Savaime amplifikuojančios mRNR (saRNR): naujos kartos RNR platforma vakcinoms 

Unlike conventional mRNA vakcinos 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 iRNR. 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 vakcinos and therapeutics cannot be underemphasised.  

The extraordinary situation presented by the COVID-19 pandemic provided an opportunity for the promising RNR technology to come out of age. Clinical trials could be completed at a record pace and iRNR based COVID Vakcinos, BNT162b2 (manufactured by Pfizer/BioNTech) and iRNR-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 vakcinos 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.  

iRNR vakcinos currently in use (sometimes referred to as conventional or 1st generation iRNR vakcinos) 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 RNR 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) iRNR which has codes only for the targeted viral antigen, the self-amplifying iRNR (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 iRNR vakcinos. 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 vakcinos against COVID-19, and several vaccine and therapeutics candidates in pipeline such as ŽIV vakcina ir gydymas Charcot-Marie-Tooth liga.  

saRNA vakcinos kandidatai nuo COVID-19  

Susidomėjimas saRNR vakcina nėra labai naujas. Per kelis mėnesius nuo pandemijos pradžios, 2020 m. viduryje, McKay et al. pateikė saRNR pagrindu pagamintą vakciną, kuri parodė aukštus antikūnų titrus pelių serume ir gerą viruso neutralizavimą⁶. The phase-1 clinical trial of VLPCOV–01 (a self-amplifying RNR vaccine candidate) on 92 healthy adults whose results were published on preprint last month concluded that low dose administration of this saRNR 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 RNR (saRNA) COVID-19 vaccine plus a UK authorised vaccine⁸. A pre-clinical trial of novel oral vaccine candidate based on self-amplifying RNR on mouse model elicited high antibody titre⁹.  

saRNR vakcinos kandidatas nuo gripo  

Gripas vakcinos currently in use are based on inactivated viruses or synthetic recombinant (synthetic HA gene combined with a baculovirus)¹⁰. A self-amplifying iRNR-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.  

Dėl akivaizdžių priežasčių skiepai nuo COVID-19 sulaukė didelio dėmesio. Kai kurie ikiklinikiniai RNR platformų taikymo darbai buvo atlikti kitoms infekcijoms ir neinfekciniams sutrikimams, pvz., vėžiui, Alzheimerio ligai ir paveldimiems sutrikimams, gydyti; tačiau jokia saRNR pagrindu sukurta vakcina ar vaistas dar nėra patvirtintas žmonėms vartoti. Reikia atlikti daugiau tyrimų, susijusių su saRNR pagrindu pagamintų vakcinų naudojimu, kad būtų galima visapusiškai suprasti jų saugumą ir veiksmingumą naudojant žmonėms.

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Nuorodos:  

1. Prasad U., 2020. COVID-19 mRNR vakcina: mokslo įvykis ir medicinos keitiklis. Mokslinis Europos. Paskelbta 29 m. gruodžio 2020 d. Prieiga internete adresu 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. Self-ampliifying RNR vakcinos nuo infekcinių ligų. Gene Ther 28, 117–129 (2021). https://doi.org/10.1038/s41434-020-00204-y 

3. Pourseif MM et al 2022 m. Savaime amplifikuojančios mRNR vakcinos: veikimo būdas, dizainas, kūrimas ir optimizavimas. Narkotikų atradimas šiandien. 27 tomas, 11 leidimas, 2022 m. lapkričio mėn., 103341. DOI: https://doi.org/10.1016/j.drudis.2022.103341  

4. Blakney AK et al 2021 m. Savaime amplifikuojančios mRNR vakcinos kūrimo atnaujinimas. Vakcinos 2021, 9 (2), 97; https://doi.org/10.3390/vaccines9020097  

5. Anna Blakney; Naujos kartos RNR vakcinos: savaime amplifikuojanti RNR. Biochemas (Londonas), 13 m. rugpjūčio 2021 d.; 43 (4): 14–17. doi: https://doi.org/10.1042/bio_2021_142 

6. McKay, PF, Hu, K., Blakney, AK ir kt. Savaime amplifikuojančios RNR SARS-CoV-2 lipidų nanodalelių vakcinos kandidatas pelėms sukelia aukštus neutralizuojančių antikūnų titrus. Nat Commun 11, 3523 (2020). https://doi.org/10.1038/s41467-020-17409-9 

7. Akahata W. ir kt., 2022. SARS-CoV-2 savaime amplifikuojančios RNR vakcinos, išreiškiančios pritvirtintą UBR, saugumas ir imunogeniškumas: atsitiktinių imčių, aklas stebėtojo, 1 fazės tyrimas. Preprint medRxiv 2022.11.21.22281000; Paskelbta 22 m. lapkričio 2022 d. doi: https://doi.org/10.1101/2022.11.21.22281000  

8. Elliott T ir kt. (2022) Sustiprėjęs imuninis atsakas po heterologinės vakcinacijos savaime amplifikuojančiomis RNR ir mRNR vakcinomis nuo COVID-19. PLoS patologija 18(10): e1010885. Paskelbta: 4 m. spalio 2022 d. DOI: https://doi.org/10.1371/journal.ppat.1010885 

9. Keikha, R., Hashemi-Shahri, SM & Jebali, A. Naujų geriamųjų vakcinų, pagrįstų savaime amplifikuojančiomis RNR lipidų nandalelėmis (saRNR LNP), saRNR transfekuotomis Lactobacillus plantarum LNP ir saRNR transfekuotomis Lactobacillus plantarum SARS-CoV, įvertinimas siekiant neutralizuoti -2 alfa ir delta variantai. Sci Rep 11, 21308 (2021). Paskelbta: 29 m. spalio 2021 d. https://doi.org/10.1038/s41598-021-00830-5 

10. CDC 2022. Kaip gaminamos gripo (gripo) vakcinos. Galima internetu adresu https://www.cdc.gov/flu/prevent/how-fluvaccine-made.htm pasiekiama 18 gruodžio 2022. 

11. Chang C. ir kt., 2022. Savaime amplifikuojančios mRNR bicistroninio gripo vakcinos sukelia kryžminį reaktyvųjį imuninį atsaką pelėms ir užkerta kelią šeškų infekcijai. Molekulinės terapijos metodai ir klinikinė raida. 27 tomas, 8 m. gruodžio 2022 d., 195-205 psl. https://doi.org/10.1016/j.omtm.2022.09.013  

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