser Gly
660 665 670
Ser Gly Ser Gly Ser Gly Ser Met Gln Lys Gly Asp Gln Asn Pro Gln
675 680 685
Ile Ala Ala His Val Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser Val
690 695 700
Leu Gln Trp Ala Glu Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu Val
705 710 715 720
Thr Leu Glu Asn Gly Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr
725 730 735
Tyr Ile Tyr Ala Gln Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser
740 745 750
Gln Ala Pro Phe Ile Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg Phe
755 760 765
Glu Arg Ile Leu Leu Arg Ala Ala Asn Thr His Ser Ser Ala Lys Pro
770 775 780
Cys Gly Gln Gln Ser Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro
785 790 795 800
Gly Ala Ser Val Phe Val Asn Val Thr Asp Pro Ser Gln Val Ser His
805 810 815
Gly Thr Gly Phe Thr Ser Phe Gly Leu Leu Lys Leu
820 825
<210> 4
<211> 1357
<212> PRT
<213> Artificial Sequence
<220>
<223> SARS CoV-2 S1S2 delta TM/IC-sCD40L
<400> 4
Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser
1 5 10 15
Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val
20 25 30
Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr
35 40 45
Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe
50 55 60
Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr
65 70 75 80
Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp
85 90 95
Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val
100 105 110
Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val
115 120 125
Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val
130 135 140
Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe
145 150 155 160
Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu
165 170 175
Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His
180 185 190
Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu
195 200 205
Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln
210 215 220
Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser
225 230 235 240
Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln
245 250 255
Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp
260 265 270
Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu
275 280 285
Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg
290 295 300
Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu
305 310 315 320
Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr
325 330 335
Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val
340 345 350
Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser
355 360 365
Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser
370 375 380
Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr
385 390 395 400
Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly
405 410 415
Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly
420 425 430
Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro
435 440 445
Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro
450 455 460
Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr
465 470 475 480
Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val
485 490 495
Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro
500 505 510
Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe
515 520 525
Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe
530 535 540
Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala
545 550 555 560
Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser
565 570 575
Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln
580 585 590
Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala
595 600 605
Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly
610 615 620
Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His
625 630 635 640
Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys
645 650 655
Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val
660 665 670
Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn
675 680 685
Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr
690 695 700
Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser
705 710 715 720
Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn
725 730 735
Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu
740 745 750
Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala
755 760 765
Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly
770 775 780
Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg
785 790 795 800
Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala
805 810 815
Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg
820 825 830
Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro
835 840 845
Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala
850 855 860
Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln
865 870 875 880
Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val
885 890 895
Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe
900 905 910
Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser
915 920 925
Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu
930 935 940
Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser
945 950 955 960
Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val
965 970 975
Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr
980 985 990
Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
995 1000 1005
Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg
1010 1015 1020
Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser
1025 1030 1035 1040
Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln
1045 1050 1055
Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala
1060 1065 1070
His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe
1075 1080 1085
Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn
1090 1095 1100
Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn
1105 1110 1115 1120
Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu
1125 1130 1135
Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly
1140 1145 1150
Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile
1155 1160 1165
Asp Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp
1170 1175 1180
Leu Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Gly Ser
1185 1190 1195 1200
Gly Ser Gly Ser Gly Ser Gly Ser Met Gln Lys Gly Asp Gln Asn Pro
1205 1210 1215
Gln Ile Ala Ala His Val Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser
1220 1225 1230
Val Leu Gln Trp Ala Glu Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu
1235 1240 1245
