KR20230059897A - SARS-CoV-2의 스파이크 단백질 전부 또는 일부를 포함하는 바이러스 유사입자 및 이를 이용한 백신 - Google Patents
SARS-CoV-2의 스파이크 단백질 전부 또는 일부를 포함하는 바이러스 유사입자 및 이를 이용한 백신 Download PDFInfo
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Abstract
인플루엔자 바이러스 매트릭스 단백질1(M1)으로 이루어진 코어 및 상기 코어의 표면에 디스플레이된 SARS-CoV-2 스파이크 단백질의 전부 또는 일부를 포함하는 바이러스 유사 입자 및 이를 포함하는 백신이 개시된다.
Description
본 발명은 SARS-CoV-2의 스파이크 단백질 전부 또는 일부를 포함하는 바이러스 유사입자 및 이를 이용한 백신에 관한 것이다.
SARS-CoV-2에 의한 중증급성호흡기증후군(COVID-19)에 의해 전세계적으로 300만명 이상이 사망했으며, 이에 대한 여러 백신들이 긴급 사용이 승인되었다. 그러나 현재 사용되고 있는 백신들은 COVID-19의 감염을 완벽히 차단하지 못하며, 사망에 이를 수 있는 심각한 부작용을 나타내고 있어 효과가 우수하고 안전성 높은 백신에 대한 수요가 여전히 높다.
한편, 바이러스 유사입자(Virus-like particle, VLP)는 본래 바이러스와 유사한 단백질 복합체를 의미한다. 바이러스 유사입자는 바이러스 유전자가 결여되어 있고 대량 생산이 가능하므로 안전하고 면역 효과가 우수한 백신으로 사용될 수 있다.
배큘로바이러스(Baculovirus)는 곤충 세포를 감염시키는 바이러스로서, 프로모터 하류에 다른 유전자를 삽입하여 재조합 단백질 발현을 위한 벡터로 사용될 수 있다. 배큘로바이러스는 곤충에서 병원성이 있으나 인간 등 척추동물에는 병원성이 없으며, 배큘로바이러스 발현 시스템에 의한 VLP 생산이 가능함이 알려져 있다.
Influenza M2 virus-like particle vaccination enhances protection in combination with avian influenza HA VLPs. PLoS ONE 2019, 14, e0216871.
Influenza Virus-like Particle (VLP) Vaccines Expressing the SARS-CoV-2 S Glycoprotein, S1, or S2 Domains, Vaccines 2021, 9, 920.
일 구체예에 따르면, 인플루엔자 바이러스 매트릭스 단백질1(M1)으로 이루어진 코어 및 상기 코어의 표면에 디스플레이된 SARS-CoV-2 스파이크 단백질의 전부 또는 일부를 포함하는 바이러스 유사 입자 및 이를 포함하는 백신을 제공한다.
일 양상은, 인플루엔자 바이러스 매트릭스 단백질1(M1)으로 이루어진 코어; 및 항원 단백질을 포함하고, 상기 항원 단백질은 SARS-CoV-2의 스파이크 전장 단백질, 스파이크 단백질의 S1 도메인 잔기와 인플루엔자 헤마글루티닌(HA)의 막관통 도메인(TM) 및 세포질 꼬리(CT)의 융합 단백질, 또는 스파이크 단백질의 S2 도메인 잔기인, SARS-CoV-2 바이러스 유사 입자(Virus-like Particle, VLP)를 제공한다.
상기 바이러스 유사 입자(Virus like particle, VLP)는 바이러스의 단백질을 포함하지만 유전 물질을 포함하지 않기 때문에 감염성이 없는 입자이다. 바이러스 유사 입자는 바이러스 구조 단백질의 개별 발현 및 자가 조립에 의해 합성될 수 있다.
상기 인플루엔자 바이러스 매트릭스 단백질 1(M1)은 인플루엔자 바이러스의 구조 단백질로서, 인플루엔자 바이러스의 외피(envelop) 안쪽에 코트(coat)를 형성하는 기질단백질(matrix protein)을 의미한다. 일 실시예에 따르면, M1 단백질은 바이러스 유사 입자의 구조 단백질로서 이용될 수 있다. 상기 M1 단백질은 서열번호 4의 아미노산 서열로 이루어진 것일 수 있다.
본 발명자는 M1 단백질 및 스파이크 전장(S-full) 단백질을 포함하는 VLP(S-full VLP), M1 단백질 및 S1 도메인과 HA-TM 및 HA-CT를 융합한 단백질을 포함하는 VLP(S1 VLP), M1 단백질 및 S2 도메인을 포함하는 VLP(S2 VLP)를 배큘로바이러스 발현 시스템(Baculovirus expression system)으로 제작하고, 이들의 항체 형성 및 바이러스 중화능을 확인하였다. 일 실시예에 따르면, S-full VLP 및 S1 VLP는 우수한 바이러스 중화능을 나타내었으며, S2 VLP는 IgG, IgG2a, IgG1, IgG2b 생산 유도가 우수하여 세포성 면역반응을 유도하는 능력이 우수한 것으로 확인되었다.
상기 항원 단백질은 상기 바이러스 유사 입자 또는 코어의 표면에 디스플레이된 것일 수 있다.
상기 인플루엔자 헤마글루티닌의 막관통 도메인(TM) 및 세포질 꼬리(CT)은 서열번호 5의 아미노산 서열로 이루어진 것일 수 있다.
일 구체예에 따르면, 상기 스파이크 전장 단백질은 서열번호 1의 아미노산 서열로 이루어진 것일 수 있고, 상기 S1 도메인 잔기는 서열번호 2의 아미노산 서열로 이루어진 것일 수 있고, 상기 S2 도메인 잔기는 서열번호 3의 아미노산 서열로 이루어진 것일 수 있다.
일 구체예에 따르면, 상기 SARS-CoV-2 바이러스 유사 입자는 Sf9 세포에 대해 감염성이 없는 것일 수 있다. 일 실시예에 따르면, 수크로스 구배로 정제된 VLP는 Sf9 세포에 접촉시켜도 증식에 영향을 미치지 않는 것으로 확인되었다.
상기 바이러스 유사 입자는 당해 기술 분야에서 통상기술자에게 알려진 방법으로 제조될 수 있으며, 예를 들면 배큘로바이러스 발현 시스템으로 제조될 수 있다.
다른 양상은, 상기 SARS-CoV-2 바이러스 유사 입자를 포함하는, 코로나바이러스감염증(COVID)-19 예방 또는 치료용 백신 조성물을 제공한다.
상기 SARS-CoV-2 바이러스 유사 입자는 항원으로 작용할 수 있으며, 유전 물질을 포함하지 않으므로 감염 위험이 없어 안전하므로 COVID-19에 대한 백신으로 사용될 수 있다.
상기 백신 조성물은 S-full VLP, S1 VLP, 및 S2 VLP으로 이루어진 군에서 선택된 하나 이상의 VLP를 포함할 수 있다. 일 실시예에 따르면, S-full VLP 또는 S1 VLP으로 면역화된 마우스 혈청은 바이러스 중화능이 우수하여 세포성 면역을 활성화시키는 것으로 확인되었으며, S2 VLP로 면역화된 마우스 혈청은 IgG 등 생산이 현저히 증가하여 세포성 면역을 활성화시키는 것으로 확인되었다. S-full VLP, S1 VLP, 및 S2 VLP을 조합하여 투여하면 체액성 면역 및 세포성 면역 모두를 활성화시킬 수 있다.
상기 백신 조성물은 어쥬번트(Adjuvant)를 더 포함할 수 있다. 상기 아주번트(Adjuvant)는 백신 또는 약학적으로 활성 있는 성분들에 첨가되어 면역반응을 증가시키거나 영향을 주는 물질 또는 조성물을 의미한다. 상기 어쥬번트는 예를 들면 알루미늄 염, 톨 유사 수용체 (TLR) 효현제, 모노포스포릴 지질 A (MLA), 합성 지질 A, 지질 A 모방체 또는 유사체, MLA 유도체, 사이토킨, 사포닌, 무라밀 디펩티드 (MDP) 유도체, CpG 올리고, 그람 음성균의 지질다당류 (LPS), 폴리포스파젠, 에멀션, 비로솜, 카클리어트, 폴리(락티드-코-글리콜리드) (PLG) 마이크로입자, 폴록사머 입자, 마이크로입자, 리포솜, 완전한 프로인드 어쥬번트 (CFA), 및 불완전 프로인드 어쥬번트 (IFA)로 이루어진 군으로부터 선택된 것일 수 있으며, 알루미늄 염은 알루미늄 하이드록사이드 또는 알루미늄 포스페이트가 사용될 수 있으나 특별히 한정되는 것은 아니다.
