Hello, and thank you very much for joining
us today.
I'm Augustine Choi, Dean of Weill Cornell
Medicine, and I'm pleased to present to you
our Weill Cornell Medicine Insights webinar
series.
Each webinar is a lively and interactive discussion
with distinguished Weill Cornell faculty members
who are experts in a range of important topics
during these extraordinary times.
Each of us has faced our own unique challenges
over these last few months, and our hope is
that this series can help us continue to stay
connected and informed.
Today's webinar is COVID Clinical Trials:
Antibodies, Immunity, and Vaccine Development.
We have a remarkable panel of experts for
you, all of whom are authorities in their
respective fields.
Dr. Roy Gulick, Dr. Marshall Glesby, and Dr.
Kristen Marks.
They'll be joined by your moderator Dr. Carl
Nathan, chairman of microbiology and immunology.
Thank you very much again for joining us today.
We appreciate your time, your support, and
all you do for Weill Cornell Medicine.
Now, I'll hand you over to your moderator,
Dr. Carl Nathan, to get things started.
Welcome, everyone.
Thank you for joining us in this discussion
of COVID Clinical Trial: Antibodies, Immunity,
and Vaccines.
I'm Carl Nathan, chairman of the Department
of Microbiology and Immunology at Weill Cornell,
and it's a real privilege for me to share
this discussion with three people I admire
very, very much.
Trip is the co-chair of National Institutes
of Health's COVID Treatments Guidelines panel,
and he's the chair of Weill Cornell Medicine's
clinical trials task force.
He's joined by Professor Marshall Glesby,
who's associate chief of the division.
Marshall has conducted a trial of a drug called
sarilumab, and he's launching a trial of a
therapy based on convalescent plasma.
We'll hear more about both of those in a minute.
Associate Professor Kristen Marks, who likewise
has conducted a trial of an antiviral Remdesivir,
and is beginning a very exciting trial of
a vaccine produced my Moderna whom we'll hear
about those as well.
I understand there's a very large audience,
so we'd prefer this as a completely open discussion,
but in the interest of efficiency we've decided
I will ask the questions for about half the
session; but please keep your questions ready.
In fact, it would be better if you write them
down, keep them handy.
At 35 minutes in, we'll open the chat room.
Please post your questions then, and we'll
try to address them at that time.
Now, this is a new disease, and that, of course,
is the biggest challenge in trying to cope
with it, but there are three other challenges
I just want to tick off at the beginning to
set the framework.
One is that the approaches are different for
prevention, and they overlap to an extent,
but not completely with those for treatment.
Not only that, but when you get into treatment,
the approaches that are appropriate may be
completely different for treating early mild
disease, trying to prevent progression, or
for treating later disease that's more severe.
Immunity plays a big part in this, so the
second complication in this discussion is
that we want to promote immunity to it, but
there are times when we want to suppress aspects
of immunity as well.
When we're dealing with immunity, there are
two different forms of it, passive and active,
and we'll talk about that.
But let's jump in with the big question, how
do you conduct a clinical trial in the midst
of a pandemic?
Now back in April my phone lit up, my email
inbox filled up, just about everybody I ever
knew had an idea how Weill Cornell Medicine
could test a good idea for COVID.
In fact, now there are over 2,000 registered
clinical trials worldwide.
So let me throw the first question, maybe
it's the hardest one of all, to Trip, Dr.
Gulick.
Of all the suggestions that have flooded into
Weill Cornell Medicine for what to try, how
have you sorted through that?
Carl, I'm actually going to take a step back
and say that COVID-19 really posed an enormous
challenge to us here at Weill Cornell on many
levels.
People may remember the first case of COVID-19
was reported in New York state March 1st,
and the first case at our institution March
5th.
By the second week in April, we had close
to 500 patients hospitalized with COVID-19
here Weill Cornell, and over 200 of them were
on ventilators, on respirators.
This was an incredibly ill group of people,
and the basic approach to care for those patients
was supportive, meaning we treated their fevers
with Tylenol or non-steroidal anti-inflammatories,
and we gave them oxygen, including respirators.
We had no effective treatments at all.
So early on, the sheer number of people was
quite overwhelming from a clinical point of
view.
We rapidly expanded our infectious disease
team from two teams to six simply to accommodate
all the patients that we had.
The question came up early, what can we possibly
do to help people?
With no available drugs at all, we turned
to research early on.
Kristy Marks, who's right here, suggested
very early on let's convene a group of people
and let's see what's out there.
Let's try to assess all the available possibilities
to test drugs that people are thinking about,
and let's go with the most promising ones.
So we formed a small group, we met in a conference
room on a Friday afternoon, and we shared
thoughts about which studies we thought were
the most promising and could really help our
patients.
Really quickly we mobilized to try to do that.
Both my colleagues here, Kristy Marks and
Marshall Glesby, really did everything they
could to make sure that we had the most cutting-edge
trials of drugs here at Weill Cornell.