Val Thr Leu Glu Asn Gly Lys Gln Leu Thr Val Lys Arg Gln Gly Leu
1250 1255 1260
Tyr Tyr Ile Tyr Ala Gln Val Thr Phe Cys Ser Asn Arg Glu Ala Ser
1265 1270 1275 1280
Ser Gln Ala Pro Phe Ile Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg
1285 1290 1295
Phe Glu Arg Ile Leu Leu Arg Ala Ala Asn Thr His Ser Ser Ala Lys
1300 1305 1310
Pro Cys Gly Gln Gln Ser Ile His Leu Gly Gly Val Phe Glu Leu Gln
1315 1320 1325
Pro Gly Ala Ser Val Phe Val Asn Val Thr Asp Pro Ser Gln Val Ser
1330 1335 1340
His Gly Thr Gly Phe Thr Ser Phe Gly Leu Leu Lys Leu
1345 1350 1355
<210> 5
<211> 149
<212> PRT
<213> Artificial Sequence
<220>
<223> sCD40L113-261
<400> 5
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
1 5 10 15
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
20 25 30
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
35 40 45
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
50 55 60
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
65 70 75 80
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
85 90 95
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
100 105 110
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
115 120 125
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
130 135 140
Gly Leu Leu Lys Leu
145
<210> 6
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 6
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
1 5 10
<210> 7
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 7
Gly Gly Gly Gly Ser
1 5
<210> 8
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 8
Gly Ser Ser Gly Gly Ser
1 5
<210> 9
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 9
Lys Glu Ser Gly Ser Val Ser Ser Glu Gln Leu Ala Gln Phe Arg Ser
1 5 10 15
Leu Asp
<210> 10
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 10
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr
1 5 10
<210> 11
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 11
Gly Ser Ala Gly Ser Ala Ala Gly Ser Gly Glu Phe
1 5 10
<210> 12
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 12
Glu Ala Ala Ala Lys
1 5
<210> 13
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 13
Cys Arg Arg Arg Arg Arg Arg Glu Ala Glu Ala Cys
1 5 10
<210> 14
<211> 46
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 14
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
Glu Ala Ala Ala Lys Ala Leu Glu Ala Glu Ala Ala Ala Lys Glu Ala
20 25 30
Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala
35 40 45
<210> 15
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 15
Gly Gly Gly Gly Gly Gly Gly Gly
1 5
<210> 16
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 16
Gly Gly Gly Gly Gly Gly
1 5
<210> 17
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 17
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Ala Lys Ala
1 5 10
<210> 18
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 18
Pro Ala Pro Ala Pro
1 5
<210> 19
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 19
Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp
1 5 10 15
Val
<210> 20
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 20
Pro Leu Gly Leu Trp Ala
1 5
<210> 21
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 21
Thr Arg His Arg Gln Pro Arg Gly Trp Glu
1 5 10
<210> 22
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 22
Ala Gly Asn Arg Val Arg Arg Ser Val Gly
1 5 10
<210> 23
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 23
Arg Arg Arg Arg Arg Arg Arg Arg
1 5
<210> 24
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 24
Gly Phe Leu Gly
1
<210> 25
<211> 31
<212> PRT
<213> Artificial Sequence
<220>
<223> linker peptide
<400> 25
Gly Ser Ser Gly Gly Ser Gly Ser Ser Gly Gly Ser Gly Gly Gly Asp
1 5 10 15
Glu Ala Asp Gly Ser Arg Gly Ser Gln Lys Ala Gly Val Asp Glu
20 25 30
<210> 26
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> tPA leader sequence
<400> 26
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser His Ala
20 25
<210> 27
<211> 156
<212> PRT
<213> Artificial Sequence
<220>
<223> Flt3L
<400> 27
Thr Gln Asp Cys Ser Phe Gln His Ser Pro Ile Ser Ser Asp Phe Ala
1 5 10 15
Val Lys Ile Arg Glu Leu Ser Asp Tyr Leu Leu Gln Asp Tyr Pro Val
20 25 30
Thr Val Ala Ser Asn Leu Gln Asp Glu Glu Leu Cys Gly Gly Leu Trp
35 40 45
Arg Leu Val Leu Ala Gln Arg Trp Met Glu Arg Leu Lys Thr Val Ala
50 55 60
Gly Ser Lys Met Gln Gly Leu Leu Glu Arg Val Asn Thr Glu Ile His
65 70 75 80
Phe Val Thr Lys Cys Ala Phe Gln Pro Pro Pro Ser Cys Leu Arg Phe
85 90 95
Val Gln Thr Asn Ile Ser Arg Leu Leu Gln Glu Thr Ser Glu Gln Leu
100 105 110
Val Ala Leu Lys Pro Trp Ile Thr Arg Gln Asn Phe Ser Arg Cys Leu
115 120 125
Glu Leu Gln Cys Gln Pro Asp Ser Ser Thr Leu Pro Pro Pro Trp Ser
130 135 140
Pro Arg Pro Leu Glu Ala Thr Ala Pro Thr Ala Pro
145 150 155
<210> 28
<211> 75
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding tPA leader sequence
<400> 28
atggatgcta tgaagagggg cctgtgctgc gtgctgcttc tgtgtggcgc tgtgtttgtg 60
tctcctagcc acgcc 75
<210> 29
<211> 2007
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding SARS CoV-2 S1
<400> 29
gtgaacctga ccaccagaac acaactgcct ccagcctaca ccaacagctt caccagaggc 60
gtgtactacc ccgacaaggt gttcagatcc agcgtgctgc actctaccca ggacctgttc 120
ctgcctttct tcagcaacgt gacctggttc cacgccatcc atgtgtccgg caccaatggc 180
accaagagat tcgacaaccc cgtgctgccc ttcaacgacg gggtgtactt tgccagcacc 240
gagaagtcca acatcatcag aggctggatc ttcggcacca cactggacag caagacccag 300
agcctgctga tcgtgaacaa cgccaccaac gtggtcatca aagtgtgcga gttccagttc 360
tgcaacgacc ccttcctggg cgtctactac cacaagaaca acaagagctg gatggaaagc 420
gagttccggg tgtacagcag cgccaacaac tgcaccttcg agtacgtgtc ccagcctttc 480
ctgatggacc tggaaggcaa gcagggcaac ttcaagaacc tgcgcgagtt cgtgttcaag 540
aacatcgacg gctacttcaa gatctacagc aagcacaccc ctatcaacct cgtgcgggat 600
ctgcctcagg gcttctctgc tctggaaccc ctggtggatc tgcccatcgg catcaacatc 660
acccggtttc agacactgct ggccctgcac agaagctacc tgacacctgg cgatagcagc 720
tctggatgga cagctggcgc cgctgcctac tatgtgggat atctgcaacc taggaccttc 780
ctgctgaagt acaacgagaa cggcaccatc accgacgccg tggattgtgc tctggatccc 840
ctgagcgaga caaagtgcac cctgaagtcc ttcaccgtgg aaaagggcat ctaccagacc 900
agcaacttcc gggtgcagcc caccgaatcc atcgtgcggt tccccaacat caccaatctg 960
tgccctttcg gcgaggtgtt caacgccacc agattcgcct ctgtgtacgc ctggaaccgg 1020
aagcggatca gcaattgcgt ggccgactac agcgtgctgt acaacagcgc cagcttcagc 1080
accttcaagt gctacggcgt gtcccctacc aagctgaacg acctgtgctt caccaacgtg 1140
tacgccgaca gcttcgtgat cagaggcgac gaagtgcggc agattgcccc tggacagaca 1200
ggcaagatcg ccgattacaa ctacaagctg cccgacgact tcaccggctg tgtgattgcc 1260