상기 백신 조성물은 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 제제화할 때는 보통 사용되는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제할 수 있다. 경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함될 수 있으며, 이러한 고형제제는 상기 레시틴 유사 유화제에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 슈크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제할 수 있다. 또한, 단순한 부형제 이외에 마그네슘스티레이트 탈크 같은 윤활제들도 사용할 수 있다. 경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등을 사용할 수 있으며, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수용성제, 현탁제, 유제, 동결건조제가 포함된다. 비수용성 제제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브유와 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다.
상기 백신 조성물의 투여 경로는 특별히 한정되는 것은 아니며, 예를 들면 경구 또는 비경구 투여될 수 있고, 상세하게는 구강, 정맥 내, 근육 내, 동맥 내, 골수 내, 경막 내, 심장 내, 경피, 피하, 복강 내, 비강 내, 장관, 국소, 설하 또는 직장에 투여할 수 있다. 비경구 투여는 피하, 피내, 정맥 내, 근육 내, 관절 내, 활액낭내, 흉골 내, 경막 내, 병소 내 및 두개골 내 주사를 포함할 수 있다.
상기 백신 조성물의 투여량은 개체의 연령, 체중, 성별, 신체 상태 등을 고려하여 선택될 수 있다. 별다른 부작용 없이 개체에 면역반응을 유도하기에 필요한 양은 면역원으로써 사용된 VLP 및 다른 성분의 존재에 따라 다양할 수 있으며, 이는 통상기술자에게 알려진 방법으로 결정될 수 있다.
또 다른 양상은, 인플루엔자 바이러스 매트릭스 단백질1(M1)을 발현하는 제 1 재조합 배큘로바이러스 및 SARS-CoV-2의 스파이크 전장 단백질, 스파이크 단백질의 S1 도메인 잔기와 인플루엔자 헤마글루티닌의 막관통 도메인 및 세포질 꼬리의 융합 단백질, 또는 스파이크 단백질의 S2 도메인 잔기를 발현하는 제 2 재조합 배큘로바이러스를 곤충세포에 공동 감염시키는 단계; 공동 감염된 곤충세포를 배양하고 바이러스 유사 입자를 정제하는 단계를 포함하는, SARS-CoV-2 바이러스 유사 입자의 제조 방법을 제공한다.
또 다른 양상은, 인플루엔자 바이러스 매트릭스 단백질1(M1)을 발현하는 제 1 재조합 배큘로바이러스; 및 SARS-CoV-2의 스파이크 전장 단백질, 스파이크 단백질의 S1 도메인 잔기와 인플루엔자 헤마글루티닌의 막관통 도메인 및 세포질 꼬리의 융합 단백질, 또는 스파이크 단백질의 S2 도메인 잔기를 발현하는 제 2 재조합 배큘로바이러스를 포함하는 SARS-CoV-2 바이러스 유사 입자 제조용 조성물을 제공한다.
일 구체예에 따른 SARS-CoV-2 바이러스 유사 입자 및 이를 포함하는 백신은 SARS-CoV-2 바이러스에 대한 면역 반응을 유도할 수 있다.
도 1은 SARS-CoV-2의 스파이크 단백질(S), S1 도메인, S2 도메인의 막관통 단백질 토폴로지 예측(Transmembrane protein topology prediction) 결과이다.
도 2는 일 실시예에서 제작된 유전자 구조체를 나타낸 것이다.
도 3은 코돈 최적화된 S 전장 유전자(S-full), S1 유전자 구조체, S2 유전자 구조체를 클로닝 결과 및 이들이 삽입된 백미드(Bacmid) DNA를 분석한 결과를 나타낸 것이다. 도 3A는 코돈 최적화된 유전자가 pFastBac 벡터에 성공적으로 클로닝되었음을 확인한 결과이다. 도 3B는 상기 벡터로 형질전환된 DH10Bac 컴피턴트 세포(competent cell)의 백미드(bacmid)를 콜로니 PCR로 분석한 결과이다. 두 패널의 레인 식별은 다음과 같다. M, 마커; 1, S 전체; 2, S1; 3, S2; 4, pFastBac 벡터.
도 4는 재조합 백미드로 형질감염된 Sf9 세포에서 재조합 배큘로바이러스(rBV) 발현됨을 확인한 결과이다. S RBD(receptor binding domain)에 대한 항체 및 S2에 대한 항체를 사용한 면역세포화학을 통해 bacmid DNA가 Sf9 세포로 성공적으로 형질감염되었음을 확인하였다. S RBD 항체는 S 전체 및 S1 rBV에서 발현된 단백질을 검출하는 데 사용되고, S2 항체는 S2 rBV에서 발현된 단백질을 검출하는데 사용되었다.
도 5는 S full, S1 또는 S2를 발현하는 rBV와 인플루엔자 M1-발현 rBV로 공동감염된 Sf9 세포를 수크로스 구배 원심분리하여 VLP를 정제한 결과이다.
도 6은 정제된 VLP의 세포 감염성을 확인하기 위해 Sf9 세포를 현미경으로 4일간 모니터링한 결과이다. 이미지 배율은 100x이다.
도 7은 웨스턴 블롯으로 VLP의 특성을 규명한 결과이다. VLP에 S full, S1, S2 및 M1 단백질이 포함되어 있는지 평가하였다. 레인 1, 2, 3은 각각 40 ㎍, 20 ㎍ 및 10 ㎍의 VLP 단백질 로딩 농도에 해당한다.
도 8은 S full VLP, S1 VLP, S2 VLP의 TEM 이미지이다.
도 9는 VLP로 면역화된 마우스의 혈청으로 항원 특이적 항체 반응을 확인한 결과이다. 최종 면역화 후 1주가 경과한 마우스의 혈청을 수집하고 ELISA를 통해 항원-특이적 항체 반응을 평가하였다. 도 9A는 혈청을 S full VLP 코팅된 플레이트에 첨가하고 IgG 항체를 첨가하켜 VLP 면역화 및 부스팅 효과를 확인한 결과이다. 그 외 도 9B, 도 9C, 도 9D, 도 9E는 S1 및 S2 항원이 코팅된 플레이트에서 IgG(B), IgG1(C), IgG2a(D), IgG2b(E)에 대한 반응을 확인한 결과이다. 데이터는 평균 ± SEM으로 표시되었다(* p < 0.05, ** p < 0.01, *** p < 0.001).
도 10은 VLP로 면역화된 마우스 혈청의 바이러스 중화 능력을 중화항체 간접측정 시험(surrogate virus neutralization test, sVNT)로 평가한 결과를 나타낸 것이다. 면역화된 마우스의 혈청을 열-불활성화시키고 연속 희석하여 중화항체 간접측정 시험을 수행하였다. 데이터는 평균 ± SEM으로 표시되었다. (*p < 0.05 vs. 미접촉(Naive) 대조군)
도 2는 일 실시예에서 제작된 유전자 구조체를 나타낸 것이다.
도 3은 코돈 최적화된 S 전장 유전자(S-full), S1 유전자 구조체, S2 유전자 구조체를 클로닝 결과 및 이들이 삽입된 백미드(Bacmid) DNA를 분석한 결과를 나타낸 것이다. 도 3A는 코돈 최적화된 유전자가 pFastBac 벡터에 성공적으로 클로닝되었음을 확인한 결과이다. 도 3B는 상기 벡터로 형질전환된 DH10Bac 컴피턴트 세포(competent cell)의 백미드(bacmid)를 콜로니 PCR로 분석한 결과이다. 두 패널의 레인 식별은 다음과 같다. M, 마커; 1, S 전체; 2, S1; 3, S2; 4, pFastBac 벡터.
도 4는 재조합 백미드로 형질감염된 Sf9 세포에서 재조합 배큘로바이러스(rBV) 발현됨을 확인한 결과이다. S RBD(receptor binding domain)에 대한 항체 및 S2에 대한 항체를 사용한 면역세포화학을 통해 bacmid DNA가 Sf9 세포로 성공적으로 형질감염되었음을 확인하였다. S RBD 항체는 S 전체 및 S1 rBV에서 발현된 단백질을 검출하는 데 사용되고, S2 항체는 S2 rBV에서 발현된 단백질을 검출하는데 사용되었다.
도 5는 S full, S1 또는 S2를 발현하는 rBV와 인플루엔자 M1-발현 rBV로 공동감염된 Sf9 세포를 수크로스 구배 원심분리하여 VLP를 정제한 결과이다.
