Kyle Allred: Professor Crotty, the research from you and your
team that's been featured in the New York Times and has been recently held up by Dr. Fauci at
a congressional hearing has been key to our understanding about how our immune system reacts
to this new coronavirus and its implications for vaccines. I've gathered a lot of questions from
our viewers about immunity and vaccines including the basic question, how safe are mRNA vaccines? But
before we get to those questions, can you briefly explain your most recent research about SARS-CoV-2
Professor Crotty: Sure, the most recent was to ask, essentially, do people have immune memory to this virus
or not? And what does that memory look like? An immune memory really is a lot like brain
memory; it's you've seen something before and your immune system has figured out how to
recognize it and remember it. It's really one of three major parts that you've got: antibodies, then
you've got helper T cells, and you've got killer T cells. And the the simple way to think about those
is antibodies are really good at stopping a virus outside of cells, but once a virus has infected
the cells, then you really need T cells. T cells are specialized for dealing with infected cells and
antibodies get made by B cells, and so in terms of memory, you've really got memory B cells that can
make the antibodies. You've got the antibodies that are actually circulating in your blood and then
you've got these two kinds of T cells that can either kill cells or have other jobs, and so what
we did was to ask in people who had had COVID-19, do they have these four kinds of memory and
some sub flavors of those? How much of that, and how long did it last? And the quick answer
was essentially like 95 percent of people at six to eight months post-infection really
had a robust amount of immune memory based on on these measurements we did, and this is
the largest study of immune memory ever in people to actually measure all of these
different parts of immune memory. So it was a lot of work, but the results were
pretty interesting that people's immune system do tend to be remembering this virus
pretty well. So that was our recent study. Kyle: SARS-CoV-2 is made up of, what is it, 25 or 28
major proteins?
Professor Crotty: Correct Kyle: The scientists at Pfizer and BioNTech and Moderna have
isolated the messenger RNA for just the spike protein. Is that correct? Is this spike protein
made up of one protein or of multiple proteins? Professor Crotty: It's one protein, so it's
a it's a trimer, so it ends up being three copies of the same protein, so it's all encoded by one RNA.
It's the same sequence just three folded together three times.
Kyle: Got it. Why did both
companies choose to use spike protein for their target for this vaccine?
Professor Crotty: Right, so there are
about 29 licensed human vaccines, depending on how you count, and almost all of them work on
the basis of protective antibody responses, and so when you're trying to move fast
with with vaccine development, the most obvious target is to try and make antibodies
against the protein that's on the surface of the virus, because antibodies work by binding
to the surface of a virus and essentially covering the virus and keeping the virus from doing
anything. That's really the simple way to think about antibodies working, and so
for previous coronaviruses, it was known that there are a couple of different proteins on the
surface of of the virus, but it's really the spike protein that's the major one and probably the most
important antibody target, and sure enough, in the months subsequent to those decisions, lots of
data have accumulated that have said, essentially, all of the neutralizing antibodies, the important
antibodies against SARS-CoV-2, are against the spike protein. So the spike protein is the best
target to focus on for antibodies, and when I talk to you about, you know there really being
three parts of the immune system, one of the concerns has been that sometimes antibodies
aren't that great at stopping all viruses, and then you really need the T cells to kick in,
and the T cells don't necessarily recognize spike. They might recognize some of those other 25
proteins, and so that was actually our first major scientific study on COVID-19 was to ask infected
people: do people make T cells that recognize spike also or only other proteins? And what we found
was that it infected people, actually people make a lot of T cell responses to spike also, and
so that was a really that was a good sign supporting the vaccine development at all that.
If you are, some viruses you have to choose more than one protein. For this virus,
it looks like, "yeah just choosing one protein is a reasonable way to try and get antibody
responses and T cell responses."
Kyle: Along those lines, f this virus mutated, well we know it's
mutating all the time, but if there was a mutation, I guess, is it possible that there's a mutation
where this virus could infect and can cause harm without the spike protein?
Professor Crotty: No, not without the
spike protein. The question's really about whether you know if this is the spike protein.
