Skip to main content
Research and Innovation

Vaccine Q&A: Vaccines 101, mRNA and Adenoviruses

bottles of vaccine
Image credit: Daniel Schludi.

COVID-19 has had a profound impact on the lives of people across the United States and around the world. Vaccines are now becoming available that can help us address this public health crisis, but many people have questions about these new vaccines.

To address some of these questions, we sat down (socially distantly) with experts from NC State to address issues ranging from safety to manufacturing to how the vaccines will be distributed.

Because there are so many questions, we have broken the Q&As up into a series of posts about vaccines. We will be adding to the series over time.

In this post, we focus on how vaccines work and what mRNA and adenovirus vaccines are. To address those questions, we spoke with Matt Koci, a virologist and immunologist whose work focuses on host-microbe interactions in birds. Koci is a professor in NC State’s Prestage Department of Poultry Science.

The Abstract: What are vaccines and how do they work?

Matt Koci: If you think of getting sick from disease and letting your immune system fight it off as “on the job training,” then vaccines are the equivalent of vocational-technical school for your immune system.

There are a lot of things you can learn “on the job”: sweeping up, running the register, locking up at night. But there are a lot of skills at work where learning on the job can be dangerous. If you are getting new brakes, you want to be sure your mechanic already knows how to install them. Vaccines teach the immune system how to recognize diseases, so that when you are exposed to the real disease, your immune system can respond immediately. Ideally, you’ll never even know you were infected.

There are lots of different types of vaccines, but they all work by exposing healthy people to parts of a pathogen.

There are lots of different types of vaccines, but they all work by exposing healthy people to parts of a pathogen. This allows their immune system to develop the cells and proteins it needs to fight off the pathogen when they come across the real disease.

There are several different ways this can work. We can find (or even make) close cousins of a pathogen. Something that doesn’t make us sick, but still looks enough like the pathogen to give us immunity to both. This is known as an attenuated vaccine. Some of the most successful vaccines are attenuated vaccines. Smallpox, measles and chickenpox vaccines are all attenuated vaccines.

Another major approach is what’s called an inactivated vaccine; the flu shot is a good example. Here, instead of a close cousin, we use the pathogen itself. But we can’t just inject the pathogen, because that will make everyone sick. So, we boil it or do something that otherwise makes the pathogen harmless. We then use the inactivated pathogen to show the immune system what the pathogen looks like. The immune system uses that to develop the tools it needs to protect you from the real pathogen.

There are currently over 100 potential COVID-19 vaccines in some stage of testing around the world.

Still another approach is to make just a few of the proteins from the pathogen in the lab and inject those. This is called a subunit vaccine. The HPV vaccine is a good example of this kind of vaccine.

Then there are vaccines that don’t involve the pathogen or its proteins directly but rather trick your cells into making the proteins. These involve injecting DNA or RNA packaged in different ways. Some use protective chemical shells – or even other viruses – to deliver the vaccine. In either case, the DNA or RNA is delivered to the inside of your cells. This then gets your cells to make the pathogen proteins, and those proteins then induce your immune system to develop resistance to the relevant pathogen. So in a sense, your cells make the vaccine.

There are currently over 100 potential COVID-19 vaccines in some stage of testing around the world. Across all these potential vaccines people are trying every kind of vaccine technology.

TA: Over 100? What are the ones being developed for use in the U.S.?

Koci: This is going to be a global effort, so we really can’t afford for there to be vaccines just for one country, but the U.S. government put a lot of money into helping companies speed up the development time of their vaccines. That’s “Operation Warp Speed.” Through that program the U.S. invested about $11 billion in six different vaccines. Two of the vaccines in Operation Warp Speed are subunit vaccines, where the company is making viral proteins that will be used as the vaccine. Three of the vaccines use different viruses that we’ve engineered to be harmless, but are still capable of inducing your cells to make the proteins we need your immune system to respond to. And the last one is just mRNA packaged in a protective shell.

Transmission electron microscope image of the SARS-CoV-2 virus that causes COVID-19. Image credit: NIAID-RML.

TA: The Pfizer vaccine is an mRNA vaccine right? That’s the one that has been authorized for use in the U.K. and the U.S.?

Koci: Yes. The Pfizer-BioNTech vaccine is the mRNA vaccine that was just granted emergency use authorization for use in the U.S. and U.K. To be clear, Pfizer initially opted out of U.S. funding for vaccine development from Operation Warp Speed, but will receive U.S. support for distribution. There’s actually another mRNA vaccine close behind the Pfizer-BioNTech vaccine in the review process. That’s the one from Moderna, and that’s the one that Operation Warp Speed invested in more heavily from the start.

In fact, by the time anyone reads this, the Moderna vaccine will probably also have received its own authorization – the preliminary analysis from the FDA was promising.

TA: What are mRNA vaccines? Have they been used in people before?

Koci: These vaccines fall under that last category of vaccines I mentioned above, where we effectively get your cells to make their own vaccines. But to answer this question we have to take a step back and explain what mRNA is. Bear with me for a second.

Your high school biology teacher likely told you that the flow of genetic information in a cell goes from DNA to RNA to protein. It’s one of the many concepts that likely made you mutter “when am I ever going to use this.” Well, send your teacher an apology, because today’s the day.

An organism’s genome is the complete set of genes and genetic instructions needed to make that organism. These genetic instructions are encoded in the DNA that is stored in the nucleus of nearly every cell in your body. These cells carry all that DNA around with it. But in order for your liver cell to be a liver cell and not a heart cell, your liver cells only follow the set of instructions in your genome related to liver cells.

Think of the genome like the reference section in a library that won’t let you check out books. If you need specific instructions on how to do something, you have to go to the library to read the book. And you take notes. You don’t copy the whole book, just the specific instructions you need for the job you’re doing. The way the cell takes these notes is by using a molecule called RNA, and we call these notes “messenger RNA” or mRNA. There are proteins in your cells whose job is to go into the nucleus and write down the specific instructions for certain tasks. These instructions, or mRNAs, are then carried to another part of the cell where they are used to build proteins.

Every protein a cell makes goes through this process. DNA is copied into RNA and that mRNA is translated into protein. Okay so far?