도 6은 정제된 VLP의 세포 감염성을 확인하기 위해 Sf9 세포를 현미경으로 4일간 모니터링한 결과이다. 이미지 배율은 100x이다.
도 7은 웨스턴 블롯으로 VLP의 특성을 규명한 결과이다. VLP에 S full, S1, S2 및 M1 단백질이 포함되어 있는지 평가하였다. 레인 1, 2, 3은 각각 40 ㎍, 20 ㎍ 및 10 ㎍의 VLP 단백질 로딩 농도에 해당한다.
도 8은 S full VLP, S1 VLP, S2 VLP의 TEM 이미지이다.
도 9는 VLP로 면역화된 마우스의 혈청으로 항원 특이적 항체 반응을 확인한 결과이다. 최종 면역화 후 1주가 경과한 마우스의 혈청을 수집하고 ELISA를 통해 항원-특이적 항체 반응을 평가하였다. 도 9A는 혈청을 S full VLP 코팅된 플레이트에 첨가하고 IgG 항체를 첨가하켜 VLP 면역화 및 부스팅 효과를 확인한 결과이다. 그 외 도 9B, 도 9C, 도 9D, 도 9E는 S1 및 S2 항원이 코팅된 플레이트에서 IgG(B), IgG1(C), IgG2a(D), IgG2b(E)에 대한 반응을 확인한 결과이다. 데이터는 평균 ± SEM으로 표시되었다(* p < 0.05, ** p < 0.01, *** p < 0.001).
도 10은 VLP로 면역화된 마우스 혈청의 바이러스 중화 능력을 중화항체 간접측정 시험(surrogate virus neutralization test, sVNT)로 평가한 결과를 나타낸 것이다. 면역화된 마우스의 혈청을 열-불활성화시키고 연속 희석하여 중화항체 간접측정 시험을 수행하였다. 데이터는 평균 ± SEM으로 표시되었다. (*p < 0.05 vs. 미접촉(Naive) 대조군)
이하 하나 이상의 구체예를 실시예를 통해 보다 상세하게 설명한다. 그러나, 이들 실시예는 하나 이상의 구체예를 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.
실험방법
1. 곤충 세포 및 실험동물 준비
무혈청 SF900 II 배지(Invitrogen, Carlsbad, CA, USA)에서 배양된 Spodoptera frugiperda(Sf9) 곤충 세포를 사용하여 재조합 배큘로바이러스(rBV) 및 VLP를 생산했다. 자세한 생산방법은 Influenza M2 virus-like particle vaccination enhances protection in combination with avian influenza HA VLPs. PLoS ONE 2019, 14, e0216871에 기재되어 있다.
27주령 암컷 BALB/c 마우스는 나라 바이오텍(서울, 한국)에서 구입하였다. 모든 동물 실험 절차는 경희대학교 IACUC(허가번호: KHSASP-20-666)에서 정한 지침에 따라 승인 및 수행되었다.
2. 코돈 최적화, 유전자 클로닝, 재조합 배큘로바이러스, 및 VLP 생산
코돈 최적화된 S-full 유전자(3822 bp, GenBank 수탁 번호: QHD43416.1 및 MN908947.3의 21563~25384), S1 도메인(2058 bp)을 포함하는 S1 유전자 구조체 및 S2 도메인(1764 bp)을 포함하는 S2 유전자 구조체는 GenScript(Piscataway, NJ, USA)에서 합성되었다.
S1 유전자 구조체는 인플루엔자 바이러스 헤마글루티닌(HA)의 막관통 도메인(Transmembrane domain, TM)과 세포질 꼬리(cytoplasmic tail, CT) 영역을 S1 유전자의 3' 말단에 융합하여 제작하였다. S2 유전자 구조체는 멜리틴 신호 펩티드(SP)를 S2 유전자 5' 말단에 융합하여 제작하였다.
콜로니 PCR 및 재조합 배큘로바이러스 생산은 Bac-to-Bac Expression System(ThermoFisher)에 설명된 제조업체의 지침에 따라 수행되었다. 구체적으로, 각각의 유전자 구조체를 포함하는 벡터(pFastBac)로 DH10BacTM 컴피턴트 세포를 형질전환(transformation)시켰다. 형질전환된 DH10Bac 세포에서 전위(transposition)된 재조합 bacmid DNA를 분리하였다. 재조합 bacmid DNA 및 Cellfectin II 시약(Invitrogen)으로 Sf9 세포를 형질감염(transfection)시켰다. 형질감염된 Sf 세포를 이용하여 S full, S1 또는 S2를 발현하는 재조합 배큘로바이러스(rBV)를 생산하였다.
Sf9 세포를 S full, S1 또는 S2를 발현하는 rBV와 인플루엔자 M1-발현 rBV를 공동 형질감염(co-transfection)시켜 본 발명의 VLP를 생산하였다. 상기 인플루엔자 M1-발현 rBV 제조 및 공동 형질감염 방법은 Virus-like particle vaccines expressing Toxoplasma gondii rhoptry protein 18 and microneme protein 8 provide enhanced protection. Vaccine 2018, 36, 5692-5700에 기재되어 있다. 공동 형질감염 3일 후, 형질감염된 Sf9 세포를 4℃, 6000 RPM에서 30분 동안 원심분리하고 상층액(pre-sucrose로 지칭)을 수집하였다. 상층액을 30,000 RPM, 1시간, 4℃에서 초원심분리하고 침전된 입자를 4℃에서 밤새 PBS에 재현탁시켰다. 재현탁액을 불연속 수크로오스 구배 및 30,000 RPM, 4℃, 1시간 조건으로 초원심분리하고 VLP에 해당하는 밴드를 수집하여 M1과 S를 포함하는 VLP 입자를 정제하였다. VLP를 PBS에 재현탁하고 동일한 조건에서 초원심분리하여 불순물을 제거하였다. 펠렛화된 VLP를 PBS 100㎕에 담그고 BCA 분석 키트(ThermoFisher)를 사용하여 단백질 농도를 측정하였다.
Sf9 세포에 정제 및 비정제 VLP를 접종하여 배큘로바이러스 발아 입자(baculoviruses budded particle)의 존재를 확인하였다. 이는 정제된 VLP에 감염성 있는 budded baculovirus particle이 제거되었음을 확인하기 위함이다. 구체적으로, Sf9 세포를 12웰 배양 플레이트에 접종하고 rBV 대조군, 정제되지 않은 VLP(pre-sucrose) 및 정제된 VLP(밴드 1, 밴드 2)로 감염시켰다.
Post-sucrose는 상등액의 최상층(uppermost supernatant layer, 15% sucrose의 윗부분)에서 얻었다. 밴드 1과 밴드 2는 각각 15%/30% 및 30%/60% 수크로스 구배의 경계면에 위치한 두 개의 불투명한 밴드에서 수집되었다. 각 분획물을 1mL 채취한 후 protein assay를 시행하여 동일한 농도(5 ㎍)를 각 well에 접종하였다. Sf9 세포 감염성을 평가하기 위해 4일 동안 세포를 모니터링하였다. 현미경(Leica Microsystems)을 사용하여 이미지를 획득했다.
3. 형질감염된 rBV를 이용한 면역세포화학(Immunocytochemistry)
S 단백질의 RBD(Receptor Binding Domain) 및 S2 도메인을 표적으로 하는 다클론 항체는 Sino Biological(China)에서 구입했으며 면역세포화학을 위한 1차 항체로 사용되었다.
Sf9 세포를 MOI 0.1에서 재조합 배큘로바이러스(rBV)로 형질감염시키고, 형질감염 7일 후에 세포를 수집하고 1000RPM에서 3분 동안 원심분리했다. 세척을 위해 상층액을 제거하고 펠렛화된 세포를 PBS에 재현탁하고 1000RPM에서 3분 동안 원심분리하였으며, 3회 반복하였다. 1% BSA 및 0.1% Tween 20이 포함된 PBS를 사용하여 세포를 차단(blocking)하였다. 세포를 PBS로 3회 세척하고 S full 및 S1 rBV 형질감염 Sf9 세포와 RBD 표적 1차 항체(PBS에서 1:1000 희석), 또는 S2 rBv 형질감염 Sf9 세포와 S2 도메인 표적 1차 항체(PBS에서 1:1000 희석)를 37℃에서 1시간 동안 인큐베이션했다.
세포를 PBS로 3회 세척하고 CFL-488(Santa Cruz Biotechnology, Dallas, TX, USA)이 결합된 항-토끼 IgG 2차 항체(1:2000 희석)와 함께 37℃에서 1시간 동안 인큐베이션하였다.