As you said, we got suggestions from all over
the medical center and actually all over the
country about different compounds that people
wanted to try, that they thought had promise
for patients with COVID-19, and we had to
sort through that.
My chairman in medicine, Tony Hollenberg,
asked to put together a task force to assess
all the ideas and come up with the most promising
as well.
We had input not only from infectious diseases
but from pulmonary, critical care, rheumatology,
all kinds of other fields.
We met as a group twice a week to really sort
through everything and get everybody involved.
It was a tremendous effort.
I will say that usually, the tempo of clinical
research is thoughtful and slow and reflective,
and you go through the process of getting
institutional review board, ethics committee
approval, and the contracting.
I can tell you that here at Weill Cornell,
we had an enormous commitment to put everything
on hyperspeed.
Everything went incredibly quickly.
So from the time that we received a protocol
to the time we could enroll the first patient,
in some cases, was as short as a week.
That's really unprecedented, has never happened
before.
Trip, isn't it the case that I sent you a
couple of ideas what to try, and the most
recent was about two hours ago?
Yeah.
I'm still looking at that, Carl, but I'll
get back to you.
Tell us a little about what it's like to conduct
a clinical trial while your hospital is overwhelmed
with very, very sick people with a contagious
disease.
Yeah, I think both Kristy and Marshall would
be great to speak on that.
They were right in the thick of it.
Kristy, maybe you want to start, what was
it like to actually approach patients about
investigational therapies when they were so
sick themselves?
For me it was a new experience, although I've
been doing clinical trials for a long time,
I hadn't been approaching people who were
so critically ill at the time where they were
having to make these decisions about whether
to also participate in research.
Usually, you talk to people, they have quite
a bit of time to mull it over, but obviously,
time was of the essence for sick patients
with COVID.
The other difference was often their family
members weren't there with them.
At that point, family members weren't allowed
in the hospital so often it was using technology
to call daughters, siblings, or uncle who's
a doctor, things like that to help them make
the decisions that were often when you're
not feeling your best challenging to even
make at all.
That part, I just was incredibly moved by
the bravery of the participants and that people
were willing to participate in research at
such a critical time.
So Marshall, could I ask you, randomized control
trials are even harder than observational
urgently started trials; can you comment on
the distinction, and when is it important
to insist on taking that harder route?
That's a great question, Carl.
Observational studies refer to just really
looking at how people do if they get a certain
intervention.
The challenge with those types of studies
is that they can garner some important information
often about safety of an intervention, but
it's very hard to evaluate whether the intervention
works or not, that's because a lot of people,
even those very sick with COVID-19 would recover,
will recover.
If you don't have a control group to compare
the people to who've got the intervention,
that is an adequate control group, meaning
that the people are really comparable to the
people getting the intervention, then you
can't really make any valid inferences about
whether the intervention works.
So that's why we do randomized control trials.
We randomly assign people to the intervention
or the control group, which may be a placebo
in many cases in order to make sure that the
people are comparable in every way.
It's not that the sicker people are getting
the intervention and healthier people are
not or vice versa.
It's really critical to get the efficacy information
that we need to do randomized control trial.
Of course, they pose a challenge, they're
harder to do.
On normal days they would take months to implement.
As Trip already mentioned, things got up and
running very, very quickly in this setting
due to the enormous efforts of many people
of this institution.
Really the institutional buy-in starting from
high up with Dean Choi and below in terms
of the importance of doing these types of
trials.
Let's turn now to-
Carl, I was just going to add it's worth pointing
out that typically in the field of medicine,
we wait for published data to change our practice
from definitive studies in high-profile journals.
Things were going so fast with COVID that
people were reacting to information that was
put out in press releases or unpeer reviewed
data, or rumors, or anecdotes.
There was tremendous pressure to find something
that worked, so to really stick to our guns
and do randomized control trials was really
something we felt was important to get real
answers that we knew would benefit our patients.
I, for one, am very grateful that you took
that stance.
I think it's incredibly important.
Let's turn now to prevention and the approach
of active vaccination.
There are at least five main types of vaccines
that are in clinical trials already and many
versions of each that differ in features that
are quite important.
These include viral vectors, these are usually
cold viruses that have been modified not to
cause a cold but they express the gene for
the so-called spike protein of the COVID virus;
or the RNA that encodes that which a host
cell, human cell can translate and make the
protein in your own body; or DNA that codes
for the RNA that the host cell can translate.
Some of them are purified recombinant S protein,
or parts of it, and some of them are the virus
itself.
It can be attenuated, or it can be virulent
but inactivated, dead.
So back to you, Dr. Gulick, what do we want
to achieve with these vaccines?
What's the goal?
The goal with any vaccine is to give a portion
of the microorganism, in this case, a virus,
to the body that's not infectious itself but
that the body sees as foreign and it makes
the response to it.
Either an antibody response or a cellular
response.
That response that's made by the immune system
is then primed, so if the person ever gets
exposed to the actual virus, the body has
already preformed a whole response that would
hopefully neutralize the virus and make sure
that the person did not get sick.
So that's what's going on with COVID.