So, mRNA vaccines are just a type of vaccine where we package the RNA instructions for some of the SARS-CoV-2 proteins (the virus that causes COVID-19). We inject that mRNA into a person’s arm, the mRNA is introduced into cells in your body, and the SARS-CoV-2 mRNA is treated like mRNA that comes from the cell’s own nucleus and is translated into protein. Basically, the vaccine tricks your cells into creating these specific proteins from SARS-CoV-2.

However – and this is important – the vaccine doesn’t have the instructions to make the whole SARS-CoV-2 virus. Instead, it just makes the “spike protein,” which is what the virus uses to bind and get into our cells. The ultimate idea is that the vaccine drives the immune system to make cells and proteins that recognize and destroy the spike protein, which protects us from COVID-19.

This is a relatively new approach to making vaccines. The idea has been around for a while, but has not previously been used in a vaccine approved by the FDA. That’s not a comment on its safety or effectiveness – there are several different mRNA based vaccines working their way through the normal approval process. It’s just that normally that process is a lot slower.

TA: What are the advantages to mRNA vaccines?

Koci: Probably the biggest advantage of this approach is, at least on paper, its simplicity. It’s just mRNA encoding the genes you want the immune system to respond to, and some sort of protective shell to help get it into the cells so it can be translated into protein to drive the immune response. This simplicity means vaccine companies can start making vaccine as soon as someone gives them the genetic sequence of the pathogen. So the biggest advantage is how quickly you can get started testing a new vaccine.

However, mRNA is extremely fragile and if not handled properly it can fall apart. If it does, that’s the end of your vaccine. That’s why this vaccine has to be kept extremely cold: -112 F or -80 C for the Pfizer vaccine and -4 F or -20 C for the Moderna vaccine. I’m not sure what Moderna is doing differently that allows them to get away with the warmer temperature but it still needs to be kept well below freezing.

TA: If the mRNA vaccines are the first, what vaccines might be released next? I’ve also heard some talk about adenovirus vaccines. What are adenovirus vaccines? Are any of them being considered as COVID-19 vaccines?

Koci: Yes. Adenovirus-vectored vaccines are the other technology that has been close behind the mRNA-based vaccines in clinical testing. Of the six vaccines backed by Operation Warp Speed, the adenovirus vectored vaccines are the only other vaccines, besides mRNA vaccines, to make it to Phase III testing. That means, assuming things go well with this phase of testing, they will be the next ones that should get emergency use authorization – probably in January or February 2021.

Instead of hiding Greek soldiers, the adenovirus releases genes.

Like the mRNA vaccines, the main idea behind adenovirus vaccines is to get genetic material that encodes SARS-CoV-2 genes into your cells and get your cells to make the virus proteins. The difference is in how they do this. Where the mRNA vaccine is just the mRNA protected by a chemical shell, adenovirus vectored vaccines use a virus we know is harmless to act as a Trojan horse. But instead of hiding Greek soldiers, or anything dangerous, the adenovirus releases genes that encode the SARS-CoV-2 spike protein.

Adenoviruses are a family of viruses that have dozens, maybe hundreds, of members. Most don’t cause any known disease, or they only cause mild “common cold”-like symptoms. Scientists developed a way to use strains of adenoviruses that don’t cause disease as a delivery system for vaccines. So we’re using one virus to deliver the vaccine against another.

The genes for the protein that we want the immune system to respond to are inserted into the adenovirus genome as DNA. Then the person to be vaccinated against SARS-CoV-2 is infected with this harmless adenovirus. When the adenovirus gets into your cells the DNA is turned into mRNA, causing the cells to make the vaccine proteins, which triggers the immune response. I’ll also point out that when we insert these vaccine genes into the adenovirus, we also remove genes from the adenovirus so that it can’t replicate in the vaccinated person. This is done as an added safety precaution.

Like the mRNA vaccines, this type of vaccine has been around as an idea for a while, and there are several adenovirus-vectored vaccines in phase 1 and 2 clinical trials but none that I’m aware of that are FDA approved and currently being used in people.

Cell infected with adenovirus. Image credit: ZEISS Microscopy.

TA: What are the advantages to adenovirus vaccines?

Koci: The biggest advantage here is, even though there aren’t any adenovirus-vectored vaccines being used in people today that I’m aware of, scientists have been using this technology in the lab for decades. The process of inserting genes into the adenovirus vectors is routine for a lot of labs. It does involve more steps than mRNA vaccines, but those steps have been optimized so it can still be done pretty quickly. That makes these types of vaccines easy to make a lot of quickly and relatively cheaply. Also, once assembled, adenovirus-vectored vaccines are pretty stable, so they don’t have to be kept at really low temperatures.

One issue that has slowed down the development of these vaccines is all the other adenoviruses out in nature. Many don’t make us sick, and some are unknown to science. Vaccine producers have been trying to find the right adenovirus to use for the vaccine – one that your immune system hasn’t seen before. If the adenovirus carrying the vaccine looks too much like an adenovirus your immune system has seen before, your immune system will attack and destroy the vaccine before it has a chance to do its job. Companies have been working for years to fix this issue. Looking at the early data from the Oxford/AstraZeneca and Johnson and Johnson trials suggests they may have succeeded.

TA: So are you going to get the vaccine?

Koci: Yes. As soon as it is made available to me.

Leave a Response

Your email address will not be published. All fields are required.

  1. What happens to the lipid after it delivers the MRNA? Can it accumulate in different organs and cause inflammation? How long do the lipids stay in your body?

    1. The lipids used to deliver the mRNA in vaccines are engineered to be nontoxic and to biodegrade very quickly. So, basically, they deliver the mRNA into the cell, then break down into non-toxic parts that get absorbed by your body or excreted. How long do they stay in the body? I think it can vary a bit, but we’re talking about hours, not weeks.

  2. In #7, typo error: “shorting after the 1st shot” should be “showing after the 1st shot.”

    In #10, the referenced BMJ letter is https://www.bmj.com/content/373/bmj.n883/rr-1.

    Finally, one more question:
    11) For #8, #9, and #10, it seems that reducing the dosage of the 1st dose of the DNA vaccine will reduce the size of local inflammation in the endothelium and concomitantly the clot size. What do you think?

  3. Thank you Matt for the detailed explanation.

    6) The NYT explainer is great. But it also shows the spike proteins free floating in the extracellular fluid after the transfected cell is lysed (presumably by CD8+ T cells from Day 7 onwards). Now if these spike poke at other cells, like asked in previous question #5, they are going to cause inflammation left and right, won’t they?