세포를 PBS로 최종 세척하고, 세포 현탁액을 슬라이드 글라스에 놓고 40,6-diamidino-2-phenylindole(DAPI)을 포함하는 마운트 배지(mount medium)를 사용하여 마운트하고, 형광현미경으로 이미지를 촬영하였다.
4. VLP 특성 분석(characterization)
VLP 구조체는 웨스턴 블롯팅 및 투과 전자 현미경(TEM)을 사용하여 특성화되었다. 구체적으로, 다양한 농도의 VLP를 SDS-PAGE를 통해 분리하고, 단백질을 니트로셀룰로오스 멤브레인으로 옮겼다.
5% 탈지유를 사용하여 실온에서 1시간 동안 멤브레인을 차단(block)하고 다클론 항체(1:1000 희석)로 4℃에서 밤새 인큐베이션 하였다. 멤브레인을 TBST로 3회 세척하고 호스래디쉬 퍼옥시다제(HRP)-접합 이차 항체(1:2000 희석)와 함께 실온에서 1시간 동안 인큐베이션했다. 멤브레인을 TBST로 세척하고, 증강 화학 발광(enhanced chemiluminescence, ECL) 방법으로 암실에서 X선 필름에 밴드를 현상했다.
또한 TEM으로 VLP를 관찰하였다. 구체적으로, 샘플을 글로우 방전된(glow-discharged) 탄소 코팅된 구리 그리드에 적용하고 2분 동안 흡수되도록 하였다. 과잉 샘플을 Whatman 종이로 닦아낸 후 샘플 그리드를 1분 동안 2% uranyl acetate 로 염색했다. 과잉 시약을 제거한 후, 한국기초과학연구원에서 Bio-High voltage EM system(JEM-1400 Plus at 120 kV and JEM-1000BEF at 1000 kV, JEOL Ltd.)으로 결과를 기록하였다.
5. 실험동물의 면역화 및 샘플 수집
마우스를 다음 4개의 그룹(그룹당 n = 5개)으로 나누었다: (1) 나이브(미접종), (2) S-full VLP로 면역화된 그룹, (3) S1 VLP로 면역화된 그룹, 및 (4) S2 VLP 면역로 면역화된 그룹. 마우스의 대퇴사두근에 VLP 100㎍을 4주 간격으로 3회(prime, 1st boost, 2nd boost) 근육주사(intramuscular)하여 마우스를 면역화시켰다. 각 면역화 1주일 후에 혈청을 수집하였다. 모든 마우스는 최종 면역화 4주 후에 희생되었다.
6. SARS-CoV-2의 S1 및 S2 단백질에 대한 항체 반응
S1 및 S2 항원은 Sino Biological(중국 베이징)에서 구입했다. 항원 특이적 항체 반응은 ELISA로 측정하였다. 구체적으로, 탄산염 코팅 완충액과 S1 및 S2 항원(각각 1 ㎍/mL)을 사용하여 4℃에서 밤새 96-웰 플레이트를 코팅하였다. 또한 성공적인 면역화 및 부스팅 효과를 평가하기 위해 S full VLPs를 1g/mL로 코팅하였다.
96-웰을 PBST로 세척하고 37℃에서 1시간 동안 0.2% 젤라틴으로 차단하였다. 코팅이 완료된 웰에 마우스의 희석된 혈청(1:100 희석)을 첨가하고 37℃에서 1시간 동안 인큐베이션 하였다. 웰을 PBST로 3회 세척한 후, goat anti-mouse HRP-conjugated IgG, IgG1, IgG2a 및 IgG2b 2차 항체(1:2000 희석; Southern Biotech, USA)를 각각의 웰에 접종하였다. 플레이트를 37℃에서 1시간 동안 인큐베이션하고 최종 세척하였다. H2O2가 포함된 시트레이트 완충액에 100 ㎕의 o-phenylenediamine substrate(Sigma Aldrich)을 용해시켜 각 웰에 첨가하였다. 2N H2SO4로 반응을 중단시키고 EZ Read 400 마이크로플레이트 판독기(Biochrom Ltd.)를 사용하여 450 nm에서의 흡광도 값을 측정했다.
7. 중화항체 간접측정 시험(Surrogate Virus Neutralization Assay, sVNT)
BSL-3 시설 없이 바이러스 억제를 평가할 수 있는 중화항체 간접측정 시험(sVNT)을 실시했다. 중화항체 간접측정 시험은 HRP-conjugated RBD(Optipharm, Korea)과 HRP conjugation kit(Abcam)를 사용하여 수행되었다. hACE2(SARS-CoV-2 human angiotensin-converting enzyme 2) 수용체 단백질은 GenScript(Piscataway)에서 구입했다.
96-웰 플레이트를 hACE2 100ng을 포함하는 탄산염 코팅 완충액으로 4℃에서 밤새 처리하여 코팅한 후, 플레이트를 PBST로 세척하고 실온에서 1시간 동안 BD OptEIA assay diluent(BD Bioscience)로 차단하였다.
최종 면역 1주일이 경과한 마우스로부터 채취한 혈청을 PBS에 연속 희석하고 56℃에서 30분간 인큐베이션하여 혈청을 보체(complement) 불활성화시켰다.
불활성화된 혈청과 HRP-conjugated RBD(Receptor binding domain)를 동량 혼합하여 각 웰에 접종하고 37℃에서 1시간 동안 배양하였다. 웰을 PBST로 세척하고 TMB substrate(BD Bioscience)로 발색 반응(chromogenic reaction)을 전개했다. 2N H2SO4로 반응을 멈추고 450 nm에서 흡광도 값을 측정하였다. 억제 백분율은 다음 식으로 계산하였다: inhibition(%) = (1 - sample OD450 / control OD450) X 100.
8. 통계분석
데이터는 평균 ± SEM으로 표시하였다. GraphPad Prism 5 소프트웨어를 사용하여 통계 분석을 수행했다. 그룹 간의 통계적 유의성은 Tukey의 사후 검정과 함께 일원 분산 분석(ANOVA)을 사용하여 결정되었다. 0.05 미만의 p 값은 유의미한 것으로 간주되며 별표로 표시하였다.
실시예 1: 막관통 단백질 토폴로지 분석 및 유전자 구조체 제작
TMHMM Server v.2.0 데이터베이스를 사용하여 SARS-CoV-2 스파이크(S) 당단백질의 Original 아미노산 서열(QHD43416.1)을 기준으로 전장 S 당단백질(1-1273), S1 도메인(1-685 잔기) 및 S2 도메인(686-1273 잔기)의 막관통 단백질 토폴로지를 예측하였다.
도 1에 따르면, S1 도메인에는 막관통 도메인이 포함되어 있지 않고 S2 도메인에는 막관통 단백질이 포함되어 있으나 시작 코돈 및 signal peptide가 포함되어 있지 않았다.
상기 분석 결과에 따라, S1 도메인을 암호화하는 염기 서열의 3' 말단에 H1N1 인플루엔자 바이러스(A/Puerto Rico/8/34)의 막관통 도메인(TM) 및 세포질 꼬리(CT)를 암호화하는 염기 서열을 통합하여 S1 유전자 구조체를 제작하였다.
그리고 S2 도메인을 암호화하는 염기 서열의 5' 말단에 꿀벌 멜리틴 신호 펩티드(honey bee melittin signal peptide) 서열을 통합하여 S2 유전자 구조체를 제작하였다. 멜리틴 신호 펩티드는 배큘로바이러스 기반 곤충 세포주에서 외래 단백질 발현의 발현을 향상시킬 수 있다.
도 2에는 S 전장(full length) 유전자, S1 유전자 구조체, S2 유전자 구조체로부터 발현된 펩타이드의 구조가 표시되어 있다.
상기 S 유전자, S1 유전자 구조체, S2 유전자 구조체의 염기 서열은 모두 코돈 최적화되었다. S 전장 유전자, HA TM-CT 및 멜리틴 신호 펩티드에 대한 코돈 최적화 서열은 GenScript에 의해 합성되었다. 코돈 최적화를 위한 뉴클레오티드 서열은 NCBI 데이터베이스(GenBank 수탁 번호: MN908947.3의 21563 ~ 25384(S-full), NC_002017.1(HA TM-CT) 및 NM_001011607.2(Melittin SP))에서 획득했다.
코돈 최적화된 스파이크 단백질 서열은 하기 표 1 에 개시되어 있다.
