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( Silence )
[00:00:04.076]
>> Welcome to the third lecture
in this 2009 series
[00:00:09.826]
on global diseases, Voices from the Vanguard.
[00:00:13.156]
This is a joint effort between the Center
for Tropical and Emerging Global Diseases
[00:00:20.236]
and the night chair in Health and Medical
Journalism, Pat Thomas of the Grady College
[00:00:25.786]
of Journalism and Mass Communication and
I am pleased that each of you is here.
[00:00:31.766]
I know outside if it is very tempting,
the first nice day in about four days.
[00:00:38.216]
As most of you know, the lecture series is
intended to create interest in global diseases
[00:00:44.876]
across the campus from north to south campus
[00:00:48.516]
and today we have Dr. Barney
Graham, who will talk to us.
[00:00:52.696]
But let me first remind you that we have a
reception immediately following the lecture
[00:00:58.536]
over in Dennison (assumed
spelling) Hall, right next door.
[00:01:01.776]
The next Voices from the Vanguard will be April
14th and that will be Dr. Jennifer Freidman
[00:01:09.336]
from Brown University and she will probably
talk to us about her work in the Philippines
[00:01:15.796]
on a variety of neglected tropical diseases.
[00:01:19.926]
So tonight, Pat and I have asked Dr. Barbara
Schuster to introduce Dr. Graham to you.
[00:01:26.746]
But before I do that, it is first a distinct
pleasure to introduce Dr. Schuster to you.
[00:01:34.436]
Dr. Barbara Schuster is the new campus
dean of the medical college of Georgia,
[00:01:39.046]
University of Georgia medical
partnership, campus in Athens.
[00:01:43.916]
She is a proven educator,
physician and administrator.
[00:01:49.506]
Barbara comes to us from Wright State University
and Ohio and there she chaired internal medicine
[00:01:59.426]
and has most recently taken a year to work
[00:02:03.076]
with the American Medical Association
in terms of doing some research.
[00:02:09.256]
So it is a pleasure to introduce her.
[00:02:11.156]
She is new to the campus and I think
it is terrific that she took the time
[00:02:16.246]
out from putting together her medical school,
[00:02:18.636]
which is literally what she is
doing to be with us tonight.
[00:02:22.786]
So it is my pleasure to introduce
Barbara to you.
[00:02:25.966]
I would ask you to welcome her and her husband
Richard, who is a professor of UGIA's public
[00:02:32.186]
of college health and they
are both here tonight.
[00:02:45.796]
So please introduce yourself to them too.
[00:02:49.446]
( Applause )
[00:02:49.513]
>> Barbara: Thank you very much
for that wonderful introduction.
[00:02:51.776]
My husband is here in the second row with
me, so I hope I will get to meet each
[00:02:57.246]
of you later after Dr. Graham presents.
[00:03:00.236]
It is really my pleasure
to introduce a colleague.
[00:03:03.616]
I don't know Dr. Graham, but we have
mutual friends in Rochester, New York,
[00:03:09.786]
people who also work in the field of virology,
but Dr. Graham is a graduate of Kansas,
[00:03:18.106]
the University of Kansas where he received his
MD degree after graduating from Rice University.
[00:03:25.256]
He went on to do post medical school
work called residency in Vanderbilt
[00:03:30.796]
and completed a fellowship there after
internal medicine in infectious disease.
[00:03:35.866]
The infectious disease folks
are always close to my heart,
[00:03:39.296]
because had I chosen a specialty I had thought
about infectious disease and so microbiology
[00:03:45.886]
and infectious disease is something
I have always had an interest in.
[00:03:49.406]
He, of course, has you know rose in the ranks,
became a professor and has done outstanding work
[00:03:55.376]
in the fields of RSV, also known as Respiratory
syncytial virus and HIV and today he is going
[00:04:03.346]
to speak to us on the HIV vaccine development,
[00:04:06.616]
what is the next step, so
please welcome Dr. Graham.
[00:04:09.436]
( Applause )
[00:04:09.676]
>> Dr. Graham: Well thank you very
much and it is my pleasure to be here.
[00:04:22.866]
I have to tell you a little bit about my
connection to Dr. Collin (assumed spelling)
[00:04:28.456]
because he rescued me during my dissertation
work when I was getting my PhD at Vanderbilt,
[00:04:34.916]
even though I was a virologist and wanted to
be a virologist and he was a parasitologist,
[00:04:41.206]
he helped me finish that dissertation project
[00:04:44.576]
and I think it may be his only virology
paper ever, but he does have one.