    7) Dr Hamid Merchant in the UK posted a letter last month to the British Medical Journal (BMJ) providing facts that rules out the total confinement of vaccine particles (LNP or viral) to the injection site (here, the muscle). https://www.bmj.com/content/372/bmj.n699/rapid-responses. Separately, a separate study of Moderna/Pfizer vaccinees presenting cutaneous reactions on various parts of the body (face, feet, back) besides the injection site shorting after the 1st shot and from D7 (Devon McMahon et al. https://www.jaad.org/article/S0190-9622(21)00658-7/fulltext#%20). Is there any reason to believe that the LNP (or AdV particles) are totally confined at the injection site?

    8) Between the mRNA vaccine (Moderna, Pfizer) and the DNA vaccine (J&J, Oxford-AstraZeneca, or OAZ), is it true that the latter results in continuous production of S proteins all the way till the transfected cells are lysed by CD8+ T cells on D7+ (whereas the production in the former stops within the first 2 days, possibly sooner)? If so, would the latter results in a lot more S proteins being produced and studded on the cell membrane? Or is there some self limiting mechanism that prevents such ‘runaway’ production? It seems that the DNA vaccines potentially results in way more debris that carry the S proteins post-lysis that potentially can result in larger local inflammation and microbleeding and thus larger clot sizes that can the mRNA vaccine because of this mechanism. Can you comment?

    9) From a recent report from the UK, the OAZ vaccine results in 3x the T cell response as the Pfizer vaccine. In a separate report from Singapore, cognate T cells show up on by D7. It seems then that lysis could happen 3x as fast post OAZ 1st dose compared with Pfizer. Now, if and when this happens on an endothelial site, won’t the endothelial wall perforation be larger and the clot size be larger as well, and therefore more lethal?

    10) In another one of Dr. Hamid Merchant’s letter to the BMJ, he reported the numbers of thrombotic events reported on the British MHRA YellowCard registry for OAZ (~205; 12 fatal) and Pfizer (~71; 1 fatal), separately. From these, and combined with the number of people who received at least 1 dose by March 7 (20m) & the quantity of orders for OAZ (100m) and Pfizer (40m), resp., by the UK government, I estimated that, if OAZ and Pfizer are equally likely to produce such events, the ratio of thrombotic events would be 2.5:1, which is really close to the actual of 3:1. But the fatality events are 12:1, which 4x as high. I would think that, from this, the max clot sizes in each thrombotic event have to be larger in the OAZ cases than in the Pfizer case. Is there any other factor that can similarly skew the fatality?

  4. Matt, 5 question for you:

    1) Do cells other than non-APC (Antigen-Presenting Cells, such as dendritic cells, macrophases and B lymphocytes) endocytose (i.e. engulf) the lipid nano-particles? Or is it strictly the APCs that will? How about neutrophils?

    2) After the spike protein are produced in large number in the cytoplasm, do they get exocytosed into extracellular fluid?

    3) How does the chopped up very short strands of spike protein fragments that get presented on the MHC-II molecules of the APC effective, since they likely have different geometry that when they are part of the whole S protein and so the antibody made against them may not match the real thing in the whole virus?

    4) There are discussions that the 2P substitution made to the S protein DNA to stabilize the S1 and S2 protein subunits together is important for immune system recognition, but how does this make sense unless the whole S protein is exocytozed to the extracellular space instead of merely getting chopped up in the APCs?

    5) If the S proteins are exocytosed, won’t they flow with the lymph, not all will get picked off in the lymph and travel onwards to other parts of the blood system? And the S protein being good at binding to ACE2 receptor on endothelial cells everywhere, won’t that make the endothelial cell that bind with the S protein a target of attack by the complement system causing inflammation and local endothelial cell lysis? Same with platelets, which also have ACE2 receptor on them and building a MAC (Membrane Attack Complex) that pokes a hole in a platelet is a known way to activate it.

    1. Jay, great questions, but some of these get pretty deep into the inner workings of the immune system, so I’ll try and keep myself from nerding out too much in these answers, but no promises.
      Question by question:
      1) The lipid particles are likely going to enter most of the cells around the immediate area where it is injected. APCs (dendritic cells most of all) will be primarily responsible for initiating the immune response. However other cells, like the muscle cells in the area, will also take up the nano-particles and make the spike protein. After the APCs have gotten the response started, and other immune cells start coming to the site of injection they will respond to the muscle cells expressing the spike protein like they were infected with SARS-CoV-2. If there were any neutrophils in the area at the time of injection, I would expect them to take up the particles too, but typically, neutrophils stay in the bloodstream until they are called in. When they get the call they leave the bloodstream, enter the tissue, and migrate to the site of infection (or injection in the case of the vaccine) to help with the response. So they’ll be one of the first types of cells to show up to the site of injection, but by then I would expect most/all of the mRNA would have already found a cell to enter.

      2) No, the spike protein encoded by the mRNA would not be released from the cell. It will insert itself into the cell membrane so most of the spike protein is sticking out of the cell in a way that B-cells and antibodies can see it, but it is tethered to the cell, not free-floating (See “Entering A Cell” section in the NYTimes explainer page here https://nyti.ms/3tkm9LK).

      3) This is because of the different ways different immune cells go about doing their jobs. B-cells, the cells that make antibodies, recognize antigens (proteins or other molecules that aren’t part of the body) found outside cells. This could be free-floating between cells (in the case of viruses looking for new cells to infect) or on the outer surface of a cell. For B-cells to recognize antigens and make antibodies they don’t need MHC. In fact, most antibodies recognize antigens bigger and more complex than the short pieces presented by MHC.

      T-cells, on the other hand, can only recognize antigen that is presented to them by MHC proteins. There are 2 types of MHC proteins. MHC I and II. Only APCs use MHC II and they show short fragments of antigens to a class of T-cells known as helper T-cells. These cells help direct and coordinate the actions of B-cells as well as the other type of T-cell, the killer T-cell.

      The killer T-cells only recognize antigens presented to them as short fragments in MHC I. MHC I is on almost all cells of the body and it’s a way for normal cells to tell T-cells if they’ve been taken over by a virus.