실시예 2: 유전자 클로닝 및 형질전환용 벡터 제작
코돈 최적화된 S 전장 유전자(S-full), S1 유전자 구조체, S2 유전자 구조체를 클로닝하였다. 겔 전기영동으로 유전자가 성공적으로 클로닝되었음을 확인하였다. 도 3A에 따르면, S 전장 유전자가 삽입된 벡터의 길이는 8.7 kbp(lane 1), S1 유전자 구조체가 삽입된 벡터의 길이는 6.7 kbp(lane 2), S2 유전자 구조체가 삽입된 벡터의 길이는 6.4 kbp(lane 3), 대조군 pFastBac 벡터의 유전자 길이는 4.8 kbp(lane 4)였다.
상기 클로닝한 유전자들 각각을 pFastBac 벡터에 삽입하여 재조합 도너(donor) 플라스미드를 제작하고, 도너 플라스미드를 DH10Bac 컴피턴트 세포에 도입하여 형질전환(transformation)시키고, 항생제 배지에 세포를 배양하여 백미드(Bacmid)에 유전자가 전위된(transposition) 컴피턴트 세포를 선별하였다. 재조합 백미드가 제작되었는지 확인하기 위해 콜로니 PCR로 재조합 백미드(bacmid) DNA를 분석하였다. 도 3B에 다르면, 대조군 pFastBac 벡터에 의해 전위된 bacmid는 대략 2.3kbp인 점을 고려하면, S-full 도입 재조합 백미드(lane 1), S1 유전자 구조체 도입 재조합 백미드(lane 2), S2 유전자 구조체 도입 재조합 백미드(lane 3)은 S-full, S1, S2의 크기와 비례하였으므로 S-full, S1, 또는 S2이 삽입된 재조합 백미드가 성공적으로 제작되었음을 알 수 있다.
실시예 3: 스파이크 단백질(S) 발현 재조합 배큘로바이러스 제작
S 단백질의 RBD(receptor binding domain) 및 S2를 표적으로 하는 폴리클로날 항체의 결합 능력을 평가하였다. 면역세포화학(Immunocytochemistry)은 상기 폴리클로날항체와 재조합 배큘로바이러스로(rBV) 형질감염(transfection)된 Sf9 세포를 사용하여 수행되었다.
도 4에 따르면, Sf9 세포 핵은 DAPI로 염색되었지만, 세포 표면의 형광은 관찰되지 않았다. S full 포함 rBV 및 S1 포함 rBV로 형질감염된 Sf9 세포는 S RBD에 대한 항체에 의해 녹색 형광을 나타냈으므로 RBD를 포함하는 재조합 배큘로바이러스(rBV)를 생산함이 확인되었다. S2 포함 rBV로 형질감염된 Sf9 세포 또한 다클론성 S2 항체에 의해 녹색 형광을 나타냈으므로 S2를 포함하는 rBV를 생산함이 확인되었다.
실시예 4: 웨스턴 블롯 및 TEM에 의한 VLP 특성규명(characterization)
S full, S1 또는 S2를 발현하는 rBV와 인플루엔자 M1-발현 rBV를 Sf9 세포에 공동 형질감염(co-transfection)시켰다. 상기 공동 형질감염 3일 후, 형질감염된 Sf9 세포를 수집하고 4℃, 6000 RPM에서 30분 동안 원심분리하고 상층액을 수집하였다.(pre-sucrose) 상층액을 30,000 RPM, 1시간, 4℃에서 초원심분리하고 침전된 입자를 4℃에서 밤새 PBS에 재현탁시켰다. 재현탁액을 불연속 수크로오스 구배 및 30,000 RPM, 4℃, 1시간 조건으로 초원심분리하고 VLP에 해당하는 밴드를 수집하여 M1과 S를 포함하는 VLP 입자를 정제하였다. VLP(Band 1), VLP(Bnad 2), 그리고 Band1 과 Band 2 사이를 post-sucrose로 지칭하였다.
도 5에 따르면, 수크로스층 사이의 경계면에서 VLP에 해당하는 두 개의 불투명 밴드(band 1 및 band2)가 형성되었다.
Pre-sucrose, post-sucrose, VLP band1(VLP1) 및 VLP band2(VLP2)를 수집하고 이들로 Sf9 세포를 감염시켰다.
도 6에 따르면, VLP1 처리 세포, VLP2 처리 세포는 4일째에도 cell only 대조군과 유사한 세포 밀도를 나타냈으므로 세포가 원활히 증식하는 것으로 나타났다. 이는 정제된 VLP에 M1 및 S 단백질이 존재하지만 감염성 있는 배큘로바이러스 입자가 존재하지 않음을 의미한다.
그러나, rBV control, pre-sucrose 및 post-sucrose로 처리된 Sf9 세포는 상대적으로 세포 밀도가 낮고, 세포 사멸이 나타났으며, 각각의 세포의 크기가 상대적으로 비대해진 것으로 확인되었다. 이는 감염성 있는 재조합 배큘로바이러스가 존재함을 나타낸다.
VLP가 적절하게 구성되었는지 확인하기 위해 Western blotting 및 TEM 분석을 수행했다. 상기 실시예 3의 rBV 면역세포화학 결과와 동일하게, S full, S1 또는 S2 단백질을 발현하는 VLP는 다클론항체와 성공적으로 상호작용했다.
도 7에 따르면, 정제된 VLP를 니트로셀룰로오스 막으로 전달하고 다클론 항체로 탐침한 결과, S full VLP, S1 VLP, S2 VLP 모두에서 각각 S full(약 140kDa), S1(약 74kDa), S2(약 66kDa)가 검출되었다. 또한 VLP를 M1 단일클론 항체로 탐침한 결과 스파이크 단백질을 발현하는 재조합 배큘로바이러스에서 M1 단백질이 성공적으로 표지되었다.
또한, 도 8의 TEM 분석 결과에 따르면, VLP의 표면에 S 전체, S1 및 S2 단백질이 성공적으로 발현하였음을 알 수 있었다.
따라서 제조된 VLP에는 스파이크 단백질의 전체 또는 일부, 그리고 M1 단백질을 포함하며, 감염성 있는 배큘로바이러스 입자는 포함하지 않는다는 것을 알 수 있다.
실시예 5: VLP 면역화된 혈청의 항체 반응
VLP의 면역원성을 확인하기 위해 VLP 100 ㎍을 마우스에 4일 간격으로 2번 근육주사하였다. 2차 접종 1주일 후, 마우스의 혈액을 채취하고 ELISA를 수행하여 면역 및 부스팅 효과를 확인하였다.
도 9A에 따르면, S-full VLP, S1 VLP, S2 VLP로 면역화된 그룹에서 수집된 혈청은 S-full VLP로 코팅된 plate에서 강력한 항체 반응을 나타낸 반면, 무접종군(naive)의 혈청은 유의한 항체 반응이 일어나지 않았다.
VLP로 면역화된 혈청이 S1 서브유닛 또는 S2 서브유닛에 대해 항체반응이 일어나는지 확인하기 위해 S1 항원 및 S2 항원이 코팅된 플레이트로 ELISA를 수행하였다. 1차 부스트 접종 1주일 후 채취한 혈액으로 실험한 결과, S2 VLP로 면역화된 마우스 혈청에서 가장 강한 IgG 항체 반응 유도가 관찰되었다.(도 9B 참고) 또한 S-full VLP 면역화 혈청 및 S1 VLP 면역화 혈청에서도 미접종 대조군과 비교하여 유의한 항체 반응이 관찰되었다. 2차 부스트 접종 마우스에서 채취한 혈액으로 실험한 결과, S2 VLP로 면역화된 마우스 혈청은 IgG 항체 반응이 더 강하게 나타났다. 그러나, S full VLP 및 S1 VLP로 2차 부스트 접종한 마우스의 혈청에서는 증강된 항체 유도가 검출되지 않았다.
IgG1 항체 반응을 확인한 결과, S full VLP 및 S2 VLP로 2차 부스트 접종한 마우스의 혈청은 IgG1 항체 반응이 유의한 수준으로 유도되었지만, S1 VLP 접종군은 유의한 변화가 관찰되지 않았다(도 9C). S 단백질 특이적 IgG2a 반응은 IgG의 반응과 유사했다. S2 VLP로 면역화된 마우스의 혈청에서 강력한 항체 반응이 나타났다. 도 9D에 따르면, S full VLP 접종군은 1차 부스트 후 향상된 IgG2a 반응을 유도했지만, 2차 부스트에 의한 후속 면역화는 영향이 크지 않았다. IgG2b 서브클래스 반응은 S2 VLP에서만 2차 부스트 면역화 후 유의한 유도가 관찰되었으며, 이는 IgG1 반응과 다소 유사했다(도 9E).
