RICHARD YOUNG: Hello, everyone.
We're about nine months
into the COVID pandemic.
In that time, a remarkable
amount of information
has been learned about
the novel coronavirus
and about host cell biology,
immunology, epidemiology,
and clinical disease.
There are complexities
in these subjects
that confound even the experts.
The purpose of this
course is to learn
what we know about
these subjects
from the world's top scientists.
I'm Richard Young, and together
with for Facundo Batista
and our teaching
assistant Lena Afeyan,
we are core faculty for
MIT's course 700 on COVID-19,
SARS-CoV-2, and the pandemic.
I'm going to make a few
remarks to the students who
are registered for this
course and then introduce
our first speaker.
Students, if you miss any of
the following instructions,
you can find them in the
course's Canvas site.
First, live
attendance of lectures
is encouraged but not required.
Recordings of the
lectures will be posted
with a link on the Canvas site.
Your TA, Lena, will post
an after-lecture prompt
as a survey on Canvas,
a response to which
will be required before the
start of the next week's
lecture.
Answers will be graded
for participation,
and students need to
participate in at least 90%
of these prompts
to pass the class.
Lena will hold a session
Mondays from 1:00 to 2:00 PM,
except for holidays, reviewing
relevant basic material
to help you better understand
the next day's lecture.
Recommended reading and
other reading materials
are posted on the Canvas
site and will be suggested
alongside the prompts.
Students are encouraged,
but not required,
to engage with these materials.
Finally, during each
session, students
can submit questions via the
Q&A function in Zoom Webinar.
Selected questions
will be discussed
at the end of the
lecture, and students
are welcome to ask any
unanswered questions
during office hours.
Our first speaker for this
course is Dr. Bruce Walker.
Dr. Walker is a physician
scientist and immunologist,
the founding director of the
Ragon Institute of MGH, MIT,
and Harvard, a Howard Hughes
Medical Institute professor,
a professor of medicine
at Harvard Medical School,
and a professor of the
practice of medicine at MIT.
He is also adjunct professor of
medicine at the Nelson Mandela
School of Medicine at the
University of KwaZulu-Natal
in Durban, South
Africa, where he
has catalyzed the creation
of two important research
institutes.
Dr. Walker is one of
my scientific heroes,
a person who has played a major
role in addressing the AIDS
pandemic, and who now is helping
us address the COVID pandemic.
Just last week, he
and his collaborators
published an important
story in Nature,
showing that T cells
in some individuals
can apparently
cure HIV infection.
Together with Arlene Sharpe,
he is the co-director
of the recently established
Massachusetts Consortium
on Pathogen Readiness,
a collaboration
among more than 500 local
scientists focused on COVID-19
research from Harvard,
MIT, BU, Tufts, UMass,
and the academic teaching
hospitals in Boston.
Bruce, thank you so much
for giving the first lecture
in our course.
BRUCE WALKER: Well,
Rick, thanks very much.
I'm delighted to do this.
So as Rick indicated, I'm
a physician scientist.
I graduated from medical school
in 1980, came to Mass General,
intending to become
a family physician,
but then something
very odd happened,
which was the emergence
of a new disease.
None of us knew what it was.
People that had it were
dying left and right.
We had no treatments,
and it became clear to me
very quickly that if we
didn't, as physicians
on the front lines, learn
from our patients, then
we would watch a
lot of people die.
So I then took the route of
both taking care of patients
and doing scientific
research, and I've
continued to work on
HIV my entire career.
And in January of this year,
to put this in the perspective
I have on it, I was
teaching a course
to MIT and Harvard
undergraduates
in KwaZulu-Natal,
South Africa, called
"Evolution of an Epidemic."
And this is a
course that uses HIV
as a model to try and understand
how an epidemic emerges,
how clues from patients
guide scientific discovery,
and how policy and
advocacy influence
the course of an epidemic.
Now, as chance
would have it, one
of the things that
we did was we were
visiting traditional healers.
And as chance would have it,
one of the people in the course
was an MIT student who had
just returned from Wuhan,
and another was the Director of
Emerging Pathogens for Gilead,
a former trainee of mine
who I'd invited along
as one of the speakers.
The student from Wuhan
started getting text messages
multiple times a
day from her family,
talking about what a desperate
situation it was there
related to this new
pneumonia that was emerging.
And Diana Brainard,
the person from Gilead,
was getting phone calls every
day from physicians in China,
asking her to release a
drug that they had developed
for Ebola, called Remdesivir,
so that they could try it to see
if it had any effect on
this new, deadly pathogen.
It became clear to me
from those conversations
that this had the potential
to be a big problem.
As Rick said, I'm the director
of the Ragon Institute.
