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Self-amplifying mRNAs (saRNAs): The Next Generation RNA Platform for Vaccines 

Unlike conventional mRNA vaccines 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 vaccines 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 Vaccines, 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 vaccines 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 vaccines currently in use (sometimes referred to as conventional or 1st generation mRNA vaccines) 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 vaccines. 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 vaccines against COVID-19, and several vaccine and therapeutics candidates in pipeline such as HIV Vaccine and treatment of Charcot-Marie-Tooth disease.  

saRNA Vaccine candidates against COVID-19  

Interest in saRNA vaccine is not very new. Within few months of beginning of the pandemic, in mid 2020, McKay et al. had presented a saRNA based vaccine candidate that showed high antibody titers in mouse sera and good neutralization of the virus6. 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 Vaccine candidate against Influenza  

Influenza vaccines 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.  

Vaccines against COVID-19 has received focused attention for obvious reasons. Some pre-clinical works towards application of RNA platforms has been done for other infections and non-infective disorders such as cancers, Alzheimer’s disease and inherited disorders; however, no saRNA-based vaccine or drug is approved for human use yet. More research needs to be performed on the use of saRNA based vaccines in order to understand comprehensively their safety and efficacy for use on human subjects.

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References:  

  1. Prasad U., 2020. COVID-19 mRNA Vaccine: A Milestone in Science and a Game Changer in Medicine. Scientific European. Published 29 December 2020. Available online at http://scientificeuropean.co.uk/medicine/covid-19-mrna-vaccine-a-milestone-in-science-and-a-game-changer-in-medicine/  
  1. Bloom, K., van den Berg, F. & Arbuthnot, P. Self-amplifying RNA vaccines for infectious diseases. Gene Ther 28, 117–129 (2021). https://doi.org/10.1038/s41434-020-00204-y 
  1. Pourseif MM et al 2022. Self-amplifying mRNA vaccines: Mode of action, design, development and optimization. Drug Discovery Today. Volume 27, Issue 11, November 2022, 103341. DOI: https://doi.org/10.1016/j.drudis.2022.103341  
  1. Blakney AK et al 2021. An Update on Self-Amplifying mRNA Vaccine Development. Vaccines 2021, 9(2), 97; https://doi.org/10.3390/vaccines9020097  
  1. Anna Blakney; The next generation of RNA vaccines: self-amplifying RNA. Biochem (Lond) 13 August 2021; 43 (4): 14–17. doi: https://doi.org/10.1042/bio_2021_142 
  1. McKay, P.F., Hu, K., Blakney, A.K. et al. Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine candidate induces high neutralizing antibody titers in mice. Nat Commun 11, 3523 (2020). https://doi.org/10.1038/s41467-020-17409-9 
  1. Akahata W., et al 2022. Safety and immunogenicity of SARS-CoV-2 self-amplifying RNA vaccine expressing anchored RBD: a randomised, observer-blind, phase 1 study. Preprint medRxiv 2022.11.21.22281000; Posted November 22, 2022. doi: https://doi.org/10.1101/2022.11.21.22281000  
  1. Elliott T, et al. (2022) Enhanced immune responses following heterologous vaccination with self-amplifying RNA and mRNA COVID-19 vaccines. PLoS Pathog 18(10): e1010885. Published: October 4, 2022. DOI: https://doi.org/10.1371/journal.ppat.1010885 
  1. Keikha, R., Hashemi-Shahri, S.M. & Jebali, A. The evaluation of novel oral vaccines based on self-amplifying RNA lipid nanparticles (saRNA LNPs), saRNA transfected Lactobacillus plantarum LNPs, and saRNA transfected Lactobacillus plantarum to neutralize SARS-CoV-2 variants alpha and delta. Sci Rep 11, 21308 (2021). Published: 29 October 2021. https://doi.org/10.1038/s41598-021-00830-5 
  1. CDC 2022. How Influenza (Flu) Vaccines Are Made. Available online at https://www.cdc.gov/flu/prevent/how-fluvaccine-made.htm accessed on 18 December 2022. 
  1. Chang C., et al 2022. Self-amplifying mRNA bicistronic influenza vaccines raise cross-reactive immune responses in mice and prevent infection in ferrets. Molecular Therapy Methods & Clinical Development. Volume 27, 8 December 2022, Pages 195-205. https://doi.org/10.1016/j.omtm.2022.09.013  

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Umesh Prasad
Umesh Prasad
Science journalist | Founder editor, Scientific European magazine

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