By Marina Artemiou
Vaccines are biological substances that provide a simple, safe and effective way of protecting humans against harmful pathogens and the disorders that are caused upon infection. Vaccinations are considered to be one of the major achievements of modern medicine; since their discovery, the incidence of highly contagious and deadly diseases, such as polio and measles, has decreased drastically and the eradication of others, such as smallpox, has been achieved. Conventional vaccines commonly consist of either attenuated strains, inactivated strains or antigens of the pathogen that individuals seek immunisation against. Despite the success of conventional vaccines in the past, the recent Coronavirus pandemic has brought to light some major drawbacks regarding their use and method of development (PHG Foundation, 2020). These include challenges with efficacy, safety, cost and speed of development. Currently, companies such as Moderna as well as Imperial College London aim to challenge the use of conventional vaccines by developing novel mRNA vaccines against SARS-CoV-2, which are more efficient, safer, faster and cheaper to mass produce and distribute to the public.
At this time, there are three different types of novel mRNA vaccines being developed by various pharmaceutical companies and universities globally. These include: Non-replicating mRNA, in vivo self-replicating mRNA and in vitro dendritic cell non-replicating mRNA vaccines (PHG Foundation. 2020).
Non-replicating mRNA vaccines are the simplest types of mRNA vaccine. Such vaccines consist of modified mRNA strands which code for viral or bacterial antigens. Often, to prevent degradation of naked mRNA in extracellular fluid, the RNA strand is incorporated into a larger molecule to form a more stable complex and/or is packaged within liposomes, i.e. DC-cholesterol liposomes. These liposomes are utilised to form unilamellar vesicles that can complex with DNA, DNA/protein complexes or mRNA and mediate their delivery into cells via endocytosis. Once inside the cells, the translation apparatus of infected host cells is used to produce a polypeptide with a chemical structure similar to the surface antigens on virions or bacteria. The modified polypeptides are then secreted from the host cells into the bloodstream where activated dendritic cells elicit an immune response from white blood cells, producing antibodies and memory cells that provide long lasting immunity (Hubaud A., 2015).
In vivo self-replicating RNA vaccines provide an identical immune response with non-replicating mRNA vaccines, however, there are some fundamental differences in their composition (PHG Foundation, 2020). In vivo self-replicating RNA is derived from the genome of an alphavirus where genes encoding for viral RNA replication machinery (replicase protein complex) remain intact but those coding for viral structural proteins are replaced with genes coding for the antigen of interest. There are multiple ways in which the delivery of self-amplifying mRNA can be achieved. The most common methods include transfecting cells with DNA plasmid-based self-amplifying RNA or using virus-like particles to deliver self-amplifying RNA. Plasmid DNA carries replicase genes and the transgene into the nucleus where it is transcribed to generate replicon RNA. Replicon RNA is transported to the cytoplasm where RNA self-amplification ensues followed by mRNA production and translation of the vaccine antigen. Virus-like RNA particles are used to deliver replicon RNA directly into the cytoplasm via endocytosis and the process that ensues is the same as mentioned above. The final result is the elicitation of an immune response against the foreign antigens which produces a reservoir of antibodies and memory cells in the bloodstream to provide long lasting immunity (Fuller et al., 2020).
Finally, in vitro dendritic cell non-replicating mRNA vaccines are also being developed and put through safety evaluations and clinical trials. Dendritic cells are phagocytotic cells which can present fragments of antigens on their surface to stimulate T cell activation and initiate the adaptive immune response (PHG Foundation, 2020). This method of vaccination involves extracting and isolating dendritic cells from a patient’s blood and transfecting them with mRNA which codes for the antigens of interest. Subsequently, the mRNA will be translated into the antigen and complexed with major histocompatibility complexes (MHC class I and class II) on the surface of dendritic cells. Once dendritic cells become mature APCs, they travel to lymph nodes where activation of T helper and cytotoxic T cells follows, triggering the adaptive immune response and the production of antibodies as well as memory cells (McCullough et al., 2015).
The benefits of mRNA vaccines over the conventional approach are multiple and include advantages with safety, efficacy and method and speed of production. mRNA vaccines are considerably safer than their conventional counterparts as they do not contain pathogen particles (attenuated or inactivated) which could potentially revert back to their wild-type version. The RNA strand is degraded following translation and does not integrate itself into the host genome. Moreover, early clinical trials indicate that mRNA vaccines can generate an immune response similar to that generated by conventional vaccines, are well tolerated by healthy participants and show very few side effects. Finally, mRNA vaccines can be produced in laboratories in a process that can be standardised and scaled up to shorten reaction time to emerging. This standardised process reduces production cost, lessening the price of each vaccine and making them ever more accessible to poorer population and less developed countries (PHG Foundation, 2020).
Taking into consideration all the benefits that come from developing and using mRNA vaccines over their conventional counterparts, it is safe to say that they may be the future of vaccination and the prevention of long-lasting global pandemics such as the one we are facing now.
McCullough K., Milona P., Demoulins T., Englezou P., Ruggli N. (2015) Journal of Blood and Lymph. Dendritic Cell Targets for Self-Replicating RNA Vaccines. 5(1). Available from: DOI: 10.4172/2165-7831.1000132.
PHG Foundation – University of Cambridge. (2020) RNA vaccines: an introduction. Available from: https://www.phgfoundation.org/briefing/rna-vaccines. [Accessed on 25th September]
Fuller D., Berglund P. (2020) The New England Journal of Medicine. Amplifying RNA Vaccine Development. 382:2469-2471. Available from: DOI: 10.1056/NEJMcibr2009737
Hubaud A – Harvard University. (2015) RNA vaccines: a novel technology to prevent and treat disease. Available from: http://sitn.hms.harvard.edu/flash/2015/rna-vaccines-a-novel-technology-to-prevent-and-treat-disease/ [Accessed on 25th September]