Like other vaccines that people know well,
that we've had for years, what we're trying
to do is stimulate the immune system and to
make an effective immune response.
So what's the scorecard so far in terms of
immunogenicity and safety and results in non-human
primates?
There are many animal models, but those are
the most relevant.
There's a lot of excitement and a lot of need
out there for a COVID vaccine.
There's been more than 100, perhaps more than
200 candidate vaccines that have been identified,
and some of these have made it to the earliest
stages of human study.
We call those phase one studies, those are
the first in human.
The goal of those studies is simply to establish
that it's a safe thing to do, to inject whatever
piece of the virus into a human body to make
sure that's a safe thing.
The next step is phase two, and that's where
we look at that immune response.
Is the person's immune system responding to
that injection?
Are they making an immune response to it?
So safety first, immune response second, and
then what we're finally getting up to right
here at Weill Cornell is phase three.
That's where you figure out is it effective?
Did the immune response that was formed by
the injection, by the vaccine actually protect
against the disease?
We're pretty excited to get started here,
and Kristy Marks is leading the effort here
at Weill Cornell.
Very good.
My own reading of the literature, and there's
a flood of it, so it's really hard to keep
up; but it sounds like all the boxes are being
checked, at least as far as we can tell from
limited reports, by each of the vaccines.
They induce antibodies that seem to be neutralizing,
they have not produced adverse reactions that
we know about as yet.
When these antibodies are given to experimental
animals they do seem to protect, they don't
seem to cause an adverse reaction, and when
non-human primates are infected and spontaneously
recover, they're immune to rechallenge, which
is very encouraging.
So far, so good, but there are a lot of things
that differ among these vaccines.
Some need a cold chain, most of them need
two doses, some of them are very hard to make
in scale, so there are many different parameters
that remain to be seen.
But I want to go exactly to the point you
just introduced and turn to Kristen.
Why phase three, what are you looking for?
Why does it have to be randomized, or why
should it be?
Why are the numbers so large of the patients
that are enrolled?
Great questions.
The phase three study, like Trip mentioned,
is looking to see does the vaccine work?
In case of the trial of the mRNA 1273 or the
Moderna vaccine, it's actually looking at
does it prevent illness?
So it takes such large numbers because even
though we're in a pandemic not everyone will
be exposed to the vaccine.
People have gotten pretty good at protecting
themselves from getting infection, although
it's not perfect, not everyone in the study
will even be exposed to the virus.
Then of those exposed, we know many people
are asymptomatic, and not everyone will get
sick.
So this study is looking at 30,000 people,
15,000 of which will get vaccine, and 15,000
will get a placebo.
In this case, it's just simply saline.
People will not know what they got, it's important
that they're blinded because they may change
their behaviors if they believe they got the
vaccine.
Similarly, I will not know or the other study
investigators or study staff what they received
because we don't want our knowledge of that
to affect or bias our interpretation of their
symptoms as we evaluate the safety of it.
So it's a double-blinded study, and we will
be looking at how well it works as well as
safety.
So over time, I just want us to be clear,
no one is intentionally being exposed to virus
in this study, but we are enriching for populations
that if they're exposed they're more likely
to get ill with COVID, so that includes people
who are older.
At Cornell, we're targeting to enroll 50%
who are 65 or older, patients who are black
or Hispanic where we know that there's been
disproportionate death rates in New York in
those groups, and also people who have pre-existing
medical conditions like diabetes or heart
disease or liver disease.
Those are people who will be enrolled preferentially
in this study, the inclusion criteria of the
study actually mandate that.
Well, thank you.
That brings up the question, I hate to think
about this, but let's say we're lucky enough
that the vaccine you're testing or another
or any are effective, but supplies are limited
at the beginning.
Then the question of who should get the vaccine
first?
This is something that the National Academy
of Medicine is considering very carefully
in a process that they've gone to great lengths
to make inclusive, transparent, and public.
They haven't issued their recommendations
yet, but I'm sure this is on your mind, and
I'd really be interested to hear your thoughts.
One view is equitable allocation is based
on individual health risks like factors like
you just listed, diabetes, hypertension, and
obesity.
Or it might be population-based incidents
rates as you also referred to, for example,
the higher incidents of severe disease in
black and Hispanic communities.
Or it could be occupationally-based like healthcare
workers or public transport workers or resident
space, people in nursing homes, prison, or
military garrisons.
How do you think about this issue which we're
hopefully going to face?
Right, I really look forward to reading that
paper.
I definitely think priority must be given
to those people who get the sickest from COVID
or who will have the maximal benefit from
it.
I think those certainly need to be priority
groups, and I think there needs to be a fair
allocation, and I definitely would consider
health disparities as part of that making
fair allocation of vaccine.
But I do think where transmission is occurring
the most and who gets the sickest are probably
two different groups.
We see obviously all these college outbreaks
are showing that the transmission is widespread
amongst young people, yet they're the least
likely to get ill.
So I think both need to be consider when you're
considering the public health perspective.