Can it mutate the spike protein so it looks a little bit different and now antibodies are
recognizing the three-dimensional structure they're physically binding? It's sort of like if,
well I mean, it's like anything. It's like ,you know, it's like my mouse, right? And it's like, well, maybe
the antibodies are really recognizing this little knobby wheel, and if they're just recognizing
that and the virus mutates that, well now you're in trouble, because you're not seeing
the other parts of it, and so that's something people have been spending a lot of attention to. Of
where exactly are those virus mutations? And then, where are the antibody responses people are making?
And viruses behave different ways, so flu is a really big problem in that way, where flu is
clearly able to mutate, but lots of other viruses aren't. So like measles, there's been a
measles vaccine for, what, 70 years now? And the virus has never managed to mutate away from that.
And same thing with polio and hepatitis B, and so far it looks like 95 percent of people still
had antibodies that neutralize that virus very well, and that's probably because every single
person is making multiple different antibodies, so even if the virus has one mutation, that
doesn't escape, because it's only escaping one little part of the immune response.
Kyle Allred: The scientists
have been able to isolate this one strand of mRNA that just codes for the spike protein, and
then they've packaged it into what are called lipid nanoparticles, is that correct?
Professor Crotty: Yes, that's correct.
Kyle: Basically just little fat droplets, if you will, right? Very small uh microscopic fat droplets.
Professor Crotty: Super tiny butter droplets. Yep, that's basically what you're talking about.
Kyle: So, why do they package it that way and also how do they package that way? They have this mRNA,
how do they get it into the lipid nanoparticle? Professor Crotty: Yeah, so um and so I think for that we also need
to deal with just what is RNA, and why is an RNA vaccine a reasonable approach? So RNA is a really
common molecule in your body; essentially all living things use RNA as messages, and
those messages encode within a cell. At any one of your cells, at any given time, you've got
like 5,000 different RNAs and those RNAs are each encoding different messages that tell the cells
to do different things, make different proteins, and RNAs are made to be transient, so they're
really a lot like, it's like 5,000 Post-It notes, and they'll be around for minutes or hours,
and then they get shredded up, and they're gone, they're temporary, and so an RNA vaccine
is same thing, it's a temporary message, but it has to get into the cell, and so if it's in
the cell, the cell will now read that message and do what the message says, which helps then instruct
the immune system. And then the message goes away okay. So RNA are these temporary
messages, or like snapchat messages was the other analogy that I've used. There's a
message and then it it expires. Technologically one of the big challenges there is that RNA
is temporary, it gets shredded up really easily -- again like just shredding up a Post-It note -- and so you got to get it into the cells without
it all getting shredded up. So if you just inject RNA from a syringe into somebody's skin,
it doesn't get into the cells. S the the trick that people figured out over the past
10 years was, "oh you can put it in these little butter droplets, and those little
droplets will basically fuse with the cells and release the RNA into the cell." So now you've got,
the message has now made it into the cell where it needs to be read, and then it can be shredded up
afterwards. So it's just, it's a delivery system to get them all get the RNA into the cells.
Kyle: The lipid nanoparticle that's taken this mRNA vaccine, what cells in our body does it actually
go into? Is it just muscle cells in our arm where we get the injection?
Professor Crotty: Yeah, it's a good question. So it definitely goes into muscle cells, and I think, and scientists are still learning which
cells are the important cells, basically. Most of the cells that are getting the
RNA are the muscle cells, and it's possible that specialized cells of the immune system
that aren't very common, but they may get the RNA, and those may be the more important for
starting the immune response, but yeah most of the RNA is going into the muscle cells and I'm
sure the protein expression there matters. It's just, that might not be the only cell type that
matters.
Kyle: A question a lot of people have had is, once that mRNA gets into our cells and codes for
that spike protein, does it just code, does each strand of mRNA just code for one spike protein? And
then does the Post-It note, or the mRNA get destroyed or dissolve, or does it code for
multiple proteins and last for maybe an hour or a day? Like how long does the mRNA from this
vaccine actually last in our cells, approximately? Professor Crotty: Yeah, it's a good question. So the goal, so the
RNA gets read multiple times, so it'll just keep -- it gets read over and over and over again,
so that you make a lot of the spike protein, which will then get expressed on the surface
of the cell to stimulate the immune system. And I'd say average RNAs in your cell will last
some time, generally minutes to hours, but some of them will last a day or more, and these, the RNA
vaccines are engineered to be stable, and so um the information I've seen is that they'll last
a couple of days.
