Sjálfmagnandi mRNA (saRNA): Næsta kynslóð RNA pallur fyrir bóluefni 

Unlike conventional mRNA bóluefni 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 bóluefni 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 Bóluefni, 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 bóluefni 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 bóluefni currently in use (sometimes referred to as conventional or 1st generation mRNA bóluefni) 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 bóluefni. These offer better opportunities in terms of lower dosage requirements, relatively fewer side effects, and longer duration of action/effects ^(2-5). 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 bóluefni against COVID-19, and several vaccine and therapeutics candidates in pipeline such as HIV bóluefni og meðferð á Charcot-Marie-Tooth sjúkdómur.  

saRNA bóluefnisframbjóðendur gegn COVID-19  

Áhugi á saRNA bóluefni er ekki mjög nýr. Innan nokkurra mánaða frá upphafi heimsfaraldursins, um mitt ár 2020, McKay et al. hafði kynnt saRNA byggt bóluefni sem sýndi háa mótefnatítra í sermi músa og góða hlutleysingu veirunnar⁶. 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.  

saRNA bóluefni gegn inflúensu  

Inflúensa bóluefni 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.  

Bóluefni gegn COVID-19 hafa fengið markvissa athygli af augljósum ástæðum. Sum forklínísk verk í átt að beitingu RNA vettvanga hafa verið unnin fyrir aðrar sýkingar og ósýkingarsjúkdóma eins og krabbamein, Alzheimerssjúkdóm og arfgenga sjúkdóma; þó er ekkert bóluefni eða lyf sem byggir á saRNA enn samþykkt til notkunar í mönnum. Fleiri rannsóknir þurfa að fara fram á notkun bóluefna sem byggjast á saRNA til að skilja ítarlega öryggi þeirra og verkun til notkunar á mönnum.

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Tilvísanir:  

1. Prasad U., 2020. COVID-19 mRNA bóluefni: Áfangi í vísindum og breyting á leik í læknisfræði. Vísindaleg Evrópu. Birt 29. desember 2020. Aðgengilegt á netinu á 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. Sjálfmagnandi RNA bóluefni fyrir smitsjúkdóma. Gen Ther 28, 117–129 (2021). https://doi.org/10.1038/s41434-020-00204-y 

3. Pourseif MM et al 2022. Sjálfmagnandi mRNA bóluefni: Verkunarháttur, hönnun, þróun og hagræðing. Fíkniefnauppgötvun í dag. 27. bindi, 11. tölublað, nóvember 2022, 103341. DOI: https://doi.org/10.1016/j.drudis.2022.103341  

4. Blakney AK et al 2021. Uppfærsla á sjálf-magnandi mRNA bóluefni þróun. Bóluefni 2021, 9(2), 97; https://doi.org/10.3390/vaccines9020097  

5. Anna Blakney; Næsta kynslóð RNA bóluefna: sjálfmagnandi RNA. Biochem (Lond) 13. ágúst 2021; 43 (4): 14–17. doi: https://doi.org/10.1042/bio_2021_142 

6. McKay, PF, Hu, K., Blakney, AK o.fl. Sjálfmagnandi RNA SARS-CoV-2 lípíð nanóagnabóluefni framkallar háa hlutleysandi mótefnatítra í músum. Nat Commun 11, 3523 (2020). https://doi.org/10.1038/s41467-020-17409-9 

7. Akahata W., et al 2022. Öryggi og ónæmingargeta SARS-CoV-2 sjálf-magnandi RNA bóluefnis sem tjáir akkerað RBD: slembiraðað, áhorfendablind, 1. stigs rannsókn. Preprint medRxiv 2022.11.21.22281000; Birt 22. nóvember 2022. doi: https://doi.org/10.1101/2022.11.21.22281000  

8. Elliot T, o.fl. (2022) Aukin ónæmissvörun eftir misleita bólusetningu með sjálfmagnandi RNA og mRNA COVID-19 bóluefnum. PLoS Pathog 18(10): e1010885. Birt: 4. október 2022. DOI: https://doi.org/10.1371/journal.ppat.1010885 

9. Keikha, R., Hashemi-Shahri, SM & Jebali, A. Mat á nýjum bóluefnum til inntöku byggt á sjálfmagnandi RNA lípíð nanögnum (saRNA LNPs), saRNA transfected Lactobacillus plantarum LNPs og saRNA transfected Lactobacillus SARS plantarum til að hlutleysa -2 afbrigði alfa og delta. Sci Rep 11, 21308 (2021). Birt: 29. október 2021. https://doi.org/10.1038/s41598-021-00830-5 

10. CDC 2022. Hvernig bóluefni gegn inflúensu (flensu) eru gerð. Fæst á netinu á https://www.cdc.gov/flu/prevent/how-fluvaccine-made.htm skoðað 18. desember 2022. 

11. Chang C., et al 2022. Sjálfmagnandi mRNA bicistronic inflúensubóluefni hækka krossviðbrögð ónæmissvörunar í músum og koma í veg fyrir sýkingu í frettum. Sameindameðferðaraðferðir og klínísk þróun. 27. árgangur, 8. desember 2022, bls. 195-205. https://doi.org/10.1016/j.omtm.2022.09.013  

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