A little over a week ago, as a result of something kind of stupid that my dad shared on Facebook, he sincerely asked a scientific question about viruses.
You
have me curious as to the major differences in the Flu Vaccine, and
these (now at least 4) Covid-19 Vaccine? I would assume their are
similarities--- and of course I wonder and even can speculate some of
the differences.
That was a surprisingly reasonable way for him to ask about this topic, given the usual crap I see on Facebook. So I wrote a long answer. Since I spent a bit of time just typing the answer up, I decided to save a copy of it here, where it will be easier to find if I ever want to look at it again in the future. Also, if anyone happens to read this blog post and spots an error in my description, please let me know! I was typing most of this up from memory and my biology classes are many years behind me. Anyway, I thought I did a decent job of explaining these concepts to someone like my dad, and while that won't necessarily translate to an explanation that would work for someone else, maybe it could work? I don't know. I found it worth preserving. So deal with it...
There are some pretty big differences. To start with, I need to recapitulate something you might have learned a long time ago.
In
our cells and (most of) the cells of any animal, there are different
membranes holding structures, and all those little bits are made out of
mostly proteins and lipids, with smaller components made up of sugars
and of certain kinds of RNA. There's a big membrane in the middle of a
cell called the nucleus, and that's where the DNA for the cell is
stored, bundled up around little balls of special proteins. In order for
cells to live, they need to make lots of different proteins and each
protein has to have its own shape, which is very specific. It's the DNA
that stores the information for which building blocks to use, and in
which order, for making those proteins.
The
nucleus uses chemical signals to control which parts of that bundled up
mess of DNA gets unwound, and then special proteins follow the DNA like
a track. As the protein moves along the DNA, it puts a building block
of the corresponding RNA up and makes a new track out of RNA. So
remember how the building blocks in DNA are A, C, G, and T? The proteins
that move along the DNA do a process called transcription, and for
every C they put down a G, for every G they put down a C, for every T
they put down an A, and for every A they put down a U (not a T, for
reasons I won't get into right now). Once the segment of DNA has been
transcribed, you have a segment of what's called mRNA (short for
messenger RNA). The DNA stays in the nucleus, but proteins ship the RNA
out of the nucleus, where it gets fed into globs of rRNA (ribosomal RNA)
and protein called ribosomes. The As the mRNA is fed through the
ribosome, sections of it get matched up to sections of tRNA (transfer
RNA), with A matching to U, U matching to A, C matching to G, and G
matching to C.
Each
piece of tRNA has two business ends. One end has three building blocks
(AAG, CUA, etc.) and the other end fits onto a specific nucleic acid. As
the tRNA gets lined up on a ribosome, it forms a sequence of amino
acids in a specific order, and that string of amino acids is the first
step in building a new protein. This process is called translation.
Generally the mRNA will also present signals that cause certain parts to
get trimmed or other parts to be fitted onto the protein, but that
depends on what you're building.
That's
a long refresher, but I needed to explain transcription and translation
because different viruses hijack these systems in different ways. Some
viruses have DNA. Other viruses have RNA. All viruses have protein
because they need to do three things...
Step
1: Get inside the right kind of cell. Not just any cell will do. The
proteins in a virus are adapted to do their own in a specific
environment, and might not work properly in the wrong kind of cell. Each
virus has proteins on the outside of it that are shaped in a way to
hijack receptors on the outside of a certain kind of cell. It simply
"docks" onto a receptor. Once docked, there are a few different ways in,
which I'll gloss over for now.
Step
2: Hijack the proteins and ribosomes of the host cell and use those to
build the proteins of the virus instead. The DNA or RNA in the middle of
the virus stores the information for what it will hijack the host cell
into building. It will also cause copies to be made of its own DNA or
RNA, and those copies get assembled into new copies of the virus.
Step
3: Get the new copies of the virus out of the host cell so that they
can spread out and infect more cells. There are a few different ways to
do this. Just like there are different ways to get into a cell, there
are different ways to get out, but I'll gloss over those for now.