Our mission is to
harness the immune system
to prevent and cure human
disease with a focus
on infectious pathogens
of global importance,
and our strategy
is really to use
cross-disciplinary
collaboration, coupled
with flexible funding,
to try and make advances.
And we're fortunate to
be embedded in, I think,
one of the best biomedical
research ecosystems anywhere.
So we started working on
this, really, right away,
and what I would like to do
now, as the first speaker,
is to give you a bit of an
overview of what we know.
How did this pandemic start?
How does it cause disease,
the virus, SARS-CoV-2?
What are the prospects
for treatment?
And what are the
prospects for vaccines?
So getting right into
this, let's put it
in the perspective of what
we experienced with HIV.
So HIV was recognized in
1981, but the infection
started being transmitted in the
US at least as early as in 1978
or even earlier.
So in 1981, it was clear
that something was going on.
It was '83, two years
later, before we
knew what was causing
this new disease,
and it took two more years to
develop a diagnostic test so we
could know actually who had it.
Now, let's compare what happened
with this particular pandemic.
So what happened
was that patients
started coming to
hospitals in Wuhan
with a pneumonia
of unknown cause.
And looking back at this,
it was the end of December
when this cluster
of cases happened,
and there was a really
important observation
made by health care workers.
And that was that these
people had a common experience
of having been at
a Hunan market,
suggesting that this might
be a transmissible agent.
That led to the use
of shotgun sequencing
to identify the etiologic
agent and to the development
of a diagnostic
test based on PCR.
That all, which took
four years for HIV,
occurred in less than a month,
so an extraordinary tribute
to the advances that have been
made in science over the years.
The sequencing
allowed scientists
to recognize this as
a beta coronavirus,
which is an RNA virus that
has a single strand of RNA
and then an outer envelope with
a predominant spike protein
that's a major target
for the immune response.
The origin of the virus
is almost certainly
from bats, originally.
It also is very closely
related to a coronavirus
that's been identified
from pangolins,
but, likely, the transmission
went from bat to pangolin, back
to bat, and then to humans,
although the epidemiology
is still not certain
on that score.
This is not the first
pathogenic human coronavirus
that we've seen.
SARS, in 2003, caused
a total of 8,000 cases
with a fatality rate of
11%, but, thankfully,
the transmissibility of
SARS was not that high.
MERS came along in 2011
and still persists.
There've been 2,500 some
cases with a much higher case
fatality rate of 34%,
but, again, thankfully,
low transmissibility.
But look at the
contrast to SARS-CoV-2.
We now have over 25 million
cases as of this morning.
The estimated fatality rate is
somewhere between 1/2% and 1%.
That varies widely
depending upon the age
group and the geography,
and it's very transmissible.
I think the important
thing for everybody
to recognize from this
slide is that we can expect
to have additional
coronaviruses in our future,
and the big fear,
and I think what's
an existential
threat to humanity,
is the possibility
of a coronavirus
with the transmissibility
of SARS-CoV-2 and the case
fatality rate of MERS.
So it really does behoove us
to monitor for these emerging
pathogens.
Why is it that SARS-CoV-2
has spread so effectively?
Well, it's in large part because
the transmissibility begins
before the onset of symptoms.
And, in fact, this is very
different than MERS and SARS,
which only are at
peak transmissibility
a number of days after
onset of symptoms.
This makes it very hard to do
case tracking and isolation
of infectious individuals.
Not surprisingly, we have
a huge pandemic, 25 million
global cases, 850,000 deaths,
and over 6 million infections
in the US, which is the most
affected country in the world.
So how is it that
SARS-CoV-2 causes disease?
I'd like, because of
the diverse audience,
to start out with just a basic
concept of understanding what's
the difference between
a virus and a bacterium.
Looking here at E. coli
compared in size to SARS-CoV-2,
I've exaggerated the
size of the virus
here compared to the
bacterium, but there
are significant differences
between these two.
E. coli has over 4,000 genes.
It, like other bacteria,
is metabolically active,
and it's capable of
independent reproduction.
SARS-CoV-2, on the
other hand, has
a total of 10 genes and
14 open reading frames.
It's metabolically inert, and it
cannot reproduce independently.
Instead, it depends
on the ability
to infect the human host and
to commandeer the human host
to actually make the genes that
are normally making proteins
for the cell to use
for its own purposes,
to hijack that
and force the cell
to make viral proteins so
that the virus can replicate
and make new copies of itself.
When the initial infections were
identified to be in the lungs,
that immediately
focused clinicians
on obtaining
specimens and trying
to find the etiologic
agent, which
is what happened through
sequencing of lung epithelial
cells, and that
also led to a search
for understanding how the virus
was actually gaining entry
into those cells.
And that led to the
identification of ACE-2
as the receptor.
There was a head start
on this because this
is the same receptor
that SARS uses,
the original SARS coronavirus.
That is, however, not the--
those are not the only
cells that become infected.
