- Welcome everyone to Wednesday Nite @ the Lab.
I'm Tom Zinnen, I work at the UW-Madison Biotechnology Center.
I also work for the Division of Extension Wisconsin 4H,
and on behalf of those folks
and our other co-organizers, PBS Wisconsin,
the Wisconsin Alumni Association,
and the UW Madison-Science Alliance,
thanks again for coming to Wednesday Nite @ the Lab.
We do this every Wednesday night by Zoom, 50 times a year.
Tonight, it's my pleasure to introduce to you Mary Hayney.
She's a professor at the School of Pharmacy here at UW-Madison.
She was born in Easton, Minnesota
and went to Good Counsel Academy
and Delavan Minnesota High School.
Then she went to Creighton University in pre-pharmacy,
then went to the University of Minnesota
to get her doctorate of pharmacy.
Then she post-doced at the Mayo Clinic,
and in 1997, came here to UW-Madison
to serve on the faculty.
Tonight, she's gonna speak with us about insights
into the development of COVID vaccines.
Would you please join me in welcoming Mary Hayney
to Wednesday Nite @ the Lab.
- Thanks, Tom.
My presentation today is entitled
"Vaccines for COVID-19:
Our Shot at Ending the Pandemic."
I'm gonna start with a little bit about
what pandemics are,
but I'm gonna take a little bit of liberty
and talk about significant disease outbreaks
from history as well.
Let's start with the one that is probably most famous.
It happened in the mid 1300s, and it was called Black Death.
It was caused by a bacteria named Yersinia pestis,
and it is estimated that a third to half
of the entire population of Europe
died during that disease outbreak.
Some other pandemics that I wanted to talk about
is one that was important for the Americas,
and it was the 16th century,
when many settlers from Europe came to North America
and brought with them their infectious diseases.
And it is estimated that some of these infectious diseases
wiped out as many as 90% of the Indigenous population.
Another one, this isn't a pandemic,
but I think it's interesting
from the American history point of view.
In 1793, there was a yellow fever outbreak in Philadelphia.
Yellow fever is a mosquito-borne disease,
and there were about 5,000 people who died that summer,
and interestingly, and of course you'll go "Yeah,"
it subsided in the fall
when frost came and the mosquitoes died.
Influenza was an important pandemic,
which is maybe the other one you might think of,
and I'm gonna talk more about that one coming up,
but in 1889 and 1890,
there was an influenza pandemic that started in Russia
and swept across Europe
with an estimated 1 million deaths.
Another pandemic, I think I'm exaggerating a little bit
about this one being a pandemic,
but certainly it did cause worldwide endemic death,
and certainly disability is polio.
In 1916 was about when polio started in the world,
really interestingly, and there were sporadic outbreaks
until 1955 and then after that, there was a vaccine available.
This diagram that I've put up is a map of the world
that shows the individual cases of polio
in the entire world in 2020.
So we are putting dots for individual cases.
Therefore, we are on the verge
of polio eradication from the world.
Another one that you will be very familiar with,
we just celebrated-- celebrated, is that the right word?
The 100th anniversary of the Spanish flu.
Spanish flu is also an interesting name for it,
but that is the one that came about.
And it is estimated that this influenza outbreak
caused 500 million cases and at least 50 million deaths.
Other influenza pandemics are listed on this slide,
so I'm gonna go out of order a little bit.
There was a 1957-58 one, a 1968 one,
and then of course, many of us will remember
the 2009 H1N1 influenza pandemic.
The first two caused about a million deaths worldwide,
and about 100,000 deaths in the United States.
And the H1N1 influenza pandemic, interestingly,
affected young people more than the old people.
And it is estimated that about 80% of the deaths
were in people under the age of 65.
Again, I have a relatively wide range
of how many deaths that influenza outbreak caused,
but we don't have a good way to know.
And then another pandemic, it's a worldwide disease,
started in 1981, or that was at least
when it was first recognized widely, is HIV/AIDS,
and there've been 35 million people who have died of this.
It has now become an endemic disease,
and has particularly affected Sub-Saharan Africa.
The next one, again, was a localized disease outbreak,
which was Ebola with almost 29,000 cases reported,
and 11,000 of those died.
The next disease outbreak I wanted to talk about,
which is actually one that spread
to many areas of the world, is Zika.
Zika was first known and discovered in the 1940s,
but it came to South America in 2015
and spread into North America as well.
It still continues to go on and cause diseases,
cases of disease, and we don't really know
the total impact of Zika virus yet.
So we're in a current pandemic again,
and I think that we obviously know the effects
of the coronavirus pandemic.
It is a global outbreak of disease.