Coronaviruses
and influenzaviruses are both RNA viruses. They don't make their own
DNA. Some viruses do, but we can ignore those for now and focus on RNA
viruses only. So they both use RNA, but right from the start, there's a
huge difference in how they use it. A coronavirus has what's called
"+ssRNA." Basically, once proteins in the coronavirus sneak their own
RNA into a host cell, is masqueraded as regular old mRNA, like what
would normally have come out of the nucleus of the cell. That RNA, which
is viral +ssRNA but is being presented as mRNA, gets translated and the
proteins that the RNA codes for get built in the same way that a
regular protein would get built, but these are proteins that the virus
uses instead. Ultimately, the new viruses exit the host cell. This
doesn't kill the host cell right away, but it's an energy-intensive
process.
Like
a lot of viruses, coronaviruses use a little trick to lock down the
ribosomes that the are translating their RNA. So those ribosomes would
normally get refreshed and prepared to receive new mRNA, but the viral
RNA keeps them jammed up, copying viral RNA over and over. That means
lots of new viruses. The process that coronaviruses use to exits host
cells (called exocytosis) is energy-intensive. The host cell uses its
own energy to build a membrane around the viruses, transport that
membrane to the outer membrane of the cell, and then push those packets
from the inside of the cell to the outside. Cells can only keep doing
that for so long before they break down.
Now,
coronaviruses use +ssRNA, but influenzaviruses have -ssRNA instead.
Unlike a coronavirus, an influenzavirus contains RNA that cannot be fed
directly into a ribosome as mRNA. Influenzaviruses take a different
approach. While a coronavirus would have a mechanism to enter, and then
try to get its proteins hooked up to the parts of the cell that have the
most ribosomes, influenzaviruses have a two-stage entry sytem. They
enter the cell membrane, then the parts that are left over form a new
package that itself gets inside the nucleus. Remember how the nucleus is
where mRNA first gets made? Well, the proteins in the influenzavirus
snag some of that, and then have their own RNA tag along for the ride.
They form a complex that makes strands of mRNA by stealing mRNA that the
host cell was making, and those strands get exported by the normal
systems to the ribosomes, which dutifully read them and inadvertently
build new viruses.
In
some ways, the proteins that the influenzavirus makes are quite
aggressive. They don't just passively form new viruses, but start
breaking down RNA that cell was using for other things, so that more
material will be available for making new viruses. They also line the
cell membrane with proteins to build the outside layers for new viruses,
and a whole bunch of viruses start budding off from the host cell,
which kills it.
So
you see, even though coronaviruses and influenzaviruses have some
things in common, and even though both of them contain single-stranded
RNA, they also have some pretty extreme differences. Most of what I've
said has to do with what the viruses do while inside a cell. But the
outsides of the two viruses also look different from each other, because
the systems they use for docking and entering host cells are different
too. Coronaviruses got their name because under an electron microscope,
their spike proteins look like a halo, and people thought that it looked
like the corona around the sun. The outside of the virus is a lipid
membrane with three different types of protein embedded in that
membrane. The "spike" proteins are the ones that stick out the furthest
and form the "corona", and they're the ones that dock onto host cells.
Influenza
viruses are bigger and more oblong than coronaviruses (sometimes only a
little oblong and sometimes they can be very oblong). It has a
protein-based shell that sits inside a larger membrane. Compared to the
size of the overall virus, its spike proteins don't stick out as far,
but they're embedded in that outer membrane in a similar manner.
As
you might imagine, these differences have some implications for
vaccines. There are two big issues I'll get to when it comes to vaccines
specifically. But for now, I'm out of time. More later.
At this point I took a break. So my dad responded.
It’s
nice having a Scientist in the Family. Who can also write and explain
that even a high school educated good looking guy can understand. I
appreciate it!