      The short pieces that get presented in MHC I and II are different sizes. So the net effect is B-cell and both types of T-cells each recognize the antigen through different means. It’s a safety check. The immune system is really powerful, and it can do a lot of damage. So the body wants to make sure the threat is real before it unleashes the full force of the immune system. B-cells can respond to antigen by themselves, but it’s typically not a very strong response. But if T-cells, and especially the helper T-cells are also activated (by APCs presenting them antigen with their MHC II) then B-cells get fully activated and produce a lot more antibodies.

      4) Hopefully the answer above helped answer some of this. You’re right. This change would not really make much difference for the bits of the protein that get chopped up and presented to T-cells via MHC I or II. But this does make a big difference for what B-cells would be stimulated and what antibodies get made.

      By making these changes, the S protein is locked in the form that is the most vulnerable to being neutralized by antibodies. This helps make sure that when your B-cells respond to the vaccine they are making antibodies that have the greatest likelihood of being able to block the virus from infecting your cells.

      5) The spike protein isn’t released from the cells. So this isn’t something to be worried about. If this was occurring, we would have seen evidence of it in the vaccine trials.

  5. Matt, I read in a men’s health article that fewer people in J&J’s covid trials had adverse effects in the vaccine group than the placebo group. It was implied that is not true for the Mrna trials. Are you able to shed any light on this as it is hard to decipher what is true and what is not?

    1. Leslie, I’m not familiar with the article you’re referring to. While each company submits similar data, it’s not reported exactly the same because the trials weren’t run exactly the same. One trial has just one shot and the others 2, plus the timing between shots is different, so all that makes it hard to line things up to compare cleanly line by line.
      There are one or two lines in the J&J data tables where numerically more people reported some type of an event from the placebo group than the vaccine group, but on a percentage bases the differences are really small (1.4% vs 1.9%) or actually not different at all.
      The important take away from the data as a whole is that the numbers of serious (needed to see a doctor) events is a very small percentage for all 3 vaccines (0.5% or lower).
      For reports of things like fevers, the data is pretty similar however the numbers tend to be a little higher with the mRNA vaccines (15-20%) as compared to the J&J vaccine (10-15%) in the vaccin groups. And the reports of fevers and such in the placebo group are pretty much the same across the vaccine types. Not sure if that addresses your question or not.

    1. That’s a great question — it’s one that I’ve asked all the experts I interviewed for this series! The answer was the same for all of them: whichever one they could get first.

    2. Wayne&Maureen, In the interest of full disclosure, I got the Pfizer/BioNtech vaccine, but I didn’t know that until I was actually in the room rolling up my sleeve.

      I honestly thought very long and hard about whether I had a preference for one type over the other, and at the end of the day, I decided I didn’t. So when I was eligible, I got the first available appointment and didn’t even ask what vaccine it was.

      Right before the injection, the nurse asked to confirm I was there for the Pfizer vaccine, and my response was “Whatever you’re selling, I’m buying.”

  6. Can I get any of the Covid vaccines if I have autoimmune issues already?
    Does the chemical coating on the mRNA vaccines offer any potential risks or threats to a person’s body?
    Could you build your own immune system up with vitamins to prevent the severity of Covid if contracted instead of a vaccine?

    1. Jane, thanks for your important question. First, and most importantly, I would ask your doctor for their opinion since they know more about your specific condition. That said, I am not aware of any issues with any of the vaccines that would suggest one is better or worse for those with autoimmune issues.
      As for the chemicals in the mRNA vaccines, the short answer is no. You probably heard reports on the news when these vaccines were first used a few health care workers experienced an allergic reaction to the Pfizer vaccine. Subsequent investigations in the UK and the US have shown these reactions are extremely rare, and no more likely than with any other vaccine. However, to be sure that we catch and treat anyone who has an allergic reaction, vaccination centers have people sit and wait for 15 min before they leave. For your last question: a healthy diet, where you are eating all the nutrition, vitamins, and minerals your body needs is important to a healthy immune response, but it is NOT a replacement for vaccinations. If eating Kingsfoil made your immune system bulletproof we wouldn’t be in the situation we’re in right now. At the same time, vaccines aren’t an excuse for a horrible diet either. If you want to get the most mileage out of your vaccine, eating well will help make sure your immune system is able to provide you the best response to the vaccine and therefore the best protection from getting COIVD-19.

  7. My understanding is that the J&J vaccine is made in part with with cells from a cell line grown from human tissue derived from aborted baby body parts. I do not know what type of cells specifically.
    However, that each of the three vaccines available in the U.S., is tested with HEK from aborted baby cell lines.

    As a Catholic, I am not morally comfortable with any of the available vaccines. Also am uncomfortable with the ’emergency’ approval status as opposed to the normal long term testing vaccines are required to go through.

    1.) Please provide what information you have on this topic of ingredients and test method.
    2.) Are there test methods that can be used which don’t involve abortion derived cell lines? (Hasn’t always been this way, correct?)
    3.) What are your thoughts on the speed with which all were developed and released?
    4.) Are there any vaccines being developed which do not in any way involve the use of aborted babies cell lines, which I might wait for?

      1. looks J&J does indeed use decendents of fetal tissue so essentially clones of fetal tissue. Why are living humans not harvested for this same reason? Is it a cost factor since that 1985 fetal cell was used already so much in testing or some other scientific reason why a fetal cell clone had to be used for the vaccine?

        1. Marius thanks for the question. I think my answer to Ken’s question addressed some of your question, but just to be sure… There are a few reasons for this. It is partly because of how long they’ve been around, the royal we of science has worked with them and know how to get the most out of them. It’s also because out of all the cell lines that get used, whether adult human, animal, whatever, these cells are the best at producing things in large quantities. We don’t know why that is, and people are always trying to find others that work better, or even as good, but so far there aren’t a lot of good contenders. And then finally, if you were to find a new cell line that worked as well, it can take years to go through the process to fully validate that these cell lines are safe to use in the production of vaccines and other medicines.

    1. Ken, thanks for your questions. I know your concern is shared by others. There’s a lot to unpack here and a lot of it is complicated and nuanced. The short-short answer is: while they were made in record time, these are some of the most intensely scrutinized vaccines ever produced. Now that we have vaccines and a way out of the pandemic we all have to balance what’s best for us as individuals AS WELL AS what’s best for the “herd”, and doing that in a way that is consistent with our individual risk tolerance and morals isn’t always easy. At the end of the day, our friends and neighbors are counting on us to get vaccinated. The extent to which I can help you make a decision that you’re comfortable with, I’m happy to do so.