It starts as an epidemic,
which is a localized disease outbreak,
and then when it becomes worldwide,
it becomes a pandemic.
The World Health Organization declares the pandemic.
It declared the pandemic for SARS-CoV-2,
which is the virus that causes COVID-19,
in mid March in 2020.
It's typically caused by a new infection,
new meaning new to the population,
because the population has very little immunity to it,
which makes it easy to transmit from person to person.
So we have the opportunity now to talk
about COVID-19 vaccines.
I feel so lucky to do that,
because who would have thought we would be able
to have a vaccine in just a few months?
Well, a few months, nine months
following the first call for a COVID--
that COVID was a disease and a pandemic.
So I want to assure you that the vaccine licensure
and development process was followed carefully
for the COVID-19 vaccines.
So let's talk about what that process is,
and then I'm going to apply that process
to how the COVID-19 vaccines were developed.
So every vaccine starts with a preclinical phase,
a phase in which most of the work is done
just in the laboratory.
Then phase one, two, three,
and after phase three, the vaccine will be licensed,
or in the case for the COVID-19 vaccines,
it has an emergency use authorization.
I'll talk more about all of these individual parts
coming up, starting with phase one.
Phase one starts with a new vaccine,
and you get a IND submitted to the FDA,
the Food and Drug Administration.
So the Food and Drug Administration
is involved right away.
An IND is an investigational new drug application.
And so that allows scientists
to start testing the drug in humans.
And so you get a very small number of healthy humans,
typically healthy humans,
who maybe are not at any particular risk
for the disease in question.
The main goal of phase one trials
is safety and tolerability,
and maybe you'll get a little bit of immunogenicity,
or does this vaccine induce an immune response?
And then we also look at different doses,
different schedules.
This is where those kind of data
or information associated with the vaccine come from,
is in these early phase one trials.
Now typically, phase one trials take 8 to 12 months.
They're often done in academic settings
or a small biotech startup kind of setting.
But it also can be done
in large pharmaceutical companies as well.
Phase two studies typically involve
larger numbers of volunteers,
somewhere between 50 and 500 people.
And they usually are a mix of low risk
and higher risk individuals from the population
where the phase three trials will be done.
I know I'm getting ahead of myself
by starting to talk about phase three
while I'm still trying to talk about phase two,
but bear with me for a second.
The main goal of phase two trials
is to generate safety data.
We really want to know that this vaccine does not cause harm.
It also gives us an opportunity
to work with vaccine formulations,
make sure that we can make it again and again in a new batch.
You know, that's a critical component
of a pharmaceutical agent.
You also might get some preliminary data on efficacy.
And these trials typically take 18 to 24 months
because of screening, enrolling larger numbers of participants.
Phase three trials are typically
those large ones that we hear about.
And I'm in fact gonna talk about phase three trials
almost exclusively when I talk to you about the vaccines
that are available for the use, to prevent COVID right now.
They're blinded and randomized.
Blinded means that the individuals won't know
which group they got, they're assigned to,
whether it's placebo or active vaccine,
and neither will the investigators.
There's only one person in a data closet somewhere
who knows who got what, and they don't tell.
So it's, typically they involve thousands of participants,
and in fact, the COVID-19 trials
typically had tens of thousands of participants
from this target population who are at risk for the disease.
The goal of the phase three trials is primarily
to determine vaccine efficacy and vaccine safety,
and this then can lead to licensure application.
In phase three trials,
particularly for vaccines anyway,
we need a key component is surveillance.
We need to know when people are getting disease,
and we need to know how much disease there is
in the population.
And so we need active
and passive surveillance for disease.
We need to look for cases.
So you can see that we needed to be able to know
a lot about COVID-19 and who was getting COVID-19,
where the cases were, and how many cases
that could be accrued.
This, in fact, the large COVID outbreaks in the summer
actually speeded along the development of the vaccines
because the vaccines need to collect so many cases,
or in this case, on the slide,
I've written a specified number of events,
in this case meaning cases of disease have to occur
in the study population in order to make,
to hit the study endpoint.
So then the study becomes unblinded,
and we see in which group each case might have been.
And so what investigators and scientists are hoping for
is that the cases are primarily in the placebo group
and not in the vaccine group.
That would indicate that the vaccine probably protected
or likely protected people from infection.
These trials typically take years to complete.
The Food and Drug Administration
is involved in vaccine licensure,
and as our expert recommendation bodies.
So let's start with the Food and Drug Administration,
or the FDA.
They review data regarding the safety
and efficacy of vaccines.
They use advisory panels.
These advisory panels are typically made up
of experts in the area.
So they give advice to the FDA.