You
and I have talked about this before... I had a friend who is a doctor,
who also served in the Coast Guard Reserves, who wrote his Thesis on the
Swine Flu Epidemic in the early 70s ...I think around 74... Anyway, he
made a case for only getting essential Vaccines because of (either I am
not sure— White Cell memory or T Cell memory) has set capacity. And if
you get every flu shot annually and a ton of low risk Vaccines
introduced into your body’s defense system you are actually compromising
your body’s defenses.
I
personally believe there is logic to it. However, I would think anybody
at a High Risk should protect themselves. But Don’t Believe Everything
You Read....especially is Sound Bites!
Thanks Again! You Are Awesome—- like your Dad
The
Compromise of the Defense System... His point was because you have
already committed those cells and now have a lower Threshold.
Now back to me...
So,
T-cells are a kind of "white cells." There are lots of different
specialized cells in the immune system, and some of them have very
specialized functions. Some cells are part of the "innate" immune system
and others are part of the "adaptive" immune system, which can grow
cells targeted at specific things called "antigens." An antigen is
usually a molecular structure on the outside of a cell or virus, and the
adaptive immune system can learn to recognize those structures and
target them. Generally, these are the B-cells and the T-cells. B-cells
produce immunoglobulin antibodies, and those have business ends that form
shapes to match the shapes of antigens, like little molecular jigsaw
puzzle pieces. The antibodies latch onto their antigens. On a virus like
an influenzavirus or a coronavirus, the antigens that you want to get
targeted are those spike proteins that I mentioned earlier. This does
two things. Firstly, the spike proteins that have antibodies latched
onto them cannot dock onto a cell. So once a virus gets hit by enough
antibodies, it loses its tool to invade cells. Secondly, this tags the
virus, which makes it easy for other cells in the immune system to
recognize it as a threat.
T-cells
use lots of little proteins called "cytokines" that act as signals to
control other cells in the immune system. They'll send signals like
"these are the wrong B-cells for this infection, bring me different
B-cells" or "there are a lot of antibodies tagging invaders here, bring
in the big eaters to come eat these invaders." Scientists still aren't
sure what all of the functions are for every kind of T-cell, but they've
figured out a lot of this. Sadly, one of the main reasons that they've
figured so much of this because HIV messes with the function of T-cells
and it also mutates a lot, so there is a large population of human
subjects who have had their T-cells messed with by a virus. That has let
researchers see the effects that happen when T-cells aren't doing their
jobs correctly.
The
question has come up as to whether the adaptive immune system can
become "overloaded" or run out of memory. There are B-cells and T-cells
that are called "memory cells" and they do store information on their
own unique antigens. Do we eventually run out of those? The answer seems
to be no, not really. At least, not under normal circumstances. The
vast majority of memory cells that get created have nothing to do with
vaccines, nor with when you're very sick fighting off a severe
infection. They're just part of day-to-day life, and they barely take up
any room. Your immune system doesn't store huge amounts of cells
targeting every kind of virus, bacteria, or parasite you've ever been
exposed to. Instead, it keeps tiny reserve amounts of those memory
cells, and then when it find it needs a certain kind, it sends signals
to clone a whole bunch of that one kind. And then, once the infection is
gone, it decommissions most of those cells. It turns out that healthy
people, even ones who are super-old like you, have plenty of spare
memory cells ready to be activated in response to new antigens. Like
other parts of the body, the immune system does start having problems
with age, but that isn't because the immune system is running out of
cells! In fact, it's kind of the opposite problem. Most of the
age-related problems with the immune system are because some kind of
physiological breakdown means that there are too many of the wrong kind
of cell, and the aging immune system stops correcting for this in the
way that it used to.
This
is a matter that has been very well-studied, by the way. There's been
some concern in medicine over whether vaccines need to be spaced out or
if they'd interfere with each other. That doesn't seem to happen. There
can be problems with vaccines (mostly allergic reactions), but none of
that seems to be linked to scheduling too many vaccines.