      Now, for the much longer point-by-point answer!

      1) The Pfizer and Moderna vaccines are not made using human embryo cell lines.

      For the mRNA vaccines, as I understand things, both Pfizer and Moderna do use the HEK cells at the very beginning. When they were first figuring out what mRNA to put into their vaccine. The first quality control check was to make sure human cells could/would make the spike protein the way they wanted.

      This would be like if you were going to send out 100s of printed invitations to some big event with directions to the venue. You’d give the directions to a friend to make sure they made sense and got people to the right place. If the directions worked you’d move on to getting the invitations mass-produced, but you wouldn’t involve your friend in the rest of the process. Similarly, once Pfizer and Moderna know human cells can read and follow the direction to make the spike protein, they moved on to making the vaccine and the Phase 1, 2, and 3 testing it in people.

      The J&J and the AstraZeneca Oxford vaccine use one of 2 different embryo cell lines (PER.C6 or HEK293) to make the vaccine. To make this vaccine, cells are given the DNA instructions for how to make the adenovirus vaccine. To try and stretch my directions to some big event a bit further, you likely know people who get lost in their own house, or who you know are going to lose the directions you send, or just plain forget about the event altogether. Those people aren’t the ones you’re going to count on if you actually need help with something. If you need someone to bring extra folding chairs, you’re not going to ask flaky uncle Jimmy who you don’t expect to show up anyway. You’re going to ask a dependable family member. That’s what these cells are. Scientists are always looking for new cell lines, ones that work better than the ones we have. Ones that grow better and produce proteins better, but so far these two are some of the best.

      2) Is it possible to use other human cells, for some stuff, probably, possibly, but it’s complicated. The list of cells approved by the FDA for use in the production of vaccines and other biologics is pretty short. The process to get new cells added to that list can take years and cost millions of dollars. Finding a cell line that passes all the FDA safety standards and most importantly is able to do what is needed to make or test a product is still, unfortunately, a lot of luck.

      3) As to concerns about how quickly the vaccines were developed. Given how long things can normally take it’s not unreasonable to wonder how we did that. Let me be clear, no medical or scientific corners were cut. Under normal conditions, non-pandemic times, the process is slow largely because of money. Making vaccines is expensive. Companies will develop an idea for a vaccine in the lab, and then do a lot of market research to figure out how many people do they think realistically would buy it. Do those numbers look like something that would add up to something that makes it worth the company’s investment? If the initial answer is yes, then they may move to animal experiments. If things still look promising, they’ll move to Phase 1 trials in humans, then 2, then 3. At each step along the way there will likely be long pauses where the company looks at all of the products in development and what to prioritize based on what might be the best return on investment. Then at the end of Phase 3, they submit the data to the FDA and wait for approval. No company is going to start building a new manufacturing plant, and hiring 100s-1000s of new employees to make a product until they know they have FDA approval. It could take a year or more to build the infrastructure to actually make the vaccine once the FDA gives approval. That’s why the process takes as long as it does.

      This year any step where money was the reason things were slow, the Federal Government and private foundations stepped to keep the process moving. Any steps that could be run at the same time instead of one after the other, without affecting safety we did that. The funds companies got from Operation Warp Speed, allowed them to focus on making an effective, safe vaccine without having to worry about normal market forces. And importantly, it told companies to start working on the infrastructure to produce 100s of millions of vaccine before they even knew if the vaccine would work. The Federal Government agreed to eat those costs if it turned out some of those vaccines didn’t work because it was important enough to not have to wait a year for mass production to start.

      4) Looking over the different technologies and what information I can find about the different vaccines, the Novavax vaccine is probably the one I would look at given your concerns. This vaccine is made using insect cells in a process similar to how the HPV vaccine is made. And more importantly, this vaccine seems to be working as well as the others so far. As bad as the past year has been, we’ve really been lucky in the fact that so many of the vaccines have been highly effective. With a little more luck, hopefully, we won’t see any new variants any worse than the ones circulating now.

      As many of us need to get vaccinated as possible, not just for ourselves, but to help protect each other. I greatly appreciate your thoughtful approach to this and your willingness to get vaccinated. Hopefully, this helps you make the decision that is best for you and your faith.

  8. Thank you!!: Being a layperson, this is the most easily understandable and comprehensive info I’ve read about the Covid-19 vaccines. And, the Q&A is most helpful as well. I’m in group 1b (over 65 in NH) with no health issues, and I’m trying to hold out for the single dose Johnson&Johnson adenovirus vectored vaccine. In the meantime, I’m staying masked and keeping my distance!

  9. Hi there! Thanks for taking the time to answer all our questions.

    Given the emergence of variants around the world, is the type of vaccine relevant to how effective it will be against variants? In other words, is there something inherent to, say, the mRNA vaccines that will make it easier for it to adapt to these variants, or does the type of vaccine just not matter?

    1. Advyt, Thanks for your question. Looking at the 3 vaccines currently being used in the US, they’re all designed to target the same part of the virus. There is a little difference in how each of them has gone about it, but nothing that would make me think one would be any better at handling one variant vs another. But time will tell. Fingers crossed, they all continue to work as well as they do against all the variants.

  10. Questions: (1)Does J&J use viral particles containing the Adenovirus vector plus S protein DNA or Adenovirus vector plus S protein coated with nanoparticles, lipids, or that sort for permeabilizing into the host (human) cells?
    (2) Do all the S protein-producing hosts (human cells) get destroyed by APCs or other immune cells?
    (3) Since J&J introducing dsDNA into your cells that eventually get into your nucleus, whether one should be worried that this dsDNA somehow would integrate into the host genome through a yet unknown mechanism and generate mutations in the genome?