They'll review all of the study data
and look at it very, very carefully,
and then make a recommendation to the FDA
for licensure, or in this case, let's talk a little bit about
emergency use authorization, or EUA.
Probably a new term
in everybody's vocabulary is the EUA.
This is actually a relatively new strategy.
It's only been around since the early 2000s
to make products available to the public very quickly
during an emergency.
And, of course, the COVID-19 pandemic
is certainly an emergency.
It allows the FDA to weigh risks that are known.
Actually, I guess I should start with what the slide says,
which weigh known and potential benefits
of the product against the risks of the product.
And please know that an EUA is based on very high-quality data.
It doesn't mean, the EUA doesn't mean
that the vaccines are not proven
or that the data is, that data are suspect.
In fact, the EUA is based on very high-quality data,
or the EUA would not be granted.
A second group that's incredibly important
in our use of vaccines in the United States,
including the COVID-19 vaccines,
is the Advisory Committee on Immunization Practices.
This is a committee of the CDC,
or the Centers for Disease Control and Prevention,
and this committee makes recommendations
on how to use vaccines to control diseases
in the United States.
The recommendations stand as public health advice
to reduce the incidence of vaccine preventable diseases,
and then of course, to promote safe use of vaccines.
The COVID-19 vaccine recommendations from the ACIP
were made within days following the EUA.
Their recommendations included priority groups.
In fact, like who should be first in line
to get the vaccines.
So you might remember, the first people who got...
for whom COVID-19 vaccines were recommended
included healthcare workers
and individuals who lived in long-term care facilities.
And the reasons for this is, in advance,
the ACIP put together a committee that decided
what, on what, how are we gonna decide
who gets the vaccines first?
So they chose these ethical principles
to maximize benefits, minimize harms, promote justice,
and mitigate health disparities.
Those were their guiding principles.
So you can see it's natural
that individuals in long-term care facilities,
I'll use that one as the example,
would get vaccine first,
because they were a very important group in outbreaks
as well as deaths associated with outbreaks.
So now moving on to Operation Warp Speed,
because how did we then apply
these vaccine licensure and EUA and study principles
to the development of the COVID vaccine?
So first, although I don't love the name
Operation Warp Speed, it was what was chosen,
so we'll go with it.
I won't try to change it at this point.
Operation Warp Speed was overseen
by the Department of Health and Human Services,
as well as the Department of Defense,
and vaccines weren't the only thing under their auspices.
They also had a big role in developing of diagnostics.
Remember, when we didn't have this,
we didn't have this disease before early 2020.
Therefore, we wouldn't have a strategy
or any tests to diagnose it.
So those had to come really quickly.
We've also done pretty well,
although not as well as I had hoped,
in the therapeutics or drugs that can be used
to treat COVID-19 when people are infected.
And then finally, vaccines,
which are gonna be the drug or the agent
in this Operation Warp Speed effort
that reaches the most people.
In fact, we'd like to reach everyone in the whole world.
The reason that this was able to be done so quickly
is because it was done with investment,
monetary investment, and big people effort as well.
And it was also done with a significant amount
of cooperation and coordination
with many, many partners, both public and private.
The federal government oversaw the whole process,
including the protocols that were used
for studying the vaccines as well as the other agents,
but I'm gonna focus on vaccines.
In fact, the protocols,
the study protocols were made public.
Now, ordinarily, when you do studies,
such as these phase three clinical trials,
the protocols are the property of the company
that's sponsoring the trial,
and you sign a confidentiality agreement
if you happen to be an investigator
associated with this,
with the study, but in this case,
and very differently from the, you know,
way we usually do things,
the protocols were overseen by the federal government
and were public.
You could find those protocols on the internet.
But here's the really important thing
that I want you to know is that no steps were eliminated.
The steps proceeded simultaneously.
So for instance, phase one trials and phase two trials
were going on at the same time.
And planning for the phase three trials
were being done while the phase two trials
were still being conducted.
While the phase three trials were ongoing,
vaccine production was already underway.
The vaccines were being made and packaged.
Now you can see that, should the vaccine fail
to meet its efficacy goal,
those vaccines would have been wasted.
So you could see there was significant financial risk
associated with this, but please know that human risk
or the risk associated with the product or adverse events
were not, are not part of that risk, when I talk about risk.
There are a couple of hundred COVID-19 vaccines
that are in development or in various phases.
So you can see that there are four vaccines
that are approved.
This is global data.
There are no approved vaccines in the United States.
We have the authorized vaccines.
We have three authorized vaccines at this time,
and those vaccines, I'm gonna go through each one of those.
But look, we have a lot of other vaccines
that are still coming,
and some interesting ones that are coming
and will probably soon be available in the United States.