Goblet cells and ciliated
cells in the nose
are quite infectible, and
that actually, probably,
facilitates transmission.
Lung pneumocytes are infectible.
That's how we get pneumonia.
The gut is also infectible,
resulting in diarrhea
in some individuals.
The virus can also
infect endothelial cells
in the circulation,
and this leads to,
is thought to lead to, a
coagulopathy and clotting
that results in a great
amount of morbidity.
Cardiac myocytes can
also express the receptor
for this coronavirus.
And myocarditis has been another
disease that's been noted,
and it's even appears possible
that the central nervous system
cells can also be infected,
such as olfactory neurons.
This infection doesn't happen
without the body taking notice,
and one of the ways
the body fights back
is that these B cells, one
arm of the immune response,
start to making antibodies,
which are proteins that
directly bind to the virus.
They're generated in
response to the virus.
They learn in lymph nodes how
to recognize it effectively,
and then they target
it and destroy it.
If, however, cells get
infected, then another arm
of the immune system kicks
in, so-called killer cells,
or cytotoxic T cells.
These recognize infected cells
because once a cell's infected,
it alerts the body to the fact
that something bad is going
on inside that cell by
presenting viral peptides
at the cell surface
in conjunction
with an HLA class I
molecule, a surface
receptor on these cells.
Foreign peptide in the HLA
molecule in the binding groove
alerts these killer
cells to the fact
that something bad is going on.
They recognize that and deliver
a lethal hit to the cell,
killing it, and thereby
eliminating infectious virus.
So OK, so we have these
immune responses that
are being generated to
this virus the same way
that they are to other viruses.
Why is it that they're
not doing a better job?
Well, it turns out that B
cell antibody production
is impaired, and
this is work that's
from Shiv Pallai, who will be
speaking later in this course,
where he noted through
autopsy studies
that, in fact, unlike a
normal immune response
that gets generated
within a lymph node,
where these germinal centers
result in antibody maturation
and affinity maturation that
allows recognition, what
happens in COVID-19 disease
is that these germinal centers
don't form.
So there's an abnormal
immune response underway
that we're all attempting
to understand better.
Let me introduce now a
second concept, and that
is to make sure
that we understand
the difference between
infection and inflammation.
Infection is invasion of the
body by disease-causing agents,
their multiplication
in the body,
and then the reaction of host
tissues to that pathogen.
Inflammation, on
the other hand, is
the body's process of fighting
against things that harm it,
such as infections, by releasing
chemicals, that are also
called cytokines, that call
the immune system into action
and recruit other cells.
So a second reason
why the immune system
doesn't do a better
job is because it
appears that these killer cells
are ineffective at eliminating
infected cells, but they do
produce a lot of cytokines,
these chemical messengers.
In the same way infected cells
release chemical messengers,
these then act on other
cells and activate them
to elicit even further
chemical messengers,
and all of this
immune activation
leads to bystander problems.
And we see this
hyperimmune state,
which has been termed
an inflammatory storm,
or a cytokine storm.
And here, looking
at a normal lung
on the left, you can see
that the alveolar air sacs,
which is where gas exchange
happens between taking
a breath in and getting
oxygen into the bloodstream,
you can see that those are
very fine membranes that
allow for ready passage.
On the right, you see what
happens in COVID-19 disease.
There's this
massive infiltration
of inflammatory cells, a marked
thickening of the septae,
and an impairment
of gas exchange,
leading, then, to the clinical
problems with lung disease.
Now, essentially,
what I've just told
you is that we have an
immune response that's
designed to basically generate
an antiviral immune response,
and that happens early on.
But what we believe
happens in COVID-19 disease
is that that is actually
replaced by a host
inflammatory response that
actually, rather than acting
as friend, actually
acts more as foe
in the later stages
of disease as there's
increasing disease severity.
We know that this disease does
not affect everybody equally,
probably not surprisingly
because the older people get,
the more likely they're
going to have comorbidities
that make them less resilient
to diseases in general.
And in fact, what
was striking early on
was a sense that children
did not get infected,
but, sadly, that is not true.
And in fact, in data that
just came out yesterday
from the American
Academy of Pediatrics,
there has been recently a
greater increase in cases,
hospitalizations, and deaths of
percentage increase in children
compared to the percentage
increase that we've
been seeing in adults.
On top of that, there's a
unique inflammatory syndrome
that has been recognized
in children, which
is similar to Kawasaki
disease, which
is an inflammatory disease
of unclear etiology.
But what you can
see on this slide
is that between 2015 and 2019,
before the advent of COVID-19
disease, there
were sporadic cases
of non-severe Kawasaki disease
and occasional severe cases.
But look at what
happened in 2020.
Suddenly, this enormous
spike in infections.
