Kansas readers, today’s newsletter is a bit different in that it is entirely focused on the new vaccines that are being deployed against COVID-19. We’ll be back to discussing Kansas numbers tomorrow.
Today the Advisory Committee for Immunization Practices (ACIP), a collection of medical and scientific experts from various academic institutions and public health departments across the US and headquartered at the Centers for Disease Control and Prevention, met today to discuss the next steps in the vaccine roll out. You can see the slides from this meeting including the many considerations they had to weigh and discuss in forming their recommendations. But the recommendation for who receives the vaccine after healthcare workers and long term care facility residents is to first vaccinate those 75+ and those considered frontline essential workers. These people are in what’s called Phase 1b. The phase that follows will aim to vaccinate those aged 65-74 and anyone aged 16-64 who have high-risk medical conditions as well as other essential workers not included in Phase 1b.
They also provided a list of who they consider to be essential workers. Frontline essential workers (left side) will be offered vaccination in Phase 1b. Other essential workers (right side of the list below) will be offered vaccination in Phase 1c.
I have to admit that when I went through these slides from the meeting and recognized all that these people had to weigh, I was surprised to have an emotional response of intense pride. Not pride for having anything to do with the decisions they are making, obviously, but proud of the collective effort that it took to get to this point where America now has its marching orders to the end of this pandemic. Way to go Team Science and Team Public Health! Their effort to balance science, implementation and ethics is an incredible breath of fresh air when so much of this pandemic response has featured none of those things.
This week’s episode of This American Life featured a story about the COVID-19 vaccine development process, connecting the basic science to the vaccine that will save us so much suffering and death and the emotions of all involved.
How do these vaccines work?
Today I’m planning to teach you about how the COVID-19 vaccines by Pfizer-BioNTech and Moderna. This is going to require us to dust the mental cobwebs of what we learned in high school (and perhaps college) biology classes. But I promise to keep things as simple as I can.
Cell and Molecular biology
Cell and molecular biology are huge fields and we are only going to scratch the surface of them today because, after all, this is not a biology course. You might know that your body is made up of cells and your cells contain a nucleus (purple ball inside the cell in the image below). That nucleus is where your DNA is stored, the genetic material you inherited from your parents. The DNA is the master instruction manual for every protein your body will ever need to make. It is found in every cell of your body, but only certain genes are activated (or turned on) for certain cells. For example, your liver cells don’t need to make the proteins that make up the unique structures of your eyeball. The process of taking the DNA instructions and making proteins with them is called gene expression.
Gene expression doesn’t go straight from DNA to protein though. There’s an intermediate biomolecule called mRNA (“m” = messenger). Structurally, it’s very similar to DNA. But unlike the double helix you’ve seen for DNA that provides a lot of stability, the mRNA molecule is single stranded, more like a string than a ladder. Because of this, mRNA molecules are really unstable and are easily degraded. mRNA is like the snapchat of a molecular message - a short-lived set of instructions. But the mRNA acts as a middle man of sorts between the master instruction manual (your DNA) and the ribosomes in the cytoplasm of your cells. Cytoplasm is just the liquid that is inside your cells that’s outside of the nucleus. Ribosomes are the protein builders. They “read” the temporary RNA message and then use that code to put the right building blocks in order to make the protein of interest. Keep in mind that the master instruction manual (DNA) and the builders (ribosomes) are held in different parts of the cell - we’ll come back to that. We just need temporary copies of the instructions so the ribosomes can do their job. The process of making this temporary copy of mRNA is called transcription. The process of taking the temporary mRNA message and making protein (the action of the ribosome) is called translation. It is called “translation” because you are converting genetic language into protein language.
This process of DNA -> RNA -> protein is referred to as “The Central Dogma” of molecular biology. Every living cell does this process and it always, always, always proceeds in this order. Notice that the arrows for transcription and translation are unidirectional. You can not go backwards in this process and make RNA from protein, for example. Remember I said all living things follow this sequence and never go backwards? There are certain viruses that can convert RNA to DNA, such as HIV. But there’s a debate whether viruses are technically living things, since they can’t replicate on their own - they have to hijack a cell in order to reproduce. So technically, it is still correct to say that no living thing violates the Central Dogma. In any case, neither does SARS-CoV-2, the virus that causes COVID-19. Nor do any of your cells.
Stability of RNA
Like I described in the section above, RNA has some structural features that make it really unstable. In fact, I spent five years isolating and working with RNA from bacterial cells during my graduate work. I can tell you from personal experience that it is an absolute pain to work with. It has to be constantly held on ice, in just the right solution, and it degrades very rapidly once it is removed from a cell. For example, whatever I hadn’t used in my experiments after a week was thrown out, because by that time it was worthless, even if held in cold temperatures. Compare that to working with DNA (remember this is double stranded and more stable). This molecule, once isolated from a cell, could be stored in a standard refrigerator freezer for months. But this helps us to see why the RNA vaccines from Pfizer-BioNTech and Moderna have a cold-chain requirement. They have to be held at cold temperature until they’re prepared for administration to vaccine recipients because the RNA itself is an unstable molecule.