I'm gonna start with the mRNA vaccines,
and it's because they did it chronologically,
it's which vaccine was available first,
so that's how I chose which vaccine to present first.
We think of mRNA vaccines as being brand new, cutting edge.
How did this happen?
But they're not that new.
They have been studied for more than 10 years,
and they have been targeted at diseases like influenza,
cytomegalovirus, that's a infection that causes disease
in people who are immunosuppressed,
like solid organ transplant patients.
Also, it's a particular threat to pregnant females
for their fetuses, similar to Zika virus.
Rabies, and also has been a target
for maybe development of a cancer vaccine.
Early efforts with these mRNA vaccines
were plagued by mRNA's instability.
So I'm gonna guess there's a few of you out there
who have worked with mRNA in the lab,
or as an experiment somewhere along the line,
and mRNA can just disappear.
It's a very unstable molecule in that it just rapidly degrades.
So we needed to come up with a strategy
that would prevent it from rapidly degrading
so that we could use it as a vaccine.
But important things, about the mRNA vaccine platform anyway,
is that they're are non-infectious.
There is no part of the pathogen in that vaccine.
MRNA is not integrating,
meaning it doesn't get into your DNA,
doesn't change the DNA.
In fact, it doesn't even enter the nucleus of the cell.
MRNA, as I mentioned already,
is degraded by natural cellular processes,
and in fact, if you put it in a beaker on the bench,
it might degrade on its own.
Its duration can be regulated by specific modifications
and changing the delivery method.
And then we don't have immunity to the vector
as a consideration.
I'll talk more about immunity to the vector coming up
when I talk about the adenovirus vaccines,
or the viral vector vaccine.
This is a diagram that shows you how mRNA vaccines work.
Firstly, I'm gonna start at about 7 o'clock
on that slide, where you have the machine
in the lower left-hand corner.
That is a, best I can...
machine that would make nucleic acid
and hook 'em together for us.
So it takes the As, Ts, Cs and Gs,
and in this case, there's probably some Us in it,
and hooks 'em together as a messenger RNA.
That messenger RNA is then, once it's synthesized,
it's coated in a lipid, mice cell kind of thing.
And that lipid coat protects the messenger RNA
from being degraded in storage.
And then it becomes a vaccine.
And in addition, the lipid coat,
once it's injected into the person,
helps the messenger RNA get into the cell
'cause it's like a soap.
It'll get through the cell membrane.
Then the messenger RNA leaves the lipid coat
and gets translated into a protein.
And in this case, this messenger RNA
codes for the coronavirus spike,
and that spike protein is a dominant protein
to which we make an immune response.
So that immune response is made by the cells
once they recognize the spike protein.
So in this case, I didn't draw out the whole immune response,
but rather I have an antigen-presenting cell,
which looks like the spider and is labeled an APC,
presenting that coronavirus peptide
or spike protein to the other cells of the immune system,
which they'll make cellular immune responses,
as well as antibody responses.
Another huge advantage of messenger RNA
is that it is easy to modify it
to either increase a translation in the cytoplasm,
and it's actually pretty easy to rapidly upscale
and relatively inexpensively produce the mRNA.
So there are two mRNAs available for use in the United States.
The first one is the Pfizer vaccine.
It's a two-dose series.
It was studied in about 30,000 participants
in a large clinical trial.
Notice that it included 18 to 85-year-olds.
The Moderna vaccine is also a two-dose vaccine,
and it had about 30,000 people in its study,
and it too included 18-year-olds up past people
over the age of 65 with no upper limit of age.
The vaccines, both of them induced great immune responses.
They induced robust neutralizing antibody responses.
A neutralizing antibody response
is exactly kind of like how it sounds.
It's a response, an antibody response
that can neutralize the virus and prevent it from, you know,
prevent it from causing infection.
Some cellular immune responses are also done, including a CD4,
and a Th polarization is also a CD4 type response,
and that is oriented more toward a cellular immune response.
So this kind of essentially covers
all of the immune responses that might be necessary
for making a vigorous immune response to a virus infection.
The Moderna vaccine is given at a 28-day interval,
about a month apart,
and was found in clinical trials to be about 95% effective.
The Pfizer vaccine has a 21-day interval, three weeks,
and was found to be about 95% effective.
And then, I also have some real world effectiveness data.
The mRNA vaccine, so it was either vaccine,
it was administered first to some healthcare providers.
About 4,000 healthcare providers were swabbed
every week for coronavirus.
Essentially, they had a COVID-19 test every week,
whether they were symptomatic or not,
and in fact, if they became symptomatic,
they were swabbed again.
