How do mRNA vaccines work?
AHMAD NISAR – The development of vaccines has had stunning effects on epidemiology, medicine and wider human history. Vaccines utilize the immune system’s robust memory by exposing native lymphocytes to degraded forms of a given viral strain. This enacts selective proliferation of antagonistic antibodies in response, and therefore the acquisition of immunity to viral diseases at little risk to the individual. In the span of a century, pervasive diseases ranging from polio to smallpox have been de facto eliminated, not only in developed nations, but among the entire global human population. With the advent of COVID-19, however, vaccine technology has been enhanced by an exciting innovation. For the first time in history, various nations approved the manufacture and distribution of mRNA vaccines by the companies BioNTech/Pfizer and Moderna to resolve the COVID-19 pandemic. What mechanisms guide mRNA vaccines in ‘training’ the body’s immune system to resist viral infection, how do they differ from traditional vaccines and what advantages and disadvantages do they offer in comparison?
Every student of the life sciences has internalized the ‘central dogma’: biological information is encoded in DNA, transcribed into mRNA and finally translated into protein. This flow of information is the structural basis underlying each and every organism, from viral particles to complex mammals like ourselves. Traditional vaccines require large-scale, artificial production of whole viral capsules or specific surface proteins through cloning of recombinant bacteria expressing the complementary viral genomes, and subsequent harvesting these products to create vaccine-introduced antigens. Though this process may sound simple, it requires laborious cultivation of large amounts of bacteria, a luxury that cannot be afforded in the case of highly infectious diseases like SARS-CoV-2. mRNA vaccines bypass this time-consuming process entirely by retreating to the second step in the central dogma. Instead of artificially manufacturing antigen proteins, only mRNA is produced — and our own cells do the rest of the work.
Firstly, a viral genome is scanned for a gene of interest, i.e. a sequence encoding a protein that can reliably be used as a representative antigen by which to train lymphocytes to respond to subsequent viral infections. When an adequate sequence is found, this viral DNA is isolated and used as a template to synthesize mRNA via specialized RNA polymerases. The resulting mRNA, like naturally-synthesized nucleic acids of this type, has a 5’ 7-methylguanylate cap, an open-reading frame encoding the protein (flanked by untranslatable sequences) and a 3’ polyadenylated tail, all of which ensure enough stability of the mRNA molecule to reach human cells intact. However, mRNA is still too fragile to be injected into the body without additional protection. To provide this extra protection, a ground-breaking innovation in the form of lipid nanoparticles (LNP) has been adapted to vaccine delivery and other pharmaceutical formulations. LNP transfection has been used to augment the delivery of ‘naked’ nucleic acids into in vitro cell environments (such as through electroporation). These devices are composed of a singular sheath of a phospholipid bilayer (also called a micelle) around a spheroid embedded with mRNA or drugs of choice. These hydrophobic spheroids can easily fuse with the phospholipid bilayer that formulate cell membranes, allowing mRNA to be efficiently and selectively released into the interior cytoplasm of human cells. Once the naked mRNA has been unloaded from lipid nanoparticles into the cytoplasm, the nucleic acids are translated into antigenic protein by cytosolic ribosomes (sites of mRNA translation into protein), just as the cell’s endogenous mRNA are translated. Thus, antigens can be endogenously produced by the body’s own cellular machinery without the interjection of artificial proteins intensively cultivated in foreign settings (as is the case with traditional vaccines).
In the case of the SARS-CoV-2 vaccine, introduced mRNA encodes for the ‘spike protein’, a transmembrane (cell surface) marker that is specific to COVID-19 and can be reliably recognized by the body’s immune defenses. As the endogenous production of this foreign antigen increases, lymphocytes are trained to recognize and bind to this protein. If actual infection of COVID-19 occurs later on, immune cells will recognize the spike protein on viruses and can proceed to agglutinate and liquidate the intrusive viroids. This vaccine has not only shown the ingenuity of researchers and healthcare workers under the stress of a global pandemic, but has also revealed the increasing power of emerging technologies like genetic engineering to advance and transform medicine in the modern world.
Sources:
https://www.nejm.org/doi/full/10.1056/NEJMoa2034577
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906799/
Copy Editor: Sophia Bartell
Photography Source: Shweta Mistry, https://www.pri.org/stories/2020-11-18/how-mrna-vaccines-work-so-brilliantly-and-why-they-must-be-kept-so-cold