The coronavirus pandemic could launch us into a new era of vaccines.
The first US coronavirus vaccine trial is an mRNA vaccine. What’s that?
The race is on for a vaccine to SARS-CoV-2, the virus that causes COVID-19. Many groups are taking different approaches to find a vaccine and find one quick. However, there is one vaccine platform that holds the potential to change our whole approach to vaccination, and it just happens to be the first vaccine that went into trials (outside of China). This promising approach to vaccine is built on an mRNA platform. I thought it would be good to take this opportunity to talk about how vaccines work, the new mRNA vaccine platform and how the mRNA vaccine could completely change how we approach vaccination.
How do vaccines work?
Vaccination is something like giving a search dog an article of clothing from a wanted person for the dog to pick up his scent without needing to sniff the person first. In this analogy, the dog is our immune system and the article of clothing is the vaccine. For simplicity’s sake, we will describe the immune system and vaccination in the context of a virus[1]; however, the same process is used to recognize other foreign antigens such as bacteria and allergens.
Two major types of immune cells — B cells and T cells — play a critical role during infection and immunity. B cells produce a Y-shaped protein called an antibody that recognizes and binds to a virus to neutralize and destroy them through different mechanisms. T cells come in a few different varieties that play roles in killing infected cells, producing proteins that kill the virus (“cytokines”), and signaling other immune cells (including B cells) to mount an immune response to an infection. Millions of B cells and T cells circulate in our bloodstream on constant lookout for viruses.
Each B cell produces a specific antibody that has a particular shape that can recognize proteins on the outside of viral membranes that fit into the top of the “Y”. When an antibody recognizes an “antigen” (such as a virus or part of a virus that a cell has digested and “presented” on its membrane), the immune system gets a signal to copy (“clone”) the specific B cell that produced the antibody that recognized the virus, thus allowing the body to produce millions of antibodies specific to the invader to neutralize and destroy it. This is called “clonal expansion”.
T cells also have recognition proteins to search for foreign antigens and undergo similar processes of clonal expansion when they are presented with a virus by other immune cells (i.e., anther immune cell “eats” a virus, chops it up, and presents parts of the chopped up virus on its outer membrane for T cells to recognize).[2]
This defense mechanism is very effective, but it is not very fast. We start with millions of different antibodies in an effort to be prepared to recognize any unknown pathogen, but this means we must start with very few of each different B and T cell. Once a B or T cell recognizes a specific virus, it usually takes 5–7 days for our bodies to clone the B cells to get the amount necessary to produce enough antibodies to fight the infection, and the antibodies typically don’t peak until day 14.[3] This is where immunity comes in. Once you have been infected with a specific virus, triggering the process of B cell clonal expansion, a subsection of these B cells turns into “memory B cells”.[4] (A subset of T cells also become “memory T cells”, see notes 1–4). These memory B cells can live for decades or more[5] and stay in our bloodstream on high alert for their specific pathogen that has already infected you, on high alert for that pathogen. When the pathogen enters the body a second time, memory B cells are ready to rapidly copy themselves and take care of the invader very quickly, often before it can establish a second infection. When we have memory B cells primed to a specific pathogen, we say we are “immune” to that pathogen.
So how does a vaccine work? When we vaccinate ourselves against a pathogen, we are in effect giving our search dog (the immune system) the scent of a specific item we want to locate (the pathogen). Most viral vaccinations use a weakened or inactivated virus that cannot produce an actual infection but nevertheless trigger the immune response. As described above, when the inactivated virus enters our body, certain B cells recognize the foreign invader, produce antibodies against the virus and a subset of memory B cells are produced that recognize the specific virus that was in the vaccination. So, we can get the outcome of a natural infection (memory B cells) without having to actually get sick. Pretty neat.