Kyle: So we have the mRNA inside of a lipid nanoparticle, what else goes in in the
vaccine obviously it's got to be some type of saline solution or something?
Professor Crotty: Right, that's it.
It's basically, um, it's basically just delivered in some, essentially, some, yeah, salt water set to match
the the saltiness of your own body. So that it's essentially as "natural" as possible.
Kyle: It seems like a question that a lot of people have with vaccines in general is, "okay, well what else
do they put in them?" And from my understanding with this Pfizer and BioNTech vaccine, they
came out and said, "we didn't put any adjuvants or preservatives in this particular vaccine." Why
are adjuvants used sometimes in vaccines? Professor Crotty: Yeah, that's a great question. So essentially, usually
adjuvants are are used, and it goes back to what I said about immune memory at the beginning,
you know your immune system, some remembers some things really well and remembers other things
really poorly, and there are complexities there, but the the rule of thumb is that the bigger
the threat, then the bigger the memory. It's a lot like, you know, you might not be able to
remember what socks you put on two days ago, but if you're almost in a car accident
at some particular intersection, you're going to remember that intersection for a very long time,
right? Because it was a memorable event, and so vaccines have to deal with the same thing:
that the immune system is good at ignoring things that aren't very threatening, and so adjuvants are
a way of providing the immune system a stimulation that says, "hey, this thing that you're about to see,
this is a potential threat, and you should make a substantial immune response to it and remember
it," and so that's if you just inject a protein by itself. That protein's inert; it's non-threatening;
it's not replicating; it's not going to do anything to you. And so the adjuvant is the immune
stimulus to get you going. An RNA vaccine essentially ends up encoding its own
stimulation, so it accomplishes that on its own. Kyle: The lipid nanoparticle has done its job. It's
brought the mRNA into the cell, and now it's the ribosome's job to actually code, or basically
essentially build a protein out of that structure? Professor Crotty: Right, so what your immune system ends up needing
to see in the end are proteins, because that's what the virus itself is made out of, proteins. The spike
proteins are on the surface of the virus, and it's those proteins that an antibody or T cells would recognize and your cells are making proteins all the time, as instructed by
RNA messages. So now instead they're going to make these viral spike proteins, and that's what
the immune system will start recognizing, and that does get triggered by just the normal protein
synthesis machinery in the cells, which is, um yeah, which are the ribosomes and the amino acids
already in your cells.
Kyle: Why not just skip a step and use a vaccine that uses the spike protein
itself? Why go through this extra step of the of the RNA?
Professor Crotty: Right, that's a really good question, so and
one of the classic ways to make a vaccine is to have the vaccine be the protein, be the
viral spike protein or be a viral nanoparticle. And there are vaccines that work
fantastically well that way, and some of the original vaccines going back
to the early 20th century are that way; that's the tetanus vaccine and diphtheria
vaccine, which are incredibly successful. And in fact, some of the COVID-19 vaccines
currently being worked on are protein vaccines, and there's a reasonable chance those will succeed
as vaccines. A downside to protein vaccines is that you have to manufacture the protein, and
the manufacturing process for any given protein is its own unique manufacturing problem, and so in
terms of just a physical production problem, you've got to solve that production problem. And since
that's unique, the FDA has to basically review every step of it and agree that everything
is fine about that. And viral proteins tend to be kind of unusual proteins; they're
not super simple to manufacture, so it can take some time and energy to figure out
how to solve that, basically, manufacturing problem, that biochemistry protein synthesis
problem. The RNA vaccines bypass that problem, because the manufacturing process is always
the same. The RNA encodes a different sequence, but molecularly, it's the same manufacturing
process, and so FDA approval and what not is all really fast, because it just it looks
the same from a manufacturing standpoint. So that's why the RNA vaccines have gone through phase
one, phase two, phase three trial so fast and gotten FDA approval so quick is because they were they
were very fast to manufacture and very fast to approve, because it's, largely, once they solve
the problem once, it's plug and play.
