What's All The Hype About mRNA Vaccinology?

The realization of medicines based on mRNA technology is a relatively recent breakthrough, with several products under trial. Moreover, the COVID-19 vaccine success is spurring a further stream of medicines to come. An mRNA-based medicine is a different concept; it does not fall into small molecule-based pharmaceuticals or within conventional biologics (recombinant proteins and monoclonal antibodies) but rather falls within the emergent field of nucleic acid therapeutics.¹ mRNA medicines function like sets of instructions directed at human cells to make proteins to prevent or fight disease.

The application of mRNA technology came to the fore with the launch of the Pfizer/BioNTech and Moderna vaccines, designed to combat the SARS-CoV-2 virus responsible for COVID-19.² Until this point, vaccines were either inactivated viruses designed to trigger the immune system, which is the case with most influenza vaccines, or vaccines comprising individual proteins.

mRNA: An Overview

Genes are sections of the deoxyribonucleic acid (DNA) that code for the biosynthesis of a specific protein sequence in a cell. Generally, genes encode a functional polypeptide chain or ribonucleic acid (RNA) molecule. This requires the activity of transfer ribonucleic acid (tRNA), ribosomal ribonucleic acid (rRNA), and messenger ribonucleic acid (mRNA) to direct protein synthesis in a cell. A gene is said to be expressed in a cell when it is transcribed (i.e., copied) into mRNA and then translated into proteins. Gene expression is controlled in vivo at several levels by some transcriptional and translational factors. The control of gene expression in the cell is critical because it ensures that the correct type of protein molecule is synthesized at the correct time and in the right cell.³

With these factors, during transcription, the RNA polymerase reads from the DNA strand (by reading the RNA polymerase builds a new RNA molecule). This is complementary to the RNA molecule and it is used to construct the complementary mRNA required for gene expression in the cell. Translation is the process by which the cellular machinery reads the genetic code encoded by the mRNA and then creates a polypeptide chain required for protein synthesis in the ribosome. It is the phase of protein synthesis where information in the mRNA is used to guide the sequence of amino acids or polypeptide chain assembled by the ribosomes.

With the research into mRNA vaccines to combat pathogens, the mRNA coding is created within a laboratory and then delivered in vivo to human cells with the aim of creating antibodies.

mRNA Vaccines

mRNA vaccines are highly specific and are designed to trigger an immune response against an aspect of the target pathogen. In the case of SARS-CoV-2, the target is the virus’ spike protein, the component of the viral membrane that enables the virus to invade human cells. The mRNA instructs some human cells to manufacture spike proteins. The presence of these spike proteins then triggers the body’s immune cells to assemble antibodies capable of recognizing them and thereby combat the invasive virus.⁴ Effectiveness is measured by high SARS-CoV-2 neutralizing antibody titers and assessed through clinical trials.⁵

The mRNA medicine development process is associated with advancing different techniques, such as transcriptomics analysis. Transcriptomics is the measurement of the expression levels of the mRNA of the cell, monitoring the relative level of transcriptome (the total set of mRNA produced in an organism) in the cell. Identification is achieved by using high-throughput equipment like a DNA microarray, a hybridization method. Another area in development is improving carrier molecules to increase the rapid uptake of the mRNA by cell cytoplasm.⁶

Clinical data compiled to date indicates that the mRNA vaccines developed pose no additional safety risk to the patient. For example, the risk of genetic change is not a factor because mRNA does not enter the nucleus of human cells (that is, DNA). However, as a novel medicine, any longer-term effects cannot be assessed at this time. With future developments, patient safety will continue to be the most important factor, and the primary risk to be monitored is ensuring that the vaccine does not trigger an unwanted immune response in the patient. Side effects are also a consideration, although the prospect of side effects exists with any medication. For mRNA vaccines, an inflammatory response will occur at the site of injection and the effects range from muscle stiffness to a short period of fever.

Future Developments

The legacy of the COVID-19 vaccine success, in line with other vaccines in development, is a blueprint for addressing future pandemics. The technology can be deployed very rapidly, placing mRNA platforms at the center of responses to new pathogens as they emerge. This is because mRNA vaccines are based on sequences of viral proteins, which means making a new vaccine may only involve changing the mRNA sequence, provided virologists understand what proteins they want to make.

A limitation to expanding application of mRNA vaccines is related to the vaccines not being very stable at high temperatures, which places pressures on the supply chain and reduces the ability to distribute the vaccines to remote communities. Additionally, there are the general complexities of scale-up, meeting cGMP, and securing regulatory approval.

The success of the two COVID-19 mRNA vaccines presents a gateway to other vaccines based on the same technology. Over 40 clinical trials are in progress, with some dating back over a decade (relating to cancer treatments based on precision medicine where the heterogeneity of tumors slows down progress). In terms of infectious diseases, mRNA vaccines are being researched to act against viruses and viral diseases like influenza, cytomegalovirus, dengue fever, Zika, and rabies as well as against malaria parasites.  

References

1. Suschak, J., Williams, J. and Schmaljohn, C. Advancements in DNA vaccine vectors, non-mechanical delivery methods, and molecular adjuvants to increase immunogenicity. Hum. Vaccin. Immunother. 13, 2837–2848 (2017).
2. Jain S, Venkataraman A, Wechsler ME, Peppas NA. Messenger RNA-based vaccines: Past, present, and future directions in the context of the COVID-19 pandemic. Adv Drug Deliv Rev. 2021, 179:114000. doi: 10.1016/j.addr.2021.114000
3. Weissman, D. mRNA transcript therapy. Expert Rev. Vaccines 14, 265–281 (2015)
4. Verbeke R, Lentacker I, De Smedt SC, Dewitte H. The dawn of mRNA vaccines: The COVID-19 case. J Control Release. 2021;333:511-520. doi: 10.1016/j.jconrel.2021.03.043
5. Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020;367:1260-1263
6. Guan, S. & Rosenecker, J. Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems. Gene Ther. 24, 133–143 (2017).

About The Author:

Tim Sandle, Ph.D., is a pharmaceutical professional with wide experience in microbiology and quality assurance. He is the author of more than 30 books relating to pharmaceuticals, healthcare, and life sciences, as well as over 170 peer-reviewed papers and some 500 technical articles. Sandle has presented at over 200 events and he currently works at Bio Products Laboratory Ltd. (BPL), and he is a visiting professor at the University of Manchester and University College London, as well as a consultant to the pharmaceutical industry. Visit his microbiology website at https://www.pharmamicroresources.com.