tggaacagca acaacctgga cagcaaagtc ggcggcaact acaactacct gtaccggctg 1320
ttccggaagt ccaacctgaa gcctttcgag cgggacatca gcaccgagat ctatcaggcc 1380
ggcagcaccc cttgcaatgg cgtggaaggc ttcaactgct acttcccact gcagtcctac 1440
ggcttccagc ctacaaacgg cgtgggctac cagccttaca gagtggtggt gctgagcttc 1500
gagctgctgc atgctcctgc cacagtgtgc ggccctaaga aaagcaccaa cctggtcaag 1560
aacaaatgcg tgaacttcaa cttcaacggc ctgaccggca ccggcgtgct gacagagagc 1620
aacaagaagt tcctgccttt ccagcagttc ggccgggata tcgccgatac cacagatgct 1680
gtcagagatc cccagacact ggaaatcctg gacatcaccc catgcagctt cggcggagtg 1740
tctgtgatca cccctggcac caacaccagc aatcaggtgg ccgtgctgta tcaggacgtg 1800
aactgtaccg aagtgcccgt ggccattcac gccgatcagc tgacacctac atggcgggtg 1860
tactccaccg gcagcaacgt gttccagaca agagccggct gtctgatcgg agccgagcat 1920
gtgaacaaca gctacgagtg cgacatcccc atcggcgctg gcatctgtgc cagctaccag 1980
acacagacaa acagccccag aagggcc 2007
<210> 30
<211> 1587
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding SARS CoV-2 S2 delta TM/IC
<400> 30
agatctgtgg ccagccagag catcattgcc tacaccatgt ctctgggcgc cgagaacagc 60
gtggcctaca gcaacaactc tatcgctatc cccaccaact tcaccatcag cgtgaccacc 120
gagatcctgc ctgtgtccat gaccaagacc agcgtggact gcaccatgta catctgcggc 180
gatagcaccg agtgcagcaa cctgctgctg cagtacggca gcttctgcac ccagctgaat 240
agagccctga ccggaatcgc cgtggaacag gacaagaaca cccaagaggt gttcgcccaa 300
gtgaagcaga tctacaagac ccctcctatc aaggacttcg gcggcttcaa cttcagccag 360
attctgcccg atcctagcaa gcccagcaag cggagcttca tcgaggacct gctgttcaac 420
aaagtgaccc tggccgacgc cggcttcatc aagcagtatg gcgattgcct gggcgacatt 480
gccgccaggg atctgatttg cgcccagaag tttaacggcc tgaccgtgct gcctcctctg 540
ctgaccgatg agatgatcgc ccagtacaca tctgccctgc tggccggcac aatcacaagc 600
ggctggacat ttggagctgg cgccgctctg cagatcccct ttgctatgca gatggcctac 660
cggttcaacg gcatcggcgt gacccagaac gtgctgtacg agaaccagaa gctgatcgcc 720
aaccagttca acagcgccat cggcaagatc caggacagcc tgagcagtac agccagcgct 780
ctgggaaagc tgcaggacgt ggtcaaccag aatgcccagg ctctgaacac cctggtcaag 840
cagctgagca gcaacttcgg cgccatcagc agcgtgctga acgacatcct gagccgcctg 900
gataaggtgg aagccgaggt gcagatcgac cggctgatta caggcagact gcagagcctg 960
cagacctacg tgacacagca gctgatcaga gccgccgaga ttagagcctc tgccaatctg 1020
gccgccacca agatgtctga gtgtgtgctg ggccagagca agagagtgga cttttgcggc 1080
aagggctacc acctgatgag cttccctcag tctgctcctc acggcgtggt gtttctgcat 1140
gtgacatacg tgcccgctca agagaagaat ttcaccaccg ctccagccat ctgccacgac 1200
ggcaaagccc actttcctag agaaggcgtg ttcgtgtcca acggcaccca ttggttcgtg 1260
actcagcgga acttctacga gccccagatc atcaccaccg acaacacctt cgtgtccggc 1320
aactgcgacg tcgtgatcgg catcgtgaac aataccgtgt acgaccctct gcagcccgag 1380
ctggacagct tcaaagagga actggacaag tacttcaaga accacacaag ccccgacgtg 1440
gacctgggcg atatcagcgg aatcaatgcc agcgtcgtga acatccagaa agagatcgac 1500
agactgaacg aggtggccaa gaacctgaac gagagcctga tcgacctgca agagctgggg 1560
aagtacgagc agtatatcaa gtggcct 1587
<210> 31
<211> 1587
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding SARS CoV-2 S2 delta TM/IC
<400> 31
agatctgtgg ccagccagag catcattgcc tacaccatgt ctctgggcgc cgagaacagc 60
gtggcctaca gcaacaactc tatcgctatc cccaccaact tcaccatcag cgtgaccacc 120
gagatcctgc ctgtgtccat gaccaagacc agcgtggact gcaccatgta catctgcggc 180
gatagcaccg agtgcagcaa cctgctgctg cagtacggca gcttctgcac ccagctgaat 240
agagccctga ccggaatcgc cgtggaacag gacaagaaca cccaagaggt gttcgcccaa 300
gtgaagcaga tctacaagac ccctcctatc aaggacttcg gcggcttcaa cttcagccag 360
attctgcccg atcctagcaa gcccagcaag cggagcttca tcgaggacct gctgttcaac 420
aaagtgaccc tggccgacgc cggcttcatc aagcagtatg gcgattgcct gggcgacatt 480
gccgccaggg atctgatttg cgcccagaag tttaacggcc tgaccgtgct gcctcctctg 540
ctgaccgatg agatgatcgc ccagtacaca tctgccctgc tggccggcac aatcacaagc 600
ggctggacat ttggagctgg cgccgctctg cagatcccct ttgctatgca gatggcctac 660
cggttcaacg gcatcggcgt gacccagaac gtgctgtacg agaaccagaa gctgatcgcc 720
aaccagttca acagcgccat cggcaagatc caggacagcc tgagcagtac agccagcgct 780
ctgggaaagc tgcaggacgt ggtcaaccag aatgcccagg ctctgaacac cctggtcaag 840
cagctgagca gcaacttcgg cgccatcagc agcgtgctga acgacatcct gagccgcctg 900
gataaggtgg aagccgaggt gcagatcgac cggctgatta caggcagact gcagagcctg 960
cagacctacg tgacacagca gctgatcaga gccgccgaga ttagagcctc tgccaatctg 1020
gccgccacca agatgtctga gtgtgtgctg ggccagagca agagagtgga cttttgcggc 1080
aagggctacc acctgatgag cttccctcag tctgctcctc acggcgtggt gtttctgcat 1140
gtgacatacg tgcccgctca agagaagaat ttcaccaccg ctccagccat ctgccacgac 1200
ggcaaagccc actttcctag agaaggcgtg ttcgtgtcca acggcaccca ttggttcgtg 1260
actcagcgga acttctacga gccccagatc atcaccaccg acaacacctt cgtgtccggc 1320
aactgcgacg tcgtgatcgg catcgtgaac aataccgtgt acgaccctct gcagcccgag 1380
ctggacagct tcaaagagga actggacaag tacttcaaga accacacaag ccccgacgtg 1440
gacctgggcg atatcagcgg aatcaatgcc agcgtcgtga acatccagaa agagatcgac 1500
agactgaacg aggtggccaa gaacctgaac gagagcctga tcgacctgca agagctgggg 1560
aagtacgagc agtatatcaa gtggccc 1587
<210> 32
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding (GS)5 linker peptide
<400> 32
ggcagcggca gcggatctgg ctctggatct 30
<210> 33
<211> 447
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding sCD40L113-261
<400> 33
atgcagaagg gcgaccagaa tcctcagatc gccgctcatg tgatcagcga ggccagctct 60
aagaccacct ctgtgctgca gtgggccgag aagggctact acacaatgag caacaacctg 120
gtcaccctgg aaaacggcaa acagctgacc gtgaagcggc agggcctgta ctacatctac 180
gctcaagtga ccttctgctc caacagagag gcctcctctc aggccccttt tatcgccagc 240
ctgtgcctga agtcccctgg cagattcgag cggattctgc tgagagccgc caacacacac 300
agctccgcca aaccttgtgg acagcagtct atccacctcg gcggagtgtt tgaactgcag 360
cctggcgcct ccgtgtttgt gaacgtgacc gatccttctc aggtgtccca cggaaccggc 420
ttcacctctt ttggcctgct gaagctg 447
<210> 34
<211> 3594
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding SARS CoV-2 S1S2 delta TM/IC
<400> 34
gtgaacctga ccaccagaac acaactgcct ccagcctaca ccaacagctt caccagaggc 60
gtgtactacc ccgacaaggt gttcagatcc agcgtgctgc actctaccca ggacctgttc 120
ctgcctttct tcagcaacgt gacctggttc cacgccatcc atgtgtccgg caccaatggc 180
accaagagat tcgacaaccc cgtgctgccc ttcaacgacg gggtgtactt tgccagcacc 240
gagaagtcca acatcatcag aggctggatc ttcggcacca cactggacag caagacccag 300
agcctgctga tcgtgaacaa cgccaccaac gtggtcatca aagtgtgcga gttccagttc 360
tgcaacgacc ccttcctggg cgtctactac cacaagaaca acaagagctg gatggaaagc 420
gagttccggg tgtacagcag cgccaacaac tgcaccttcg agtacgtgtc ccagcctttc 480
ctgatggacc tggaaggcaa gcagggcaac ttcaagaacc tgcgcgagtt cgtgttcaag 540
aacatcgacg gctacttcaa gatctacagc aagcacaccc ctatcaacct cgtgcgggat 600