Kyle: So along those lines, do you think this is really the future of
vaccine development, using this type of technology? Professor Crotty: I mean, the results are incredibly encouraging, right?
I mean this is the first time ever in human history there's been a vaccine developed within a
calendar year, and not only that, now it's actually been three, right? There have been three
successful phase three clinical trials within a single calendar year. That's never happened for
anything. So those are phenomenal successes in the RNA vaccine showing 95 efficacy,
right? And fantastic efficacy in the elderly and fantastic efficacy against severe disease. I mean,
those are huge wins and RNA vaccines are definitely going to be successful solutions
again in the future. I think they're likely to still be part of the vaccine toolbox. I don't
think they'll solve every problem. There are some things that I think they're
good at, and there are other things that other vaccine technologies may be better at. But in
terms of speed, I mean, nothing can match this. You know, I mean vaccine development, classically,
is frequently a 20-year process, right? Or, you know, let's say a 10-year process, and instead you're
talking about a 10-month process. You know, it's not only a 10-month process, but a 10-month process
that really involved a huge amount of safety data on all, right? I mean, you know, 70,000 doses being
given and tested to validate both the efficacy and the safety that clearly RNA vaccines have a
very promising future.
Kyle: From my understanding, mRNA does its work just in the cytoplasm of our
cells. Is that correct?
Professor Crotty: That's correct. So yeah, I've gotten lots of questions about, "well wait,
isn't this genetic engineering? I don't want to be genetically engineered." I'm like, well, fair enough,
I don't want to be genetically engineered either, but this is RNA; it's just messages.
They're transient, temporary, they don't become part of your body.
It's just not the same thing as DNA. Kyle: Now what about, speaking of DNA, the AstraZeneca vaccine candidate that utilizes DNA? Professor Crotty: Yeah, so both the AstraZeneca
approach and the Johnson & Johnson approach use a viral vector, and it is a viral vector that
contains DAN, but really it's about the virus. So they're using a different virus and
adenovirus as a delivery system into your cells, essentially, you know, sort of like giving you one
viral infection to teach your immune system how to fight another viral infection. That's also
transient DNA that doesn't become part of your DNA, That's just the virus's DNA, and those
viral vectors they've been "gutted," so that they can't become another adenovirus.
It's like taking a car and taking out the engine, you know, and even and taking out the
seats. It still looks like a car from the outside and you can put some new stuff in it, and you're
sort of showing that to the immune system to teach you what something looks like, but it's not going
to go drive off on its own or anything. Kyle: Got it. Okay so going back to our kind of step-by-step
process, we have the mRNA. The ribosome then codes for a spike protein. Does that spike protein
then get released from our our cells? Does it get expressed on the surface of our cells or both?
Professor Crotty: Both. Predominantly, it's getting expressed on the surface of the cells, and that's just um, that's
where, well, that's a good way for it to be shown to the immune system, basically.
Kyle: So it gets shown to
the immune system and then what happens? Professor Crotty: Uhhh, so, a thousand different things. [Laughter] An immune response
is a really complicated, orchestrated dance but, essentially, you have in your body right
now parts of your adaptive immune system that can potentially recognize any possible
virus that would ever exist. But to do that, you have billions of cells that are all really rare, so
it's basically, there's like one in a million cells somewhere that could actually make the antibodies
that would recognize the virus that would stop it. And same thing with the T cells, so what has to
happen is those very rare cells have to be exposed to this new protein, and then since those cells
are so rare, they're not very useful when they're, you know, one in a million, one in a billion
cells in your body. So those cells have to grow and divide and multiply until there
are millions of them, and that takes time. And that's one of the big goals of a vaccine
is to, really, the whole point of a vaccine is to show your immune system what the
virus looks like before you're infected, so that your immune system can go through
that learning process and that growth process on its own, on your immune system's own time,
and get you to a point where now, okay, you've got the antibodies, and you've got the T cells,
and you're going to have that immune memory all before you ever get exposed to the virus.
So normally when you get exposed to the virus, the virus gets the head start. Okay and then your
immune system is playing catch-up; your immune system has these rare cells that can potentially
protect you, but they're rare, and they have to grow from one cell into a million cells, and
usually that takes a week, and you get sick for that week in the meantime.