The RNA vaccines
I recognize that not everyone is the sort of learner who understands from reading. The Journal of the American Medical Association has put together this helpful video to educate us on how the RNA vaccines (and all the COVID-19 vaccines in development) work. However, I will note that the video is a bit outdated and the concerns they had about whether the RNA vaccines would work have been overcome with the Phase III clinical trial data.
But for those who do better with reading, here goes. The RNA vaccines do not contain the virus genome or its spike protein. Instead they have a piece of RNA that codes for the SARS-CoV-2 spike protein that coats the outside of the viral particle. In the vaccine, those spikes aren’t present and the RNA is held inside of a pretend virus particle with a lipid membrane that looks kind of like our cell membranes (see “lipid coat” in the graphic below). So when the vaccine is administered, there is no virus in it at all, just the short-lived instructions (called mRNA) for how to make the spike protein. When the vaccine particles arrive at your cell and the cell brings them in, the RNA is released from the particle and runs into the ribosomes that are in the cytoplasm. Ribosomes don’t really discriminate mRNA messages - as long as they have the right chemical composition at the beginning of the sequence, the ribosomes use them to make proteins, whatever the mRNA (temporary message) says. So the ribosomes aren’t paying attention to what is my mRNA versus the vaccine’s mRNA. The spike protein is then produced by the ribosomes in the cytoplasm of the cell and then presented on the membrane of the cell by the “name tag” holders of the immune system. From our last lesson, every cell in your body has a name tag holder (technical term is MHC molecule) that shows either your proteins (called self-antigens) or something they found in their cytoplasm (foreign antigens). If the immune system cells that surveil your body find a name tag (foreign antigen) that they don’t recognize, then they send out the alert and this recruits other immune system cells so they can learn about the new threat and develop antibodies and memory against the threat. So the bottom line is that the vaccine is taking a temporary, short-lived instruction set for making the virus spike protein and getting your cells to make the protein temporarily. And this spike protein is a foreign antigen, it has the wrong name tag in my analogy. Your cells show the spike protein to your antibody producing cells (there are several intermediate steps here, I’m simplifying) and they recognize that it is not a self antigen. So they begin to produce antibodies. Both the mRNA that was in the vaccine and the spike protein we produce from it will degrade over time, but the memory remains. So I called this vaccine’s mRNA like a snapchat, but it’s also kind of like the messages sent in the movie/show “Mission Impossible”: this message will self-destruct in 5…4…3…2…1. Meanwhile, your cells now know their mission.
So let’s address some of the safety myths with this mechanism of action in mind. Can the vaccine give you COVID-19? Absolutely not. The vaccine does not contain the virus, nor its genome or proteins. The only thing it has in it from the virus is a temporary copy of the instructions to make just one of the viral proteins. Can the vaccine alter my DNA? Highly unlikely - your DNA is held in your cell’s nucleus (the purple ball in the first diagram). The vaccine mRNA has no reason to enter the nucleus - it has no purpose there because the ribosomes that translate mRNA into protein are in the cytoplasm. In essence, your DNA genome (your master instruction manual) is sequestered away from the action. Generally speaking, mRNA is made in the nucleus (transcription) and then leaves the nucleus immediately to be processed by a ribosome. RNA does not re-enter the nucleus. This compartmentalization of the processes makes it very unlikely that the mRNA in the vaccine ever enters the nucleus and therefore it never is in close proximity to the genome. In addition, the cell has no mechanism by which to convert the vaccine mRNA into DNA to then insert into your genome - remember your cells follow the Central Dogma.
The Pfizer-BioNTech vaccine has already arrived across the country and is being administered to its first recipients. I have to say, seeing the photos and video of those healthcare workers and seniors being immunized made Monday the best day of 2020 on social media, at least for me. Usually, Halloween is my favorite day of the year, when I can see all the kids dressed up, see them growing up, etc. But no amount of pumpkin or fairy costumes can touch the joy and relief of what the first immunizations against this virus represent. This is when humanity strikes back. If you find yourself surprisingly emotional over this, you’re not alone. The Washington Post wrote this interesting article about the emotional release provided by this really, really important event.
Does this vaccine actually work? YES!
Over the course of this pandemic, I have encouraged you to become more comfortable with data and to use data to make evidence-based decisions. The possible hesitancy surrounding taking the COVID-19 vaccines is worrying many in public health. But to me, I see some of this hesitancy as the people we’ve been teaching to be more data-driven doing exactly that. People want the data and they want to understand it. To that end, I’m linking the safety and efficacy data that Pfizer-BioNTech and Moderna briefed to the FDA in their applications for Emergency Use Authorization (EUA). Each document is >50 pages long and the data and verbiage will likely overwhelm most people. For those who are really overwhelmed, the area where I would focus most is the executive summary. But the document goes over their study design, the number of participants, and safety data including the types of reactions people experienced and how common they were.