Now,
there are two traditional types of vaccines that have been in use for a
long time. The first kind is a dead virus vaccine (also called an
inactivated virus vaccine). To make that, a pharmaceutical company grows
a bunch of viruses and then kills them, usually by heating them up, but
sometimes by exposing them to chemicals. The second traditional kind of
vaccine is a live attenuated virus vaccine (also called a weakened
virus vaccine). To make that, a pharmaceutical company grows a bunch of
viruses in a medium (usually eggs, but sometimes animals) that causes it
to basically breed viruses that are weaker versions. Once they get a
strain that can infect human cells without doing much damage, they use
that to make the attenuated virus vaccine. Influenza vaccines used to be
made with both approaches, but it turned out that the influenzavirus
was a poor candidate for an attenuated virus vaccine. So flu shots are
made using dead viruses.
Dead
virus vaccines are pretty common, but they've had issues that have been
known for a long time. Here are some issues with these vaccines...
1.
The immune system might not respond at all. These aren't active
viruses, so once they get into your body, they're just rapidly degrading
clumps of protein. They'll get broken down on their own. If that
happens, it can't hurt you, but it also means you don't get any
immunity.
2. The innate
immune system might respond before the adaptive immune system formulates
a strong response itself. If cells in the innate immune system (such as
phagocytes) destroy the dead viruses before the adaptive immune system
finishes working on them, then you might not get immunity.
3.
Because these are dead viruses, they tend to get broken up. There's a
chance that the adaptive immune system might pick the wrong thing as an
antigen. If you had a real infection, then that response wouldn't work
and the adaptive immune system would keep trying until it got it right
(or until you died). But since this isn't the real thing, your adaptive
immune system might start working on the wrong protein or on a broken
version of the right protein. It will most likely select the correct
antigen, but might also generate antibodies that don't properly stick to
that antigen. In a real infection, you'd be making a lot more of the
cells that produce the immune response, so you'd get the right kind of
memory cells eventually. But with a vaccine, your T-cells and B-cells
might create a less effective response.
4.
In a real infection, your T-cells can learn to target not just viruses
themselves, but cells that are infected with viruses. You don't get that
kind of immunity from a vaccine. If you get an immune response so good
that it's killing the viruses before the have a chance to infect very
many cells, that's not a problem. But if your response is too weak, then
this issue compounds that.
Despite
these issues, it's sometimes better to use dead viruses than weakened
ones. They've tried making influenza vaccines using live attenuated
viruses, but it didn't work very well. Also, even though these issues
mean that a dead virus vaccine might not always work, that doesn't mean
the vaccine is no good. For one thing, vaccine researchers have come up
with better techniques to make influenza vaccines have a better rate of
success than they used to. The flu shots in the last few years have been
better flu shots than what used to come out every year. For another
thing, vaccines that are only mostly successful can help create herd
immunity. That's the reason I get the flu shot. If I became infected
with an influenzavirus, I'd probably be fine. But if we have lots of
healthy people getting the vaccine, then people who are
immunocompromised or vulnerable to the virus are less likely to ever
come in contact with it. Until relatively recently, we'd wiped out
measles in this country with a live attentuated virus vaccine. The
vaccine didn't work on 100% of the people who got it, but it does work
about 97% of the time. And if almost everyone who could get the vaccine
got it, there'd be no way for the virus to spread, even if someone from
another country brought measles here, there wouldn't be enough
non-immune people coming into contact with that person for it to spread
through our population. That was true for a long time, but by 2018,
antivaxxers had made it so that there were enough unvaccinated children
for measles outbreaks to happen in the U.S.
There's
one more issue with vaccines that's specific to influenza and doesn't
apply to most other viruses, and unfortunately it's a big one. Remember
how I said that the genome of the influenzavirus is made up of -ssRNA?
Well, in some viruses, the genome would be "circular." In an
influenzavirus, the RNA in its genome comes in eight separate strings.
