What is an mRNA Vaccine?

Now that we understand the basics of innate and adaptive immunity, we can begin to understand how vaccines work. At a high level, the goal of a vaccine is to prime the adaptive immune system so that it is prepared to fight a particular virus without having to survive a real infection by the virus first. Conventional vaccines take several forms, including:

  • Inactivated (“killed”) vaccines can be produced by denaturing viruses in a lab (eg, the Salk polio vaccine or certain flu vaccines)

  • Attenuated vaccines use weakened but live forms of viruses, either produced in a lab by modifying the virus or derived from a related-but-not-pathogenic strain of virus (eg,  the Sabin polio vaccine or the cowpox-based vaccine for smallpox)

These types of vaccines have played an important role in protecting humans from viral disease, but not all viruses can be inactivated or attenuated effectively. Modern vaccinology has therefore started looking to new means of creating vaccines like subunit vaccines, in which viral proteins can be used to stimulate an appropriate immune response without ever introducing the whole virus into the host.  

One novel vaccination strategy has gained a lot of attention in the age of COVID-19: mRNA vaccines. mRNA vaccines for SARS-CoV-2 are being developed by Moderna Therapeutics, among others, and they are now progressing through clinical trials. Without commenting on Moderna’s specific implementation of an mRNA vaccine, let’s learn more about how mRNA vaccines work in general.

You may recall that eukaryotic cells have DNA in their nucleus, and that DNA gets transcribed into RNA, which in turn gets translated into proteins. This is the process that viruses hijack to replicate themselves; an RNA virus gets translated by the same cellular machinery that translates standard cellular RNA. 

Recap: the "central dogma" of biology says that DNA makes RNA makes proteins.

RNA vaccines leverage the same principle: if we can get RNA into host cells, we can leverage the cellular machinery to make whatever proteins we want. Now, what should we make if we want to make vaccines? You might think that we should try to make host proteins that fight viruses, but the host immune response is so complex that such an approach would be less effective than administering immune signaling proteins directly. Thinking back to how conventional viruses work, you might instead think that we should make a form of the virus, so that the host can “see” it without needing to be actually infected. This might work, but it would of course be very risky to intentionally infect people with whole viral RNA sequences, as these could easily form whole viruses in the host. But-- what if we instead encoded just the viral fragments that get recognized by MHC complexes and the adaptive immune system? Then we could cause an immune response, along with the immunity-providing expansion of T cells and B cells that respond to the viral proteins we’ve encoded, with little chance that the small viral segments we’ve encoded could replicate or cause damage. Et voila-- an mRNA vaccine with lots of potential and minimal infection risk.

(An aside: what is the “m” in mRNA for? It stands for “messenger RNA.” When RNA is transcribed from the genome, it often has extra sections that aren’t necessary for making proteins. These sections are cleaved out, and only the protein-coding portions of the RNA are then released from the nucleus for translation. These shortened and modified RNAs that are ready for translation are called mRNA. To call a vaccine an mRNA vaccine, then, means that it has pre-prepped the sections of RNA that we want to turn into proteins, rather than strictly including all RNA that would be transcribed from the genomic DNA.)

Challenges and innovations

This seems like a brilliant strategy, but why don’t we already have mRNA vaccines for all viruses? It turns out that actually developing an mRNA vaccine has a number of different challenges. Just to name a few:

  1. Not any mRNA sequence will do. The sequence used must encode protein subunits that are pathogenic enough to stimulate an immune response. Many protein subunits from a given virus are not themselves pathogenic, and many more are pathogenic only for certain individuals with certain genetic backgrounds.

  2. Naked RNA molecules can get tangled up and become double-stranded, which makes them untranslatable by cells and can also stimulate innate immune responses that complicate the effect of the vaccine.

  3. RNA usually starts in the nucleus and moves into the cytoplasm of a cell. In the case of an RNA vaccines, we need a way to take RNA from the lab and get it not just into humans, but into cell cytoplasms. This is made especially difficult by the fact that RNA outside of cells is quickly degraded, so the RNA has to be packaged in such a way that preserves the payload and gets it into cells.

Many technological innovations in recent years have therefore been crucial in moving RNA vaccines from a great but impractical theory to the fastest moving vaccine candidate for SARS-CoV-2. Considering just the three challenges mentioned above:

  1. The ability to quickly sequence viruses and to use both bioinformatic and laboratory methods to analyze the viral genome, identify protein subunits, and test immune responses to those subunits is critical to correctly designing the mRNA sequences that will be used in vaccines.

  2. mRNA vaccine candidates can take advantage of many innovations developed in the last few decades that increase RNA stability and increase translation efficiency in cells. For example: scientists can replace individual nucleotides in the target sequence to create versions of the sequence that still encode the same exact protein subunit but are easier for the cell to translate; RNA produced in cell culture can be purified to remove double-stranded sequences that might cause an unintentional immune response; and the length and nature of the starts and ends of the RNA can be modified to increase its stability.

  3. In order to deliver RNA sequences to the cytoplasm of cells, scientists have devised a number of delivery methods. One approach requires cells from the host; dendritic cells, which are innate immune cells that are especially good at presenting pathogen fragments to adaptive immune cells in the body, are extracted and loaded with target RNA in cell culture, and then infused back into the host. Another popular delivery method, and the one used by Moderna, is to encase the RNA sequences using lipids and polymers. As with live viruses, lipid packaging allows the RNA to pass cellular lipid membranes and enter the cytoplasm, though the actual mechanism by which the lipid particles dump the RNA sequences into cells is incompletely understood.

RNA vaccines can be delivered in lipid particles that help the RNA gain cell entry.

So to recap, RNA-based approaches offer a whole new set of possibilities in vaccine design-- if we can get them to work in practice. There have been a number of clinical trials demonstrating positive results, though those have been primarily focused on cancer treatment rather than infectious disease. The current rush to make an RNA-based vaccine for SARS-CoV-2 has the potential to really accelerate the field, though we are still in the early days of exploration in this space.



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