Welcome to another MedCram COVID-19 update. It's
been a little while because I've been in the intensive care unit treating COVID patients. Sorry
to say that we are starting to expand a little bit in southern California, and we are seeing more
patients now in the intensive care unit with COVID-19. If we look at daily new cases in the
United States they are certainly on the uptick here, and whereas we had not seen an increase in
the new daily death rate in the United States it is now starting to increase. So where I work, which
is in San Bernardino county, which is in southern California, since the beginning of the pandemic
what's happened to hospitalizations, you can see here the green graph is the confirmed COVID-19
positive patient representation, and the pink here on top are those that are suspected. You can
see overall that hospitalizations here in southern California are on the rise, and that is not unique
in terms of the United States, we're starting to see daily new cases in South Dakota start to reach
all-time highs and the death rate is also going along with that as well. We're also seeing that in
North Dakota as well in terms of daily new cases and also the daily death rate as well, but perhaps
the epicenter here in the United States would be the state of Texas, where we can see that daily new
cases in Texas has reached an all-time high, but daily deaths have not yet increased. That could
be because of a time lag, of course. This is not just the United States, but it's going up. Around
the world, we see daily new cases increasing here and are at an all-time high, and daily deaths
around the world are also at an all-time high. As an example, daily cases in the United Kingdom
are quite elevated and whereas before we do not see deaths increasing, we're starting to see
daily death rates increase in the United Kingdom. In Italy, we are again seeing a increase in the
daily new cases, and this is reminiscent of what we saw in March in northern Italy where we're seeing
an increase in daily deaths as well at this point, and this is all to say that, of course, there's
a lot of bad news around the world regarding this virus, and of course, recently there's been
some good news, and we're going to talk about vaccines, and a great website to follow this is
RAPS, or Regulatory Affairs Professional Society, which has a great COVID-19 vaccine tracker, and for
the next couple of videos we're going to highlight different vaccines that are being developed
around the world for COVID-19. In the next few months or even weeks there's going to be vaccines
that are going to be released brought to market and consumers are going to have to make a choice
as to which vaccine they want to get. It's going to be really important to understand and know about
those vaccines and their track records, so we're going to dig deep and look at these vaccines and
compare them looking at various characteristics, safety data, and efficacy, and the first one
that we're going to look at is the vaccine that is being put out by Pfizer and BioNTec, and
you can see here on the COVID-19 vaccine tracker, there are a number of different vaccines that
you can click on them, and there are links so that you can look at the different publications
and be educated on these vaccines. So the first thing that we're going to look at is the Pfizer
BioNTech one that is here and let's get started. So the first thing that you've got to understand
is the biochemistry of what's happening with an infection. Now as we've talked about before, you
have a cell and on that cell is a ACE2 receptor, and then what you have is the virus and on the
virus, as you've heard by now, are spike proteins, and so what happens is the spike protein interacts
with this ACE2 receptor and the virus gets internalized in the cell and it basically takes
over the cell or hijacks the machinery of the cell, and so really this interaction between the spike
protein and this ACE2 receptor needs to be blocked if you want to prevent infection, and one of the
ways of doing that, traditionally, is by injecting fragments of the protein into the body and have
antibodies be made against these spike proteins, so that the virus is not allowed to bind this ACE2
receptor and you neutralize this infection and that's generally how vaccines have worked in the
past and the way that this virus SARS-CoV-2. How it does this is that there is this mRNA genome,
which is inside of the virus and so when the virus binds with the cell, the cell internalizes the
envelope, but it also internalizes the messenger RNA inside the cell now. If we were to blow
this up and show you what happens inside it would look something like this: here's the cell
with the nucleus. In the nucleus you have DNA and that DNA is converted into RNA and these are
made up of nucleotides. Well, that RNA is converted into messenger RNA, and it's exported out of the
nucleus into the cytoplasm where you then have something called messenger RNA, which is still in
the same language as the DNA is, but now you've got mRNA and mRNA is a very specific structure
it has something we call a five prime cap, it has information, and then it has a
non-transcribed region at the end with a poly-A tail, and this is what allows you to make
proteins, because this messenger RNA is translated by something called ribosomes into protein, and
it's this protein that can turn into just about any type of protein you want, depending on the
instructions here in the mRNA. Now as we talked about before, when SARS-CoV-2 infects the cells, it
causes the machinery in the cell to make proteins for more viruses, and so it's making more spike
proteins. It's making more proteins that go on its surface. It's making a whole bunch of other
things that go into making more SARS-CoV-2 virus, and of course these proteins here can be
incorporated into the cell membrane, or they can be exported to outside the cell so this sort of
brings us to why Pfizer and BioNTech are teaming up. It's because the German company BioNTech has
perfected, or at least significantly advanced, the technology of infecting with messenger RNA, and so