We think that it's due
to a post-inflammatory,
a post-infectious
inflammatory response.
What exactly causes it is still
being investigated, but is
of critical significance
related to vaccine
development for children.
I'd like to say a few
words about diagnostics
now as a key component to
trying to curtail the pandemic.
What you're probably
most familiar with
are RNA tests, which
is PCR, and this
is what's being done
through the Broad Institute
for all of the MIT and
Harvard undergraduates.
These RNA tests use polymerase
chain reaction to amplify
fragments of a viral RNA.
So they don't tell you
whether what's being amplified
is actually infectious or not.
They just tell you that there
is viral genetic material there.
And if you look, as was done
at Mass General Hospital,
at RNA detection rates following
admission to the hospital,
what you see is that the percent
of people that are admitted who
start out positive
declines over time,
but some people remain RNA
positive for four weeks
or more.
The question is,
are these people
infectious all that time?
Because we're right now
using the RNA detection
assay as a yes-or-no assay.
Well, it turns out that there's
declining infectiousness
over time to the point
that the CDC revamped
its definition of recovery
to mean 10 days after symptom
onset, and at least three days
of the absence of symptoms.
It's really critical that we
develop an assay that we still
don't have that tells us--
that measures the
infectiousness of a person.
Now, another diagnostic
test that's been developed
is called-- it's
a category called
antigen tests, where
you're not looking
for viral genetic material.
You're looking for
viral proteins,
such as the membrane
proteins in blue
or the spike protein
in brown here.
And the way that these
diagnostic tests are being done
is very much like the
point-of-care diagnostic test
that's used as a pregnancy
test, where what one does is put
a detection strip into urine,
in the case of a pregnancy test,
and in the case of--
hang on.
And in the case of COVID-19,
what you would ideally use
is saliva or a
nasal swab, and then
use a swab that would
tell you whether or not
you're infected by having one
or two bands on this strip light
up.
These are now
actually available;
they're less sensitive.
But, in fact, less sensitive
may actually be better.
So let's just think about
the different assays I just
told you about.
The RNA-based tests are
much more expensive,
and they require, really,
much more extensive machinery,
although that also
is being addressed.
Rapid antigen tests
are much cheaper.
Sensitivity is lower,
but scale-up ability
is higher, easier to get
to underserved areas,
easier for frequent
testing, easier ease of use.
But at least right now,
they're not quantitative.
RNA tests can be
quantitative, but we
haven't used them
that way, and I
think there's a move
afoot to do that,
and there are supply
chain issues that
are predominantly
for the RNA tests,
but not so much for the
rapid antigen tests.
So another important
diagnostic is
to figure out who's had
the infection already,
and this is done by testing
for antibodies, which
are proteins in the
blood that are generated
in response to infection.
When somebody gets
infected, initially, there's
a wave of virus that occurs.
The immune response responds
by generating antibodies,
and, ideally, these
antibodies then,
after the infection's
cleared, come down to a level
and persist to protect
against subsequent infection
in the future.
If you look at antibody
responses in people
who were hospitalized
as same cohort,
you can see that they
come up slowly over time,
and within about three
weeks, almost everybody
has antibodies.
So they're-- sorry--
so we have ways to now
really track the infection,
figure out who's infected.
And this is-- these
antibody tests
are going to be a really
important epidemiologic tool.
Well, let's go on
and talk about,
what are the prospects
for treatment?
There, basically, are
two approaches that
in general are being pursued.
One is antiviral therapies
that directly attack the virus,
and an example of
this is Remdesivir.
Remember, in the
beginning, I told you
Diana Brainard was getting
calls in South Africa
to release a drug that had
been developed for Ebola.
That drug was
Remdesivir, and it's now
been shown to have some effect.
Now, the important thing to
note from this paper that
was published in The
New England Journal
is that, although Remdesivir
does have an effect in speeding
the time to recovery, there's
no change in mortality that's
statistically significant.
So it's really a
marginal benefit,
and it has to be
given intravenously.
We need drugs that
can be given orally,
that can be given early
in the onset of disease,
and/or in later disease,
and have an effect.
It probably makes
a big difference
when drugs are given in
terms of their ability
to make an effect, and
I'll come back to that.
Another approach is to use
neutralizing SARS-CoV-2
antibodies, and these can come
from convalescent plasma, which
has been given an
emergency use authorization
and has been a subject of much
controversy as to whether it
really works.
Another therapy on the horizon
is monoclonal antibodies
that are able to neutralize
the virus that could be given
prophylactically or
potentially therapeutically,
but those are not yet licensed.
Another way to approach therapy
is to have directed therapies
to block the cytokine storm.
So these are
host-directed therapies,
such as antibodies
to interleukin 6,
which is elevated.
It's a pro-inflammatory
cytokine and helps
to create this cytokine storm.