    1. B Dey, Thanks for your questions
      1) The J&J vaccine, similar to the AstraZeneca/Oxford vaccine, doesn’t carry the S protein with it, but rather it has the genetic code for making the S protein in its DNA. So when they enter a host cell, that cell will make the S protein.
      2) Almost certainly. I would expect all the cells that make the S protein will be killed by the immune system. A lot of people think that sounds like the vaccine is triggering an autoimmune reaction, but no, that’s how the immune system is supposed to work. Your immune system is designed to kill pathogens. If those pathogens are hiding inside your cells, as viruses do, then it kills them too. If you had COVID-19, your immune system would kill all the cells of the body that were infected with the SARS-CoV-2 virus. And during COVID-19 you’d have a lot more cells making the S protein than you’ll ever have from the vaccine.
      3) This is another good question. It’s actually a concern scientists had when the idea of adenovirus vectored vaccines were first proposed 30-40 years ago. So the royal “we” or science have looked for evidence of integration a lot to make sure these viruses were as safe as possible for use as a vaccine delivery vehicle. Scientists have used different adenovirus vectors in research, pre-clinical, and clinical studies (humans) for decades. There are no cases I know of where adenoviruses have integrated into the genomes of the host cells. This is biology, so I’m never going to say something would never happen, but the risk here is so low it is nothing I’m concerned about. Plus, even if it did, those cells would be making viral proteins which would flag them for killing by the immune system.

  11. It scares me when humans start messing around with our DNA. Can I not get vaccinated and just rely on herd immunity? Thank you

    1. Bibliogirl,
      Thanks for the great question. First, just to be clear, NONE of the vaccines do anything to your DNA. That is a myth out there. So don’t let that be the reason you don’t get vaccinated.

      Second, the only path to herd immunity is through vaccines. The way viruses spread, if they were to induced herd immunity “naturally” it would result in their own extinction. Nature is smarter than that. As viruses move through a population they don’t infect everyone at the same time. There is wave after wave of infections and by the time the last people in the population get infected for the first time, the virus has mutated enough that the very first people to get infected (in the first wave) are likely susceptible again. And the cycle goes on and on.

      Even if it was possible, it would mean sacrificing over 2.5 million people in the US alone. That’s how many people would likely die if we wait for everyone in the US to get COVID-19 and recover.

    2. I say, if you are concerned about being a guinea pig for the long term unknown effects, just beef up your immune systems with herb and good health practices and wait it out. Eventually Covid will mutate weaker and weaker and your natural immune system with deal with getting it in a less severe way in the future.

      1. Marius, there is no reason to think the SARS-CoV-2 virus “will mutate weaker and weaker”. We have no way of knowing which way the evolutionary ball will bounce. It could just as likely mutate to be worse. In fact, the new variant B.1.1.7 (the one that emerged in the UK) spreads faster and seems to be more deadly, and possibly even more of an issue for children. So we need to protect ourselves and not hope that the killer decides to just start maiming people instead.

        Our best chance at protecting ourselves, and our friends and family, is to get vaccinated. Good nutrition and health practices are essential to a properly functioning immune system, but they aren’t enough. We’ve seen many millions of healthy people around the world affected by COVID. Many are dealing with ongoing health effects that have lasted for months and may last the rest of their lives. There are no immune-boosting superfoods that can protect you from COVID or any other infectious disease. The vaccines can.

  12. Hi! I have narcolepsy and I’m concerned about the possibility of further hypocretin depletion from an adjuvant in the vaccine (obviously I’m already genetically predisposed) like the fluke that happened in Sweden many years ago. Obviously I’m concerned about it happening from getting Covid as well… Which vaccine is safest for me?

    1. Flip, first, ultimately, the answer to that question is something you and your doctor need to work out. It’s never a good idea to make medical decisions based solely on something someone in the comments section said 🙂
      What I can tell you is none of the vaccines that have been given an EUA so far (as of Feb 11) use the adjuvant associated with the vaccine in Sweden, 10-11 years ago. In fact, they don’t list any adjuvants or preservatives in their list of ingredients. And I would not expect the J&J or Oxford/AZ vaccines to either, but we have to wait to see what details are released when they are granted EUA. As for other vaccines that may come out later, some may use adjuvants, but we’ll have to see which adjuvants they are when that data is released at the end of their Phase 3 trials.

  13. In your opinion, with all of the COVID vaccines void of any long term data, which method do YOU consider to be of less risk for possible complications from the vaccine in years to come.
    ie. Is using a adenovirus possibly safer than using a manufactured mRNA ?

    1. Karen, Thanks for the great question. There’s nothing in any of the near term data, or any of the long-term data we have with previous clinical trials (same methods different targets) to make me think any of these methods will have any more complications than another.

  14. Excellent story. By the way, the Oxford/AZ vaccine is based on an adenovirus. And, although it not approved yet by the US’s FDA, it has already been used for lots of people in the UK, Europe, and maybe some other places too.

  15. I have heard that in past trials mRNA vaccines cause issues in mammal Placental formation. Can not seem to find any trust worthy information.

    1. Hi Jason — thanks for asking this question! The short answer here is that the rumor is bogus. Here’s the longer version: There is a rumor that vaccines will cause fertility issues because the protein that the vaccines target has four amino acids in common with a protein that plays a role in placenta formation. This rumor is not true. If it were, then everyone who got COVID-19 would also have fertility problems (since the protein the vaccines target is part of the SARS-CoV-2 virus). Here’s the deal: there are only 21 different amino acids. And every protein — from the keratin in your fingernails to the neurexin in your nerve cells — is made up of different combinations of these 21 amino acids. The protein that vaccines target has 1273 amino acids in it. The protein that’s important for placenta formation contains 538 amino acids. The fact that there is a random stretch where four of those hundreds of amino acids are in the same order is not surprising. Most, if not all, proteins are going to have really short regions that match with most (if not all) other proteins. To put it in a slightly different context, this comment probably has at least one string of four words in common with one of the Harry Potter books. 🙂 I hope this was helpful!

  16. I am so grateful for the information you have given your readers! I do have a question. I’m sure the answer is out there but I am struggling to find it.

    As our body creates immunity we have CTLs (cytotoxic T lymphocytes) along with B cells and many other things involved in the immune system activation. This is for both antigen induced vaccines and mRNA. This is my big confusion…. Is it possible with this vaccine to have continued immune response (AKA excess CTL production) that could down the road cause tissue damage or dangerous autoimmune responses? I know mRNA is used in cancer treatments and that makes sense bc you can target that exact tumor. I would assume when those cancer tumor cells are gone the mRNA:s job is done and don’t “target” other cells. With this vaccine if we give a lot of mRNA does it keep finding cells and initiate the antigen/antibody reaction over and over? Wouldn’t that mean too much CTL? Perhaps there is no such thing as too much CTL??? I’m confused about excess CTL and an autoimmune response.