But they were swabbed about every week.
And interestingly, the vaccine was about 90% effective.
So they were about nine--
Those who were immunized and fully vaccinated
were about 90% less likely to get infected
compared to individuals who were not immunized.
Great news, and this is just real-world data.
I want to talk a little bit about adverse events,
because I think that's something
that's really important to think about,
and it is a concern of many people
regarding these vaccines.
Interestingly, older people
have less vigorous immune response,
or less vigorous adverse events following the vaccine.
So those who are over 56 years of age
had milder and less frequent adverse events.
Reactogenicity, which is a word that means
an adverse event immediately following the vaccine.
But they were, those adverse events
were typically mild to moderate and short-lived, a day or two.
The incidence of discontinuation
of the vaccine series due to adverse events was low.
And interestingly, it was similar
in the vaccine and the placebo groups.
So those are really important,
that's a really important adverse event
for me as a scientist to monitor,
because if the adverse event was so bad
after the first vaccine dose,
most people who have really bad reaction
aren't gonna get the second dose.
But in this case, there was no difference
between those who got the vaccine
or those who got the placebo
who refused to get the second dose.
The main adverse events associated
with the Pfizer vaccine were pain,
headache, chills, and fever.
The Moderna vaccine had actually
quite a similar adverse event profile,
but because the trials were were not exactly the same,
I can report them in different ways.
Let's start with grade three local reactions.
Those are local reactions that happen at the injection site.
And I've defined the grade three at the bottom of this slide,
and you'll see that the grade three local reaction
requires narcotics for pain
or has caused a significant discomfort, at rest,
redness or induration, meaning redness with swelling,
of about 10 centimeters or more.
Or that it prevents daily activity.
So you can see grade three reactions
happened more frequently after the second dose
compared to the first dose.
Local adverse events had an onset day one.
So remember, day zero is the day of the vaccine,
day one this is the day after the vaccine was administered.
Typically onset at day one and lasted two days
after dose one, and three days after dose two.
What I'm telling you is that dose two
is a little bit worse than dose one
for the Moderna vaccine.
A fever, about 1% after dose one and almost 15% after dose two.
Systemic reactions,
reactions that kind of affect a whole body.
Muscle aches, fever would be included in that,
persisting beyond seven days
were about 12% in the vaccine group.
Now that sounds kind of high,
but it was almost 10% in the placebo group.
So I think we just have a lot of systemic reactions
that we might report following in a vaccine,
or maybe we just all have a lot of systemic reactions
that we report any day.
One other adverse event that I want to spend a little time
talking about with the messenger RNA vaccines
is anaphylaxis.
Anaphylaxis is an allergic reaction
that is life-threatening,
and this was noted actually very shortly
after the vaccines became available in the public,
following the EUA.
There were no anaphylaxis episodes in the clinical trials,
but when we put it out in millions,
you'll be able to find these things.
So the most recent report showed about,
a risk of about five per million in the Pfizer group,
and about two and a half per million in the Moderna group.
Now, the ordinary rate of anaphylaxis following vaccines
in, you know, previous to the COVID-19 vaccines,
I would teach the students that it's about
one and a half cases of anaphylaxis
per million doses of vaccine.
So it's a really rare side effect.
Now, of course, we've dramatically increased that risk
with the messenger RNA vaccines,
but please know, take a step back
and really look at these numbers.
The risk is still incredibly low.
We try to find some risk factors
associated with anaphylaxis with these vaccines,
and about a third of them had had
a prior episode of anaphylaxis.
So for those of you who have already received
your COVID vaccine, or for those of you who will,
you'll get a question about anaphylaxis
or your experience with serious allergic reactions.
All of the cases in this series required some kind of treatment.
Epinephrin is virtually the magic bullet
for treatment of anaphylaxis,
and over 90% of people did receive
a dose of epinephrin.
Please know that although we screen for anaphylaxis,
we, you know, only about a third would have this risk factor
of a previous episode of anaphylaxis,
but know that those people who are vaccinating
and providing vaccines are ready to make an emergency response
should someone in their care be,
experience a case of anaphylaxis following vaccine.
So they're ready.
They monitor people for a period of time following the vaccine,
and they can make an emergency response should it be needed.
So current contraindications to the
messenger RNA vaccines do include allergy.
I want to take another step now
and talk about the third type of vaccine,
the third vaccine that is,
is available in the United States,
and it is a viral vector vaccine.
So starting with the spaceship-looking thing,
that's my diagram of a virus, that's an adenovirus.
This adenovirus, though, has been significantly engineered.
One is that it is replication deficient.
When a virus is replication deficient,
that means it can't multiply and make more of itself.