And another is
dexamethasone, a steroid.
Dexamethasone has been
shown to have some effect
and is now being used, but there
are lots and lots of trials
that are underway and
still no clear front
runner of a drug that truly
meets the requirements,
I think, to have an impact of
being readily available, orally
ingestible, rapidly
acting, and active
during all phases of infection.
So let me move on now to
talk a little bit about what
the prospects for vaccines
are, which is really
what I think it's going
to take for us to get out
of this pandemic.
Again, a basic concept
to make sure that we're--
or basic concepts to
make sure that we're all
on the same page.
Immunity is protection
from an infectious disease.
If you're immune
to a disease, you
can be exposed to it
without becoming infected,
or you can have a very
attenuated infection, such
that you don't even notice
that you've been infected.
Immunity can be induced by at
least two different mechanisms.
One is infection itself,
and that, hopefully,
leads to immunity to
any subsequent encounter
by generating, for example,
antibodies that persist.
Another is by
immunization, which
is the giving of
a vaccine product
that stimulates a person's
immune system to produce
immunity to a specific
disease, protecting
that person from disease.
So in other words, you're
training the immune system
to attack the virus,
without the person ever
having seen the
virus, by giving just
a portion of the
virus in a vaccine
and using that as
your training vehicle.
So right now, there are
probably close to 200 vaccines
in development.
In terms of where we
are in human trials,
there is a plethora of
vaccines that have already
entered human trials.
23 vaccines are
in phase 1, which
is the first phase of study,
where you test whether vaccines
are safe, and you determine
what sort of dosage
can be tolerated.
Phase 2, there are
now 14 vaccines
in that stage, which is an
expansion of the phase 1 trial
to get more safety information
and learn something
about immunogenicity.
Phase 3 trials, of
which there are nine,
is when large efficacy
trials are begun.
I think you've all
heard that the goal is
to determine efficacy of a
vaccine as quickly as possible,
and the way that
that will be done
is by dramatically increasing
the number of individuals
that receive the vaccine.
So the trials that are planned
are somewhere between 30,000
and 50,000 patients
because you have
to have enough
infections occurring
to show that the vaccine
works better than the placebo.
Finally, there
are three vaccines
that have been approved
for earlier limited use,
not by the FDA, but
by other countries,
China and Russia in particular,
but there are no vaccines
yet approved for full use.
There are four different
general categories of vaccine
that are being pursued.
One is genetic vaccines.
The Moderna vaccine here
in Boston is one of those.
They're based on messenger RNA.
DNA is another form.
These used one or more genes to
stimulate an immune response,
genes from SARS-CoV-2.
Inactivated viral vectors
is another approach
that's in part being done
here in Boston by Dan
Barouch in collaboration
with Janssen
and also by AstraZeneca in
collaboration with Oxford.
This is the use of
another virus to deliver
SARS-CoV-2 genes to cells to
stimulate an immune response.
A more standard approach
that's been used for years
is viral protein plus adjuvant.
This is a little further
behind in the pipeline,
but it uses SARS-CoV-2
protein or protein
fragment, along with
something to help stimulate
the local milieu
where the injection is
made in order to stimulate
an immune response.
And finally,
inactivated SARS-CoV-2,
which is just inactivation
of full virus, which
has also been used
in the past and is
what the Chinese
have already started
using in some circumstances.
Let me tell you a
little bit about what
we know from the work that
we've done here in Boston.
This has been led
by Dan Barouch, one
of the founding members
of the Ragon Institute,
who is also a
physician-scientist
and at the Beth Israel
Deaconess Medical Center.
As soon as the virus
sequence was released,
Dan ordered synthetic genes,
started vaccine design built
on a collaboration already
existing with Janssen, Johnson
& Johnson, by the end of
January to work together,
then tested the vaccines
in animals during February,
established a challenge stock,
and by the end of March already
had data suggesting that this
was immunogenic in monkeys.
And Janssen made the
decision to go forward
with making, scaling
up production
in case the subsequent studies
would show that the vaccine was
safe and effective.
The first human studies are
going to be done in this month,
and the expectation
is by early 2021
there'll be massive
scale-up and emergency use
authorization for the vaccine.
Here are the data in monkeys.
On the left, sham vaccination.
Red is the composite
for 10 animals.
You can see that there
is a marked increase
in virus, and in this case,
following vaccination and then
challenge.
But on the right, you
see the marked difference
using the spike protein
as a vaccine antigen.
And of the four animals
that were in this,
two of them actually never had
a blip in virus, and two of them
had a markedly attenuated level
of virus in the bloodstream.
So the goal here
is that, instead
of what happens with
infection where you generate
an antibody response,
what will happen here
is that through vaccination
you'll generate antibodies.
