자체 증폭 mRNA(saRNA): 백신을 위한 차세대 RNA 플랫폼 

Unlike conventional mRNA 백신 which encodes only for the target antigens, the self-amplifying mRNAs (saRNAs) encodes for non-structural proteins and promotor as well which makes saRNAs replicons capable of transcribing in vivo in the host cells. Early results indicates that their effectiveness, when given in smaller doses, is at par with that of regular doses of conventional mRNA. Due to low dose requirements, fewer side effects and longer duration of action, saRNA appears as better RNA platform for vaccines (including for v.2.0 of mRNA COVID vaccines) and newer therapeutics. No saRNA-based vaccine or drug is approved for human use yet. However, significant progress in this area has the potential to usher in a renaissance in prevention and treatment of infections and degenerative disorders.  

Needless to say, mankind is frail before pandemics like COVID. We all experienced it and were impacted by it in one way or other; millions could not live to see the next morning. Given China too had massive COVID-19 immunisations programme, the latest media reports of spurts of cases and mortality in and around Beijing is concerning. The need of preparedness and relentless pursuit of more effective 백신 and therapeutics cannot be underemphasised.  

The extraordinary situation presented by the COVID-19 pandemic provided an opportunity for the promising RNA technology to come out of age. Clinical trials could be completed at a record pace and mRNA based COVID 백신, BNT162b2 (manufactured by Pfizer/BioNTech) and mRNA-1273 (by Moderna) received EUA from the regulators and, in due course, played an important role in providing protection against the pandemic to the people especially in Europe and North America¹. These mRNA 백신 are based on synthetic RNA platforms. This allows for rapid, scalable and cell-free industrial production. But these are not without limitations such as high cost, cold supply chain, diminishing antibody titres, to name a few.  

mRNA 백신 currently in use (sometimes referred to as conventional or 1st generation mRNA 백신) are based on encoding the viral antigen in synthetic RNA. A non-viral delivery system transports the transcript to the host cell cytoplasm where the viral antigen is expressed. The expressed antigen then induces immune response and provide active immunity. Because RNA degrades easily and this mRNA in the vaccine cannot self-transcribe, an appreciable amount of synthetic viral RNA transcripts (mRNA) need to be administered in the vaccine for eliciting desired immune response. But what if the synthetic RNA transcript is incorporated also with non-structural proteins and promotor genes, in addition to the desired viral antigen? Such an RNA transcript will have ability to transcribe or self-amplify itself when transported into the host cell though it will be longer and heavier and its transport to the host cells may be more complex.  

Unlike conventional (or, non-amplifying) mRNA which has codes only for the targeted viral antigen, the self-amplifying mRNA (saRNA), has ability to transcribe itself when in vivo in the host cells by virtue of presence of required codes for non-structural proteins and a promotor. mRNA vaccine candidates based on self-amplifying mRNAs are referred to as second or next generation mRNA 백신. These offer better opportunities in terms of lower dosage requirements, relatively fewer side effects, and longer duration of action/effects ^{(2-5학년도)}. Both the versions of RNA platform are known to the scientific community for some time. In pandemic response, researchers opted for non-replicating version of mRNA platform for vaccine development in view of its simplicity and exigencies of pandemic situation and to gain experience with non-amplifying version first as prudence warranted. Now, we have two approved mRNA 백신 against COVID-19, and several vaccine and therapeutics candidates in pipeline such as HIV 백신 및 치료 샤르코-마리-투스병.  

COVID-19에 대한 saRNA 백신 후보  

saRNA 백신에 대한 관심은 그리 새로운 것이 아닙니다. 팬데믹이 시작된 지 몇 개월이 지나지 않은 2020년 중반, McKay는 외. 마우스 혈청에서 높은 항체 역가와 우수한 바이러스 중화성을 나타내는 saRNA 기반 백신 후보를 제시했습니다.⁶. The phase-1 clinical trial of VLPCOV–01 (a self-amplifying RNA vaccine candidate) on 92 healthy adults whose results were published on preprint last month concluded that low dose administration of this saRNA based vaccine candidate induced immune response comparable to conventional mRNA vaccine BNT162b2 and recommends its further development as booster vaccine⁷. In another recently published study conducted as part of the COVAC1 clinical trial to develop booster dose administration strategy, a superior immune response was found in people who had previous COVID-19 and received a novel self-amplifying RNA (saRNA) COVID-19 vaccine plus a UK authorised vaccine⁸. A pre-clinical trial of novel oral vaccine candidate based on self-amplifying RNA on mouse model elicited high antibody titre⁹.  