실시예 6: VLP 면역화된 혈청의 바이러스 중화능 평가
VLP 면역화된 마우스의 항체가 SARS-CoV-2 바이러스를 중화시킬 수 있는지 확인하기 위해 sVNT를 수행하였다. S RBD와 HRP의 접합 정도를 ELISA로 평가하였다. 도 10A에 따르면, TMB 기질과의 반응 시 강력한 비색 반응이 즉시 발생하였으며, 이는 RBD(Receptor Binding Domain)와 HRP이 접합되었음을 나타낸다.
RBD-HRP가 hACE2 수용체에 결합할 수 있는지 확인하기 위해 ELISA를 수행하였다. 도 10B에 따르면, PBS에서 연속 희석된 RBD-HRP는 100ng의 hACE2와 반응했으며 가장 강한 반응은 102 희석에서 관찰되었다.
상기 실험 결과를 기반으로 100ng의 hACE2 및 102 희석된 RBD-HRP 혼합물로 sVNT 분석을 수행하였다.
하기 표 2에 따르면, 무접종 마우스의 혈청은 바이러스 중화 활성이 나타나지 않았다. S1 VLP 접종군의 혈청은 RBD-hACE2 결합을 부분적으로 억제하였다. 앞서 S2 VLP 접종군의 혈청은 앞서 강력한 항체 반응을 나타냈음에도 불구하고, RBD와 hACE2 수용체의 결합 억제 활성이 나타나지 않았다. 따라서, 바이러스 중화 활성은 S full VLP 접종군 및 S1 VLP 접종군의 1:50 희석 혈청에서 가장 높게 나타나는 것으로 확인되었다.
Naive | S full VLP | S1 VLP | S2 VLP | M1 VLP | |||||||||||
1:50 dilution | 0 | 0 | 0 | 34 | 19 | 30 | 19 | 47 | 27 | 0 | 0 | 0 | 0 | 0 | 0 |
1:100 dilution | 0 | 0 | 0 | 0 | 14 | 0 | 0 | 34 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
1:200 dilution | 0 | 0 | 0 | 0 | 7 | 0 | 0 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
1:400 dilution | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
상기 실험결과를 종합하면, S 단백질 전체, S1 도메인, 또는 S2 도메인을 표면에 디스플레이하는 VLP는 SARS-CoV-2를 억제하는 항체 반응을 이끌어낼 수 있다. S2 VLP로 면역화된 그룹의 혈청은 강력한 IgG 및 IgG2a 항체 반응을 유도하였으며, 이는 S full VLP 및 S1 VLP로 면역화된 그룹의 반응보다 높았다. 다만 바이러스 중화능은 S full VLP 및 S1 VLP로 면역화된 그룹이 더 높은 것으로 나타났다. S2 도메인 발현 VLP는 Th1과 연관된 IgG2a 항체반응이 Th2와 연관된 IgG1 항체반응보다 훨씬 높았으므로 세포성 면역에 편향된 면역반응을 나타낸 것으로 평가할 수 있다.
S2 도메인은 보존된 영역이므로 SARS-CoV-2의 새로운 변이에 대해서도 면역 반응 효과를 나타내는데 유리할 수 있다. 또한 COVID-19로부터 회복된 환자들의 혈청 분석결과에 따르면, SARS-CoV-2 감염시 비중화항체의 발현도 크게 상승하므로 중화항체 뿐만 아니라 비중화항체의 형성도 중요한 것으로 보고되었다. 따라서 S full VLP, S1 VLP, S2 VLP를 각각 또는 조합하여 투여하는 것은 COVID-19를 치료 또는 예방하기 위한 훌륭한 백신 접종 전략이 될 수 있다.
<110> University-Industry Cooperation Group of Kyung Hee University
<120> Virus-like particle including all or part of SARS-CoV-2 spike
protein and vaccine using same
<130> CDP2021-0761
<160> 10
<170> KoPatentIn 3.0
<210> 1
<211> 1273
<212> PRT
<213> Artificial Sequence
<220>
<223> SARS-CoV-2 Spike protein full length
<400> 1
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> 2
<211> 685
<212> PRT
<213> Artificial Sequence
<220>
<223> SARS-CoV-2 Spike protein S1 domain
<400> 2
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
675 680 685
<210> 3
<211> 588
<212> PRT
<213> Artificial Sequence
<220>
<223> SARS-CoV-2 Spike protein S2 domain
<400> 3
Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala
1 5 10 15
Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn
20 25 30
Phe Thr Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys
35 40 45
Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys
50 55 60
Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg
65 70 75 80
Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val
85 90 95
Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe
100 105 110
Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser
115 120 125
Lys Arg Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala
130 135 140
Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala
145 150 155 160
Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu
165 170 175
Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu
180 185 190
Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala
195 200 205
Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile
210 215 220
Gly Val Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn
225 230 235 240
Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr
245 250 255
Ala Ser Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln
260 265 270
Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile
275 280 285
Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala
290 295 300
Glu Val Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln
305 310 315 320
Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser
325 330 335
Ala Asn Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser
340 345 350
Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
355 360 365
Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro
370 375 380
Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly
385 390 395 400
Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His
405 410 415
Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr
420 425 430
Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val
435 440 445
Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys
450 455 460
Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp
465 470 475 480
Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys
485 490 495
Glu Ile Asp Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu
500 505 510
Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro
515 520 525
Trp Tyr Ile Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met
530 535 540
Val Thr Ile Met Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys
545 550 555 560
Gly Cys Cys Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser
565 570 575
Glu Pro Val Leu Lys Gly Val Lys Leu His Tyr Thr
580 585
<210> 4
<211> 252
<212> PRT
<213> Artificial Sequence
<220>
<223> Influenza virus M1 protein
<400> 4
Met Ser Leu Leu Thr Glu Val Glu Thr Tyr Val Leu Ser Ile Ile Pro
1 5 10 15
Ser Gly Pro Leu Lys Ala Glu Ile Ala Gln Arg Leu Glu Asp Val Phe
20 25 30
Ala Gly Lys Asn Thr Asp Leu Glu Val Leu Met Glu Trp Leu Lys Thr
35 40 45
Arg Pro Ile Leu Ser Pro Leu Thr Lys Gly Ile Leu Gly Phe Val Phe
50 55 60
Thr Leu Thr Val Pro Ser Glu Arg Gly Leu Gln Arg Arg Arg Phe Val
65 70 75 80
Gln Asn Ala Leu Asn Gly Asn Gly Asp Pro Asn Asn Met Asp Lys Ala
85 90 95
Val Lys Leu Tyr Arg Lys Leu Lys Arg Glu Ile Thr Phe His Gly Ala
100 105 110
Lys Glu Ile Ser Leu Ser Tyr Ser Ala Gly Ala Leu Ala Ser Cys Met
115 120 125
Gly Leu Ile Tyr Asn Arg Met Gly Ala Val Thr Thr Glu Val Ala Phe
130 135 140
Gly Leu Val Cys Ala Thr Cys Glu Gln Ile Ala Asp Ser Gln His Arg