And then if the
person then encounters
virus, what will happen is
either minimal infection
or, in fact, no
infection related
to a massive increase
in antibodies
when they encounter the
true virus infection.
So how are we going to know
if a vaccine is effective?
Well, we have to
test it in a place
where there's a lot
of transmission,
and, sadly, in the
world there's still
a lot of transmission occurring,
most of it in Asia, but also
in South America,
and North America,
and rising numbers in Europe.
In The New York Times
on the front page
this morning was an article
about concern in Spain
that there's a
recrudescence of new cases.
South Africa has had a major
spike, but that has dwindled,
but it's with extensive
curtailment of activities.
Also, we know, as shown in The
New York Times vaccine tracker,
that we're seeing lots
of cases of infection
that are being detected
in colleges, which
may be another place to test a
vaccine, although many of these
are actually going more
to online education.
So as we move
forward, we're going
to have to ultimately
prioritize and decide,
what are the vaccines that
we really want to take?
And what do we really
want to promote
to make 7 billion doses
to be able to make it
available for the entire world?
The one question is, will the
vaccine protect from infection
or does it just
protect from disease?
And, ideally, we'd like to
have a vaccine that completely
protects from infection.
That would be an
antibody-based vaccine
to get free virus before
it can infect cells,
but even something that
protects from disease
and keeps virus slow enough
that people won't transmit
would be extremely
beneficial, and that
would likely depend on T cells.
How many doses are
needed for protection?
Well, if you need three
doses given over six months
to get to protection,
that means that a vaccine
available to be
given in December
won't actually protect
people until next June.
Will there be enough new
infections to show it protects?
I've just gone over that.
How soon can the
vaccine be available?
And here, I think, one has to be
aware of when the first vaccine
is in a vial and can be
given to a person versus when
that vaccine is
available worldwide,
and you go into your
doctor's office,
and he's got it on a
shelf, or her shelf,
and can pull it off
and give it to you.
And so that's going to
require massive scale-up,
and I think all of us hope that
multiple vaccines will actually
make it to the finish
line because none of these
is going to easily make it to
the level of 7 billion doses.
For the vaccine that Dan
Barouch is making with the Ragon
Institute and the BIDMC,
they have committed
to making a billion doses.
So the next topic is kind of
enough of the vaccine be made.
It's going to be
challenging, but people
are scaling that up right now.
A critically important
question is, does the vaccine
work regardless of age?
Most of the vaccine
trials are not
including people
that are much older.
The few that have
in humans have shown
that people that are most
susceptible in terms of age
are less likely to make an
immune response to the vaccine
vectors that they've been given.
Another critical question is
whether a vaccine requires
a "cold chain," and
this is really critical
when one thinks about
global delivery.
If you have to keep
the vaccine on dry ice,
and you have to deliver it
to rural areas in Africa--
moreover, if you have to
aliquot the vaccine once you
get to the community that you're
trying to administer it in,
that requires special facilities
and special measures that
will make it much, much
more difficult. So,
ideally, we want no
"cold chain" requirement.
How durable is the immunity
the vaccine induces?
Well, there already have
been some suggestions
of reinfection of people that
have already been infected.
Shiv Pallai's work suggests that
the antibodies being produced
are not normal in
that the lymph nodes
themselves are not normal.
They don't generate
germinal centers.
So I think, personally, I
think the word is still out.
It's still unclear whether
these immune responses that
are generated by
natural immunity
actually do provide long-term
protection, and time will tell.
Another critical question is,
do vaccine-induced antibodies
enhance infection?
Or is it possible
even that they may
contribute to multifocal
inflammatory syndrome
in children?
And another thing
that's not on this slide
is that, in fact, children, or
people less than 18 years old,
is a whole other category
of individuals that,
appropriately, are
not being tested right
now in the first wave
of these vaccines,
as we're looking for safety.
But when they when
the trials are
done in people that are 18 to
65 years old, the question is,
will there need to be a
whole separate set of studies
done in children in order
to get licensure to give
these things to children to know
that they're safe in children?
So this is a really
important point
that I don't think has been
given enough attention.
At least, it's not
clear from what
I've read what the
actual plans are
for development and licensure
of these vaccines for children.
So I think, while we're
waiting for a vaccine,
we have to ask what
else can we do.
We, in the Boston
and Cambridge area,
I think, as a group of
scientists recognized that this
was going to be a really
challenging problem,
and we felt we had
something to contribute.
In fact, we felt we had
something to contribute
on a grander scale if we could
get everybody collaborating
together.
So on March 3, I had, I
think, what for all of us
was a really unique experience,
where we got together
with about 85 scientists from
Harvard, MIT, UMass, Tufts,
and Boston University
to talk about what
we as a scientific
community could do,
and a clinical community could
do, to address this pandemic.