Carl, it's worth adding that this is the first
phase three COVID vaccine study that's been
mounted.
This is a National Institute of Health sponsored
study, and they did a clever thing, which
is when COVID came along they didn't try to
recreate a whole network to try to do clinical
trials, they turned to clinical trials networks
that they had already established and asked
them, turn your attention to this challenge,
turn your attention to COVID.
The NHI funds quite a few networks that look
at vaccines or other kinds of diseases, and
we're one of those.
We study HIV/AIDS here for many years in our
clinical trial unit, and they came to us and
said, "Please take this on."
So this is the first phase three COVID study
that's been mounted here in the United States,
and we're so proud that Weill Cornell was
picked as the site for this.
We are the only site in New York City doing
this first phase three vaccine site.
Kristy Marks is really leading us well to
get set for that.
Trip, thank you for that comment, and also
for reminding all of us of the importance
of public health infrastructure and it's maintenance
over time so it can be used for emergent threats
that weren't originally anticipated.
The HIV clinical trials network is a great
example, and I should mention it's also being
used for TB research.
It's served many roles.
Right.
I will say a lot of people have reached out
even before we were actually enrolling about
being volunteers in this study.
If you'd like to do that, it's cctucovid@med.cornell.edu.
Maybe we can put that in the chat.
But we've had a great response from just people
who are in the Weill Cornell community about
volunteering themselves to be in the study,
so thank you for that.
Well, as promising as that is, it actually
leads to my next question, which is for you
again, Kristen.
What about vaccine hesitancy?
Particularly among some of the same communities
where a need for a vaccine is probably the
greatest.
Mm-hmm (affirmative) Right.
I think what ties into this, this is something
that pre-dates COVID of course, but I think
in the context of COVID, the idea that these
vaccines are being rushed through development
adds to that vaccine hesitancy.
I hear a lot of people talk about that.
I just want to explain that no safety steps
are being skipped, what's changed to accelerate
the development of vaccines is that the phases
of the studies are overlapping.
As Trip mentioned, clinical research usually
plods along.
This is one study is being designed before
the other one is finished, so that has accelerated
the whole process, and the vaccine is actually
being produced before we even know if it works
so that it would be available more quickly.
So there's no safety steps being skipped.
The safety is actually very, very rigorous
in these studies, and will be for people who
participate.
They'll be getting weekly calls where we ask
about safety, and completing e-diaries and
things.
So we will know everything about this vaccine
before it's approved.
It's worth having that the Russian vaccine
that everybody heard about a couple weeks
ago actually did skip a step.
They skipped phase three and went right into
people, and there were a lot of concerns from
the US medical community and many people throughout
the world that they should not have skipped
that step.
We simply don't know if that vaccine works
or not.
There's several vaccine studies planned.
So actually, the Coronavirus Prevention Network,
that's another thing people could Google.
If you go there, they have a survey you do,
and it puts people into a registry of potential
volunteers for multiple studies that are coming.
So it's a really helpful way for us to recruit
patients and including in those groups that
you mentioned that may not always be easy
to find to engage in research.
This registry I think is a very effective
tool for reaching people in all different
communities who maybe have never been a research
participant before but are interested in helping,
particularly with COVID.
We really consider these people heroes.
They're really equivalent to frontline workers
or-
Yes.
Well, thank you for that, but now a little
bit of reality testing.
I got my flu shot last year, and I got the
flu, and that's not unusual.
The flu vaccine...
By the way, I got it again today, and I urge
everyone to do that.
So that didn't discourage me, the previous
year's experience because I knew that an effective
flu vaccine is one that prevents disease in
about 50% of people, and moderates it in others.
So the official cutoff for a COVID vaccine
is also around 50%.
Even if it works there may be a lot of people
for whom it doesn't work well enough, and
that brings us to two more topics if we pick
up the pace.
One is passive immunization, I'm going to
turn to Marshall to explain about that, and
for what it is and for whom it might be more
appropriate.
Sure.
Passive immunization refers to directly administering
antibodies to a person as opposed to giving
a vaccine and waiting for the immune response
to kick in in the case of prevention, or in
terms of therapies, waiting for the person's
immune response to develop.
It's essentially what happens during pregnancy
when a mother's antibodies get passed to the
baby, and the baby is protected for the first
few months while their babies' immune system
matures and is able to ultimately to produce
antibodies on their own.
There are settings where people are discussing
this approach and beginning to study it.
In terms of hospitalized patients primarily,
there's convalescent plasma, which refers
to the liquid component of blood isolated
from people who've recovered from COVID-19
that's rich with antibodies and administering
that to people who are sick with COVID.
It's being studied in some settings as prevention.
Then there are monoclonal antibodies meaning
specific antibodies gently to the spike protein
of the virus of the outer part of the virus
that can neutralize the virus, prevent it
from infecting cells.
Those antibodies are beginning to be studied
both therapeutically and as well as prevention.
Some examples of settings where prevention
as opposed to a vaccine where passive immunization
might be appropriate would be where there
needs to be rapid implementation of prevention,
for example, a nursing home outbreak.