ctgcctcagg gcttctctgc tctggaaccc ctggtggatc tgcccatcgg catcaacatc 660
acccggtttc agacactgct ggccctgcac agaagctacc tgacacctgg cgatagcagc 720
tctggatgga cagctggcgc cgctgcctac tatgtgggat atctgcaacc taggaccttc 780
ctgctgaagt acaacgagaa cggcaccatc accgacgccg tggattgtgc tctggatccc 840
ctgagcgaga caaagtgcac cctgaagtcc ttcaccgtgg aaaagggcat ctaccagacc 900
agcaacttcc gggtgcagcc caccgaatcc atcgtgcggt tccccaacat caccaatctg 960
tgccctttcg gcgaggtgtt caacgccacc agattcgcct ctgtgtacgc ctggaaccgg 1020
aagcggatca gcaattgcgt ggccgactac agcgtgctgt acaacagcgc cagcttcagc 1080
accttcaagt gctacggcgt gtcccctacc aagctgaacg acctgtgctt caccaacgtg 1140
tacgccgaca gcttcgtgat cagaggcgac gaagtgcggc agattgcccc tggacagaca 1200
ggcaagatcg ccgattacaa ctacaagctg cccgacgact tcaccggctg tgtgattgcc 1260
tggaacagca acaacctgga cagcaaagtc ggcggcaact acaactacct gtaccggctg 1320
ttccggaagt ccaacctgaa gcctttcgag cgggacatca gcaccgagat ctatcaggcc 1380
ggcagcaccc cttgcaatgg cgtggaaggc ttcaactgct acttcccact gcagtcctac 1440
ggcttccagc ctacaaacgg cgtgggctac cagccttaca gagtggtggt gctgagcttc 1500
gagctgctgc atgctcctgc cacagtgtgc ggccctaaga aaagcaccaa cctggtcaag 1560
aacaaatgcg tgaacttcaa cttcaacggc ctgaccggca ccggcgtgct gacagagagc 1620
aacaagaagt tcctgccttt ccagcagttc ggccgggata tcgccgatac cacagatgct 1680
gtcagagatc cccagacact ggaaatcctg gacatcaccc catgcagctt cggcggagtg 1740
tctgtgatca cccctggcac caacaccagc aatcaggtgg ccgtgctgta tcaggacgtg 1800
aactgtaccg aagtgcccgt ggccattcac gccgatcagc tgacacctac atggcgggtg 1860
tactccaccg gcagcaacgt gttccagaca agagccggct gtctgatcgg agccgaacac 1920
gtgaacaaca gctacgagtg cgacatccct atcggagccg gcatctgtgc cagctaccag 1980
acacagacaa acagccccag acgggccaga tctgtggcca gccagagcat cattgcctac 2040
accatgtctc tgggcgccga gaacagcgtg gcctacagca acaactctat cgctatcccc 2100
accaacttca ccatcagcgt gaccaccgag atcctgcctg tgtccatgac caagaccagc 2160
gtggactgca ccatgtacat ctgcggcgat agcaccgagt gcagcaacct gctgctgcag 2220
tacggcagct tctgcaccca gctgaataga gccctgaccg gaatcgccgt ggaacaggac 2280
aagaacaccc aagaggtgtt cgcccaagtg aagcagatct acaagacccc tcctatcaag 2340
gacttcggcg gcttcaactt cagccagatt ctgcccgatc ctagcaagcc cagcaagcgg 2400
agcttcatcg aggacctgct gttcaacaaa gtgaccctgg ccgacgccgg cttcatcaag 2460
cagtatggcg attgcctggg cgacattgcc gccagggatc tgatttgcgc ccagaagttt 2520
aacggcctga ccgtgctgcc tcctctgctg accgatgaga tgatcgccca gtacacatct 2580
gccctgctgg ccggcacaat cacaagcggc tggacatttg gagctggcgc cgctctgcag 2640
atcccctttg ctatgcagat ggcctaccgg ttcaacggca tcggcgtgac ccagaacgtg 2700
ctgtacgaga accagaagct gatcgccaac cagttcaaca gcgccatcgg caagatccag 2760
gacagcctga gcagtacagc cagcgctctg ggaaagctgc aggacgtggt caaccagaat 2820
gcccaggctc tgaacaccct ggtcaagcag ctgagcagca acttcggcgc catcagcagc 2880
gtgctgaacg acatcctgag ccgcctggat aaggtggaag ccgaggtgca gatcgaccgg 2940
ctgattacag gcagactgca gagcctgcag acctacgtga cacagcagct gatcagagcc 3000
gccgagatta gagcctctgc caatctggcc gccaccaaga tgtctgagtg tgtgctgggc 3060
cagagcaaga gagtggactt ttgcggcaag ggctaccacc tgatgagctt ccctcagtct 3120
gctcctcacg gcgtggtgtt tctgcatgtg acatacgtgc ccgctcaaga gaagaatttc 3180
accaccgctc cagccatctg ccacgacggc aaagcccact ttcctagaga aggcgtgttc 3240
gtgtccaacg gcacccattg gttcgtgact cagcggaact tctacgagcc ccagatcatc 3300
accaccgaca acaccttcgt gtccggcaac tgcgacgtcg tgatcggcat cgtgaacaat 3360
accgtgtacg accctctgca gcccgagctg gacagcttca aagaggaact ggacaagtac 3420
ttcaagaacc acacaagccc cgacgtggac ctgggcgata tcagcggaat caatgccagc 3480
gtcgtgaaca tccagaaaga gatcgacaga ctgaacgagg tggccaagaa cctgaacgag 3540
agcctgatcg acctgcaaga gctggggaag tacgagcagt atatcaagtg gccc 3594
<210> 35
<211> 3594
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding SARS CoV-2 S1S2 delta TM/IC
<400> 35
gtgaacctga ccaccagaac acaactgcct ccagcctaca ccaacagctt caccagaggc 60
gtgtactacc ccgacaaggt gttcagatcc agcgtgctgc actctaccca ggacctgttc 120
ctgcctttct tcagcaacgt gacctggttc cacgccatcc atgtgtccgg caccaatggc 180
accaagagat tcgacaaccc cgtgctgccc ttcaacgacg gggtgtactt tgccagcacc 240
gagaagtcca acatcatcag aggctggatc ttcggcacca cactggacag caagacccag 300
agcctgctga tcgtgaacaa cgccaccaac gtggtcatca aagtgtgcga gttccagttc 360
tgcaacgacc ccttcctggg cgtctactac cacaagaaca acaagagctg gatggaaagc 420
gagttccggg tgtacagcag cgccaacaac tgcaccttcg agtacgtgtc ccagcctttc 480
ctgatggacc tggaaggcaa gcagggcaac ttcaagaacc tgcgcgagtt cgtgttcaag 540
aacatcgacg gctacttcaa gatctacagc aagcacaccc ctatcaacct cgtgcgggat 600
ctgcctcagg gcttctctgc tctggaaccc ctggtggatc tgcccatcgg catcaacatc 660
acccggtttc agacactgct ggccctgcac agaagctacc tgacacctgg cgatagcagc 720
tctggatgga cagctggcgc cgctgcctac tatgtgggat atctgcaacc taggaccttc 780
ctgctgaagt acaacgagaa cggcaccatc accgacgccg tggattgtgc tctggatccc 840
ctgagcgaga caaagtgcac cctgaagtcc ttcaccgtgg aaaagggcat ctaccagacc 900
agcaacttcc gggtgcagcc caccgaatcc atcgtgcggt tccccaacat caccaatctg 960
tgccctttcg gcgaggtgtt caacgccacc agattcgcct ctgtgtacgc ctggaaccgg 1020
aagcggatca gcaattgcgt ggccgactac agcgtgctgt acaacagcgc cagcttcagc 1080
accttcaagt gctacggcgt gtcccctacc aagctgaacg acctgtgctt caccaacgtg 1140
tacgccgaca gcttcgtgat cagaggcgac gaagtgcggc agattgcccc tggacagaca 1200
ggcaagatcg ccgattacaa ctacaagctg cccgacgact tcaccggctg tgtgattgcc 1260
tggaacagca acaacctgga cagcaaagtc ggcggcaact acaactacct gtaccggctg 1320
ttccggaagt ccaacctgaa gcctttcgag cgggacatca gcaccgagat ctatcaggcc 1380
ggcagcaccc cttgcaatgg cgtggaaggc ttcaactgct acttcccact gcagtcctac 1440
ggcttccagc ctacaaacgg cgtgggctac cagccttaca gagtggtggt gctgagcttc 1500
gagctgctgc atgctcctgc cacagtgtgc ggccctaaga aaagcaccaa cctggtcaag 1560
aacaaatgcg tgaacttcaa cttcaacggc ctgaccggca ccggcgtgct gacagagagc 1620
aacaagaagt tcctgccttt ccagcagttc ggccgggata tcgccgatac cacagatgct 1680
gtcagagatc cccagacact ggaaatcctg gacatcaccc catgcagctt cggcggagtg 1740
tctgtgatca cccctggcac caacaccagc aatcaggtgg ccgtgctgta tcaggacgtg 1800
aactgtaccg aagtgcccgt ggccattcac gccgatcagc tgacacctac atggcgggtg 1860
tactccaccg gcagcaacgt gttccagaca agagccggct gtctgatcgg agccgaacac 1920
gtgaacaaca gctacgagtg cgacatccct atcggagccg gcatctgtgc cagctaccag 1980
acacagacaa acagccccag acgggccaga tctgtggcca gccagagcat cattgcctac 2040
accatgtctc tgggcgccga gaacagcgtg gcctacagca acaactctat cgctatcccc 2100
accaacttca ccatcagcgt gaccaccgag atcctgcctg tgtccatgac caagaccagc 2160
gtggactgca ccatgtacat ctgcggcgat agcaccgagt gcagcaacct gctgctgcag 2220
tacggcagct tctgcaccca gctgaataga gccctgaccg gaatcgccgt ggaacaggac 2280
aagaacaccc aagaggtgtt cgcccaagtg aagcagatct acaagacccc tcctatcaag 2340
gacttcggcg gcttcaactt cagccagatt ctgcccgatc ctagcaagcc cagcaagcgg 2400
