Moderna (“ModeRNA”) (a biotech company in Cambridge, Massachusetts) launched the first ever human clinical trial for a SARS-CoV-2 vaccine last week on Monday, March 16, 2020, at Kaiser Permanente Washington Health Research Institute in Seattle. The study is funded by the National Institute for Alergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). That’s an incredibly fast 2-month turnaround from the time that the SARS-CoV-2 genetic sequence was publicly disclosed on January 5, 2020, to having a manufactured vaccine ready for human testing. This rapid development of a potential vaccine is unprecedented.
The key to this rapid pace is that Moderna’s core technology — synthetic mRNA encapsulated into lipid particles — is readily manufacturable and scalable (much more so than growing and purifying individual proteins in huge bioreactors). These mRNA-lipid particles are injected into muscle tissue, and the cytoplasm in muscle cells then become little temporary factories that translate the mRNA into the encoded viral protein, which then triggers the immune system to generate responses against the viral protein so the immune system can recognize and attack actual viruses that have these same proteins when they infect an immunized person. (Two German biotechs called CureVac and BioNTech have developed similar technology and are a few of many companies competing with Moderna to develop a SARS-CoV-2 vaccine.)
A 2017 article in Science by Kelly Servick described Moderna’s core technologies for synthesizing the mRNA (or “hacking” the rules for mRNA) and making the lipid particles such that they efficiently encapsulate and deliver the mRNA to cells. The following is a summary of key takeaways from this article:
By leveraging the cell’s own ribosomes in the cell’s cytoplasm to make protein encoded by the foreign mRNA, this makes it possible to deliver proteins that act inside cells or span across their plasma membranes, which is difficult to do by delivering pre-made proteins from the outside.
A drawback of DNA gene therapy is that it can unpredictably integrate into the genome; this is not the case with mRNA.
RNA invading a cell from the outside is a hallmark of viruses — it’s how SARS-CoV-2 infects cells and reproduces! Our immune system has evolved sophisticated ways to recognize and destroy invading mRNA, but obviously from the devastation that SARS-CoV-2 is causing on the human race, our cells and immune systems haven’t figured everything out yet! Moderna has modified the chemical structure (or shape) of uridine to prevent it from locking into activating immune receptors (adenosine, cytidine, uridine, and guanosine are the 4 predominant nucleosides that makeup RNA). Katalin Kariko and Drew Weissman of University of Pennsylvania figured out in the 2000s that the cell’s inflammatory response to invading mRNA can be tamed by modifying the shape of uridine into pseudouridine, which is a natural variant found in the body. They reported in 2005 that pseudouridine greatly reduced the tendency of sentinel cells called dendritic cell from shooting out inflammatory molecules in response. Moderna figured out new uridine modifications that would dampen the anti-mRNA immune response even further than pseudouridine. They found 1-methylpseudouridine was the best at evading immune detection and was stable enough to make a therapeutic. (Kariko now leads a research team at BioNTech in Germany.)
Moderna has figured out how the folding of the mRNA impacts the efficiency of ribosomes to read the mRNA and make protein (from research by Melissa Moore at the University of Massachusetts Medical School in Worcester — she’s now CSO of Moderna’s research platform). Moore discovered that mRNA strands that have more nucleosides that tightly stick together and form tighter secondary structures are more readily translated into protein by ribosomes.
Moderna has attached non-coding mRNA sequences outside of the protein coding sequence that allow mRNA translation to occur only in the specific cell subtypes that are relevant for creating a vaccine response or treating a certain disease. In other words, translation of the delivered mRNA will not occur in cells/tissues that it doesn’t belong.
Moderna has engineered lipids to make them more biodegradable and safe when administered to the body. They are also working with nonlipid formulations — polymers — which are known to have low immunogenicity.