Kyle: So you talked about this cascade of immune system effects and response to either a vaccine or
a natural infection with a vaccine. What symptoms would you expect when the immune system
is really ramping up and responding?
Professor Crotty: Yeah, it's another good question, and and I get
it a lot. Yeah, I definitely tell people, you know, these vaccines are safe; that
doesn't mean they're not gonna make it not feel so great for a day or two or
have a little bit of a fever, and that can be a really positive thing, because essentially this
goes back to your immune system is really designed to remember things that were something
of a threat, you know, and so it's, uh, you really do kind of have to earn your immunity some, a lot like
going to the gym and working out. You know, if you get really sore, that can really be a positive
sign. Same kind of thing for a vaccine; if you've got some swelling, if you've got
some redness, if you got a little bit of a fever, those are basically all straightforward signs that
your immune system is working, is doing its job of recognizing that vaccine and building
the tools and weapons to fight the virus if they see it, and usually for most vaccines, that
can go on for, you know, one day, two days, three days, and that's been what people have been seeing
with these RNA vaccines as well. Most people get a bit of redness and a bit of soreness, and and
some people get a real fever for a day, and that's honestly just a positive sign
that your immune system is fighting it. Kyle: So, I mean, "side effect" is almost the wrong
terminology for that. I mean, it's really kind of an expected immunogenic response.
Professor Crotty: Exactly,
and that's why it's important to recognize that safety is really important for
vaccines, because vaccines are given to healthy people, and that's always been a key feature
of vaccines is paying a lot of attention to to safety, but that's different than, yeah, what we're talking about here of getting sore or feeling feeling a bit tired.
Those can be sort of, essentially, "on target" effects, signs that you're immune, signs that the vaccine
is really working.
Kyle: The guidance from the FDA and the CDC with the the Pfizer-BioNTech vaccine
is that even people who have had a previous SARS-CoV-2 infection should get the vaccine. I think
a lot of people were initially confused by this. Why do you think they made that recommendation?
Professor Crotty: Yeah, it's a good question, and it's because we don't, like as of today and certainly as of
a couple weeks ago, we don't have a good grasp of how long does protective immunity last after you've had COVID-19? And we also don't know how long it lasts after
the vaccines. But, so far that the vaccines are are looking good. In our data,
when we looked at immune memory in people, right, we were seeing something like
95 percent of people had what we consider immune memory. That looks good, but that still
doesn't prove that those people are going to have protective immunity. Really, you have to have
bigger, longer studies to wait and see, you know. How long are people protected? And so,
yeah, I think the vaccine recommendation is the right one. If we knew for sure that catching COVID-19 really did give you protective immunity for a long time, then
I think the vaccine recommendation would be "no, don't bother." But as it stands right
now, we don't know that, and so it makes sense to still recommend getting the vaccine.
Kyle: And is it possible that the vaccine can actually give longer immunity than a natural infection? Professor Crotty: It's possible. There are definitely vaccines that do that. So the papillomavirus vaccine is a
fantastic example of a vaccine where the vaccine works way better than natural
infection at generating protective immunity and long lasting immunity. The opposite also occurs.
I mean, the normal flu vaccine really gives pretty short-lived immunity, but if you actually
catch the flu, your immunity to that flu is really quite long-lasting. So it can
go both ways, and since RNA vaccines are new, we don't have a historical reference point for
comparison. So far the data with the RNA vaccines has been fantastic, and really the big
unanswered question with them at this point is durability. How long are they going to last?
And right now, we don't know how long durability is going to last for the
vaccine compared to having had the infection. Kyle: The Pfizer-BioNTech vaccine and the Moderna
vaccines are very similar. Why does the Pfizer vaccine need to be stored at negative 94 degrees
fahrenheit, when the Moderna vaccine just needs regular refrigeration?
Professor Crotty: It's pretty cold, right? Well,
I think the Moderna, one requires the very cold for long-term storage but for a shorter term, it can
do better. And in fact, there are other RNA vaccine formulations that have been published later
in 2020 that could actually do room temperature storage. It comes down to the
nature, the precise nature, of those lipid nanoparticles, and
how stable they are. Kyle: I'm gonna put you on the spot here, Professor Crotty.