The mRNA vaccine platform
So, what is mRNA, what does it have to do with vaccination, and why is it a big deal? Great questions! You might be familiar with DNA, the genetic material inside our cells that holds the information, or “blueprint”, to make the proteins[6] that cells need to function. There is an intermediate step between reading the DNA code and making a protein, however. DNA is first transcribed into another molecule that contains genetic material call messenger RNA (mRNA).[7] Our cells then “read” the mRNA and build proteins from those instructions (see figure below). Many viruses, including influenza and coronaviruses, are RNA viruses, meaning the genetic material they contain is only RNA. When an RNA virus infects a cell, it hijacks the cell’s protein-building machinery to start making its own proteins that the virus needs to survive and make copies of itself. In the case of some RNA viruses, such as coronaviruses, the RNA that the virus has can effectively function as mRNA as soon as it infects the cell, immediately ready to make proteins.[8]
In the traditional vaccine model, we present our bodies with a weakened or inactivated virus so that the immune system can recognize it and make antibodies and cytokines to the proteins that are present on the outside of the virus membrane. This platform of vaccination requires the whole virus and simulates a natural infection. But what if we could just present our bodies with the specific proteins that we need to make anti-viral agents against? That’s the goal of an mRNA vaccine. If we know the genetic sequence that codes for an important outer membrane protein of a virus, then we can design a vaccine that only has the mRNA that codes for that protein, eliminating the need to use the whole virus.
Perhaps an example will clarify. In the case of the coronavirus, there is an outer membrane protein called the “spike” protein[9] that the virus uses to infect our cells. An mRNA vaccine would introduce the ‘code’ for this spike protein in our cells, which would allow the cell to produce the viral protein and then “present” it to B and T cells (see figure above). This, in turn, would trigger an immune response and begin the process of developing immunity to the specific virus. It’s the same concept as traditional vaccination; however, it skips the need for the actual virus to induce immunity.
Potential benefits and limitations
mRNA vaccines have the potential to be a game-changer for several reasons[10]:
1. Safety: There is no chance of infection from an mRNA vaccine; you can’t build a virus from only one or two of its proteins. There is also no chance of the RNA incorporating into the genome of the cell, which is a concern for similar DNA vaccines. Further, mRNA is a relatively unstable compound[11], meaning that it will break down over a short period of time inside the cell. This is good news for vaccination, as it naturally degrades and is no longer present in our cells, thus reducing safety concerns even further.
2. Rapid response: mRNA can be made very quickly and easily. Once the genetic sequence that codes for the protein of interest is known, the mRNA for the vaccine can be made in a matter of weeks. In theory, an mRNA vaccine could be developed, produced and ready for distribution just a few months after the virus is sequenced. Of course, that’s assuming that the infrastructure and clinical trials for mRNA vaccines have been established. In theory, the mRNA platform can be validated through clinical trials to ensure its safety and efficacy, and then we can use that as the baseline to quickly produce vaccines for emerging strains of virus, much like we do for influenza.[12]
3. Multiple vaccinations in one: The mRNA platform has the ability to fit the instructions for several proteins in a single vaccination. This means we could combine different strains of a given virus, or even different viruses, in a single vaccine regimen. Traditional vaccines also have this capability to a limited extent, but the mRNA platform holds the potential to expand this capability and give much more flexibility in choosing which proteins we want to be produced.
4. Generalizability: One we validate the mRNA platform, the mRNA could easily be modified to produce proteins of whatever virus we need it to produce, as long as we know the sequence and the important outer membrane proteins that the immune system can recognize.
5. Cost efficiency: Traditional vaccines require large, highly-specialized and expensive facilities to grow huge amounts of virus to use in the vaccines. In the case of influenza, this often requires facilities that can incubate a large inventory of chicken eggs. mRNA vaccines, on the other hand, do not require cell culture[13] for production. This means that mRNA vaccines can be made at much less cost than traditional vaccines.
Okay, that sounds great. So what’s the catch? That’s basically the question I had when I first heard a talk about mRNA vaccines. And with anything in science, there are always hurdles/unknowns to overcome. As I mentioned earlier, mRNA is not very stable. Whereas this is good from a safety perspective, it could be problematic from a technical point of view. If the mRNA breaks down before you get it into the cell, then it does no good. There could also be issues with long term storage of mRNA vaccines, and for use in places with limited refrigeration. There is also the question of how to efficiently get the mRNA into the cell so it can produce the protein. However, many advances in stability (both for the vaccine and for storage) and delivery have been made recently, making mRNA vaccines much more plausible and promising (see note 10).