how this new vaccine is going to work is they have a way of making messenger RNA, but delivering it to
the cells in a lipid membrane. Now if you imagine a micelle or a lipid bilayer, in which the
mRNA is enclosed into so it's well protected, these very small particles can then fuse with
these cells, and then what happens is the messenger create a protein that they have genetically
engineered, and in this case that protein is a version, if you will, of the spike protein but
it's a version that is slightly different in that it holds the position of what it looks like when
it is docked outside the SARS-CoV-2 virus not after it binds and is internalized into the cell
so that the final product of this messenger RNA after it goes into your cells and after your
cells take their messenger RNA and make the protein that they want your cells to make. It's
going to make a protein inside of your body that is going to be immunogenic and cause you
to form antibodies against this spike protein, and here's what it looks like. This is a
publication that was published on BioArchive, and we'll give you the link to it in the
description below, but you can see here that this is the messenger RNA that they've constructed here
is the five prime cap analog. Here are the coding sites for the receptor binding domain. That's
where the spike protein binds to the ACE receptor, and here is S1 S2. These are portions of the
spike protein, and then you can see here is the non- or untranslated region, and then finally the
poly A tail. These additions to the messenger RNA allow it to escape destruction in the cytoplasm of
the native cells. So in other words it preserves it, so that it gets translated into the protein, and
here's a picture of the protein here down below that your body makes from the instructions from
this vaccine. It's a very immunogenic structure that causes antibodies to be made. Now last
month in the New England Journal of Medicine. They published an article called safety and
immunogenicity of two RNA-based COVID-19 vaccine candidates, and these were the two
candidates that were put forth by Pfizer and BioNTech and they wanted to see basically
how these two candidates did, to see which ones would go on to the phase two and phase three
trials. Let's take a look at these, because one of the big questions that we're gonna have when
we take a vaccine is, how safe is this vaccine? And while we're not gonna get a full picture
early on because a lot of the data takes months and months to come out, we can certainly see up
front what type of a profile these vaccines have, and you should know what the names of these two
candidates are. The first one is BNT162b1 and the second one is BNT162b2, so we'll call this number
one and number two, and basically what they found was while they were not looking for efficacy, they
were looking for safety, they found that the second vaccine, number two, was associated with a lower
incidence and severity of systemic reactions. So the first thing we're going to do is look
at some of the side effects and we're going to look at both vaccines, both one and two, and we're
going to look at the older population and the younger population. So first let's look at
the younger population, 18 to 55 years of age. That's what we're seeing here on this graph and
the two graphs up top are vaccine number one, and the one here on the bottom is vaccine number
two, and just at first blush you can see here that vaccine number two seems to have less in
terms of side effects. Now the other thing that I should mention is that they are looking at making
this a two-step vaccine process with the first vaccine being given and then the second one being
given on day 21, or three weeks later. Interestingly also this vaccine would have to be refrigerated
in very tightly controlled refrigerators, and so here the first column is the first dose and
the second column is the second dose. So let's take a look here at vaccine number two. You can see here
that at least 60 to 70 to even 80 or 90 percent of these patients had some sort of pain at the
injection site. That's not too unreasonable, but in terms of redness, swelling, either on the first
dose or the second dose of the second vaccine, that it doesn't look like there
was a lot in terms of side effects. It seems as though the 30 microgram dose
gave the most in terms of side effects. If we look in the older population, 65 to 85, once
again, in the vaccine number two there seemed to be less side effects than in vaccine number one,
and once again the biggest problem was pain at the injection site. But in terms of redness and
swelling, we didn't see much there. What about more systemic effects? These are the kind of side
effects that we're actually looking for a little bit more carefully. Once again let's look at the
second vaccine that was being developed, that's b2 here on the bottom, 2. Fever, fatigue, chills, both
in the first dose and in the second dose were much less than that in the first vaccine that was being
developed, and that dose two seemed to give higher side effects or higher incidence of side effects,
the biggest one in terms of incidence was fatigue in both the first dose and in the second
dose ranging from about 40 to 70 percent. If you look at participants in the 65 to 85 years
of age group, you can see how the second vaccine, or b2, had far fewer side effects than b1, so you
can see the conclusions that the authors came to: they said the safety and the immunogenicity
data from this United States phase one trial added to earlier interim safety and immunogenicity
data to support the selection of b2 for advancement to a pivotal phase 2-3 safety and efficacy
evaluation, and that's exactly what they did. A press release about the preliminary results came
out about five days ago, and they had enrolled 43,538 participants in this randomized, blinded
trial, and so what they decided as they did some calculations and they figured that when they
had heard that 94 confirmed cases had occurred, they were going to take a peek at the data to see
how it looked. What they were looking for was to see how many of these patients who got COVID had