    1. Michelle, good question. mRNA is actually a pretty fragile molecule. It falls apart pretty easily. That is actually the reason why these vaccines have to be kept so cold. Also, most cells are constantly chewing up and recycling the mRNA inside themselves as a way to make sure no proteins are being made that shouldn’t be. As a result, most mRNA inside a cell is only around for a few mins to a few hours. mRNA outside cells is going to be destroyed even faster. To give the mRNA vaccines a better chance at working they are modified some, so they don’t get chewed up as fast, but still, they’ll only be around a few days at best. Once the cells that take up the mRNA vaccine express start expressing the spike protein one of two things will happen. They’ll make the protein for a time, maybe even a few days. A lot at first and then slowly less and less as the mRNA degrades until there’s none left. Those will be the lucky ones. The others, probably most, will be killed by CTLs. But what’s really clever about how CTLs work. They actually trigger a self-destruct mechanism in cells. This helps ensure that whatever is inside the cell the body wants to get rid of is bagged up and hauled off with the trash. So any leftover mRNA vaccine will be disposed of as part of this process. That said, your concern about too many CTLs is valid, but it’s one that mother nature has thought of, as there are actually there are another class of T-cells call regulatory T-cells. Their job is to keep the other T-cells from getting out of control and prevent autoimmune reactions. So for these reasons, I don’t think there is a risk of the virus causing an out of control immune response, or leading to autoimmune disease.

  17. Suppose you are vaccinated, what is the risk of you infecting, as a carrier, your spouse at home who is not vaccinated yet?

    1. We don’t know, yet, if vaccinated people can still carry the virus and transmit it to others or not. Hopefully, we’ll know the answer to that soon, but until we do it is critical that even if you’ve been vaccinated you need to continue to do all the things we’ve been trying to do to control the virus for the past 10 months. Wear a mask, wash your hands frequently, and keep your distance.

  18. I have heard that one of the vaccines could cause women of childbearing age to become sterile, is this true and which one?

    My daughter reacts to medication almost always the most rare symptons – botox for migraines almost killed her. How can she know that this is safe for her?

    1. Hi Tamy — thanks for sharing your question. The short answer here is that the rumor you’ve heard about fertility is not true. Here’s the longer version: There is a rumor that vaccines will cause fertility issues because the protein that the vaccines target has four amino acids in common with a protein that plays a role in placenta formation. This rumor is not true. If it were, then everyone who got COVID-19 would also have fertility problems (since the protein the vaccines target is part of the SARS-CoV-2 virus). Here’s the deal: there are only 21 different amino acids. And every protein — from the keratin in your fingernails to the neurexin in your nerve cells — is made up of different combinations of these 21 amino acids. The protein that vaccines target has 1273 amino acids in it. The protein that’s important for placenta formation contains 538 amino acids. The fact that there is a random stretch where four of those hundreds of amino acids are in the same order is not surprising. Most, if not all, proteins are going to have really short regions that match with most (if not all) other proteins. To put it in a slightly different context, this comment probably has at least one string of four words in common with one of the Harry Potter books. I hope this was helpful!

  19. Hi Matt. I really appreciate you taking the time to respond to my questions and it has helped in my understanding.

    Would you mind also confirming how many cells (and which cells) are targeted by the vaccines and what will the immune response be to those cells that produce the spike protein? Does it remove only the spike proteins, effectively ‘cleaning’ the cells, or does it kill the whole cell?

    Many thanks.

  20. Hi. I think I understand the mechanisms involved with both types of vaccine (layman). What I am wondering is, why is it advantageous that we make our own bodies produce an immune response to something that our own cells will be creating? I realize the cells are being ‘tricked’ into making the spike protein but if it is our own cells making it, and our own body then produces an immune response, is that not how autoimmune diseases are created, by the body mistaking its own cells as something it needs to attack?
    Thanks.

    1. Great question. That’s part of the genius of the immune system. Really early on, when you’re still a developing fetus your immune system learns how to tell what proteins come from you. All the immune cells that could react to you are eliminated. This system isn’t perfect because we do have autoimmune diseases, but autoimmune diseases are very rare. The ability of the immune system to tell the difference between you and not you is critical because viruses get inside your cells and hijack them, forcing them to produce its proteins for it. So the immune system has to have a way to still find these threats. To solve this our immune system has a subset of cells that focus on fighting threats that make their living hiding inside our cells. These are the cells that play a major role in fighting viruses.

      These cells patrol your body looking for infected cells. To help with this process, if a cell is infected it can flag itself by actually sticking some of the viral proteins on its outer surface, so the immune system sees that protein, recognizes it’s not something you normally make, and respond. Think of it like a carjacking victim locked in the trunk of their car and manages to signal other people that they’re trapped inside.

      The strategy behind the mRNA vaccines as well as the adenovirus vectored vaccines is that by tricking your cells to make these viral proteins, the vaccine does a better job of mimicking a viral infection than some other vaccines might. This should do a better job of getting all the cells of your immune that would be involved in fighting the virus primmed and ready for the real thing.

      1. Hi Matt. I really appreciate you taking the time to respond to my questions and it has helped in my understanding.

        Would you mind also confirming how many cells (and which cells) are targeted by the vaccines and what will the immune response be to those cells that produce the spike protein? Does it remove only the spike proteins, effectively ‘cleaning’ the cells, or does it kill the whole cell?

        Many thanks.

        1. Great question. Vaccines deliver their payload to muscle cells in the area where the shot goes as well as a key immune cells type called dendritic cells. These cells are part of the body’s invader suveillence system. They patrol different tissues like cops walking the beat looking for suspicious activity. These cells are constantly collecting protein “evidence” and then taking that back to the local precinct (local lymph nodes) and show it to other immune cells, T-cells and B-cells, to see if any of them recognize it as a forgein protein (something not made by the body normally). If they do, that kicks off the resposne. The cells that recognized the forgein protein (in this case the SARS-CoV-2 spike protein) start to divide like crazy, building up the body’s supply of cells who can fight off this invader. You can actually feel this cell division. Anytime you’ve been sick and your doctor told you your lymph nodes were swollen, they were swollen because these cells are multiplying and gearing up for a fight.