You could administer these antibodies potentially
to residents of the nursing home and hopefully
confer protection almost immediately as opposed
to waiting for a vaccine to kick in, which
may take two doses and many weeks.
Another setting might be somebody who's immunocompromised
and not able to respond to a vaccine adequately,
and you might be able to again confer at least
short-term protection by administering the
antibodies directly.
Very good.
There's a lot of press about the convalescent
plasma and the FDA pulling back from its decision
to authorize emergency use.
What's going on there, and why are you conducting
randomized control trial?
Okay.
There has been buzz about the FDA potentially
granting this emergency use authorization
for convalescent plasm in order to make it
more readily available in the community.
As of this past week or so, I believe there's
around 68,000 people now who've gotten convalescent
plasm through an expanded access program that
the FDA authorized and really approached the
Mayo Clinic to lead.
In that program, everyone gets plasma.
It's been largely in community hospitals,
some academic medical centers, but there's
no control group.
So as we talked about earlier, in order to
determine if something works, you need that
randomized control trial.
There are several trial that are ongoing.
We made the decision really based on high-level
discussions with Dean Choi and others with
the support of the Chair of the Department
of Medicine, Dr. Hollenberg, the Chair of
Pathology and Laboratory Medicine Dr. Loda
to join a large randomized Canadian trial
called CONCOR-1 that aims to enroll 1,200
people who are admitted to the hospital with
COVID-19 and require oxygen.
Two out of three will get convalescent plasma,
the other third will just get their routine
care.
The idea is to see whether the plasma is actually
efficacious at reducing rates of intubation,
being put on a ventilator, and improving survival.
Giving it to tens of thousands of people without
having that comparison group can help develop
a robust safety database.
In fact, we have learned that it appears to
be quite safe to give, but we really have
no idea whether it works or not, and the only
way to answer that question is by a randomized
control trial.
I feel that the Weill Cornell response has
been the appropriate one and the best one,
which is really to conduct a study that will
lead us to the answer of whether we should
be giving this intervention to people.
Cool.
Thank you very much.
Carl, this is a remarkable situation.
Realize tens of thousands of Americans have
received this, and we actually don't know
if it works or not.
Just walking to work today, I saw an ad on
the side of a bus that said "the Surgeon General,"
it says, "Donate your plasma if you've recovered
from COVID.
Save lives."
I thought, "Well that's just not true, we
don't know if it saves lives or not."
Marshall Glesby's leadership in really pursuing
a randomized trial which could answer this
question is just so key to the field.
We really need that answer.
Totally agree.
I'm proud of all of you for taking that position.
The chat room's about to open up, but while
that's happening, I want to turn to one more
aspect of immunity, and that is suppressing
it in COVID and the critical role of timing
and how you do it.
So maybe I could ask Kristen just to combine
things in the interest of time to compare
dexamethasone and it's timing, and sarilumab
Right.
I think because the approach to treating COVID,
in general, was antivirals and also then immunosuppressant
therapy, and I think we all believed antivirals
would have the biggest effect early on in
the treatment, whereas immunosuppressive therapy,
we weren't quite sure of what timing to use.
You don't want to put an immunosuppressant
on and let an infection get out of control
if you don't have to.
But clearly, there was a very severe inflammatory
response that was also harming people.
The dexamethasone story, what was found in
a well-designed, rapidly conducted, randomized
control trial was that early on before people
require oxygen, the dexamethasone really doesn't
seem to have much benefit whereas it does
benefit people who are at the point in the
disease where they're requiring oxygen.
Usually we see that about seven days into
the illness, the people who start to develop
pneumonia severe enough to need oxygen or
respiratory tract infection severe enough
to need oxygen.
It also seemed to benefit those people who
were so severe that they required mechanical
ventilation.
I'm going to have to let Marshals address
sarilumab since that was his study.
Well, actually, I'm going to jump in because
we have now questions from-
Oh, okay.
... the audience, and we should honor as best
we can.
There are quite a few.
So first comes from Ellen Alexander, who would
like you to repeat how to become part of the
study.
I just indicated they're going to post it
in the chat.
But the easiest way is to Google Coronavirus
Prevention Network.
That will add you to a registry that will
evaluate are you...
It will give people doing clinical trials
information about whether you're a good fit
for a particular study.
So not everybody's going to be a great fit
for the Moderna study, but they may be for
the next vaccine study, so it's great to have
this registry which we can keep tapping into
for different studies.
So that's probably one of the easiest ways.
You can also email us directly at cctucovid@med.cornell.edu,
and they'll put that one in the chat.
Okay.
Let me direct two questions together to Marshall.
One from Leanne Germander, and another one
from Ellen Alexander.
If you've had COVID and you've recovered,
are you protected?
If you have positive antibodies, how will
they last to protect you?
I can comment on that too if you like.
Yeah, can I call a friend?
I think we don't really definitively know
the answers to certainly the first question.
We hope that if someone has had COVID that
they will have some degree of immunity for
a period of time.