And what came out of that
was the establishment
of the Massachusetts Consortium
on Pathogen Readiness,
Mass CPR, which has been
an extraordinary experience
for all of us involved.
I've never seen the
kind of collaboration
that has evolved
from this consortium.
We have six different
working groups
in areas ranging from clinical
and outcomes research,
to diagnostics, to
therapeutics, to pathogenesis,
and to vaccines and
epidemiology, and a huge amount
of collaboration and sharing
that's been happening.
We've also been
closely collaborating
with investigators in China
who are at the Guangzhou
Institute for Respiratory
Health, which has
been a fabulous collaboration.
And I'm really optimistic, given
the number of people working
on this problem, and the
selflessness with which people
have been working,
that we will make
real progress going forward.
And I think we already have
seen extraordinary progress up
to this point.
I think the other thing that we
can do is follow the science.
We know how transmission occurs,
and there's been a lot of talk
about droplets versus
aerosols and how long they
stay in the air, et cetera.
But I think the critical
experiment has really
been done, and the
fact of the matter
is we know how to
prevent transmission.
And that experiment was
done in the hospitals, where
masks were worn by everybody.
Distancing couldn't
actually be achieved,
but hand washing could,
and what we did not see
was major outbreaks among
health care workers.
In fact, at Mass
General, the incidence
of infection among
health care workers
is less than in the community.
I think that shows
us that masks work,
and I think, while we're all
working as vigorously as we can
to come up with solutions
in terms of therapeutics
and vaccines, if
we wear our masks,
we will prevent
transmissions from happening.
So let me make a
few conclusions.
One is that advances
in other fields
have clearly accelerated
responses to COVID-19.
Everything that we've done
at the Ragon Institute
has been based on things that
we learned from working on HIV,
including the entire
backbone for Dan's vaccine.
SARS-CoV-2 infection
is transmitted
prior to symptoms, which is
how it's spread so rapidly
and why it's so important
that everybody wear masks.
Infection results in a
hyperinflammatory state,
involving multiple organs,
and that is what makes,
what we think contributes to
a lot of the pathogenesis.
There are currently no
highly-effective treatments,
even though there are some
that have marginal impact,
but we really need better drugs.
And while we're
waiting for a vaccine,
effective prevention
can be achieved
with masks, physical
distancing, and hand washing.
There has been unprecedented
progress toward a vaccine.
We have to be sure that that
vaccine is safe and effective
by the time we actually
administer it more broadly.
And, clearly, there's
still much to be
done and much that people--
no matter what your discipline
is among the students that
are listening to this talk,
it intersects with a pandemic,
whether it be in the scientific
realm, the psychological realm,
the therapeutic realm, the
economic realm, et cetera.
So we can all contribute
to a solution.
And with that, I will thank
you for your attention,
and I'm happy to
answer some questions
RICHARD YOUNG: Bruce,
thank you so much.
The students have a
number of questions.
One is asking you,
why do you think
the US is among the most
highly-infected nations
in the world?
BRUCE WALKER: Well, I
think that you can actually
see that in the
tracings that I showed,
in the last month or so,
the number of infections
have come down in
the US, and that
is directly correlated with
increased adherence to the use
of masks and social distancing.
Other countries implemented
those measures right away.
They did complete lockdowns
like we did, but came back
from the lockdowns with
continued, really vigorous
adherence to the
prevention measures that
were available to us.
And it's not really a surprise
that masks would be important.
In fact, it's important
you wear a mask so
that you protect other people.
I don't think
anybody on this call
would want to have open heart
surgery with their physician,
surgeon, and OR nurse
not wearing masks.
They don't wear
them because they're
afraid of getting some
infection from the patient.
They're wearing them to
prevent infecting the patient.
We know that masks
can do that, and so I
think that's a
critical factor here,
and one of the unknowns for
the future as to whether people
will really adhere to
that and whether people
will understand
that there are times
when we need to limit our own
freedoms in order to protect
the population at large.
And there are lots of
examples of decisions
that we as a society
make to do just that,
and I think this is a situation
where we need to do the same.
RICHARD YOUNG: And
Tara is asking,
about how long active
recovery from infection
does the antibody test
results remain positive?
BRUCE WALKER: So this is a
really critical and unanswered
question as yet.
So we only know as long as
the epidemic has been around,
and there is evidence
that in some people
antibody levels are declining
to become undetectable
over a fairly short
period of time.
There is concern I alluded
to for at least four cases
of reported reinfection of
people that have already
been infected, presumably
because antibodies, which we
have very good evidence that
the antibodies can be protective
if they're there, but these
people have gotten reinfected.
We don't know their
antibody levels
to really know how
that correlated,
but that's a really big concern.
And, obviously, that
would have a big impact
for the development
of herd immunity,
which is when enough people have
immunity that others won't--
that the virus can't easily
transmit through a population
because it doesn't have enough--
there aren't enough
susceptible hosts.