          As these cells multiply they leave the lymph node and circultate around the body looking for the invader. In the case of the vaccine, they’ll find more of the spike protein in the muscle cells around where the vaccine was injected. The B-cells are going to make antibodies that will stick to any spike protein that is free and floating between cells. The antibody is going to flag it as something that needs to be removed by other immune cells like macrophages (litterally means big eaters). These cells are one part street sweepers one part animal control. They swallow and digest cell debris, bacteria and viruses.

          As for the T-cells, their are two main types. One is called a helper cells. When activated these cells help coordinate and direct the other immune cells. They’re the coach calling the plays. The other main type are called killer cells. Their job is to kill viruses and other threats that live inside our cells, but to do that they have to kill the cell that is infected. So any cell that is making the spike protein, either because of the mRNA vaccine, or becuase they’re infected with SARS-CoV-2, are going to be killed by these killer T-cells.

          The idea is the cells have been hijacked and turned into factories to crank out new viruse. The body destroys the factory (killer T-cell), and the B-cell sprays our antibodies to neutralize any virus relased from the cell. This process repeats over and over until there’s no more spike protein to be found. Then other cells will move in and start working to repair the damage done by the immune response.

          1. Is there a possibility that another cell such as the nerve cell or the brain cell to recieve the mRNA and causing the spike, thus being killed by our immune system?

  21. You seriously don’t know that there are vaccines using adenovirus vectors? How about Gamaleyas adenovirus 5 vaccine which is linked to HIV positive results in the recipients who were previously negative? Or Johnson and Johnsons trial vaccine? I find it hard to believe you weren’t aware of these vaccines.

    1. Hi Mike – thanks for sharing your concerns, though I’m not sure which part you found confusing. The Q&A specifically refers to adenovirus vaccines that are under development, but have not yet received FDA approval (such as the Johnson & Johnson vaccine, which is specifically mentioned). You also refer to a trial for an HIV vaccine that Gamaleyas conducted 13 years ago. That trial was a disaster, and the vaccine was never made publicly available. Again, this is consistent with the observation in this piece that adenovirus vaccines have been in development for years, but have not yet received FDA approval. There is also a Gamaleyas vaccine for COVID-19 (link to relevant article below), but it also has not been approved by the FDA. I hope this addresses your confusion! https://www.sciencemag.org/news/2020/11/russia-s-claim-successful-covid-19-vaccine-doesn-t-pass-smell-test-critics-say

    2. Sorry, didn’t mean to imply there were no adenovirus vectored vaccines in development. Was trying to keep this about COVID-19 and not go down the rabbit hole on the different mechanisms or histories of each platform. This piece is long enough as it is. Yes there are several adenovirus vectored vaccines in development and have been for years, but none that I’m aware of that are fully FDA approved and currently licensed products in the US (https://www.fda.gov/vaccines-blood-biologics/vaccines/vaccines-licensed-use-united-states).

      1. Hello, thank you so much for sharing this information. I have two autoimmune conditions and am very concerned about which vaccine option is safer long term. Can you offer any insight regarding whether one platform or the other is better for people with autoimmune conditions?

        1. I have several autoimmune diseases and would like to know which vaccine would be better for me. The J & J or the Pfizer. I also have Afib and have allergies to antibiotics such as sulfa and penicillin and e-mycin. Is there one better for me than the other?

          1. Ann, thanks for your question. This is a question best answered by your physician who will have a better understanding of your specific situation and medical history. However, I’m not aware of there being any reason why people with autoimmune disease and/or Afib should get one vaccine over the other. At the start of the vaccine rollout, I know there were reports of a handful of people with a history of severe allergic reactions having allergic reactions to the Pfizer vaccine but these were not life-threatening. At the time some were suggesting those with severe allergies wait for a different vaccine, but now with over 140 million vaccines given in the US, it is clear these reactions are extremely rare. As a result, I don’t think any group is suggesting those with a history of severe allergies get one vaccine over another, but again I would check with your physician to be sure.

        2. Jehan, thanks for your question. I’m sorry I missed this until now. I think I’ve addressed this in a couple of other answers but just to not make you read all the others to find it…This is a question best answered by your physician who will have a better understanding of your specific situation and medical history. However, I’m not aware of there being any reason why people with autoimmune disease should get one vaccine over the other.

        1. It’s my understanding that J&J got approval last summer for a vector vaccine for Ebola that has been used on tens of thousands of people in Africa. Wish we could find out more about that. I was surprised to not see that recognized in the article.

        2. AM, yes. The J&J Ebola vaccine is an adenovirus vectored vaccine using the same type of adenovirus (ad26).

      2. similar to the ill fated J&J vaccine for aids making people more susceptible to aids, could this Covid vaccine by J&J make you more susceptible to catching that cold virus (one use for the vaccine). in effect your body thinks it is a good cell vs the new target (Covid-19 protein)

        1. Marius, thanks for your question. I’m not sure exactly which failed HIV vaccine you’re talking about. There have been several. I’m assuming this is related to the comment piece published in The Lancet (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32156-5/fulltext#%20) last October where some expressed concerns about the use of one type of adenovirus vector in COVID vaccines because that specific adenovirus vector was associated with increased HIV risk in some men in the clinical trial testing an HIV vaccine a few years ago.

          So that vaccine trial used a type-5 adenovirus vector. The J&J and the Astrazeneca/Oxford vaccines both use different types of adenoviruses for their vaccines (ad25 and ChAdOx1 respectively). If these vaccines increased the risk of getting COVID or some other coronavirus we likely would have seen it in the clinical trial data, just like the association with HIV was caught during that clinical trial and that vaccine was terminated. I’ll also point out that both the ad25 vector and the ChAdOx1 vectors have been used in other vaccine trials and this issue didn’t come up there either.

          Additionally, HIV is such a different beast when it comes to vaccines. HIV lives in immune cells. It wants to be in immune cells. Vaccines stimulate your immune system and make more immune cells. So it’s really difficult to make a vaccine that doesn’t give HIV what it wants.

          Certainly, we need to learn the lessons from that HIV vaccine experiment and be on the lookout for things we don’t expect, but given the fact that we haven’t seen anything in the clinical trial data yet, the fact that the adenovirus vaccines approved (or soon to be approved in the US) use different adenovirus vectors, and that HIV is such a special case, the risk here I think is very low.