agcttcatcg aggacctgct gttcaacaaa gtgaccctgg ccgacgccgg cttcatcaag 2460
cagtatggcg attgcctggg cgacattgcc gccagggatc tgatttgcgc ccagaagttt 2520
aacggcctga ccgtgctgcc tcctctgctg accgatgaga tgatcgccca gtacacatct 2580
gccctgctgg ccggcacaat cacaagcggc tggacatttg gagctggcgc cgctctgcag 2640
atcccctttg ctatgcagat ggcctaccgg ttcaacggca tcggcgtgac ccagaacgtg 2700
ctgtacgaga accagaagct gatcgccaac cagttcaaca gcgccatcgg caagatccag 2760
gacagcctga gcagtacagc cagcgctctg ggaaagctgc aggacgtggt caaccagaat 2820
gcccaggctc tgaacaccct ggtcaagcag ctgagcagca acttcggcgc catcagcagc 2880
gtgctgaacg acatcctgag ccgcctggat aaggtggaag ccgaggtgca gatcgaccgg 2940
ctgattacag gcagactgca gagcctgcag acctacgtga cacagcagct gatcagagcc 3000
gccgagatta gagcctctgc caatctggcc gccaccaaga tgtctgagtg tgtgctgggc 3060
cagagcaaga gagtggactt ttgcggcaag ggctaccacc tgatgagctt ccctcagtct 3120
gctcctcacg gcgtggtgtt tctgcatgtg acatacgtgc ccgctcaaga gaagaatttc 3180
accaccgctc cagccatctg ccacgacggc aaagcccact ttcctagaga aggcgtgttc 3240
gtgtccaacg gcacccattg gttcgtgact cagcggaact tctacgagcc ccagatcatc 3300
accaccgaca acaccttcgt gtccggcaac tgcgacgtcg tgatcggcat cgtgaacaat 3360
accgtgtacg accctctgca gcccgagctg gacagcttca aagaggaact ggacaagtac 3420
ttcaagaacc acacaagccc cgacgtggac ctgggcgata tcagcggaat caatgccagc 3480
gtcgtgaaca tccagaaaga gatcgacaga ctgaacgagg tggccaagaa cctgaacgag 3540
agcctgatcg acctgcaaga gctggggaag tacgagcagt atatcaagtg gcct 3594
<210> 36
<211> 2484
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding SARS CoV-2 S1-sCD40L fusion protein
<400> 36
gtgaacctga ccaccagaac acaactgcct ccagcctaca ccaacagctt caccagaggc 60
gtgtactacc ccgacaaggt gttcagatcc agcgtgctgc actctaccca ggacctgttc 120
ctgcctttct tcagcaacgt gacctggttc cacgccatcc atgtgtccgg caccaatggc 180
accaagagat tcgacaaccc cgtgctgccc ttcaacgacg gggtgtactt tgccagcacc 240
gagaagtcca acatcatcag aggctggatc ttcggcacca cactggacag caagacccag 300
agcctgctga tcgtgaacaa cgccaccaac gtggtcatca aagtgtgcga gttccagttc 360
tgcaacgacc ccttcctggg cgtctactac cacaagaaca acaagagctg gatggaaagc 420
gagttccggg tgtacagcag cgccaacaac tgcaccttcg agtacgtgtc ccagcctttc 480
ctgatggacc tggaaggcaa gcagggcaac ttcaagaacc tgcgcgagtt cgtgttcaag 540
aacatcgacg gctacttcaa gatctacagc aagcacaccc ctatcaacct cgtgcgggat 600
ctgcctcagg gcttctctgc tctggaaccc ctggtggatc tgcccatcgg catcaacatc 660
acccggtttc agacactgct ggccctgcac agaagctacc tgacacctgg cgatagcagc 720
tctggatgga cagctggcgc cgctgcctac tatgtgggat atctgcaacc taggaccttc 780
ctgctgaagt acaacgagaa cggcaccatc accgacgccg tggattgtgc tctggatccc 840
ctgagcgaga caaagtgcac cctgaagtcc ttcaccgtgg aaaagggcat ctaccagacc 900
agcaacttcc gggtgcagcc caccgaatcc atcgtgcggt tccccaacat caccaatctg 960
tgccctttcg gcgaggtgtt caacgccacc agattcgcct ctgtgtacgc ctggaaccgg 1020
aagcggatca gcaattgcgt ggccgactac agcgtgctgt acaacagcgc cagcttcagc 1080
accttcaagt gctacggcgt gtcccctacc aagctgaacg acctgtgctt caccaacgtg 1140
tacgccgaca gcttcgtgat cagaggcgac gaagtgcggc agattgcccc tggacagaca 1200
ggcaagatcg ccgattacaa ctacaagctg cccgacgact tcaccggctg tgtgattgcc 1260
tggaacagca acaacctgga cagcaaagtc ggcggcaact acaactacct gtaccggctg 1320
ttccggaagt ccaacctgaa gcctttcgag cgggacatca gcaccgagat ctatcaggcc 1380
ggcagcaccc cttgcaatgg cgtggaaggc ttcaactgct acttcccact gcagtcctac 1440
ggcttccagc ctacaaacgg cgtgggctac cagccttaca gagtggtggt gctgagcttc 1500
gagctgctgc atgctcctgc cacagtgtgc ggccctaaga aaagcaccaa cctggtcaag 1560
aacaaatgcg tgaacttcaa cttcaacggc ctgaccggca ccggcgtgct gacagagagc 1620
aacaagaagt tcctgccttt ccagcagttc ggccgggata tcgccgatac cacagatgct 1680
gtcagagatc cccagacact ggaaatcctg gacatcaccc catgcagctt cggcggagtg 1740
tctgtgatca cccctggcac caacaccagc aatcaggtgg ccgtgctgta tcaggacgtg 1800
aactgtaccg aagtgcccgt ggccattcac gccgatcagc tgacacctac atggcgggtg 1860
tactccaccg gcagcaacgt gttccagaca agagccggct gtctgatcgg agccgaacac 1920
gtgaacaaca gctacgagtg cgacatccct atcggagccg gcatctgtgc cagctaccag 1980
acacagacaa acagccctcg gagagccgga agcggatctg gtagtggctc tggctctatg 2040
cagaagggcg accagaatcc tcagatcgcc gctcatgtga tcagcgaggc cagcagcaag 2100
accacatctg tgctgcagtg ggccgagaag ggctactaca ccatgagcaa caacctggtc 2160
accctggaaa acggcaagca gctgaccgtg aagagacagg gcctgtacta catctacgcc 2220
caagtgacct tctgcagcaa cagagaggcc agctctcagg ccccttttat cgccagcctg 2280
tgcctgaagt cccctggcag attcgagcgg attctgctga gagccgccaa cacacacagc 2340
agcgccaaac cttgtggcca gcagtctatt cacctcggcg gagtgtttga gctgcagcct 2400
ggcgcaagcg tgttcgtgaa tgtgacagac cctagccagg tgtcccacgg caccggcttt 2460
acatctttcg gcctgctgaa gctg 2484
<210> 37
<211> 4071
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding SARS CoV-2 S1S2 delta TM/IC-sCD40L fusion
protein
<400> 37
gtgaacctga ccaccagaac acaactgcct ccagcctaca ccaacagctt caccagaggc 60
gtgtactacc ccgacaaggt gttcagatcc agcgtgctgc actctaccca ggacctgttc 120
ctgcctttct tcagcaacgt gacctggttc cacgccatcc atgtgtccgg caccaatggc 180
accaagagat tcgacaaccc cgtgctgccc ttcaacgacg gggtgtactt tgccagcacc 240
gagaagtcca acatcatcag aggctggatc ttcggcacca cactggacag caagacccag 300
agcctgctga tcgtgaacaa cgccaccaac gtggtcatca aagtgtgcga gttccagttc 360
tgcaacgacc ccttcctggg cgtctactac cacaagaaca acaagagctg gatggaaagc 420
gagttccggg tgtacagcag cgccaacaac tgcaccttcg agtacgtgtc ccagcctttc 480
ctgatggacc tggaaggcaa gcagggcaac ttcaagaacc tgcgcgagtt cgtgttcaag 540
aacatcgacg gctacttcaa gatctacagc aagcacaccc ctatcaacct cgtgcgggat 600
ctgcctcagg gcttctctgc tctggaaccc ctggtggatc tgcccatcgg catcaacatc 660
acccggtttc agacactgct ggccctgcac agaagctacc tgacacctgg cgatagcagc 720
tctggatgga cagctggcgc cgctgcctac tatgtgggat atctgcaacc taggaccttc 780
ctgctgaagt acaacgagaa cggcaccatc accgacgccg tggattgtgc tctggatccc 840
ctgagcgaga caaagtgcac cctgaagtcc ttcaccgtgg aaaagggcat ctaccagacc 900
agcaacttcc gggtgcagcc caccgaatcc atcgtgcggt tccccaacat caccaatctg 960
tgccctttcg gcgaggtgtt caacgccacc agattcgcct ctgtgtacgc ctggaaccgg 1020
aagcggatca gcaattgcgt ggccgactac agcgtgctgt acaacagcgc cagcttcagc 1080
accttcaagt gctacggcgt gtcccctacc aagctgaacg acctgtgctt caccaacgtg 1140
tacgccgaca gcttcgtgat cagaggcgac gaagtgcggc agattgcccc tggacagaca 1200
ggcaagatcg ccgattacaa ctacaagctg cccgacgact tcaccggctg tgtgattgcc 1260
tggaacagca acaacctgga cagcaaagtc ggcggcaact acaactacct gtaccggctg 1320
ttccggaagt ccaacctgaa gcctttcgag cgggacatca gcaccgagat ctatcaggcc 1380
ggcagcaccc cttgcaatgg cgtggaaggc ttcaactgct acttcccact gcagtcctac 1440
ggcttccagc ctacaaacgg cgtgggctac cagccttaca gagtggtggt gctgagcttc 1500
gagctgctgc atgctcctgc cacagtgtgc ggccctaaga aaagcaccaa cctggtcaag 1560