How long that is, I don't think we really
know.
The antibody response, it depends a little
bit on how you measure it, and it may depend
on how severe an illness a person has had.
The data I'd seen, and Carl, I'm sure you
follow this closer than I do, have been a
little bit conflicting.
There's some studies that suggest that people
who've had more of an asymptomatic or mildly
asymptomatic course may not have as robust
a response in terms of antibodies compared
to people who've been sicker with COVID, but
then also these antibody responses can wain
over the course of weeks.
The immune system has some memory, so it's
quite likely that re-exposure would generate
a memory response, and there'd be rapid reduction
of antibodies.
But I'm interested in your opinion on that,
Carl.
Yeah, thank you, Marshall.
That's exactly the point I wanted to weigh
in on.
It's true, I think the evidence that I've
seen is the worst case the disease you have
the higher antibody level you would come out
with if you recover.
It is transient, but that has been misinterpreted.
The antibodies in the blood wain over time,
that's perfectly normal, but the memory response
lasts.
If you get re-exposed those titers would go
back up again.
I think it's not appropriate to fret over
declining antibody levels or compare them
at long points of time after recovery to draw
any interpretations.
It's worth adding that there's been no convincing
case of a second infection with COVID that's
been documented once a person has had it once.
Although it may be a matter of time and everybody's
looking for it, but nobody has described that-
Yeah, it's certainly not common.
Again, I'll refer to those non-human primate
studies where deliberately infected animals
recovered, were rechallenged, and they were
protected.
Joel Greenberg is asking, "When do you think
we'll begin to see meaningful results from
phase three studies?"
I guess that's for you, Kristen.
Right.
It in part depends on like I said, selecting
the right subject so that no one is going
to intentionally going to be exposed to SARS-CoV-2.
People through their natural living their
life, working their jobs do get exposed, and
some people will get infection.
So after roughly 50 to 100 people are infected
in the study, they'll take the first look
and see if the vaccine was protective or not.
If it's highly protective, at that point,
they would move forward to trying to get it
approved by the FDA, assuming it's also safe.
So it is, to some extent, dependent on what's
going on in the background.
Obviously, they're trying to enroll places
that have a lot of COVID at the time.
Now, New York is not that situation, thank
goodness right now, I hope we stay that way,
but we are a site because of how severely
affected we were.
Right.
That relates to a question from Charles Hunt,
who says, "With low rates, is this a good
place for a trial?"
We hope it stays low, but with people traveling
through New York the way they do, one doesn't
know.
Has nebulized cortisone been used as an immunosuppresant?
Bill Netzer asked that question.
I'm not aware of any study that's looked at
that particular way of giving a steroid by
nebulizer.
But-
The steroid that showed the mortality benefit
was given orally, so that reached systemic
levels, and that may be really critical.
We know COVID is not just a disease of the
lungs, although that turns out to be the most
important early on, but then it can extend
to multiple organ systems after that.
So I think if I had to guess, I would guess
systemic administration of steroids would
be more effective.
Yeah, and the inhalation is designed to restrict
systemic distribution.
There's a very important question, we just
didn't have time to bring this up as we had
planned originally.
This is from Caroline Perkin-Los Arcos.
What about a clinic to study those with long-term
illness?
So people who've recovered by virologic criteria
but they have ongoing symptoms, often for
a considerable period.
Who wants to take that?
I could start.
Marshall, you probably can jump in too.
Our pulmonary critical care group has a long-standing
practice where they see people who had intensive
care unit care, and then came out of the intensive
care unit and recovered.
Right now, they're seeing people who were
in the intensive care unit for COVID and now
are recovering.
Our neurologists are interested in the long-term
complications that people might have, and
other people are as well, but I think it's
the critical care people who've really led
that here at Weill Cornell.
Robert Furnholtz is asking, "What's going
on with famotidine?"
I'm not sure any of us knows the answer to
that.
But, Trip, maybe you could take that.
Famotidine is the drug that's in the commonly
administered medication Pepcid, and there
was some intriguing data about this that led
to formalized clinical trials that are looking
at Pepcid.
You can give that either orally or intravenously.
There are randomized trials going on with
that right now to see if it has effects, but
we don't have any early answers.
Ellen Kane asks, "How reliable are the antibody
tests used by the large commercial labs like
Quest and Labcorp?"
I think there's some variability.
I can't speak specifically to those tests,
but these types of tests do have some varying,
we call performance characteristics, meaning
how accurate they are.
I think the bigger-
I can't resist a plug for the tests that are
going on here at Weill Cornell Medicine New
York-Presbyterian Hospital.
The plug is that the validation, the authentication
of these tests was carried out by Professor
John Moore in the Department of Microbiology
and Immunology.
So this was a great example of interdepartmental
collaboration between the basic scientists
and the clinical folks in the hospital clinical
pathology lab, Dr. Loewenstein.
We're confident in those tests, and it's harder
to comment about other tests.
Madelyn Antochek is asking, "How many people
were in phase one of the Moderna trials now
in phase three?"