gotten the placebo versus had gotten the actual vaccine, and what they were able to conclude based
on the data from those first 94 confirmed cases of COVID-19 was that the vaccine b2 was found to be
more than 90 percent effective in preventing COVID-19 in participants without evidence of prior SARS-Cov-2
infection in this analysis, and what they're actually asking for now is to continue the study
to go up to 164 confirmed cases to see if this holds up and if there are other data points that
can be made. That's important, because if they were not to do that, if they were to end the study,
it would be considered unethical to randomize someone to a placebo given the fact that the
vaccine is so effective at preventing COVID-19, a potentially deadly disease, and here is the
press release announcing these preliminary results. We don't have this in a peer-reviewed
publication as yet, but I'm sure it's coming. You know, in terms of what's actually going on
biochemically inside these people who get this vaccine, it's very interesting and there are some
hints, because if we look at some earlier trials with this very same vaccine in monkeys and
in mice, we see some very interesting things, and this was a paper that was published in Medical
Archive, which we will put in the description below. In terms of the links, what they did is in this
study, before they did the phase one trials that we just reported on, they looked at how this vaccine
candidate behaved in monkeys and in mice, and so they say here that this LNP-formulated nucleoside
modified mRNA that encodes the spike glycoprotein captured in its pre-fusion conformation, which is
what you want you want it to look exactly as it does on the SARS-CoV-2 virus, so what they found
was that these neutralizing geometric titers were 10 to 18 times that of the SARS-CoV-2 convalescent
human serum panel and not only that but this very same vaccine that they gave in humans, later on
when they gave it to macaques and to mice they found that their TH1 type CD4 positive and interferon
gamma positive response was elevated and a CD8 positive T-cell response was also activated and
all of this points toward a wide and diverse immune response, and one has to figure whether or
not this is the reason why it seems at least on preliminary data that this vaccine is 90 percent effective.
So let's talk a little bit about the vaccine. Here you can see these lipid nanoparticles that
contain the messenger RNA with the code in it. So if we look at what we have here with the vaccine
from Pfizer BioNTech, they say it's effective at preventing COVID-19 at around 90 percent. Now
realize the way these endpoints worked was that seven days after the second vaccine dose, so at 28
days after the first vaccine dose, study subjects were asked to contact the site coordinator if the
patients had any symptoms of COVID-19 and if after evaluation it was likely that they had COVID-19,
these subjects were given a COVID-19 test. The study was interrupted when the number of subjects
with COVID-19 positive test results reached 94. When this happened they unblinded the 94,
so they could see who did and who did not get the vaccine. It was at that time that they
released some preliminary results showing that the vaccine was about 90 percent effective. So some interesting
points about that is that really there are no asymptomatic subjects in this result cohort. We
don't know what this does to asymptomatic patients and furthermore we don't know how long this effect
lasts either, so those will be questions that have to be answered down the line. Of note, the data
monitoring committee reported that there was no serious safety concerns. The other question is:
does it stop infection? That's important because this vaccine may be just important in the
individual that gets it at preventing them from getting the disease, COVID-19 but the question
is: does actually stop infection with SARS-CoV- 2? That's important, because if it doesn't stop
infection, then you can still infect people with the virus, and it can still multiply
exponentially. But if it has a sterilizing effect, then it's potentially possible that you could
block the spread of the disease that is still up in the air and a question at this point.
Now a couple of numbers that you should know, Pfizer believes that they should have about
50 million doses by the end of the year, and they are working right now to try to get
emergency use authorization. They also say that they should have about 1.3 billion doses by next
year. You need to realize that there are two doses. Both doses need to be refrigerated in special
refrigerators that keep them at negative 70 degrees centigrade, and the question is how much
is this all going to cost? Well they're saying that per injection the cost will be about $19.50. But there has been some reports that they are working with the US government and for those
in the United States, it should work out to be free. Now also remember this too, is that apparently
Pfizer did not take any government money in the production of this vaccine and furthermore Pfizer
is looking at producing this vaccine worldwide, so this vaccine does have some promise. I would be
very interested to hear what you all have to say about this vaccine. It's one of four of the
vaccines that we're going to do a deep dive and look into. I think this one is interesting
because of its novel approach using messenger RNA. Of course there's another vaccine candidate that
is doing that as well, and that's of course the Moderna candidate, which we'll talk about coming up
next. Keep in mind that no mRNA-based vaccine has been approved by the FDA, but this particular
candidate is interesting because we have the preliminary safety data in, and it looks as though
we have the preliminary results of a report about the efficacy data. Of course more of
that is to come when it gets published, and so people can start to make a decision about if this
vaccine becomes available and gets emergency use authorization and when it becomes available
if they would decide to get this vaccination. And don't forget to visit us at MedCram.com for
continuing medical education. Thanks for joining us! you