aacaaatgcg tgaacttcaa cttcaacggc ctgaccggca ccggcgtgct gacagagagc 1620
aacaagaagt tcctgccttt ccagcagttc ggccgggata tcgccgatac cacagatgct 1680
gtcagagatc cccagacact ggaaatcctg gacatcaccc catgcagctt cggcggagtg 1740
tctgtgatca cccctggcac caacaccagc aatcaggtgg ccgtgctgta tcaggacgtg 1800
aactgtaccg aagtgcccgt ggccattcac gccgatcagc tgacacctac atggcgggtg 1860
tactccaccg gcagcaacgt gttccagaca agagccggct gtctgatcgg agccgaacac 1920
gtgaacaaca gctacgagtg cgacatccct atcggagccg gcatctgtgc cagctaccag 1980
acacagacaa acagccccag acgggccaga tctgtggcca gccagagcat cattgcctac 2040
accatgtctc tgggcgccga gaacagcgtg gcctacagca acaactctat cgctatcccc 2100
accaacttca ccatcagcgt gaccaccgag atcctgcctg tgtccatgac caagaccagc 2160
gtggactgca ccatgtacat ctgcggcgat agcaccgagt gcagcaacct gctgctgcag 2220
tacggcagct tctgcaccca gctgaataga gccctgaccg gaatcgccgt ggaacaggac 2280
aagaacaccc aagaggtgtt cgcccaagtg aagcagatct acaagacccc tcctatcaag 2340
gacttcggcg gcttcaactt cagccagatt ctgcccgatc ctagcaagcc cagcaagcgg 2400
agcttcatcg aggacctgct gttcaacaaa gtgaccctgg ccgacgccgg cttcatcaag 2460
cagtatggcg attgcctggg cgacattgcc gccagggatc tgatttgcgc ccagaagttt 2520
aacggcctga ccgtgctgcc tcctctgctg accgatgaga tgatcgccca gtacacatct 2580
gccctgctgg ccggcacaat cacaagcggc tggacatttg gagctggcgc cgctctgcag 2640
atcccctttg ctatgcagat ggcctaccgg ttcaacggca tcggcgtgac ccagaacgtg 2700
ctgtacgaga accagaagct gatcgccaac cagttcaaca gcgccatcgg caagatccag 2760
gacagcctga gcagtacagc cagcgctctg ggaaagctgc aggacgtggt caaccagaat 2820
gcccaggctc tgaacaccct ggtcaagcag ctgagcagca acttcggcgc catcagcagc 2880
gtgctgaacg acatcctgag ccgcctggat aaggtggaag ccgaggtgca gatcgaccgg 2940
ctgattacag gcagactgca gagcctgcag acctacgtga cacagcagct gatcagagcc 3000
gccgagatta gagcctctgc caatctggcc gccaccaaga tgtctgagtg tgtgctgggc 3060
cagagcaaga gagtggactt ttgcggcaag ggctaccacc tgatgagctt ccctcagtct 3120
gctcctcacg gcgtggtgtt tctgcatgtg acatacgtgc ccgctcaaga gaagaatttc 3180
accaccgctc cagccatctg ccacgacggc aaagcccact ttcctagaga aggcgtgttc 3240
gtgtccaacg gcacccattg gttcgtgact cagcggaact tctacgagcc ccagatcatc 3300
accaccgaca acaccttcgt gtccggcaac tgcgacgtcg tgatcggcat cgtgaacaat 3360
accgtgtacg accctctgca gcccgagctg gacagcttca aagaggaact ggacaagtac 3420
ttcaagaacc acacaagccc cgacgtggac ctgggcgata tcagcggaat caatgccagc 3480
gtcgtgaaca tccagaaaga gatcgacaga ctgaacgagg tggccaagaa cctgaacgag 3540
agcctgatcg acctgcaaga gctggggaag tacgagcagt atatcaagtg gcctggcagc 3600
ggcagcggat ctggctctgg atctatgcag aagggcgacc agaatcctca gatcgccgct 3660
catgtgatca gcgaggccag ctctaagacc acctctgtgc tgcagtgggc cgagaagggc 3720
tactacacaa tgagcaacaa cctggtcacc ctggaaaacg gcaaacagct gaccgtgaag 3780
cggcagggcc tgtactacat ctacgctcaa gtgaccttct gctccaacag agaggcctcc 3840
tctcaggccc cttttatcgc cagcctgtgc ctgaagtccc ctggcagatt cgagcggatt 3900
ctgctgagag ccgccaacac acacagctcc gccaaacctt gtggacagca gtctatccac 3960
ctcggcggag tgtttgaact gcagcctggc gcctccgtgt ttgtgaacgt gaccgatcct 4020
tctcaggtgt cccacggaac cggcttcacc tcttttggcc tgctgaagct g 4071
<210> 38
<211> 1273
<212> PRT
<213> Artificial Sequence
<220>
<223> SARS CoV-2 S glycoprotein full sequence
<400> 38
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu
1010 1015 1020
Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val
1025 1030 1035 1040
Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala
1045 1050 1055
Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln Glu
1060 1065 1070
Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala His
1075 1080 1085
Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe Val
1090 1095 1100
Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr
1105 1110 1115 1120
Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn Thr
1125 1130 1135
Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu
1140 1145 1150
Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp
1155 1160 1165
Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp
1170 1175 1180
Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu
1185 1190 1195 1200
Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile
1205 1210 1215
Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile
1220 1225 1230
Met Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro Val
1250 1255 1260
Leu Lys Gly Val Lys Leu His Tyr Thr
1265 1270
<210> 39
<211> 27
<212> PRT
<213> Artificial Sequence
<220>
<223> foldon domain
<400> 39
Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys
1 5 10 15
Asp Gly Glu Trp Val Leu Leu Ser Thr Phe Leu
20 25
<210> 40
<211> 81
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding foldon domain
<400> 40
ggttacatcc cagaagcccc aagggacggt caggcatacg tccgcaagga cggagaatgg 60
gtgttgctca gtacctttct c 81
<210> 41
<211> 223
<212> PRT
<213> Artificial Sequence
<220>
<223> receptor binding domain (RBD) of SARS CoV-2 S1 protein
<400> 41
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> 42
<211> 669
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding receptor binding domain (RBD) of SARS
CoV-2 S1 protein
<400> 42
cgggtgcagc ccaccgaatc catcgtgcgg ttccccaaca tcaccaatct gtgccctttc 60
ggcgaggtgt tcaacgccac cagattcgcc tctgtgtacg cctggaaccg gaagcggatc 120
agcaattgcg tggccgacta cagcgtgctg tacaacagcg ccagcttcag caccttcaag 180
tgctacggcg tgtcccctac caagctgaac gacctgtgct tcaccaacgt gtacgccgac 240
agcttcgtga tcagaggcga cgaagtgcgg cagattgccc ctggacagac aggcaagatc 300
gccgattaca actacaagct gcccgacgac ttcaccggct gtgtgattgc ctggaacagc 360
aacaacctgg acagcaaagt cggcggcaac tacaactacc tgtaccggct gttccggaag 420
tccaacctga agcctttcga gcgggacatc agcaccgaga tctatcaggc cggcagcacc 480
ccttgcaatg gcgtggaagg cttcaactgc tacttcccac tgcagtccta cggcttccag 540
cctacaaacg gcgtgggcta ccagccttac agagtggtgg tgctgagctt cgagctgctg 600
catgctcctg ccacagtgtg cggccctaag aaaagcacca acctggtcaa gaacaaatgc 660
gtgaacttc 669
<210> 43
<211> 260
<212> PRT
<213> Artificial Sequence
<220>
<223> SARS-CoV-2 S RBD-foldon Fusion Protein
<400> 43
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 Gly
210 215 220
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Tyr Ile Pro Glu Ala Pro
225 230 235 240
Arg Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp Val Leu Leu
245 250 255
Ser Thr Phe Leu
260
<210> 44
<211> 780
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding SARS CoV-2 S RBD-foldon fusion protein
<400> 44
cgggtgcagc ccaccgaatc catcgtgcgg ttccccaaca tcaccaatct gtgccctttc 60
ggcgaggtgt tcaacgccac cagattcgcc tctgtgtacg cctggaaccg gaagcggatc 120
agcaattgcg tggccgacta cagcgtgctg tacaacagcg ccagcttcag caccttcaag 180