Perhaps the biggest hurdle right now, however, is that we have only recently begun clinical trials of mRNA vaccines for diseases such as influenza[14], and clinical trials are the gold standard of showing whether or not a new vaccine is effective. In theory, it’s great, and it has even shown promise in pre-clinical trials. But the proof is in the pudding, or so they say. We will have to wait for the clinical trials to determine their usefulness in humans.
An optimistic outlook for the future of vaccines
So, how might the pandemic launch us into this new era of vaccines? As you can imagine, there is an unprecedented race to find a vaccine for the novel coronavirus. As I mentioned above, the first vaccine clinical trial for SARS-CoV-2 to begin (outside of China) is an mRNA vaccine developed by scientists at the National Institute of Allergy and Infectious Diseases (NIAID) in conjunction with the company Moderna.[15],[16] Whereas other mRNA vaccine clinical trials have begun, the publicity of the coronavirus and the strong push to find a vaccine will ensure that the mRNA platform will be tested rapidly, getting results sooner than even those that already are in trials.
This could be good or bad. If the vaccine does well, then it will, in theory, speed up the timeline for mRNA vaccines and propel us into a new era of vaccines.[17] However, the rush to find a vaccine and push things through could also have adverse effects on the trials themselves, causing the vaccine to perform poorly (or be analyzed poorly), which will set the field back.
But I’m an optimist, and I think this is a great opportunity to really test the potential of mRNA vaccines. Who knows- they could change the world. And right now, we all could use a little hope.
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References
A special thanks to Haley Jordan and Monica Moran for reviewing this post for glaring scientific errors. Any that remain are my own.
[1] Note also that this is a very simplified account, as the field of immunology is very large and complex. For example, whereas I will discuss mainly the B cell side of immunity here, T cells and other immune cells play vital roles in immunity in conjunction with B cells, even helping the B cells themselves. For a much more in depth review of the immune response, see https://www.sciencedirect.com/science/article/pii/S0091674909028371?via%3Dihub.
[2] Whereas I have focused on the B cell (humoral) side of immunity here, T cells are vital to the immune response and vaccination. See https://www.ncbi.nlm.nih.gov/pubmed/24795718.
[3] Kindt, T. J., Goldsby, R. A., Osborne, B. A., & Kuby, J. (2007). Kuby immunology. Macmillan. pp. 16–18.
[4] B cells are not the only cells that preform memory functions, a subset of T cells also turn into memory T cells. https://en.wikipedia.org/wiki/Memory_T_cell.
[5] See articles such as https://www.nature.com/articles/leu2016226, https://www.jimmunol.org/content/171/10/4969, and https://www.nature.com/articles/nature07231.
[6] It should be noted that DNA codes for more than just proteins. For more information, see the Wikipedia for DNA and Non-coding DNA.
[7] This is called “transcription” and “translation” of the DNA to mRNA to protein. See https://www.nature.com/scitable/topicpage/translation-dna-to-mrna-to-protein-393/ for a good overview with graphics.
[8] For more information, see https://courses.lumenlearning.com/boundless-microbiology/chapter/positive-strand-rna-viruses-in-animals/
[9] For more information, see https://www.livescience.com/coronavirus-spike-protein-structure.html
[10] For more information, see these articles: https://www.nature.com/articles/nrd.2017.243, https://www.nature.com/articles/s41577-019-0243-3, https://www.mdpi.com/2076-393X/6/2/20
[11] As compared to DNA, RNA is very unstable. This is one of the reasons our cells use DNA to store our genetic material.
[12] A novel vaccine can take anywhere from 5–20 years to pass FDA regulations and be made available to the public. In the case of influenza, the platforms we use for the flu vaccine have already been tested and approved, and this is why we can make a flu vaccine in ~6 months from the time that the strains are chosen for the following flu season to the time that the vaccine is ready.
[13] The process of mRNA production does require bacterial cell culture before it is amplified, but this is much easier and less expensive than mammalian cell or egg culture.
[14] For example, see https://www.ncbi.nlm.nih.gov/pubmed/31079849?dopt=Abstract. Also see: https://www.nature.com/articles/nrd.2017.243
[15] https://www.nih.gov/news-events/news-releases/nih-clinical-trial-investigational-vaccine-covid-19-begins
[16] https://www.kpwashingtonresearch.org/news-and-events/recent-news/news-2020/kaiser-permanente-launches-coronavirus-vaccine-study-seattle