Right.
I think it was around 20 in phase one.
Do you remember, Trip, the exact number?
[inaudible] Even though that study made the
headline of the New York Times.
They reported the early data from that study.
Phase two had hundreds of people, and the
phase three will be the thousands.
I did see a question about safety that came
up of the vaccine that I can address too.
The vaccine is a two-dose vaccine series,
and people do react to the vaccine.
The first dose, most people will have no side
effects, but after the second dose in the
phase one and in some early data I saw from
phase two, people may have some symptoms right
after they receive the vaccine, maybe for
a couple days.
Probably similar to what you see with flu
shots maybe, or shingles vaccine for people
who've had that.
The common ones would be things like headache,
a little bit of fatigue, a little bit of muscle
aches, so that's something I think to expect.
It won't happen in everyone, but I think if
you're prepared that could happen you can
plan your next couple days around it and have
some Tylenol or ibuprofen on hand, make sure
you're hydrated, things like that.
Kristy, can you say why do people get those
side effects?
It's because the immune system is reacting
to the vaccine.
We don't know that needs to happen to make
it effective, but we do know people probably
need two doses for this vaccine to reach the
titer levels we want.
So it's potentially a good thing, right?
It's showing the immune system is actually
reacting to the vaccine and hopefully forming
an effective response.
Exactly.
The other thing people ask a lot is if you
got the vaccine and then get COVID could you
actually get more severe COVID manifestations?
I will say the early research in animals as
well the type of immune response we see in
humans does not suggest that will happen,
but that's definitely something that will
be monitored in real-time with the study.
With apologies to our colleague Jim Bussel,
we'll come back to his question if there's
time, but I think we ought to focus on questions
outside the faculty.
Roger Guise, he points out there's still claims
as to the efficacy of low-dose hydroxychloroquine
in early COVID.
Comments, please.
The data are definitive now at all stages
of disease, and these are randomized controlled
trials, as we've emphasized, that compared
hydroxychloroquine to placebo.
In hospitalized patients, it made no difference
in clinical endpoints.
In people with mild COVID who were not admitted
to hospitals, it made no difference.
Even as prevention in people who were exposed
to COVID or who were not exposed but at risk,
it has made no difference in terms of clinical
endpoints.
This drug does not work.
But it does have potentially serious side
effects.
Does it not?
It can cause cardiac rhythm changes, and that
can be life-threatening in some people.
Those are rare, but they can occur.
Thank you for such a definitive statement.
It points again to the enormous impact of
randomized control trials versus observational
trials that are small, flawed, and inappropriately
used to promote treatment for everyone.
It also raises another important complication
of working in COVID-19, and that is that it
is not immune to politics and popular opinion,
and we've had to react to that.
It's been an interesting road for sure.
Ron Bose asks, "What's the status of monoclonal
antibodies?"
Marshall, do you want to take that?
They're being studied.
We're not studying them here at the moment
at Weill Cornell, although we are participating
in a study led locally by Dr. Teresa Evering
in our division.
That is one of the large National Institute
of Health's sponsored trials that is being
done through our HIV clinical trials network
that's called a platform trial.
What it'll do is different drugs will go in
and out of this large umbrella type of study
depending on whether the drug looks promising
or not.
It'll start out be given to a certain number
of people, compare it to placebo.
If it looks promising it will expand and be
given to more people.
Other drugs may go in and out depending on
how they look.
The first that will be studied is actually
a monoclonal antibody made by Lilly, and we
are getting poised to hopefully start that
study soon.
It's for outpatients who would have to come
in for an infusion of the antibody.
Yeah, I might just add to that I think there
are many reports from academic community of
neutralizing monoclonal antibodies and often
they're shown to protect different experimental
animals.
In terms of advancing into humans, I think
there at least five different companies, and
two of them are taking a somewhat different
approach.
One is Regeneron, and the other is Bristol
Myers Squibb.
In both cases, they're using cocktails of
antibodies, more than one, and this is designed
where one of them will still neutralize the
virus if it has mutated to escape being neutralized
by the other.
So this is an important difference between
monoclonals that are very specific and give
the virus an opportunity to get around them,
an active vaccination with usually a significant
part of the protein where the immune system
doesn't care how many different, what immunologists
call epitopes, it makes antibodies too.
It can make many, many different antibodies
at the same time.
Let's see, where to turn?
There's a question from Lawrence Reese, "Why
are many local physicians prescribing azithromycin
and Zinc for COVID-19?"
Once again, there's been descriptive studies,
not formal randomized clinical trials where
azithromycin and or Zinc, particularly the
combination of the two has through anecdotes
been related to improvements in COVID-19.
But these are simply not proven therapies,
and current guidelines do not suggest using
azithromycin or Zinc for COVID-19.
David Blaustein has an argument with doing
randomized control trial for convalescent
serum.
If I understand his question, he's pointing
out that the vaccine trials reference their
titers to what's seen in patients who are
convalescent and that would seem to validate
that the convalescent plasma are a benchmark.