That part of its genome has been disabled.
So it is essentially just a case of DNA,
and in that DNA, scientists have inserted
some DNA for the coronavirus spike protein.
So they've inserted the gene for that.
Then this whole replication deficient virus
is formulated into a vaccine and is administered.
The virus will enter the cell because adenoviruses do that.
The coronavirus gene, spike protein gene
will be transcribed into RNA
and then translated into a protein.
And you've heard this story before.
Then the mRNA that is made from the gene
that was in the, inserted into the adenovirus
is made into the spike protein.
The spike protein will then get presented
on an antigen-presenting cell
and will initiate an immune response to that spike protein.
But please know, because the adenovirus is there,
it can also elicit an immune response to the adenovirus.
That is one of the implications and shortcomings,
or possible shortcomings, anyway,
of an adenovirus vector vaccine, or any viral vector vaccine.
You can make an immune response to the virus
and no longer be able to use that
as a vector for your gene of interest.
The viral vector vaccines that are furthest
in clinical trials include the Johnson & Johnson,
which now has an emergency use authorization.
And it is a replication-incompetent
adenovirus number 26.
It was specifically chosen 'cause
it hasn't widely circulated in humans.
The Astra-Zeneca or University of Oxford vaccine uses a
chimp replication-deficient adenovirus.
So again, it did not circulate widely in the population.
And the Astra-Zeneca trial has not yet
made it to the EUA phase.
It's currently with the FDA with some concerns
over irregularities in how it's being reported.
You know, just, these could get ironed out very easily.
Interestingly, the Astra-Zeneca vaccine
is being used widely in many countries around the world.
So I'm gonna give you some information
about the Johnson & Johnson vaccine.
This vaccine is a single-dose vaccine.
Makes administration really easy,
because you only have to do it one time.
There were 44,000 participants in a multinational study.
So including the United States, South Africa, Brazil,
and then some other countries in South America.
And now the reason I wanted to specifically talk
about South Africa and Brazil, or specifically mention them,
is because these two countries
have had coronavirus variants appear
and appear during the vaccine trials.
I'll talk more about those coming up.
But the Johnson & Johnson vaccine was 67% effective
against moderate to severe or critical COVID-19.
It was about 85% effective against severe
or moderate disease
and 100% effective in preventing death.
I think we have a good vaccine here.
In the United States, interestingly,
it was 72% effective,
but in South Africa where there were more variants,
it was 64% effective.
And please know that this was against moderate
to severe or critical disease.
And they were 86% and 82% effective
against severe disease.
So it was any disease kind of starting up,
or more serious disease.
Still pretty effective.
Adverse events to the Johnson & Johnson COVID-19 vaccine
include injection site pain.
That's a very common adverse event with vaccination.
Headache, fatigue, and muscle aches,
all in the 30 percents.
Nausea, 14%, fever, 13%.
There was one case of anaphylaxis reported
with this vaccine in the clinical trials.
Another type of vaccine that is under development
include the subunit protein vaccines.
This is an interesting technology used widely already
for other vaccines, including the hepatitis B vaccine,
the human papilloma virus vaccine.
There's an influenza vaccine
that uses the subunit protein vaccine strategy as well.
And more recently, the newer shingles vaccine
uses this type of technology.
They usually are combined with an adjuvant.
An adjuvant is a chemical that magnifies the immune response.
It's like giving that protein,
that recombinant protein a microphone and saying,
"Hey, immune system, pay attention to me."
The Novavax is a recombinant protein.
Again, it's a spike protein.
It's stuck on microscopic particles and adjuvanted.
It will require probably two doses.
It is finishing up phase three clinical trials in adults.
There are several subunit protein vaccines
in phase two trials, so we'll probably see more of these.
The live attenuated or inactivated coronavirus vaccines
are another strategy.
This is an old and tested strategy
of a vaccine platform.
No vaccine is very far in development
in the United States.
There are several using these technologies
in phase two globally,
and there are three in phase three in China.
I also promised to get back to the variants.
We know that the variants cause lower vaccine effectiveness
in the Astra-Zeneca and the Johnson & Johnson vaccines.
And the reason we know that is because
the variants were circulating during clinical trials.
So we know that they have less effectiveness
against the variants, but still,
I think I showed you relatively reassuring data
that even though it's a little bit lower,
it's still not bad.
There is laboratory evidence
that the messenger RNA vaccines might offer protection
against the variants,
meaning that going back to that word,
the neutralizing antibodies,
the antibodies will still neutralize the variants.
It requires a higher concentration of them, though.
All of these vaccines appear to be less effective
against the B.1.351 variant.