You could almost think of them as being like chromosomes. What sometimes
happens is that a person or animal gets infected by two totally
different strains of influenzavirus at the same time, and that two
viruses with two different genomes both infect the same cells. So a
string of RNA from one influenzavirus can get swapped into copies of
another influenzavirus that is being built in a cell. Sometimes, this
makes a new virus with different features. Whenever you've heard about
issues with swine flu, that's why. You might get a virus that is really
nasty, but it can't spread from birds into humans, so it's not a threat
to us. And then you might get another virus that isn't as deadly, but is
better at jumping between species. If a pig gets infected with both
viruses and lots of its cells are being exposed to them, you could get a
new virus that can jump to humans and is also deadly to humans. This is
called "antigenic shift." It has happened before, and it caused the
1968 "Hong Kong flu." After the deaths from that flu, it was something
doctors were really worried about, which led to an event you probably
remember: the 1976 "swine flu scare." In that year, there was a vaccine
that was poorly tested and its administration was poorly documented, so
it was blamed for bad side effects in the elderly. There's been a lot of
debate since then as to whether that 1976 vaccine actually killed
anyone or not, but it became controversial anyway. For many years, it
was believed that antigenic shift caused the 1918 flu pandemic. But in
2005, studies on a frozen body that had been exhumed in Alaska proved
that it wasn't antigenic shift, but that instead a more normal type of
mutation or "antigenic drift" had caused that pandemic.
Birds,
migratory waterfowl in particular, have lots more strains of
influenzaviruses than other animal populations. Part of the improvement
in flu vaccines has been related to tracking what kind of viruses are
dominant in those waterfowl before they make their way to the biggest
areas where humans and chickens live together (southern Asia). In some
past years, researchers developing vaccines had poor information or
guessed wrong, and flu vaccines didn't really do anything because they
were to the wrong strains of flu. Those were bad seasons for flu and
more people died from it. But the past couple of years have been pretty
good, mostly because researchers learned from the mistakes of the past.
Making
new vaccines is part science, part art. The researchers who do this
work have different tools and apply them in patterns based on what has
worked in the past. So if a virus is similar to one that researchers
have been able to make very strong vaccines to in the past, there's a
good chance they'll be able to apply their techniques and make a good
vaccine to this new virus. They've been making influenzaviruses for a
long time and they've gotten pretty good at it. But even though
coronaviruses have been around for a long time, there hadn't really been
successful vaccines against them, at least not in humans. The tools
that worked on other viruses weren't as effective with coronaviruses. So
how do the coronavirus vaccines work and what are the differences
between them? Well, because of how big of a deal COVID-19 has been,
different companies have been trying some different approaches, and a
few of them work pretty well. But let's focus on the approaches that
have actually been through clinical trials and have been approved.
The
ModernaTX vaccine and the Pfizer-BioNTech vaccine are both mRNA
vaccines. This is a different type of vaccines that was pioneered in the
1980's, but abandoned back then for human use because it didn't seem to
work very well in humans back then. Why not and what changed? Well, the
idea behind an mRNA vaccine is that you make a string of mRNA that only
contains the protein in the virus that you want, the antigen. So you'd
get a sequence of mRNA that, when fed through ribosomes, would make the
spike protein of a virus and only the spike protein. This is tricky,
though: cells have other parts besides just ribosomes. There are
proteins that act as gatekeepers and regulate what kind of mRNA gets fed
through ribosomes. A real virus defeats those safeguards in some way.
Influenzavirus does it by hijacking real mRNA in the nucleus of a cell,
then replacing it partway through with is own RNA. Coronaviruses have
built in disguises that gets past the safeguards inside a cell. So in
order to make an mRNA vaccine, you have to modify the RNA to similarly
protect it from these safeguards. A set of laboratory techniques called
"nucleoside modification" is used to accomplish this. Fortunately, these
techniques have been improved since since when researchers were trying
to use them to make vaccines back in the 1980's. And just like a real
virus, you need to get it into cells in the first place. One way to do
this is to wrap the mRNA up in a package that can easily be recognized
by the innate immune system. Cells called phagocytes (eater cells)
gobble up the package, which then releases the specially modifed RNA.