인플루엔자에 대한 saRNA 백신 후보  

인플루엔자 백신 currently in use are based on inactivated viruses or synthetic recombinant (synthetic HA gene combined with a baculovirus)¹⁰. A self-amplifying mRNA-based vaccine candidate may induce immunity against multiple viral antigens. Pre-clinical trial of sa-mRNA bicistronic A/H5N1 vaccine candidate against influenza on mice and ferrets elicited potent antibody and T-cell response warranting evaluation on humans in clinical trials¹¹.  

COVID-19에 대한 백신은 분명한 이유로 집중적인 관심을 받았습니다. 암, 알츠하이머병 및 유전 장애와 같은 다른 감염 및 비감염성 장애에 대해 RNA 플랫폼의 적용을 위한 일부 전임상 작업이 수행되었습니다. 그러나 saRNA 기반 백신이나 약물은 아직 사람에게 사용하도록 승인되지 않았습니다. 인간 피험자에 대한 안전성 및 효능을 포괄적으로 이해하기 위해서는 saRNA 기반 백신의 사용에 대해 더 많은 연구가 수행되어야 합니다.

***

참조 :  

1. Prasad U., 2020. COVID-19 mRNA 백신: 과학의 이정표이자 의학의 게임 체인저. 과학적 유럽. 29년 2020월 XNUMX일 발행. 온라인에서 확인 가능: http://scientificeuropean.co.uk/medicine/covid-19-mrna-vaccine-a-milestone-in-science-and-a-game-changer-in-medicine/  

2. Bloom, K., van den Berg, F. & Arbuthnot, P. 전염병에 대한 자체 증폭 RNA 백신. 진 테르 28, 117-129 (2021). https://doi.org/10.1038/s41434-020-00204-y 

3. 푸르세이프 MM 외 2022. 자가 증폭 mRNA 백신: 작용 방식, 설계, 개발 및 최적화. 오늘의 약물 발견. 27권, 11호, 2022년 103341월, XNUMX. DOI: https://doi.org/10.1016/j.drudis.2022.103341  

4. 블래크니 AK 외 2021. 자가 증폭 mRNA 백신 개발에 대한 업데이트. 백신 2021, 9(2), 97; https://doi.org/10.3390/vaccines9020097  

5. 안나 블래크니; 차세대 RNA 백신: 자가 증폭 RNA. Biochem(런던) 13년 2021월 43일; 4(14): 17–XNUMX. 도이: https://doi.org/10.1042/bio_2021_142 

6. McKay, PF, Hu, K., Blakney, AK 외. 자가 증폭 RNA SARS-CoV-2 지질 나노입자 백신 후보는 생쥐에서 높은 중화 항체 역가를 유도합니다. Nat Commun 11, 3523 (2020). https://doi.org/10.1038/s41467-020-17409-9 

7. Akahata W., et al 2022. 고정 RBD를 발현하는 SARS-CoV-2 자가 증폭 RNA 백신의 안전성 및 면역원성: 무작위, 관찰자 ​​맹검, 1상 연구. 사전 인쇄 medRxiv 2022.11.21.22281000; 게시일: 22년 2022월 XNUMX일. https://doi.org/10.1101/2022.11.21.22281000  

8. 엘리엇 T 외. (2022) 자가 증폭 RNA 및 mRNA COVID-19 백신을 사용한 이종 백신 접종 후 향상된 면역 반응. PLoS Pathog 18(10): e1010885. 게시일: 4년 2022월 XNUMX일. DOI: https://doi.org/10.1371/journal.ppat.1010885 

9. Keikha, R., Hashemi-Shahri, SM & Jebali, A. SARS-CoV를 중화하기 위해 자가 증폭 RNA 지질 나노입자(saRNA LNP), saRNA로 형질감염된 Lactobacillus plantarum LNP 및 saRNA로 형질감염된 Lactobacillus plantarum에 기반한 새로운 경구용 백신 평가 -2 변형 알파 및 델타. Sci Rep 11, 21308 (2021). 게시일: 29년 2021월 XNUMX일. https://doi.org/10.1038/s41598-021-00830-5 

10. CDC 2022. 인플루엔자(독감) 백신 제조 방법. 에서 온라인으로 이용 가능 https://www.cdc.gov/flu/prevent/how-fluvaccine-made.htm 18 December 2022에서 액세스 할 수 있습니다. 

11. Chang C., et al 2022. 자가 증폭 mRNA 바이시스트론 인플루엔자 백신은 생쥐에서 교차 반응성 면역 반응을 일으키고 흰족제비의 감염을 예방합니다. 분자 치료 방법 및 임상 개발. 27권, 8년 2022월 195일, 페이지 205-XNUMX. https://doi.org/10.1016/j.omtm.2022.09.013  

***