【논문】 Non-viral COVID-19 vaccine delivery systems

Park, K. S., Sun, X., Aikins, M. E., & Moon, J. J. (2020). Non-viral COVID-19 vaccine delivery systems. Advanced drug delivery reviews.¹

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1. 개요

⑴ COVID-19 virus 

① single stranded RNA virus

② S protein의 S1 subunit의 RBD(receptor binding domain)가 폐에 있는 ACE2(angiotensin-converting enzyme 2)와 결합

③ S protein의 S2 subunit이 membrane fusion을 담당

 

Figure. 1. COVID-19의 침입 경로²

 

⑵ 백신 개발 전략

① identifying an antigen

② developing a delivery approach for said antigen

⑶ 백신의 종류 

① 종류 1. whole virus-based vaccine 또는 viral vector-based vaccine

② 종류 2. RNA-based vaccine

③ 종류 3. DNA-based vaccine

④ 종류 4. protein-based vaccine

⑤ 종류 5. virus-like particle (VLP)

⑥ 종류 6. peptide-based vaccine

 

 

2. 종류 1. whole virus-based vaccine 또는 viral vector-based vaccine

⑴ 1-1. live attenuated whole virus

⑵ 1-2. live inactivated whole virus : commonly used

⑶ 장점 : stronger immune response

 

 

3. 종류 2. RNA-based vaccine 

⑴ 장점 : safe, efficacy, fast

① safe : genotoxicity ↓, biological contamination ↓, biodegradable

② fast

○ 20년 1월 9일 : WHO가 우한의 unknown pneumonia case를 발표

○ 20년 1월 11일 : 중국 팀이 COVID-19의 유전자 서열을 보고

○ 20년 1월 13일 : Moderna와 NIH가 mRNA-1273 서열을 제안

○ 20년 4월 10일 : mRNA-1273이 처음으로 임상 환자에게 적용됨 

⑵ 단점 : stability ↓, dependence on permeablity to cell membrane, inflammation, toxicity, low thermal stabiltiy

⑶ 2-1. LNP(lipid nanoparticle) : BioNTech/Pfizer와 Moderna가 이용

① 재료 : cationic of ionizable lipid, cholesterol, helper phospholipid, PEGylated lipid

② 장점 : mRNA encapsulation, endosomal escape, mRNA protection, suitable for human, large scale synthesis

○ internalization → surface charge가 (+) → LNP가 분해되면서 endosomal escape ↑

③ 예 

○ DLin-KC2-DMA

○ DLin-MC3-DMA

○ C12-200

○ cKK-E12

○ L319

○ TT3

○ ssPalmE

○ Acuitas

○ mRNA-1273 : by Moderna, NIAID

○ BNT-162b2, BNT-162a1, BNT-162b1, BNT-162c2 : by BioNTech, Fosun Pharma, Pfizer 

○ ARCT-021 : by Arcturus, Duke-NUS

○ ARCoV : by People's Liveration Army (PLA) Academy of Military Sciences, Walvax Biotech

○ SARS-CoV-2 saRNA LNP : by Imperial College London

○ CVnCOV : by Curevac AG

⑷ 2-2. cationic liposome

① 예 

○ DOSPA + DOPE

○ DOTMA + DOTAP

⑸ 2-3. polymer and polymer/lipid hybrid particle

① 예  

○ self-amplifying replicon RNA (RepRNA)

○ TT3-LLN (PLGA)

○ CARTs (charge-altering releasable transporter)

○ PBAE (poly(β-amino esters))

⑹ 2-4. micelle

① 예 

○ PEG-PAsp(TEP)-Chol

○ PET-stearic acid conjugate (PSA)

⑺ 2-5. emulsion

① 예 

○ cationic emulsion (CNE)

⑻ 향후 RNA 백신의 방향

① effectively package and protect antigen-encoding mRNA

② thermal stability

③ adjuvant properties for wide range of pathogen

④ quality-controlled mass production

 

 

4. 종류 3. DNA-based vaccine 

⑴ 개요 : 진핵세포 promoter에 의해 전사가 조절되는 bacterial plasmid가 핵 내로 들어가야 함

⑵ 장점 : rapid manufacturing (2-4 weeks), good storage property, no significant adverse effect

⑶ 단점 : oncogene activation → auto-immune response, limited immunogenicity, weaker immune response

⑷ 예 

① INO-4800 : by Inovio Pharmaceuticals/International Vaccine Institute

② INO-4700, Bifidobacteria : oral

③ PittCoVacc : microneedle. by University of Pittsburgh

④ AG0301-COVID19 : by Osaka University, AnGes, Takara Bio

⑤ bacTRL-Spike : by Symvivo 

⑥ GX-19 : Genexine Consortium

 

 

5. 종류 4. protein-based vaccine 

⑴ 4-1. 일반 protein-based vaccin  

① 단점 : 비교적 immune response가 약함

⑵ 4-2. recombinant protein vaccine 또는 virus-like particle (VLP) 

① 장점 : antigenicity ↑, immunogenicity ↑

② recombinant protein vaccine의 예

○ NVX-CoV2373 : by Novavax

○ SCB-2019 : by Clover Biopharmaceuticals

○ UQ-CSL V451 : by University of Queensland

③ virus-like particle의 예

○ CoVLP : by Medicago

 

 

6. 종류 5. peptide-based vaccine 

⑴ 단점 : suboptimal immune activation

 

 

7. COVID-19 백신에 요구되는 추가적 과제

⑴ adjuvant

① mRNA-induced innate immune activation과 mRNA translation 간의 trade-off가 있음

② 예

○ AS03

○ CpG 1018

○ MF59

○ Vaxfectin

○ 3M-052 : HIV-1 치료 목적

○ R848

○ MPL

○ GL1 

⑵ route

① IM(intramuscular), ID(intradermal), SC(subcutaneous), IN(intranasal), IV(intravenous) 등

② RNA, DNA 백신은 IM으로 많이 처방

○ IM : prolonged protein expression by muscle cells

○ DNA 백신은 ID로도 많이 처방함

③ protein은 다른 경로로도 많이 처방함

④ bilosome은 oral로 많이 처방함

⑶ thermal stability

① 어떤 mRNA 백신은 freeze-drying  후 4 ℃에서 10개월간 보관할 수 있음

② ARCoV는 열적안정성이 있음

③ 일반적으로 DNA 백신이 RNA 백신보다 안정함

④ protein 백신도 불안정한 편

⑷ lymph node targeted delivery

① direct injection : 효과가 가장 뛰어남

② lymph node draining : 150 nm 리포좀도 가능함. draining을 향상시키는 약제도 존재함

 

입력: 2021.04.20 14:15

 

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2. 출처 : Rossi, G. A., Sacco, O., Mancino, E., Cristiani, L., & Midulla, F. (2020). Differences and similarities between SARS-CoV and SARS-CoV-2: spike receptor-binding domain recognition and host cell infection with support of cellular serine proteases. Infection, 1-5. [본문으로]