Phagocytes have their own ribosomes for making their own proteins, and
the vaccine basically hijacks that like a virus would. But instead of
making all the parts for viruses, it only has the RNA to make the spike
protein on the outside, the antigen. So lots and lots of spike proteins
get made inside these cells.
As
we've gone over, a real virus would need a mechanism to exit from its
host cell. Thankfully, the vaccine doesn't actually need to do that.
Part of the natural life cycle of phagocytes is called "antigen
presentation." They basically show the T-cells and B-cells some examples
of what they've eaten, so the adaptive immune system can build
countermeasures against antigens, if phagocytes provide correcte
examples of those antigens. In a real infection, they gobble up some
viruses present bits of gobbled-up virus to the T-cells and B-cells. But
by the time the adaptive immune system grows the right kind of cells to
fight the virus, there are already lots of infected cells, so the
immune system has to do a lot of work to fight back. If pharmaceutical
companies tried to make a vaccine out of inactivated viruses, as they've
been able to do with some other viruses, the antigen presentation
wouldn't work well enough for there to be a good chance that you'd get a
good response against the spike protein. These new vaccines are
different: they've had the very cells that are doing the presentation to
your immune system being used as stooges to make loads and loads of the
exact protein that you want to protect against. Instead of having to
puzzle over molecular detritus that phagocytes scooped up and exposed to
digestive proteins, they're getting large quantities of pristine
antigen to work with. And because there's so much of it coming in, they
get extra chances to form a good response. So the new mRNA vaccines to
COVID-19 are very effective. They're a lot more effective than the dead
virus vaccines used against influenza and almost as effective as the
live attenuated virus vaccines used against measles.
Most
of the technology used to make the mRNA for these vaccines has been
around for a while, but the lipid package that makes protects the mRNA
and gets it into the right cells so that it can work as an effective
vaccine requires some pretty specialized and expensive new facilities
that there aren't a lot of yet. So while those vaccines were being
developed, other companies tried other approaches. The
Oxford-AstraZeneca vaccine and the Johnson & Johnson vaccine are not
mRNA vaccines. They're another type of vaccine called a "viral vector
vaccine." This type of vaccine uses the techniques developed for gene
therapy: they build their own virus-like structure. It's modified from a
small type of virus called an adenovirus. This is yet another kind of
virus, very different from influenzaviruses and coronaviruses. Much like
an influenzavirus, an adenovirus gets its genetic material into the
nucleus of a host cell. But the genetic material in an adenovirus is
DNA, rather than -ssRNA. Instead of stealing mRNA from its host, an
adenovirus simply has the proteins in the nucleus of the host cell build
RNA for it. But while a real adenovirus would have DNA that would get
transcripted into RNA that would then be translated to build its own
proteins, this modified viral vector only has the DNA that corresponds
to an antigen. It makes that same spike protein. Even aside from
COVID-19, viral vector vaccines have become more popular with biotech
companies in recent years, and some other companies around the world are
working on their own versions, but the Oxford-Astrazeneca version and
the Johnson & Johnson version are the two big ones for this.
There
have also been attempts at getting a regular old dead virus vaccine to
work with COVID-19. Nothing in the U.S. yet, but some Chinese companies
are trying this, and there are also versions in India and one in France.
So a dead virus vaccine could be considered the third major type of
coronavirus vaccine. There are some other companies trying more exotic
approaches, but nothing so far that looks to compete with these ones.
So, to return to your original question about the difference between the
different coronavirus vaccines: ModernaTX and Pfizer-BioNTech use mRNA
vaccine technology, Oxford-AstraZeneca and Johnson & Johnson use
viral vector technology (so does the Russian vaccine if you've heard
about that one, as well as some vaccines made by smaller companies),
while Sinovac Biotech and Bharat Biotech as well as the new French
Valneva vaccine use inactivated (dead) virus.