I think that's something they do for the sake
of comparison, but that doesn't constitute
a benchmark.
Actually, people are hoping that with the
monoclonal antibodies some of the studies
might give different amounts to achieve different
titers in people who are very highly exposed
and finally answer the question, what titer
do you need to prevent infection?
But until that happens, we don't know.
Would you all agree with that, the clinicians?
Yes, that's well said.
We absolutely don't know if you develop antibodies
to COVID-19 right now, are they protective.
We hope that's true, but we simply don't know.
These vaccine trials will have to show us
that.
Joe Fischbach asks that, he's read that blood
type O decreases the chance of a serious case.
Is that true?
I'd like to volunteer.
The same genes that control the enzymes that
put the sugars on the blood group antigens
or don't, and dictate whether you get type
O control also other aspects of the immune
response.
In retrospect, there is no relationship between
blood type O and risk of COVID.
I came across that in the course of looking
up something else, so forgive me for jumping
in with an answer.
Thank you, Carl.
Now, another very important question from
Madelyn Antochek, "What is the chance of becoming
seriously ill in the phase three trial?"
Now, she might mean because it didn't work,
and you get COVID.
But I think her question is really what if
the vaccine predisposes you to serious illness?
This is an important question.
Right.
I saw another question also about how do we
know it's safe if it was only given to 20
people?
I should say the phase two study, which has
been fully enrolled, they've looked at the
safety along the way before they started dosing
the phase three study.
So even though they haven't unblinded it,
they've been following safety to make sure
that serious reactions weren't happening in
any of the groups, whether it's the people
who got placebo or the people who got the
vaccine.
They haven't seen any signal there, which
is why the phase three was allowed to open.
So that's what I was talking about with these
overlapping study designs, but not compromising
safety.
So in terms of the phase three study, we'll
be looking for, in terms of serious illness,
anything that is severe we record, and we
report.
So if there's anything unexpected that we
think could be related to the vaccine, we
categorize that as such, and those things
have to be reported immediately.
[crosstalk]
Thank you, Kristen.
I think it's worth emphasizing why this is
such an important question and it isn't dawdling
because if we think it's so safe, why wait
to enroll so many patients?
That's because in the closest relative to
this virus, SARS itself, the first one, experimental
animals who were vaccinated and then challenged
got worse lung disease.
There are other vaccines where the vaccine
made it worse.
The so-called antibody-dependent enhancement
that's been seen with Dengue virus vaccine,
which had to be pulled.
We're not seeing that yet, but if it occurred
in one percent of people who were vaccinated
and you vaccinated hundreds of millions of
people, you can do the math how many people
would get seriously ill.
What would that do to trusted vaccines in
general, which are among the most important
interventions in medicine?
That's a great point.
You do need large numbers of participants
to detect relatively rare side effects.
Yes and this is also the reason why we have
approximately 10 vaccines right now in human
studies, and they all use variable approaches.
So that's why we're doing the research, we
really need to assess the risks and the benefits
in very large studies before we could say
anything is absolutely safe and effective.
Yeah.
But Kristy, remind us, how many people have
received the Moderna vaccine already?
What's the number?
In the phase three, there's 10,000 people,
or probably more because each day it goes
up already enrolled.
We're opening soon.
I think because New York isn't a COVID hotspot
right now, we weren't appropriately the first
site to be opened.
But yeah, so there's a lot of people who've
already received this vaccine and then also
is part of the phase two study like I mentioned,
hundreds of people.
We're about to run out of time, so I want
to do two things.
I want to thank the panelists and the audience,
and pick one quick last question and see if
I get cut off.
Apologies to everyone else with all these
great questions.
Barbara Hales, "What about using interferon?"
This is another example that's reciprocal
to dexamethasone where later disease seems
to benefit from dex, and earlier, it might
be harmed or not helpful.
Interferons in animals seem to help a great
deal early, but contribute to the pulmonary
disease late.
So I'm bringing that up as an illustration
of the challenges that our clinicians and
our clinical trialists face when considering
any new intervention.
Just to add that the side effects also are
complicated with interferon and can be quite
debilitating for people.
Yes.
So I think that brings us to we're out of
time.
Again, I want to apologize to those whose
questions we didn't have time to address,
but thank everyone for participating.
Our panelists, thank you very much here, and
thank you for the work you do when you're
not on screen.
Thank you, Dr. Nathan, and a big thanks to
all of our panelists.
I'm very grateful for all your work and leadership
around these challenging and complex issues.
To all of you tuning in today, thank you.
We know your time is valuable, and we're deeply
grateful for all you do for Weill Cornell
Medicine.
If you're interested in supporting the work
of Weill Cornell or learning more about any
of the faculty participating on today's panel,
we'll be following up with more information
over email later today.
We hope you will consider getting more involved,
and I'm grateful for your interest in Weill
Cornell.
Please join me at our next webinar on Wednesday,
September 9th, Renewal at the Epicenter: COVID
and the Road Ahead.
I hope to see you next time, and until then,
please be safe and be well.