If you had a family member or a close friend say to you, "You know, professor, you've
studied vaccines in immunity your entire career. This vaccine looks promising, but it, you know
as you mentioned, the timeline has been so much shorter than what we're used to with vaccines and
it's using a new technology, this rna technology. Should I be nervous about this?" What would you say?
Professor Crotty: Yeah, great question. And the answer is no, don't be nervous. Definitely get vaccinated. If you can get vaccinated, I mean obviously for one right now, the COVID-19 threat in the population
is horrible, right? I mean, we've crossed thresholds of like 3,000 deaths a day in the
country. I mean, those are, uh, it's a really bad situation, and on the flip side, these vaccines
are, you know, 95 percent effective. That, in two totally independent trials of huge numbers of people, that
data is really strong. These vaccines definitely work, and yeah I certainly get questions
about safety, which are reasonable questions to ask, again, because you said, because of the speed.
And so there are two parts of it: one is you would be really hard-pressed to find any
medicine that has had this much safety data already by the time it becomes publicly available.
Again, 70,000 people have already gotten the vaccine and been tracked for safety. That's a huge
amount of safety data, way more than most medicines get when they come to market. So, I mean, those
are -- and the reason for accumulating all that was actually because of speed. That's actually to find results quick enough, they had to have a huge number of people involved in the study,
and so as a result, they got a ton of safety data, and they've also got safety data going,
you know, for essentially six months from the earlier clinical trials that got started
in the summer. Really the best way to think about the speed of development is one: this is
a technology that could move very fast through manufacturing and that's really where a lot of
the speed came from was manufacturing. The safety parts of it is the same amount of
time as it basically always takes. And the other thing that's been fast about it has been problems
that money could solve. So normally for developing a vaccine, somebody goes through a phase one trial
and then waits and then goes through a phase trial and waits and then goes to a phase three. They
don't invest a huge amount of money up front, because there's a good chance that they would lose
that money, and instead in this situation, right, going back to March, companies governments, and
non-government organizations were all saying, "okay, invest the billion dollars up front, you
know, and sure, we may lose that money, but if it works we'll have a vaccine, you know, a
year faster than we otherwise would, because we're just paying for the manufacturing to get going
up front." That's just the problem money can solve. You could just be losing
that money in the end, but you're not taking any shortcuts. You're just starting the process a
lot earlier than you would otherwise and, sure enough, things worked out incredibly well, right,
and these vaccines are actually working, and so now there are already vaccine doses being
delivered instead of the companies now starting to manufacture them and then being delivered, you
know, six months or more later.
Kyle: And as you mentioned, there's good data and there's a lot of data about safety in the short term. What about long-term potential side effects? I know that's another
concern.
Professor Crotty: Yeah, that's a good question, and that was one of the main ones that the FDA wanted to consider as
well, and so basically they did a review of of vaccine literature and said ,"yeah in the past
for all these other vaccines, any important vaccine safety signature was clear within two months," and
so that's why the FDA specifically demanded that there be two full months of safety data on
these large trials and that's what's being reviewed by the FDA, and they've, yeah,
they've looked fine.
Kyle: So in other words, if, based on on the extensive history we have with vaccines, if
you don't see a safety concern in the first two months of use of the vaccine, it's unlikely to see
long-term side effects down the road?
Professor Crotty: Right, yeah, that's exactly right.
Kyle: Well, Professor Crotty, thanks
so much for joining us today. We really appreciate it, and, briefly, any next projects that
you and your team there at the lab are focusing on? Professor Crotty: Yeah, so, I mean, here at the La
Jolla Institute for Immunology, we're one of the best places in the world studying the
immune system, and we can actually look at all these different immune responses to COVID-19 at
the same time, which most places can't. So we're continuing to examine that both to try
and understand acute disease, you know why people end up in the hospital, as well as immune
memory to this virus, and it's, uh yeah, it's a lot of work, but it's important. So those
are the problems we keep trying to solve. Kyle: Well, thanks so much for your time and all your research
and work. Really appreciate it.
Professor Crotty: Yeah, thanks, Kyle.