Now, the question that was
asked was about somebody
who becomes infected.
How long do those
antibodies last?
Now, I think the data
that Shiv has generated
suggests why they
may not last long,
but what about immunization?
Well, how long will
those antibodies last?
And that's something
else we don't know,
but my sense is that that's
likely to last longer because
rather than trying to generate
an antibody response in a lymph
node that's infected with
live virus, in this case,
you're taking a
fragment of virus,
delivering it to a lymph
node, and the lymph node's
learning how to--
teaching the immune
response to recognize it
without being impaired by the
ongoing virus replication.
So I think that those
are likely to be
two very different things,
but time will tell.
RICHARD YOUNG: Lena
is asking if you
can comment on the
mutability of SARS-CoV-2
and the impact of emerging
mutations on our plans
to vaccinate.
BRUCE WALKER: Yeah, this is
another really good question.
So SARS-CoV-2 is
nothing like HIV, which
mutates at an incredible rate.
In fact, if I compare an HIV
virus sequence from Boston
to one in South
Africa, they may be
40% different in the
envelope, so we've never
dealt with trying to make a
vaccine to a pathogen that
diverse.
In contrast, SARS-CoV-2
has very few mutations.
It does mutate,
and the consequence
of those mutations
on immune recognition
are still being sorted
out, but there is concern.
And, clearly, the
whole population,
the global population
of SARS has already
shifted to some extent, and
I know that Dan has already
made another vaccine with
a second strain of SARS
just in case.
What will be critical is whether
the mutations that arise,
albeit we expect them to be
far, far less than with HIV,
whether those will actually
result in immune escape.
And, again, this
is a reason why we
need to do lots of sequencing
and lots of surveillance
to keep ahead of
this, and it may
be that, like other
infections like influenza,
there is a requirement
for updating vaccines
on a regular basis.
RICHARD YOUNG: Another student's
asking for the genetic vaccine,
or vaccines using inactivated
viral vectors, what
are the concerns of long-term
effects of the vectors
or delivery methods?
BRUCE WALKER: So with
the genetic vaccines,
there's less experience
with those, and so
the clinical trials
that are ongoing now,
both for other
diseases-- for example,
Moderna has other pathogens that
they've developed vaccines for,
so they have more
human data from those.
DNA vaccines, likewise, have
been used for other pathogens,
so that data have
been generated.
In terms of inactivated viruses,
we've used those for years.
You can ask, why didn't we
do that approach with HIV?
In fact, in the monkey
model, it looked
like an inactivated
virus worked,
but the concern is just
whether the virus could somehow
become reactivated
and become infectious.
And I think that's
tempered enthusiasm
for inactivated
vaccines, but there
are, I think, ways to make
an inactivated vaccine safe,
but that's the main concern.
Another concern is that it's
more laborious and expensive
to make inactivated vaccines
because you have to grow up
a huge amount of virus
in order to do that,
and these entirely synthetic
approaches that can be used,
like with mRNA, are potentially
a real plus if we can do that
without having to
rely on cell culture
and other aspects that
are required for the more
traditional approaches.
RICHARD YOUNG: Many
students had questions
about reinfection
and the possibility
that reinfection is a
consequence of the antibodies
just not doing what
they need to do.
Do you have a view
on reinfection,
the extent to which it
happens and the implications?
BRUCE WALKER: And
there's another concern
about reinfection
based on dengue virus,
and that is where the antibodies
could actually make things
worse the second time around.
One of these cases
of reinfection,
not to alarm people, did
look like it was worse
the second time around,
but so far, there's
no evidence from the
earlier SARS data
that I think are compelling.
There's no evidence
to suggest that there
is this phenomenon of
antibody-dependent enhancement.
I think, in terms of
protecting from infection,
antibodies are going to--
neutralizing
antibodies are going
to be required to do
that, from reinfection.
So not everybody generates
sufficient levels
of neutralizing
antibodies, probably,
from their first infection.
I think, though,
that T cells may also
play a really big role
in cases of reinfection
because if the virus slips
through the first defense
of antibodies and
gets into cells,
then T cells are the
main effector mechanism
that can eliminate virus.
And so I think
attention to vaccines
that not only produce antibodies
but also produce T cells
is important.
Moreover, there's a
second kind of T cell
besides the killer cell.
Those are helper cells
that help to orchestrate
an effective antibody response
in those germinal centers,
and so generating COVID-specific
T helper cell responses,
I think, may also
be really important,
particularly for the prospect
of potential reinfection.
RICHARD YOUNG: Bruce, we so
appreciate you giving this,
an introduction to the disease,
the virus, the pandemic.
Thank you very much, and we'll
see all of you again next week.
BRUCE WALKER: Thanks very much.
I enjoyed it.