[00:04:49.616]
( Laughter )
[00:04:51.606]
The thing I learned there though that most of
the really big ideas about immunology have come
[00:04:58.316]
out of the parasitology field and it is
mostly things borrowed from parasitology
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that has populated the viral
immunology literature
[00:05:08.616]
and so I owe him a debt for that as well.
[00:05:11.566]
Okay. And I thought of him not
too long ago when I was in Uganda
[00:05:27.856]
and had an opportunity to go
rafting on the Nile River.
[00:05:33.076]
And they said it was a class five rapids
[00:05:35.926]
and so the shisto (assumed
spelling) really shouldn't be there.
[00:05:38.736]
( Laughter )
[00:05:39.006]
Because they should only be present in
very calm waters and so we did go rafting.
[00:05:44.706]
I was at the head of the boat
and we had a terrific time
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and my antibody titer a few
months later was negative.
[00:05:50.626]
( Laughter )
[00:05:50.736]
So I just, but I did think
of you during that trip.
[00:05:54.906]
[00:05:56.046]
So why do we need an HIV vaccine, this is
the main reason that there is still more
[00:06:02.616]
than 7,000 infections every day occurring
throughout the world and despite the delivery
[00:06:09.296]
of anti-retro virals in a
more efficient way globally,
[00:06:13.566]
there are still about 10 new infections
for every new person that is started
[00:06:17.626]
on anti-retro virals and if that is the
trend, we are never going to be able
[00:06:22.976]
to treat our way out of the HIV epidemic.
[00:06:26.346]
[00:06:27.456]
Unfortunately, many of these infections are in
low and middle income countries and they are
[00:06:33.806]
in our most vulnerable populations,
women and young, young children.
[00:06:41.936]
The United States, the epidemic has
gotten as much attention recently
[00:06:48.006]
as I think it should have,
but it still is significant.
[00:06:51.636]
There is still 55 to 65,000 new infections
every year and as you see it has moved more
[00:06:59.346]
into minority populations, more vulnerable
populations and it has become a disease
[00:07:05.926]
of young people particularly
within those minority populations.
[00:07:10.006]
So we do need a vaccine.
[00:07:12.626]
So why do we think vaccines would work for HIV?
[00:07:15.516]
The main reason is because
of their track record.
[00:07:18.736]
Vaccines are the most effective
and efficient way to managing
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and controlling infectious disease epidemics
[00:07:26.336]
and I am showing you just a few
examples here of vaccines for viruses.
[00:07:31.426]
The year of the peak incidence of that infection
in the United States, the number of cases
[00:07:40.366]
at present in those years, for instance,
mumps in 1967, almost 200,000 cases.
[00:07:46.186]
In the early 60s, half a million cases of
measles, those diseases have almost vanished
[00:07:53.186]
and have become very rare, except for last
year when there was 7,000 cases of mumps
[00:07:59.126]
because people stopped taking their vaccines,
because they forgot how bad mumps could be.
[00:08:04.566]
We have eradicated smallpox
that happened in 1980,
[00:08:09.316]
so no place on earth is having
smallpox now and polio is very rare,
[00:08:14.776]
if ever present, in the western hemisphere.
[00:08:17.936]
So vaccines do work, vaccines work even
[00:08:21.496]
when they are partially affective
or partially administered.
[00:08:24.226]
So this is an example from the mumps epidemic,
when the vaccine became available in 1967,
[00:08:32.346]
before very many people were immunized, the
epidemic started going away and it is one
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of our best examples of how just taking a
few transmitters and a few susceptible people
[00:08:43.576]
out of the population, these kinds of
epidemics that are requiring a large number
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of susceptible people for
transmission can start going away.
[00:08:53.896]
So even before the recommendation was
made for some people to be vaccinated
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in a more universal way,
the epidemic was vanished.
[00:09:06.816]
[00:09:08.416]
But there are problems for HIV,
very significant biological hurdles
[00:09:12.866]
that have not been accomplished in any
other vaccine effort and so HIV has a list
[00:09:20.066]
of problems, for instance,
the lack of natural immunity.
[00:09:25.406]
There is not an example of where our
natural immunity response was able
[00:09:29.736]
to fully clear a virus from an infected
human being and so the absence of the ability
[00:09:35.426]
to study the natural clearance
mechanisms is not present in HIV.
[00:09:39.896]
There is also evidence that if you are infected
with one strain of HIV, you can be affected
[00:09:45.426]
with another strain of HIV so natural virus
infection doesn't necessarily prevent you
[00:09:51.236]
from having another natural virus infection.
