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Aliahmad, P., Miyake-Stoner, S.J., Geall, A.J. et al. Next generation self-replicating RNA vectors for vaccines and immunotherapies. Cancer Gene Ther (2022). https://doi.org/10.1038/s41417-022-00435-8
Currently, vaccines use mRNA (messenger ribonucleic acid, a copy made of DNA that can be transported out of the nucleus) to transport sequences that can replicate the action of viruses. Viruses work by attaching to the receptors on the exterior of a cell and injecting their own DNA/RNA material into it, which interferes with the original DNA of the cell and makes it such that the cell starts manufacturing proteins according to the sequences of the viral DNA instead of its own. mRNA vaccines replicate this process by creating mRNA sequences that correspond to a viral protein to simulate the action of the virus and help the body develop an immunity to it by prompting the manufacturing of the corresponding antibodies.
RNA technology has developed in recent years, with the invention of srRNA (self-replicating RNA) vaccines. srRNA is RNA derived from a group of viruses whose genomes consist of single-stranded, positive sense RNA, instead of double-stranded, negatively charged DNA. This RNA is modified to remove genes that code for structural proteins and replace them with different genes of interest (like the aforementioned viral genes). Another therapeutic version of srRNA technology is VRPs (single-cycle viral replicon particles). More recently, a fully synthetic version of the technology called LNP(lipid nanoparticle)-formulated synthetic srRNA has been developed, where the structural proteins are replaced with a protective coat.
These technologies can be tested through a process known as translation, where the sequences in the genes are read and corresponding proteins are manufactured. Clinical translation of LNP-formulated synthetic srRNA showed safety and immunogenicity (the ability to elicit an immune response). Synthetic srRNAs have demonstrated many advantages over previously used mRNA technology (aka mRNA vectors). Firstly, it is much safer as the chances of the RNA being injected integrating into the patient’s genome and of it causing grave homeostatic imbalances are greatly reduced. Secondly, the manufacturing process is easier and hence, more cost-effective. It is also more cost-effective for the consumer as it has a lower efficacious dose, i.e., due to its ability to replicate within the cell, a lower dose is needed for the same effect (in comparison to mRNA vectors). Thirdly, synthetic srRNAs lack a viral shell as the structural proteins have been swapped out, making it much harder for them to elicit an anti-vector immune response, which allows repeated dosing. Viral shells are also constricting, and hence, synthetic srRNAs have more space to encode larger genes of interest. Lastly, srRNA-based vaccines have also shown the ability to help the cell build a better immunity when compared to the effects of traditional mRNA vaccines.
Unfortunately, however, the development of srRNA vaccines has had its challenges. Whilst the conducted clinical studies have not revealed an inherent toxicity in the biology of the virally derived RNA in any forms, impurities caused by poor manufacturing have led to inflammatory responses in patients. Additionally, our understanding of srRNA technology is still very limited. So far, the only virus that we have used to extract srRNA has been the Venezuelan equine encephalitis virus (VEEV). VRP vaccines/biotherapeutics have been more diverse with trials including three types of viruses. Viral candidates for both technologies need to be explored, as it is known that different viruses demonstrate different therapeutic applications; hence, finding more candidates would broaden the number of illnesses that can be treated with these technologies. For example, some viral vectors will be better suited to a pro-inflammatory response, whereas others would be better for the non-inflammatory expression of biotherapeutic proteins. Different formulations and changes in the type of srRNA technology used can also alter their use and action. For instance, it was found that LNP formulations are proinflammatory and advantaged for use in vaccines, where additional inflammation is beneficial to elicit immune responses.
Recent scientific developments have highlighted the promise of fully synthesised srRNA products in oncology and infectious disease, but also the numerous aspects that complicate their synthesis. Exploiting the diversity of vectors found in nature, combining with formulations fitting the purpose of each product, and avoiding a one-size-fits-all approach are all critical components in the successful creation of future srRNA products. Optimal drug product design will necessitate treating the biotherapeutic protein or antigen, vector, and delivery combination as independent factors that must be determined empirically. We can collaboratively accelerate the time to market for srRNA-based goods and deliver on srRNAs promise by adopting this deliberate strategy.
Works Cited
Aliahmad, Parinaz, et al. “Next Generation Self-Replicating RNA Vectors for Vaccines and Immunotherapies.” Cancer Gene Therapy, 22 Feb. 2022, 10.1038/s41417-022-00435-8. Accessed 10 June 2022.
“What Are MRNA Vaccines and How Do They Work?: MedlinePlus Genetics.” Medlineplus.gov, medlineplus.gov/genetics/understanding/therapy/mrnavaccines/#:~:text=mRNA%20vaccines%20work%20by%20introducing.
Summarised by Radhika Jain
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