tgctacggcg tgtcccctac caagctgaac gacctgtgct tcaccaacgt gtacgccgac 240
agcttcgtga tcagaggcga cgaagtgcgg cagattgccc ctggacagac aggcaagatc 300
gccgattaca actacaagct gcccgacgac ttcaccggct gtgtgattgc ctggaacagc 360
aacaacctgg acagcaaagt cggcggcaac tacaactacc tgtaccggct gttccggaag 420
tccaacctga agcctttcga gcgggacatc agcaccgaga tctatcaggc cggcagcacc 480
ccttgcaatg gcgtggaagg cttcaactgc tacttcccac tgcagtccta cggcttccag 540
cctacaaacg gcgtgggcta ccagccttac agagtggtgg tgctgagctt cgagctgctg 600
catgctcctg ccacagtgtg cggccctaag aaaagcacca acctggtcaa gaacaaatgc 660
gtgaacttcg gcggaggcgg atctggtggc ggaggtagtg gttacatccc agaagcccca 720
agggacggtc aggcatacgt ccgcaaggac ggagaatggg tgttgctcag tacctttctc 780
780
<210> 45
<211> 419
<212> PRT
<213> Artificial Sequence
<220>
<223> SARS CoV-2 Nucleocapsid protein
<400> 45
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
<210> 46
<211> 1257
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding SARS CoV-2 Nucleocapsid protein
<400> 46
atgagcgaca acggccctca gaaccagaga aacgcccctc ggatcacatt tggcggccct 60
agcgatagca ccggcagcaa tcagaatggc gagagaagcg gcgccagaag caagcagaga 120
aggcctcaag gcctgcctaa caacaccgcc agctggttca cagccctgac acagcacggc 180
aaagaggacc tgaagttccc tagaggacag ggcgtgccca tcaacaccaa cagcagcccc 240
gatgaccaga tcggctacta cagacgggcc accagaagaa tcagaggcgg cgacggcaag 300
atgaaggatc tgagccccag atggtacttc tactacctcg gcacaggacc cgaagccgga 360
cttccttatg gcgccaacaa ggacggcatc atctgggttg caacagaagg cgccctgaac 420
acccctaagg accacatcgg caccagaaat cccgccaaca atgccgccat tgtgctgcag 480
ttgcctcagg gcacaacact gcccaagggc ttttacgccg aaggcagcag aggcggatct 540
caggcctctt ccagaagctc cagcagaagc cggaactcca gccggaatag cacacctggc 600
tctagcagag gcacaagccc tgccagaatg gctggcaatg gcggagatgc tgctctggca 660
cttctgctgc tggaccggct gaatcagctg gaaagcaaga tgagcggcaa gggccagcag 720
caacagggcc agaccgtgac aaaaaagtct gccgccgagg ccagcaagaa gcccagacag 780
aaaagaaccg ccaccaaggc ctacaacgtg acccaggcct ttggcagaag aggcccagaa 840
cagacccagg gcaacttcgg cgatcaagag ctgatcagac agggcaccga ctacaagcac 900
tggcctcaga tcgcccagtt tgccccttct gccagcgcct tctttggcat gagccggatc 960
ggcatggaag tgaccccatc tggcacctgg ctgacataca caggcgccat caagctggac 1020
gacaaggacc ccaacttcaa ggaccaagtg atcctgctga acaagcacat cgacgcctac 1080
aagacattcc ctccaaccga gcctaagaag gacaagaaga agaaggccga cgagacacag 1140
gccctgcctc agcgccagaa aaagcagcag actgtgacac tgctgccagc cgccgacctg 1200
gacgattttt ctaagcagct gcagcagagc atgagcagcg ccgattctac acaagct 1257
<210> 47
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> tPA leader sequence
<400> 47
Met Asp Ala Met Leu Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser His Ala
20 25
<210> 48
<211> 75
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding tPA leader sequence
<400> 48
atggatgcca tgctgagagg cctgtgttgc gttctgctgc tgtgtggcgc tgtgttcgtg 60
tctccttctc acgcc 75
<210> 49
<211> 75
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding tPA leader sequence
<400> 49
atggacgcca tgctgagagg cctgtgttgt gtgctgctgc tgtgcggagc cgtgtttgtg 60
tctccaagcc acgcc 75
<210> 50
<211> 2007
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding CoV-2 S1 glycoprotein
<400> 50
gtgaacctga ccaccagaac acaactgcct ccagcctaca ccaacagctt caccagaggc 60
gtgtactacc ccgacaaggt gttcagatcc agcgtgctgc actctaccca ggacctgttc 120
ctgcctttct tcagcaacgt gacctggttc cacgccatcc atgtgtccgg caccaatggc 180
accaagagat tcgacaaccc cgtgctgccc ttcaacgacg gggtgtactt tgccagcacc 240
gagaagtcca acatcatcag aggctggatc ttcggcacca cactggacag caagacccag 300
agcctgctga tcgtgaacaa cgccaccaac gtggtcatca aagtgtgcga gttccagttc 360
tgcaacgacc ccttcctggg cgtctactac cacaagaaca acaagagctg gatggaaagc 420
gagttccggg tgtacagcag cgccaacaac tgcaccttcg agtacgtgtc ccagcctttc 480
ctgatggacc tggaaggcaa gcagggcaac ttcaagaacc tgcgcgagtt cgtgttcaag 540
aacatcgacg gctacttcaa gatctacagc aagcacaccc ctatcaacct cgtgcgggat 600
ctgcctcagg gcttctctgc tctggaaccc ctggtggatc tgcccatcgg catcaacatc 660
acccggtttc agacactgct ggccctgcac agaagctacc tgacacctgg cgatagcagc 720
tctggatgga cagctggcgc cgctgcctac tatgtgggat atctgcaacc taggaccttc 780
ctgctgaagt acaacgagaa cggcaccatc accgacgccg tggattgtgc tctggatccc 840
ctgagcgaga caaagtgcac cctgaagtcc ttcaccgtgg aaaagggcat ctaccagacc 900
agcaacttcc gggtgcagcc caccgaatcc atcgtgcggt tccccaacat caccaatctg 960
tgccctttcg gcgaggtgtt caacgccacc agattcgcct ctgtgtacgc ctggaaccgg 1020
aagcggatca gcaattgcgt ggccgactac agcgtgctgt acaacagcgc cagcttcagc 1080
accttcaagt gctacggcgt gtcccctacc aagctgaacg acctgtgctt caccaacgtg 1140
tacgccgaca gcttcgtgat cagaggcgac gaagtgcggc agattgcccc tggacagaca 1200
ggcaagatcg ccgattacaa ctacaagctg cccgacgact tcaccggctg tgtgattgcc 1260
tggaacagca acaacctgga cagcaaagtc ggcggcaact acaactacct gtaccggctg 1320
ttccggaagt ccaacctgaa gcctttcgag cgggacatca gcaccgagat ctatcaggcc 1380
ggcagcaccc cttgcaatgg cgtggaaggc ttcaactgct acttcccact gcagtcctac 1440
ggcttccagc ctacaaacgg cgtgggctac cagccttaca gagtggtggt gctgagcttc 1500
gagctgctgc atgctcctgc cacagtgtgc ggccctaaga aaagcaccaa cctggtcaag 1560
aacaaatgcg tgaacttcaa cttcaacggc ctgaccggca ccggcgtgct gacagagagc 1620
aacaagaagt tcctgccttt ccagcagttc ggccgggata tcgccgatac cacagatgct 1680
gtcagagatc cccagacact ggaaatcctg gacatcaccc catgcagctt cggcggagtg 1740
tctgtgatca cccctggcac caacaccagc aatcaggtgg ccgtgctgta tcaggacgtg 1800
aactgtaccg aagtgcccgt ggccattcac gccgatcagc tgacacctac atggcgggtg 1860
tactccaccg gcagcaacgt gttccagaca agagccggct gtctgatcgg agccgaacac 1920
gtgaacaaca gctacgagtg cgacatccct atcggagccg gcatctgtgc cagctaccag 1980
acacagacaa acagccctcg gagagcc 2007
<210> 51
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding (GS)5 linker peptide
<400> 51
ggaagcggat ctggtagtgg ctctggctct 30
<210> 52
<211> 447
<212> DNA
<213> Artificial Sequence
<220>
<223> polynucleotide encoding sCD40L113-261
<400> 52
atgcagaagg gcgaccagaa tcctcagatc gccgctcatg tgatcagcga ggccagcagc 60
aagaccacat ctgtgctgca gtgggccgag aagggctact acaccatgag caacaacctg 120
gtcaccctgg aaaacggcaa gcagctgacc gtgaagagac agggcctgta ctacatctac 180
gcccaagtga ccttctgcag caacagagag gccagctctc aggccccttt tatcgccagc 240
ctgtgcctga agtcccctgg cagattcgag cggattctgc tgagagccgc caacacacac 300
agcagcgcca aaccttgtgg ccagcagtct attcacctcg gcggagtgtt tgagctgcag 360
cctggcgcaa gcgtgttcgt gaatgtgaca gaccctagcc aggtgtccca cggcaccggc 420
tttacatctt tcggcctgct gaagctg 447
Claims (42)
- SARS CoV의 S 단백질을 암호화하는 제1폴리뉴클레오타이드 및 SARS CoV의 뉴클레오캡시드 단백질(NP 단백질)을 암호화하는 제2폴리뉴클레오타이드를 유효성분으로 포함하는 SARS CoV 예방 및 치료용 백신 조성물.