145 150 155 160
Ser His Arg Gln Met Val Thr Thr Thr Asn Pro Leu Ile Arg His Glu
165 170 175
Asn Arg Met Val Leu Ala Ser Thr Thr Ala Lys Ala Met Glu Gln Met
180 185 190
Ala Gly Ser Ser Glu Gln Ala Ala Glu Ala Met Glu Val Ala Ser Gln
195 200 205
Ala Arg Gln Met Val Gln Ala Met Arg Thr Ile Gly Thr His Pro Ser
210 215 220
Ser Ser Ala Gly Leu Lys Asn Asp Leu Leu Glu Asn Leu Gln Ala Tyr
225 230 235 240
Gln Lys Arg Met Gly Val Gln Met Gln Arg Phe Lys
245 250
<210> 5
<211> 38
<212> PRT
<213> Artificial Sequence
<220>
<223> TM and CT of Influenza virus HA
<400> 5
Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
155 159 164 169
Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu
174 179 184
Gln Cys Arg Ile Cys Ile
189
<210> 6
<211> 3822
<212> DNA
<213> Artificial Sequence
<220>
<223> SARS-CoV-2 Spike gene full length
<400> 6
atgttcgttt tcctcgtgct cctccccctc gtttcctccc aatgcgtcaa cctcactacc 60
cgtacccagc tcccaccagc ctacaccaac agcttcactc gcggtgtgta ctaccccgac 120
aaggtcttcc gttccagcgt gctgcacagc actcaggacc tgttcctgcc attcttctct 180
aacgtgacct ggttccacgc catccacgtg agcggcacca acggcactaa gcgcttcgac 240
aaccctgtgc tgcccttcaa cgacggtgtc tacttcgctt ccaccgagaa gtctaacatc 300
atccgtggat ggatcttcgg caccactctg gactcaaaga ctcagtccct gctgatcgtc 360
aacaacgcca ccaacgtggt catcaaggtg tgcgagttcc agttctgcaa cgaccctttc 420
ctgggcgtct actaccacaa gaacaacaag agctggatgg agtctgagtt ccgcgtctac 480
tcttcagcta acaactgcac tttcgagtac gtgagccagc ccttcctgat ggacctggaa 540
ggaaagcagg gtaacttcaa gaacctgagg gagttcgtgt tcaagaacat cgacggatac 600
ttcaagattt actcaaagca cacccctatc aacctggtgc gcgacctgcc acagggtttc 660
tccgctctgg agcctctggt ggacctgccc atcggcatca acatcacccg cttccagact 720
ctgctggctc tgcaccgttc ctacctgact cctggcgact ccagctctgg atggaccgcc 780
ggagctgccg cttactacgt gggttacctg caacccagga ccttcctgct gaagtacaac 840
gaaaacggaa ccatcacaga cgctgtggac tgcgctctgg accccctgag cgaaaccaag 900
tgcactctga agtctttcac cgtggagaag ggcatctacc agactagcaa cttcagggtg 960
cagccaaccg aatctatcgt cagattcccc aacatcacta acctgtgccc attcggagag 1020
gtcttcaacg ccaccagatt cgcttccgtg tacgcctgga acaggaagag aatcagcaac 1080
tgcgtcgctg actactctgt gctgtacaac agcgcctctt tctcaacctt caagtgctac 1140
ggcgtgagcc ctactaagct gaacgacctg tgcttcacca acgtctacgc cgactctttc 1200
gtgatcaggg gagacgaggt cagacagatc gctcccggcc agactggaaa gatcgccgac 1260
tacaactaca agctgccaga cgacttcacc ggctgcgtca tcgcttggaa ctcaaacaac 1320
ctggactcca aagtgggtgg caactacaac tacctgtacc gcctgttccg taagagcaac 1380
ctgaagcctt tcgagaggga catctcaact gaaatctacc aggctggttc caccccctgc 1440
aacggtgtcg agggcttcaa ctgctacttc ccactgcaat cttacggttt ccagcctact 1500
aacggtgtgg gctaccagcc ctacagagtg gtcgtgctgt cattcgaact gctgcacgcc 1560
ccagctactg tgtgcggtcc taagaagtcc accaacctgg tcaagaacaa gtgcgtgaac 1620
ttcaacttca acggcctgac cggaactggt gtcctgaccg agtcaaacaa gaagttcctg 1680
ccattccagc agttcggaag ggacatcgct gacaccactg acgctgtgcg cgaccctcag 1740
accctggaaa tcctggacat cactccttgc agcttcggag gtgtctctgt gatcacccct 1800
ggcaccaaca cttccaacca ggtcgctgtg ctgtaccagg acgtcaactg caccgaggtg 1860
cctgtggcta tccacgctga ccagctgacc ccaacttggc gcgtgtactc caccggctcc 1920
aacgtcttcc agactcgtgc tggttgcctg atcggcgccg agcacgtgaa caactcatac 1980
gaatgcgaca tcccaatcgg cgctggaatc tgcgcctcct accagaccca gactaactca 2040
cctcgccgtg ctcgctccgt cgcctcccag agcatcatcg cttacaccat gagcctgggc 2100
gctgaaaact ctgtggccta ctccaacaac agcatcgcca tcccaaccaa cttcactatc 2160
tcagtgacca ctgagatcct gcctgtctca atgaccaaga cttccgtgga ctgcactatg 2220
tacatctgcg gagactcaac cgaatgctcc aacctgctgc tgcaatacgg ctccttctgc 2280
acccagctga accgtgctct gactggaatc gccgtggagc aggacaagaa cactcaggaa 2340
gtcttcgctc aggtgaagca aatctacaag acccctccca tcaaggactt cggcggattc 2400
aacttctccc agatcctgcc cgacccatct aagccttcaa agcgctcctt catcgaggac 2460
ctgctgttca acaaggtcac cctggccgac gctggattca tcaagcagta cggagactgc 2520
ctgggtgaca tcgccgctcg tgacctgatc tgcgctcaga agttcaacgg tctgaccgtg 2580
ctgccacctc tgctgactga cgaaatgatc gcccagtaca cttcagccct gctggctgga 2640
accatcactt ccggttggac cttcggtgct ggtgctgctc tgcaaatccc cttcgctatg 2700
cagatggcct acaggttcaa cggaatcggt gtcacccaga acgtgctgta cgagaaccag 2760
aagctgatcg ctaaccagtt caacagcgcc atcggaaaga tccaggactc actgtcatcc 2820
actgcctccg ctctgggcaa gctgcaagac gtcgtgaacc agaacgccca ggctctgaac 2880
accctggtca agcagctgtc ctccaacttc ggtgctatct catccgtgct gaacgacatc 2940
ctgtctcgcc tggacaaggt cgaggccgaa gtgcagatcg accgcctgat caccggccgc 3000
ctgcaatccc tgcaaaccta cgtgactcag cagctgatca gggccgctga aatcagagcc 3060
tctgctaacc tggccgctac caagatgtca gagtgcgtcc tgggtcagtc caagcgtgtg 3120
gacttctgcg gcaagggata ccacctgatg agcttccccc agtctgctcc acacggcgtc 3180
gtgttcctgc acgtcaccta cgtgcctgcc caggagaaga acttcaccac tgcccccgct 3240
atctgccacg acggcaaggc tcacttccca agggaaggtg tcttcgtgtc aaacggcacc 3300
cactggttcg tcactcagag aaacttctac gagcctcaga tcatcaccac tgacaacact 3360
ttcgtgtccg gaaactgcga cgtcgtgatc ggtatcgtca acaacaccgt gtacgaccca 3420
ctgcaacctg agctggacag cttcaaggag gaactggaca aatacttcaa gaaccacacc 3480
tctcccgacg tggacctggg tgacatcagc ggaatcaacg cttctgtcgt gaacatccag 3540
aaggagatcg accgtctgaa cgaagtggct aagaacctga acgaatccct gatcgacctg 3600
caagagctgg gcaagtacga acagtacatc aagtggcctt ggtacatctg gctgggtttc 3660
atcgctggcc tgatcgccat cgtcatggtg accatcatgc tgtgctgcat gactagctgc 3720
tgctcttgcc tgaagggctg ctgctcatgc ggttcctgct gcaagttcga tgaagacgat 3780
tccgagcccg ttctcaaagg agtgaagttg cattacacat aa 3822
<210> 7
<211> 2058
<212> DNA
<213> Artificial Sequence
<220>
<223> SARS-CoV-2 Spike gene S1 domain
<400> 7
atgttcgttt tcctcgtgct cctccccctc gtttcctccc aatgcgtcaa cctcactacc 60
cgtacccagc tcccaccagc ctacaccaac agcttcactc gcggtgtgta ctaccccgac 120
aaggtcttcc gttccagcgt gctgcacagc actcaggacc tgttcctgcc attcttctct 180
aacgtgacct ggttccacgc catccacgtg agcggcacca acggcactaa gcgcttcgac 240