One really good news is the FDA
is allowing a path for vaccine modifications
to respond to the variants without redoing
all of the large-scale clinical trials.
Instead, it'll be more like the influenza vaccine
that's reformulated every year.
We know that the influenza vaccine
works as well as it does,
and that the vaccine can just be reformulated
using the same technology every year,
just with a different virus.
So this will be, at least is the plan
for how the coronavirus vaccine,
so the COVID-19 vaccine, might be modified
in response to variants that will very likely
continue to pop up
as more and more people get the infection,
and maybe in response to pressure
as more people are immune.
The next thing I want to talk about is vaccine storage.
And, of course, the ideal vaccine
would induce an immune response in everyone,
and be stable at room temperature.
Or, even better maybe, at any temperature.
However, we have no example of an ideal vaccine.
So right now, we're dealing with some vaccine storage challenges.
The best temperature for the Pfizer vaccine
is minus 80 degrees Celsius.
That's really cold.
And that requires actually even a special freezer.
Ordinary freezer cannot get that cold.
These freezers are really common in research labs,
but they're not common in places
where vaccines are typically administered.
So that presented a challenge, initially at least,
for the Pfizer vaccines.
The Pfizer vaccine is stable
at a higher temperature or a warmer temperature,
let me put that, 'cause we have trouble thinking
when we're talking about negative numbers,
for a short period of time.
And that's really how the vaccine
got widely disseminated to start with.
The Moderna vaccine is stored at normal freezer temperatures,
and normal freezer temperatures are doable
for people who administer vaccines.
And the Johnson & Johnson vaccine
is stored in a refrigerator.
So that's kind of like most vaccines
are stored in a refrigerator and they are stored, you know,
just like other vaccines, such as the influenza vaccine.
The next thing I want to move on and talk about
is kind of things about,
logical things about vaccination,
first starting with herd immunity.
Herd immunity might be a new term to you as well.
Think about the new words you've learned in the last year.
Other terms for herd immunity include community immunity,
community protection, and indirect protection.
Because some people really don't take offense
at being herd immunity.
Herd immunity is protection conferred
to susceptible individuals
when a sufficient portion of the population is immune.
I'm gonna talk a little bit
and show you some diagrams of this,
but what does this mean?
Herd immunity is the amount of people who need to be immune
in order to essentially stop widespread disease transmission
or halt a pandemic.
And the herd immunity, the level that we need
depends on the reproduction number, abbreviated R0.
The reproduction number is the number of people
to which an infected person transmits the infection.
So this makes, you know,
to have an R0 makes a lot of assumptions.
It assumes that there's equal mixing,
that meaning the entire population
mixes with the susceptible person.
And then, of course, I'm also gonna make an assumption
when I show you these data that the R0 doesn't change.
And of course, the R0 is gonna change
as the immunity in the population increases.
So it is estimated that for SARS-CoV-2,
the R0 is between two and three.
Compare that to the R0 for measles.
Measles is the most infectious disease
or contagious disease that we know of,
and it has an R0 as high as 18.
So the herd immunity threshold is calculated
as 1 minus 1 over R0.
This is a picture of the concept of herd immunity.
The red stick figures are people who are infected.
The green ones are those who are immune,
and the white ones are those who are susceptible.
So now if you look at the diagram on the left,
you'll see that the immune people
and the susceptible people are freely mixing.
Now on the right-hand side of the diagram,
we have way more immune people.
Most of the population is immune,
and therefore, fewer people would be infected.
So the infected people, again in red,
are separated physically and protected
from the susceptible people by the immune people,
thereby protecting the susceptible people.
This is a concept of herd immunity.
Let's talk a little bit more about R0s
and herd immunity thresholds that we need
for a variety of diseases.
I mentioned measles having an R0 of up to 18 before,
but in this particular example
of measuring measles immunity in the 1960s,
the R0 was 14 and a half,
but that translates into a herd immunity threshold of 94%.
I'm not gonna read all of these,
but I wanna point out SARS-CoV-2.
This was from 2020.
I took the halfway between of two and a half,
and that translates into an R0 of about 60%.
Meaning the herd immunity threshold is 60%.
Okay, what does that mean?
We need to achieve a community immunity level of about 60%.
So let's assume that about 10% have been infected,
and that the vaccine confers about 70% protection.
So to achieve herd immunity,
we need a vaccine uptake of at least 70%.
Let me show you that in graphic form.
So on the left hand, the black bar,
that's current immune.
The population gets vaccinated,
let's say 70% of people get vaccinated.
But remember, my vaccine estimate,
effectiveness estimate was only 70%.
Therefore, only 70% of the 70% are immune.
So I've got 10% plus 49% is 59%.
