This article was reviewed by a member of Caltech's Faculty.
Bjorkman, a longtime leader in the study of how the human immune system detects and defends against harmful viruses, is Caltech's David Baltimore Professor of Biology and Bioengineering. Her research group turned its focus to SARS-CoV-2, the virus that causes COVID-19, in the earliest days of the pandemic. The group produced the first images of antibodies from plasmas latching onto a part of the virus and designed vaccine technology that could one day protect against many strains of coronaviruses.
Here, Bjorkman answers audience questions on the science behind COVID-19 vaccines.
Note on Vaccine Development Status
At the time of the January 2021 webinar, 63 vaccines were in clinical development—being tested in humans—and 172 in preclinical development, according to the World Health Organization. In the U.S., mRNA vaccines made by Pfizer-BioNTech and Moderna had proved more than 90 percent effective in clinical trials and received emergency use authorization. Large-scale trials were planned or in progress in the U.S. for vaccines made by AstraZeneca, Janssen (Johnson & Johnson), and Novavax that use methods other than the mRNA platform.
The questions and answers below have been edited for clarity and concision.
Two COVID-19 vaccines are currently FDA-authorized for emergency use. How do they work?
To understand a vaccine, all you need to know is that when a virus infects your cell, it turns on your immune responses. A vaccine turns on similar immune responses, but it does not contain an infectious virus. The vaccine mimics the virus enough so that your immune system recognizes it, but the vaccine doesn't cause you any sort of illness.
Both the Pfizer-BioNTech and Moderna vaccines are called mRNA (messenger RNA) vaccines. That means that what they do is deliver a genetic message to your cells that instructs them to make a part of the SARS-CoV-2 virus called the spike protein, which is normally on the outside of the virus. When it's attached to the virus, the spike protein allows the virus to bind to a cell and then infect it.
So the vaccines deliver the genetic message, and the cells take up that message and start making the spikes, and you make an immune response against the spikes. Part of your immune response is in the form of antibodies, which are circulating proteins in your blood that can go in and out of tissues and so on. Those are directed toward the spike. Now that you have the antibodies, your body can use them to prevent illness in the event you are exposed to the SARS-CoV-2 virus.
There are no components of the virus in the vaccine, so the vaccine can't infect you or give you the disease COVID-19.
How are the Pfizer-BioNTech and Moderna vaccines different from each other?
[Academic researchers outside of these companies] don't know how the two vaccines differ. The mRNA is made in a standard way that researchers in biology, bioengineering, and so on would know. After making it, the companies encapsulate it in what they call a lipid nanoparticle, which has components of membranes and cholesterol and other things. That nanoparticle allows it to go inside cells and might actually also stimulate your immune response. We know the sequence of the mRNA that's encapsulated, and we know pretty much what components are in the lipid nanoparticles.
Those nanoparticles probably differ a little bit between Moderna and Pfizer. People at those companies know exactly what is in the lipid nanoparticles, but we [academic researchers] don't, because that's proprietary. But you can guess based on earlier papers that tell what was in earlier formations of these lipid nanoparticles. People have been making formulations to package mRNAs for eight or 10 years. All of these things have been proven to be safe in animal models and humans.
Why are mRNA vaccines being used for the first time now against SARS-CoV-2?
Well, mRNA vaccines have been previously developed for humans, but the clinical trials weren't completed. For example, Moderna had an mRNA vaccine, I think, that went into humans in 2018 or 2019 against two forms of influenza. They got through the phase one clinical trials, but they haven't yet completed the phase two and phase three, which involve enrolling tens of thousands of people. Normally, the timeline for doing that is quite slow.
There was an emergency in this case. Once the pharmaceutical companies got the mRNA formulated into these lipid nanoparticles, they went very fast through phase one, phase two, and phase three but not skimping on any safety protocols whatsoever. It's just that they were allowed to do this at a much faster pace, and a lot of money was put into it. Normally, it would take a while to complete. The phase one would be, "Is there any horrible reaction?" Phase two would be, "Is there any horrible reaction? And, does it actually have protective immune responses?" Phase three would involve tens of thousands of people, enough people that you could look for rare adverse reactions. Companies combined phase one and phase two, and then combined phase two and phase three to get these out faster. No safety protocols were bypassed.
How quickly do coronaviruses mutate? Is it likely that the vaccines people are receiving now will protect against these mutated strains?
All viruses mutate because they make a huge number of progeny, and they don't have complete fidelity in copying their genomes. That's actually to their advantage, because some of the rare mutations might have properties that allow them to spread more. But the interesting thing is that when viruses mutate, they rarely mutate to become more virulent. Usually, they mutate to [cause milder illness]—because it's to the virus's advantage to infect more people and not, for example, kill them, because they'll spread more if they don't kill their host.
With the variant [first discovered in the UK] and other variants of concern, will the present vaccines work against them? I suspect they will. The data I've seen so far are supporting this. But I want to emphasize that when you make an immune response to any virus, your immune system makes antibodies against all the different places where the virus can bind. The virus is very unlikely to mutate against the whole range of antibodies your body creates.
It could happen that there are enough mutations that a lot of your immune response is diminished. The great thing about these mRNA vaccines is that [companies] estimate they could make a new one in six weeks that would encode a new variant. So, if that's necessary, they can do that. The [original vaccine] has already been in people, they know about how to formulate it, they know what safety procedures there are. They could probably get emergency use authorization quite quickly against new variants if that is necessary.
Do we know yet if people can still transmit COVID-19 after they are vaccinated?