- 제1항에 있어서,
상기 S 단백질은 i) S1 단백질 또는 그의 수용체 결합 도메인을 포함하는 단편 또는 ii) 상기 S1 단백질 또는 그의 수용체 결합 도메인을 포함하는 단편 및 막통과 도메인이 제거된 S2 단백질을 포함하는 융합단백질인, 백신 조성물. - 제2항에 있어서,
상기 S1 단백질의 수용체 결합 도메인은 SARS CoV-2 S 단백질(서열번호 38) 기준으로 319 내지 541 번째 아미노산 잔기에 상응하는 폴리펩타이드(서열번호 41)를 포함하는, 백신 조성물. - 제2항에 있어서,
상기 막통과 도메인은 SARS CoV-2 S 단백질(서열번호 38) 기준으로 1214 내지 1234번째 아미노산 잔기에 상응하는 폴리펩타이드인, 백신 조성물. - 제2항에 있어서,
상기 S1 단백질은 서열번호 1로 기재되는 아미노산 서열을 포함하는, 백신 조성물. - 제2항에 있어서,
상기 막통과 도메인이 제거된 S2 단백질은 SARS CoV-2 S 단백질(서열번호 38) 기준으로 685 내지 1213 번째 아미노산 잔기에 상응하는 폴리펩타이드인, 백신 조성물. - 제6항에 있어서,
상기 막통과 도메인이 제거된 S2 단백질은 서열번호 2로 기재되는 아미노산 서열을 갖는 펩타이드 또는 그의 면역원성 단편인, 백신 조성물. - 제1항에 있어서,
상기 S 단백질은 SARS CoV-2 S 단백질(서열번호 38) 기준으로 16 내지 1213 번째 아미노산 잔기에 상응하는 폴리펩타이드를 포함하는, 백신 조성물. - 제1항에 있어서,
상기 S 단백질은 C-말단에 삼량체 형성 도메인이 부가된 융합단백질인, 백신 조성물. - 제9항에 있어서,
상기 삼량체 형성 도메인은 CD40L 엑토도메인, T4 박테리오파지 fibritin 또는 그의 C-말단 도메인(foldon 도메인), Fas 리간드, 41BB, OX40L, CD70, TRAIL, 또는 서펙틴인, 백신 조성물. - 제10항에 있어서,
상기 삼량체 형성 도메인은 CD40L 엑토도메인 또는 foldon 도메인인, 백신 조성물. - 제11항에 있어서,
상기 CD40L 엑토도메인은 서열번호 5로 기재되는 아미노산 서열을 포함하는, 백신 조성물. - 제11항에 있어서,
상기 foldon 도메인은 서열번호 39로 기재되는 아미노산 서열을 포함하는, 백신 조성물. - 제1항에 있어서,
상기 NP 단백질은 서열번호 45로 구성되는 아미노산 서열을 포함하는, 백신 조성물. - 제1항에 있어서,
상기 제1폴리뉴클레오타이드는 서열번호 29 내지 31, 34 내지 37 및 50 중 어느 하나로 기재되는 핵산서열을 포함하는, 백신 조성물. - 제1항에 있어서,
상기 제2폴리뉴클레오타이드는 서열번호 46으로 기재되는 핵산서열을 포함하는, 백신 조성물. - 제1항에 있어서,
상기 제1폴리뉴클레오타이드 및 상기 제2폴리뉴클레오타이드는 하나의 벡터 내에 포함되거나 별도의 벡터로 제공되는, 백신 조성물. - 제1항에 있어서,
SARS CoV의 S1 수용체 결합 도메인을 포함하는 폴리펩타이드를 암호화하는 제3폴리뉴클레오타이드를 추가로 포함하는, 백신 조성물. - 제18항에 있어서,
상기 SARS CoV의 S1 수용체 결합 도메인은 SARS CoV-2 S 단백질(서열번호 38) 기준으로 319 내지 541 번째 아미노산 잔기에 상응하는 폴리펩타이드를 포함하는, 백신 조성물. - 제19항에 있어서,
상기 폴리펩타이드는 서열번호 41로 기재되는 아미노산 서열을 포함하는, 백신 조성물. - 제18항에 있어서,
상기 SARS CoV의 S1 수용체 결합 도메인을 포함하는 폴리펩타이드는 C-말단에 삼량체 형성 도메인이 부가된 융합단백질인, 백신 조성물. - 제21항에 있어서,
상기 삼량체 형성 도메인은 CD40L 엑토도메인, T4 박테리오파지 fibritin 또는 그의 C-말단 도메인(foldon 도메인), Fas 리간드, 41BB, OX40L, CD70, TRAIL, 또는 서펙틴인, 백신 조성물. - 제22항에 있어서,
상기 삼량체 형성 도메인은 CD40L 엑토도메인 또는 foldon 도메인인, 백신 조성물. - 제23항에 있어서,
상기 CD40L 엑토도메인은 서열번호 5로 기재되는 아미노산 서열을 포함하는, 백신 조성물. - 제23항에 있어서,
상기 foldon 도메인은 서열번호 39로 기재되는 아미노산 서열을 포함하는, 백신 조성물. - 제18항에 있어서,
상기 제3폴리뉴클레오타이드는 서열번호 42 또는 44로 기재되는 핵산서열을 포함하는, 백신 조성물. - 제18항에 있어서,
상기 제1폴리뉴클레오티드 내지 제3폴리뉴클레오티드는 단일 벡터 내에 포함되거나, 두 개의 벡터에 나눠 삽입이 되거나, 또는 3개의 발현벡터 내에 하나씩 삽입되는, 백신 조성물. - 제2항, 제9항 및 제21항 중 어느 한 항에 있어서,
상기 융합 단백질은 하나 이상의 링커 펩타이드를 포함하는, 백신 조성물. - 제28항에 있어서,
상기 링커 펩타이드는 (GS)5(서열번호 6), (G4S, 서열번호 7)n, (GSSGGS, 서열번호 8)n, KESGSVSSEQLAQFRSLD(서열번호 9), EGKSSGSGSESKST(서열번호 10), GSAGSAAGSGEF(서열번호 11), (EAAAK, 서열번호 12)n, CRRRRRREAEAC(서열번호 13), A(EAAAK)4ALEA(EAAAK)4A(서열번호 14), GGGGGGGG(서열번호 15), GGGGGG(서열번호 16), AEAAAKEAAAAKA(서열번호 17), PAPAP(서열번호 18), (Ala-Pro)n, VSQTSKLTRAETVFPDV(서열번호 19), PLGLWA(서열번호 20), TRHRQPRGWE(서열번호 21), AGNRVRRSVG(서열번호 22), RRRRRRRR(서열번호 23), GFLG(서열번호 24), 또는 GSSGGSGSSGGSGGGDEADGSRGSQKAGVDE(서열번호 25)인, 백신 조성물. - 제1항 내지 제27항 중 어느 한 항에 있어서,
상기 S 단백질 또는 NP 단백질은 N-말단에 단백질 분비를 위한 분비 신호서열을 포함한 것인, 백신 조성물. - 제30항에 있어서,
상기 분비 신호서열은 tPA(tissue plasminogen activator) 신호서열(서열번호 26 또는 47), HSV gDs(단순포진 바이러스 당단백질 Ds) 신호서열 또는 성장호르몬 신호서열인, 백신 조성물. - 제1항 내지 제27항 중 어느 한 항에 있어서,
상기 SARS CoV는 SARS CoV-1 또는 SARS CoV-2인, 백신 조성물. - 제1항 내지 제27항 중 어느 한 항에 있어서,
상기 폴리뉴클레오타이드는 프로모터에 작동가능하게 연결되는 유전자 컨스트럭트를 포함하는 발현벡터로 제공되는, 백신 조성물. - 제32항에 있어서,
상기 프로모터는 CMV-HSV 티미딘 키나아제 프로모터, SV40, RSV-프로모터(로우스 육종 바이러스), 인간 신장 요소 1α-프로모터, 글루코코르티코이드-유도성 MMTV-프로모터(몰로니 마우스 종양 바이러스), 메탈로티오네인-유도성 또는 테트라사이클린-유도성 프로모터 또는, CMV 프로모터 또는 SV40 프로모터, 신경미세섬유-프로모터(neurofilament-promoter), PGDF-프로모터, NSE-프로모터, PrP-프로모터 또는 thy-1-프로모터인, 백신 조성물. - 제33항에 있어서,
상기 발현벡터는 오카야마-베르그(Okayama-Berg) cDNA 발현 벡터 pcDV1(Parmacia), pRc/CMV, pcDNA1, pcDNA3, pSPORT1, pGX27, pX, pEG202, pJG4-5람다 gt11, pGEX(Amersham-Pharmacia)인, 백신 조성물. - 제1항 내지 제27항 중 어느 한 항에 있어서,
하나 또는 둘 이상의 면역증진 펩타이드를 암호화하는 폴리뉴클레오타이드를 추가로 포함하는, 백신 조성물. - 제36항에 있어서,
상기 면역증진 펩타이드는 상기 S 단백질 또는 NP 단백질에 연결된 융합 단백질의 형태로 발현되거나 별도의 유전자 컨스트럭트를 통해 발현되는, 백신 조성물. - 제37항에 있어서,
상기 면역증진 펩타이드는 상기 폴리펩타이드의 N-말단 또는 C-말단에 부가되거나 중간에 삽입되는, 백신 조성물. - 제36항에 있어서,
상기 면역증진 펩타이드는 CD28, ICOS(inducible costimulator), CTLA4(cytotoxic T lymphocyte associated protein 4), PD1(programmed cell death protein 1), BTLA(B and T lymphocyte associated protein), DR3(death receptor 3), 4-1BB, CD2, CD40, CD40L, CD30, CD27, SLAM(signaling lymphocyte activation molecule), 2B4(CD244), NKG2D(natural-killer group 2, member D)/DAP12(DNAX-activating protein 12), TIM1(T-Cell immunoglobulin and mucin domain containing protein 1), TIM2, TIM3, TIGIT, CD226, CD160, LAG3(lymphocyte activation gene 3), B7-1, B7-H1, GITR(glucocorticoid-induced TNFR family related protein), Flt3 리간드(fms-like tyrosine kinase 3 ligand), 플라젤린(flagellin), HVEM(herpesvirus entry mediator) 또는 OX40L[ligand for CD134(OX40), CD252]의 세포질 도메인 또는 이들 중 둘 이상의 연결체인, 백신 조성물. - 제1항 내지 제27항 중 어느 한 항의 백신 조성물을 개체에 투여하는 단계를 포함하는 상기 개체의 SARS CoV 감염증 예방 및 치료방법.
- 제40항에 있어서,
상기 SARS CoV는 SARS CoV-1 또는 SARS CoV-2인, 치료방법. - 제41항에 있어서,
상기 조성물은 생체 내 전기천공법에 의해 투여되는, 치료방법.
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