So that's about where we are with calculating herd immunity.
You can do this for all kinds of different assumptions.
It doesn't have to be with the data that I've presented.
You could change it up and use it for the mRNA vaccines,
which have been shown to be 90% effective.
I just used this one because it seems like
the numbers work out, and it's cool.
The approach to herd immunity, though,
has only been done through immunization strategies.
No infection has ever achieved herd immunity,
not even measles, with as contagious as that is.
But the other thing I really, really need you to remember
this aspect of herd immunity.
Herd immunity is a theoretical concept.
It is not a goal.
Herd immunity changes with nature.
It changes with the number of immune individuals.
It's gonna change with virus mutations.
And it's also, we also need to take into account
durability of protection
conferred by both natural infection and vaccine,
and we don't know what that is.
So please, please, please don't think of herd immunity
as a goal.
We still wanna get vaccine into everybody
in order to maximize protection, okay?
So herd immunity, not the goal.
I mean, as a concept, it is, but herd immunity of 60% or 70%
or whatever we calculate that to be,
that is not the goal.
We wanna get vaccine into everybody.
Also want you to know that vaccine safety
in the United States has the best system ever.
So these are just some diagrams that I put up
of our different vaccine safety monitoring programs.
The first one is VAERS,
or Vaccine Adverse Event Reporting System.
It's a passive reporting system.
Anybody can make a report about an adverse event
following a vaccine.
And healthcare providers are required to make a report
if a vaccine adverse event happens within 30 days.
The Clinical Immunization Safety Assessment
is another system.
And the Vaccine Safety Data Link are both background systems,
systems in the background
that are constantly monitoring vaccine safety.
And then V-safe is a new system that was put in place
right for the COVID-19 vaccine.
And back when you got vaccinated,
or when you will get vaccinated,
you'll get a handout about V-safe,
and it's an app for your smartphone
and you can report adverse events that happened to you.
Makes it personal, and you do your part
for reporting vaccine adverse events.
And then finally, want to talk a little bit
about the world and vaccinating the world.
COVAX is part of the World Health Organization's response
to pandemics, and it is a multifaceted approach
to make vaccines, well, and diagnostics and treatments
available equitably to the world.
You'll know that even though a small proportion
of the population lives in the developed world,
we've hogged the vaccines so far.
So we want to figure out a way to get vaccines
to the rest of the world, because we clearly know that,
and this has been truly illustrated by the pandemic,
that unless the entire world is protected,
we remain at risk for disease outbreaks.
COVAX has a goal of providing 2 billion doses of vaccine.
So far, they have 1.1 billion purchased,
but that doesn't mean they possess 1.1 billion,
but they've purchased 1.1 billion.
So we have a strong barrier ahead of us.
What has happened as part of COVAX
is that the developed world or wealthy countries
are paying a premium for vaccines.
And then part of that premium goes to buy vaccines
for countries that can't afford them.
So this is a strategy,
I've put the link up here for you
if you'd like to know more about it.
Okay, in summary,
I've decided to end with questions.
So, and that's because there's a lot we don't know yet,
and you know, so therefore, so many questions.
The timeline for completion of phase three trials
for other vaccines, we don't really know yet.
Interestingly though, so far we've had really appropriate
and really great transparent data sharing.
I can sit here and tell you about vaccines
and their protocols and how they worked,
and what adverse events were reported,
and with great confidence that these reports
have been made with good transparency.
The Advisory Committee on Immunization Practices
got to very quickly see those data
and make recommendations for vaccine use.
Places we still need to work on, though,
are vaccine delivery logistics.
How do we get vaccines to the people of the United States,
as well as to the people in the rest of the world?
Think about getting vaccines that require frozen temperatures
or ultra cold or frozen temperatures
to places that don't have reliable electricity.
So we have a long way to go yet.
I think we also need to work on public acceptance.
In every state in the United States,
the immunization rates in Blacks
lags behind the immunization of whites.
We need to make a special effort to close disparities
for people who have been adversely affected
or disproportionately affected
by COVID-19 and get vaccines to them
and on their terms.
We also need to continue to do research
after the EUA and even into following licensure.
Then following, I think that I can close with the big impact
that COVID-19 has had on the United States.
It has become the third leading cause of death
in just one year.
You know, we didn't have COVID-19
that we widely know of anyway, in January 2020,
but by the end of January 2020,
COVID-19 was the third leading cause of death.
I think right there shows how important this information is
and how we need to get vaccines in every arm.
I thank you so much for listening.
It's been a pleasure to be able to talk to you
and bring you such good news about COVID-19 vaccines.
Roll up your sleeve, get the vaccine, and stay well.