[00:09:54.586]
The genetic diversity is difficult for two major
reasons, one is the question is what do you put
[00:10:01.146]
in the vaccine, how do you select the
antigens for the vaccine when there are
[00:10:04.416]
so many tens of thousands of choices to make.
[00:10:08.806]
And secondly, because if you do become infected,
[00:10:11.866]
even though you are vaccinated the
genetic variation in the virus growing
[00:10:16.256]
in you can help you escape
those immune responses.
[00:10:20.066]
So it is problematic on both the
population and the individual level.
[00:10:26.736]
Thirdly, there is an infection in a
deficit created in the first responders
[00:10:33.086]
for the immune system, both antigen presenting
cells are impacted and the (inaudible) 4 T cell
[00:10:40.316]
that organizes the rest of the
immune response are either destroyed
[00:10:45.146]
or their function is diminished and then HIV
can infect immune privileged sites like the eye
[00:10:54.456]
or the immune system has a hard time reaching.
[00:10:57.526]
It can become integrated into your genome and
become latent and so it can exist in a state
[00:11:03.656]
in which no antigens are seen and
the immune response can't see it
[00:11:08.306]
or it can become sequestered so a lot of HIV
[00:11:11.456]
in an infected person is actually
sitting outside of your cells.
[00:11:14.716]
It is sitting attached to the outside
of the drake (assumed spelling) cells
[00:11:17.536]
in the lymph nodes and that is not a place
it can be cleared by the immune system.
[00:11:23.336]
And then for vaccine developers, one of
the biggest problems for HIV is the failure
[00:11:28.016]
to induce neutralized antibodies,
which is the basis
[00:11:30.896]
for most effective vaccines that we have today.
[00:11:35.746]
So I will go through why despite
these biological problems,
[00:11:40.756]
I think it is still possible to have an HIV
vaccine and then I will tell you about some
[00:11:46.766]
of the difficulties we have had in the HIV
vaccine development field in the last two years
[00:11:51.346]
and then at the end I will let you
help me decide what we should do next,
[00:11:56.516]
what should be the next step.
[00:11:59.056]
So when you are infected with the virus, it
is interesting that despite the diversity
[00:12:04.736]
of viruses that a person might be exposed to,
a typical infection is a single Varian crossing
[00:12:12.506]
over and infecting the next person.
[00:12:15.706]
We know that because sequencing virus early
[00:12:18.216]
in that infection period only gives
you a single genotype and it doesn't,
[00:12:23.716]
it takes about 4 to 6 weeks before the
genotypic diversity to start developing,
[00:12:28.896]
so unless a person has ulcer disease, most
infections occur from just a single varian
[00:12:35.826]
and so the transmission efficiency
is not that high with HIV.
[00:12:39.186]
It is not a very contagious virus and it may be
a very minimal immune response of the right time
[00:12:46.156]
and the right place that had a
big impact on HIV transmission.
[00:12:52.236]
So when it infects, it infects usually through a
mucosal service, dendritic cell grabs the virus
[00:12:58.606]
and feeds it to a CD4 T-cell nearby and
within just a few hours it is spread
[00:13:04.966]
and can be detected in regional lymph nodes.
[00:13:07.926]
Within a few days, it is systemically spread
and you can find it in all the lymph nodes
[00:13:12.936]
in the body and at that time, it achieves
a dynamic equilibrium where there is a lot
[00:13:18.916]
of virus being made and a lot of virus
being cleared, but you reach a set point
[00:13:23.936]
where you have a steady state virus
level, but that process of making virus
[00:13:30.136]
and killing virus is what eventually erodes
and destroys your lymph node architecture
[00:13:35.316]
and allows you to develop immune deficiency.
[00:13:40.206]
[00:13:41.236]
We know that if we had an antibody
that was effective at blocking HIV
[00:13:45.646]
that could neutralize HIV, we
could potentially block infections.
[00:13:49.326]
That would be our best option.
[00:13:50.646]
That is how most good viral vaccines work,
but as I will explain later in more detail,
[00:13:57.686]
we do not have antigens identified that can
elicit broadly neutralizing antibodies to HIV,
[00:14:03.096]
so antibodies that can block the
most commonly transmitted strains
[00:14:06.896]
of HIV are difficult to identify.
[00:14:11.996]
We also know that when we have our
normal adaptive immune response,
[00:14:17.386]
particularly the T cell response, when
it happens, it cannot fully clear virus.
[00:14:23.286]
It just achieves this steady state
of virus resistance and we know
[00:14:28.666]
that in the meantime before
that T cell response can occur,
[00:14:32.596]
this state of latency can be
establish in a sequestration.