For now, we’re going to go over the data that shows that the vaccine works (efficacy data), using figure 2 from both documents (see graphs below). These graphs show the number of people newly infected (aka incidence) with COVID-19 following injection with either the vaccine or the placebo (basically, salt water solution like what you would receive in a bag of IV fluids). The color coding isn’t consistent between the two graphs, they were submitted by different companies and likely didn’t coordinate. For the Pfizer-BioNTech graph, the placebo is the red line whereas the vaccine is the blue line. For the Moderna graph, the color coding is opposite - the blue line is the placebo and the red line is the vaccine. The x-axis shows the number of days after the first injection for each study participant. The y-axis shows the incidence rate over the duration of the study period, or how many of the people were infected with COVID-19 over time. You can learn more about how incidence rates are calculated by reading this lesson page from the CDC.
Looking at the top graph, the incidence of COVID-19 infection was the same between two groups until about day 10 at which time the vaccine group diverges in a big way from the placebo group. That makes sense based on what I talked about in my last vaccine update - it takes about 7-10 days to start producing antibodies after an exposure, including a vaccine. The Moderna graph is similar, but it’s harder to see that divergence around day 10 because the y-axis is more compressed. But they show the same thing. After about day 10, vaccine recipients begin to have some protection against the virus and after 100 days the protection provided is huge.
Vaccine efficacy measures how well the vaccine protects against infection, comparing those who received the vaccine versus placebo. The table below comes from the Pfizer-BioNTech document. Let’s orient ourselves. Time course is in the first column. The vaccine data (BNT162b2) are the second column. The placebo data are in the third column and vaccine efficacy is in the fourth column. Of over 21,000 people in each group, 50 people who received the vaccine and 275 people who received placebo later contracted COVID-19 (see row 1). Efficacy is calculated as the number of people infected in the placebo group minus those infected who received the vaccine, divided by the number of people infected in the placebo group. So, 275 - 50 / 275 = 82% (see fourth column). Mathematically, it’s sort of like saying how much did the vaccine reduce the number of people sick compared to if no vaccine was used at all. Now this 82% is over the entire course of the study. If we look at specific time intervals, you begin to see why two doses of the vaccine are needed. Of the 50 vaccinated people who contracted COVID-19 anyway, 39 of those got sick during the interval between dose 1 and dose 2, when vaccine efficacy was only 52.4%. Even within the 7 days after the second dose, vaccine efficacy shot up to 90.5%. Finally, once a person reached 7 days after the second vaccine dose, then the vaccine efficacy increased to 94.8%. So no matter what anyone tells you, the data show that you need two doses of the Pfizer-BioNTech and Moderna vaccines.
The Moderna document shows something else that is interesting, but perhaps not surprising, in Table 17. In this table, we’re looking at how well the vaccine conferred protection based on age group. Across all adults tested, the vaccine efficacy was 94.1%. For younger adults, <65, the vaccine efficacy was 95.6%. For adults 65 and older, the efficacy dropped to 86.4%. This is not so much a flaw of the vaccine as much as it is the impact of age on the immune system. As people get older, their immune system begins to decline and has a diminished capacity to respond to infection. But what this table tells us, for now, is the importance of achieving herd immunity - to protect the 4.4% of younger adults and 13.6% of older adults who for whatever reason did not mount an immune response to the vaccine or achieve protection from the virus. And until we know that herd immunity is achieved, it will still be critically important to continue to wear masks and socially distance ourselves. Because there will be no outward way to tell who the unlucky 4.4% or 13.6% are. It very well could be you.
In addition, we see that the vaccine protects against infection, but does it protect against transmission? Until we know more about that, even the vaccinated will need to continue to be cautious.
20Dec2020 ACIP Briefing Slides: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2020-12/slides-12-20/02-COVID-Dooling.pdf
Pfizer-BioNTech FDA EUA briefing document: https://www.fda.gov/media/144245/download
Moderna FDA EUA briefing document: https://www.fda.gov/media/144434/download
Washington Post article on the surprising emotions of the COVID-19 vaccine deployment: https://www.washingtonpost.com/lifestyle/style/covid-vaccine-video-reaction/2020/12/14/05754f66-3e59-11eb-9453-fc36ba051781_story.html
CDC Measures of Risk lesson: https://www.cdc.gov/csels/dsepd/ss1978/lesson3/section2.html#:~:text=Incidence%20refers%20to%20the%20occurrence,cases%20per%20unit%20of%20population.
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My Ph.D. is in Medical Microbiology and Immunology. I've worked at places like Creighton University, the Centers for Disease Control & Prevention and Mercer University School of Medicine. All thoughts are my professional opinion and should not be considered medical advice.