aaccctgtgc tgcccttcaa cgacggtgtc tacttcgctt ccaccgagaa gtctaacatc 300
atccgtggat ggatcttcgg caccactctg gactcaaaga ctcagtccct gctgatcgtc 360
aacaacgcca ccaacgtggt catcaaggtg tgcgagttcc agttctgcaa cgaccctttc 420
ctgggcgtct actaccacaa gaacaacaag agctggatgg agtctgagtt ccgcgtctac 480
tcttcagcta acaactgcac tttcgagtac gtgagccagc ccttcctgat ggacctggaa 540
ggaaagcagg gtaacttcaa gaacctgagg gagttcgtgt tcaagaacat cgacggatac 600
ttcaagattt actcaaagca cacccctatc aacctggtgc gcgacctgcc acagggtttc 660
tccgctctgg agcctctggt ggacctgccc atcggcatca acatcacccg cttccagact 720
ctgctggctc tgcaccgttc ctacctgact cctggcgact ccagctctgg atggaccgcc 780
ggagctgccg cttactacgt gggttacctg caacccagga ccttcctgct gaagtacaac 840
gaaaacggaa ccatcacaga cgctgtggac tgcgctctgg accccctgag cgaaaccaag 900
tgcactctga agtctttcac cgtggagaag ggcatctacc agactagcaa cttcagggtg 960
cagccaaccg aatctatcgt cagattcccc aacatcacta acctgtgccc attcggagag 1020
gtcttcaacg ccaccagatt cgcttccgtg tacgcctgga acaggaagag aatcagcaac 1080
tgcgtcgctg actactctgt gctgtacaac agcgcctctt tctcaacctt caagtgctac 1140
ggcgtgagcc ctactaagct gaacgacctg tgcttcacca acgtctacgc cgactctttc 1200
gtgatcaggg gagacgaggt cagacagatc gctcccggcc agactggaaa gatcgccgac 1260
tacaactaca agctgccaga cgacttcacc ggctgcgtca tcgcttggaa ctcaaacaac 1320
ctggactcca aagtgggtgg caactacaac tacctgtacc gcctgttccg taagagcaac 1380
ctgaagcctt tcgagaggga catctcaact gaaatctacc aggctggttc caccccctgc 1440
aacggtgtcg agggcttcaa ctgctacttc ccactgcaat cttacggttt ccagcctact 1500
aacggtgtgg gctaccagcc ctacagagtg gtcgtgctgt cattcgaact gctgcacgcc 1560
ccagctactg tgtgcggtcc taagaagtcc accaacctgg tcaagaacaa gtgcgtgaac 1620
ttcaacttca acggcctgac cggaactggt gtcctgaccg agtcaaacaa gaagttcctg 1680
ccattccagc agttcggaag ggacatcgct gacaccactg acgctgtgcg cgaccctcag 1740
accctggaaa tcctggacat cactccttgc agcttcggag gtgtctctgt gatcacccct 1800
ggcaccaaca cttccaacca ggtcgctgtg ctgtaccagg acgtcaactg caccgaggtg 1860
cctgtggcta tccacgctga ccagctgacc ccaacttggc gcgtgtactc caccggctcc 1920
aacgtcttcc agactcgtgc tggttgcctg atcggcgccg agcacgtgaa caactcatac 1980
gaatgcgaca tcccaatcgg cgctggaatc tgcgcctcct accagaccca gactaactca 2040
cctcgccgtg ctcgctcc 2058
<210> 8
<211> 1404
<212> DNA
<213> Artificial Sequence
<220>
<223> SARS-CoV-2 Spike gene S2 domain
<400> 8
cccgacccat ctaagccttc aaagcgctcc ttcatcgagg acctgctgtt caacaaggtc 60
accctggccg acgctggatt catcaagcag tacggagact gcctgggtga catcgccgct 120
cgtgacctga tctgcgctca gaagttcaac ggtctgaccg tgctgccacc tctgctgact 180
gacgaaatga tcgcccagta cacttcagcc ctgctggctg gaaccatcac ttccggttgg 240
accttcggtg ctggtgctgc tctgcaaatc cccttcgcta tgcagatggc ctacaggttc 300
aacggaatcg gtgtcaccca gaacgtgctg tacgagaacc agaagctgat cgctaaccag 360
ttcaacagcg ccatcggaaa gatccaggac tcactgtcat ccactgcctc cgctctgggc 420
aagctgcaag acgtcgtgaa ccagaacgcc caggctctga acaccctggt caagcagctg 480
tcctccaact tcggtgctat ctcatccgtg ctgaacgaca tcctgtctcg cctggacaag 540
gtcgaggccg aagtgcagat cgaccgcctg atcaccggcc gcctgcaatc cctgcaaacc 600
tacgtgactc agcagctgat cagggccgct gaaatcagag cctctgctaa cctggccgct 660
accaagatgt cagagtgcgt cctgggtcag tccaagcgtg tggacttctg cggcaaggga 720
taccacctga tgagcttccc ccagtctgct ccacacggcg tcgtgttcct gcacgtcacc 780
tacgtgcctg cccaggagaa gaacttcacc actgcccccg ctatctgcca cgacggcaag 840
gctcacttcc caagggaagg tgtcttcgtg tcaaacggca cccactggtt cgtcactcag 900
agaaacttct acgagcctca gatcatcacc actgacaaca ctttcgtgtc cggaaactgc 960
gacgtcgtga tcggtatcgt caacaacacc gtgtacgacc cactgcaacc tgagctggac 1020
agcttcaagg aggaactgga caaatacttc aagaaccaca cctctcccga cgtggacctg 1080
ggtgacatca gcggaatcaa cgcttctgtc gtgaacatcc agaaggagat cgaccgtctg 1140
aacgaagtgg ctaagaacct gaacgaatcc ctgatcgacc tgcaagagct gggcaagtac 1200
gaacagtaca tcaagtggcc ttggtacatc tggctgggtt tcatcgctgg cctgatcgcc 1260
atcgtcatgg tgaccatcat gctgtgctgc atgactagct gctgctcttg cctgaagggc 1320
tgctgctcat gcggttcctg ctgcaagttc gatgaagacg attccgagcc cgttctcaaa 1380
ggagtgaagt tgcattacac ataa 1404
<210> 9
<211> 117
<212> DNA
<213> Artificial Sequence
<220>
<223> TM and CT of Influenza HA
<400> 9
cagatcctgg ctatctactc tactgtggcc tccagcctgg tgctgctggt ctccctgggt 60
gctatctctt tctggatgtg ctctaacggc tcactgcagt gccgcatctg catctaa 117
<210> 10
<211> 69
<212> DNA
<213> Artificial Sequence
<220>
<223> Melittin Signal Peptide
<400> 10
atgaagttcc tggtgaacgt cgccctggtg ttcatggtgg tctacatctc ctacatctac 60
gctgccgct 69
Claims (7)
- 인플루엔자 바이러스 매트릭스 단백질1(M1)으로 이루어진 코어; 및 항원 단백질을 포함하고,
상기 항원 단백질은 SARS-CoV-2의 스파이크 전장 단백질, 스파이크 단백질의 S1 도메인 잔기와 인플루엔자 헤마글루티닌의 막관통 도메인 및 세포질 꼬리의 융합 단백질, 또는 스파이크 단백질의 S2 도메인 잔기인,
SARS-CoV-2 바이러스 유사 입자. - 제1항에 있어서,
상기 스파이크 전장 단백질은 서열번호 1의 아미노산 서열로 이루어진 것이고,
상기 S1 도메인 잔기는 서열번호 2의 아미노산 서열로 이루어진 것이고,
상기 S2 도메인 잔기는 서열번호 3의 아미노산 서열로 이루어진 것인,
SARS-CoV-2 바이러스 유사 입자. - 제1항에 있어서,
상기 SARS-CoV-2 바이러스 유사 입자는 Sf9 세포에 대해 감염성이 없는 것인,
SARS-CoV-2 바이러스 유사 입자. - 제1항의 SARS-CoV-2 바이러스 유사 입자를 포함하는,
코로나바이러스감염증(COVID)-19 예방 또는 치료용 백신 조성물. - 제4항에 있어서,
상기 조성물은 어쥬번트를 더 포함하는,
코로나바이러스감염증(COVID)-19 예방 또는 치료용 백신 조성물. - 인플루엔자 바이러스 매트릭스 단백질1(M1)을 발현하는 제 1 재조합 배큘로바이러스 및 SARS-CoV-2의 스파이크 전장 단백질, 스파이크 단백질의 S1 도메인 잔기와 인플루엔자 헤마글루티닌의 막관통 도메인 및 세포질 꼬리의 융합 단백질, 또는 스파이크 단백질의 S2 도메인 잔기를 발현하는 제 2 재조합 배큘로바이러스를 곤충세포에 공동 감염시키는 단계;
공동 감염된 곤충세포를 배양하고 바이러스 유사 입자를 정제하는 단계를 포함하는,
SARS-CoV-2 바이러스 유사 입자의 제조 방법. - 인플루엔자 바이러스 매트릭스 단백질1(M1)을 발현하는 제 1 재조합 배큘로바이러스; 및
SARS-CoV-2의 스파이크 전장 단백질, 스파이크 단백질의 S1 도메인 잔기와 인플루엔자 헤마글루티닌의 막관통 도메인 및 세포질 꼬리의 융합 단백질, 또는 스파이크 단백질의 S2 도메인 잔기를 발현하는 제 2 재조합 배큘로바이러스를 포함하는,
SARS-CoV-2 바이러스 유사 입자 제조용 조성물.
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Non-Patent Citations (2)
Title |
---|
Influenza M2 virus-like particle vaccination enhances protection in combination with avian influenza HA VLPs. PLoS ONE 2019, 14, e0216871. |
Influenza Virus-like Particle (VLP) Vaccines Expressing the SARS-CoV-2 S Glycoprotein, S1, or S2 Domains, Vaccines 2021, 9, 920. |
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