No, we do not. That is a bit frightening. If we are so lucky as to do widespread vaccination all over the world, I think people should definitely continue with social distancing and wearing masks.
Some vaccines confer what's called sterilizing immunity, which means that you cannot get infected whatsoever. But other vaccines protect you against developing the disease that's caused by the virus. One of the polio virus vaccines is a good example. You can still be infected with polio virus, but the virus won't spread to your nervous system, so it won't cause paralysis.
Nobody has had enough time to really look at what's going on since the phase three trials. But people who have been vaccinated almost certainly can get infected. Now, can they transmit that? Nobody knows. Since it's not a vaccine that confers sterilizing immunity, I would think that vaccinated people should assume that you can transmit it and continue to wear masks and do other things to make sure they're not transmitting the virus.
We don't have long-term data from these vaccines yet. How should we think about the long-term potential side effects? What did we learn from previous vaccines?
I think the safety data from vaccines that we've all gotten—polio vaccine, measles vaccine, and so on—they're extremely good. In the long term, we have very few substantial side effects.
Some people have severe allergic responses to vaccines. I just looked up the data. In mid-December, they detected 21 cases of anaphylaxis after administering about 1.9 million doses of the Pfizer vaccine. Most of these occurred within 15 minutes of vaccination. A bit more than one person in 100,000 who's vaccinated will have a severe allergic response. But the interesting thing is, in the phase three clinical trial, they got allergic responses in 0.63 percent of the people given the vaccine, but 0.5 percent of the people who got the placebo also had allergic responses. There are going to be allergic responses. That's why, when you get these vaccines, my understanding is that you're supposed to wait for 15 minutes (or 30 minutes in the case of some previous allergic or anaphylactic reactions) and be observed to see if you're going to have one of these responses. If you do, you're given Benadryl or other things that will calm down your immune system.
Can you address misconceptions about the vaccines? Explain why it will not alter your DNA or cause fertility issues.
I honestly can't understand where the fertility issue came from. There was a very good piece by Katherine Wu in The New York Times in December that discussed this.
This is what I know scientifically: The spike protein on the coronavirus is there to fuse the membrane of the virus to the membrane of the host cell. Lots of viruses have these fusion proteins.
Somebody put out a blog that said [something like], "If you make antibodies against the viral spike protein, there's also a fusion protein that's in the placenta that plays a critical role in developing the placenta. Therefore, it will make you infertile." Well, actually, there is a fusion protein in the placenta. There are fusion proteins all over the place. They're involved in many biological functions in our body. The one in the placenta happened to have originally come from an ancient retrovirus that integrated into the host genome. It looks nothing like coronavirus fusion proteins, period.
The thing that's in common is the word fusion in a description of its function. Someone just read the word "fusion" and knew nothing about the biology behind viruses or the ordinary fusion events that happen all the time in our bodies.
Now, will the RNA get into your genome? RNA does not. They've done a lot of experiments on this using RNA vaccine studies over the years. The RNA remains in the cytoplasm of your cell. It will not go into your genome. There's no evidence for this.
A paper that had not gone through peer review said that under a very artificial situation in which you use cells and culture, you could turn on a natural enzyme that reverse transcribes RNA into DNA. In that case, you could get the SARS-CoV-2 mRNA into the genome. We have common cold coronaviruses all the time. They have basically the same machinery to copy their RNA. They do not go into the nucleus; they just don't.
It's really too bad that this paper was out there because it was picked up by a lot of people in the news. Then the idea was, "OK, if we have a vaccine, and it's got RNA in it, the RNA is going to go into your genome and alter your genome," which is a really bizarre thought to have. It doesn't do that. Even if it did, your cell is going to die anyway. So it would make no difference. But anyway, that's not right.
Why do we have to get two doses of these vaccines?
In immune responses, you mount a stronger or more potent immune response the second time you see whatever it is that you're reacting to because of what's called immunological memory. Vaccines [have typically been tested for efficacy] for years in animals to see if second dose, a boost, is necessary. It's hard for me to know exactly how they came to the decision that the boost is needed in this case. A lot of people have been saying, "Let's just get one of these. Maybe you could spread them out more if you just give the prime," which is the first dose.
The FDA put out a statement on January 4 saying that there aren't enough data to know if the prime would be effective because they didn't have enough people in that arm of their clinical trial. Therefore, they don't want to go against what was done in the phase three trials. The short answer is that boosting helps your immune system. The second or third time you see a pathogen, you mount a much stronger immune response to it.
Here are some of the other questions addressed in the video linked above:
- If someone has already had COVID-19, do they need to get vaccinated?
- What is the evidence that the SARS-CoV-2 vaccines will lead to immunity for people who are 75 or older and those who have weak immune systems?
- Could getting the vaccine cause a false positive in COVID-19 screening tests?
- How is the 90-plus-percent efficacy number generated for the two U.S. authorized vaccines?
- Why do some of these vaccines have to stay in very cold storage while others don't?
- How does the AstraZeneca DNA-based COVID-19 vaccine work in comparison to the BioNTech-Pfizer mRNA vaccines?
- Why do some vaccines protect you for life while others need to be updated?
- We heard that SARS-CoV-2 has "checking procedures to minimize errors in replication." What does this mean for the variants that are popping up around the world?
- Are there different mechanisms for how mRNA will transcribe proteins in different individuals to produce antibodies, given that everyone's DNA is different?
- In what ways are you and other scientists preparing for future pandemics?
- What do you see in the future of vaccine development? Are there any particularly exciting technologies that will change how we do things?