[00:14:39.456]
So the big question for vaccines as we are
now working on vaccines is what happens
[00:14:44.826]
if you move the T cell response sooner.
[00:14:47.466]
If the adaptive immune response
can happen a little bit earlier
[00:14:51.156]
and a little bit higher magnitude, what
effect could that have on virus replication.
[00:14:57.206]
So when you are infected with HIV, it
takes about 3 to 4 weeks for the virus
[00:15:02.006]
to reach its peak point of virania
(assumed spelling) and at that point,
[00:15:08.046]
the T cell response kicks in and a
specialized type of T cell, the CD8 T cell,
[00:15:12.516]
the killer T cell or the CTL, cytotoxic T
lymphocyte is able to recognize the virus
[00:15:20.726]
and start clearing virus infected cells and that
is what reduce the viral load to this set point
[00:15:29.606]
of virinia that you would have for 7 to 10
years untreated before you developed AIDS.
[00:15:37.506]
If we had an antibody response
preformed antibody response,
[00:15:41.256]
we may be able to block infection,
but it is not likely we will be able
[00:15:45.766]
to generate antibody response like that in
the near future, so most of the vaccines
[00:15:49.886]
that were being tested right
now are T cell based vaccines,
[00:15:53.656]
hoping that these specialized CT8 T
cells that recognized process virus
[00:15:59.626]
on the surface proteins called
MHC molecules, type 1, class 1,
[00:16:03.966]
MCH molecules can rapidly clear
those virus infected cells and then
[00:16:09.816]
if potent enough could potentially clear
your body and have an abortive infection,
[00:16:14.946]
but more likely is what is seen in animal
models reduce the (inaudible) virinia
[00:16:20.546]
and achieve a lower set point viral load that
results in a very delayed illness progression.
[00:16:28.416]
You might also have a situation where it
doesn't really reduce viral load in the host,
[00:16:34.526]
but maybe it reduces the output virus and maybe
it reduced transmission to the next person.
[00:16:40.186]
That could also have a beneficial
effect on the epidemic and then
[00:16:46.086]
because things don't always go
the way you want them to go,
[00:16:49.556]
there is also the possibility
of disease enhancement.
[00:16:52.466]
That has been something that has happened
with respiratory syncytial virus in the past
[00:16:56.086]
with measles virus in the past with
some (inaudible) viruses in the past.
[00:17:00.756]
So when you think about starting to make an
HIV vaccine and you look back at history,
[00:17:10.436]
how long does it take to make a vaccine.
[00:17:12.516]
Can you do it even in one career?
[00:17:16.616]
And the answer is only if you are
lucky and start soon, start early,
[00:17:21.796]
because it usually takes
decades to develop a vaccine.
[00:17:25.806]
From the time a virus is discovered
to the time the vaccines are available
[00:17:29.996]
for human use is usually majored in decades.
[00:17:33.886]
Right now, we are in 25 years and counting
with HIV, but there are other difficult viruses
[00:17:38.796]
with difficult biology that we also still
haven't conquered and they are common viruses.
[00:17:43.806]
Like RSV is more than 50 years, herpes
simplex virus is more than 90 years.
[00:17:49.256]
These are viruses that have properties of
latency like herpes or that inactivate some
[00:17:55.296]
of the early immune responses like
RSV that share these properties
[00:18:01.396]
with HIV, so not all viruses are easy.
[00:18:05.906]
[00:18:07.226]
In 1997, President Clinton gave an
address at Morgan State commencement
[00:18:12.236]
and said maybe we should put more effort
behind the HIV vaccine development process
[00:18:17.246]
and proposed a new center be built on the NIH
campus and so that project was started in 98,
[00:18:24.576]
the building was finished in August of 2000
and we started occupying these laboratories.
[00:18:30.746]
I went from Vanderbilt University at
that time to help start the center
[00:18:37.466]
and partly because it has unique features.
[00:18:41.006]
Most of the easy vaccines have already been made
for the viruses that we have and the formula,
[00:18:49.236]
the risk benefit and the cost benefit formula
now for vaccines is such that it may not be
[00:18:55.386]
that industry alone will be able
to develop very many more vaccines.
[00:18:59.336]
And so the unique feature of our
program is there is government money,
[00:19:06.836]
public money for public health
in vaccine manufacturing.
[00:19:10.976]
That has not occurred very often.
[00:19:12.826]
If it has occurred, it is mostly
been in the setting of the military.
[00:19:16.456]
It is a very mission oriented
program, unlike many programs at NIH
[00:19:23.046]
that are more free flowing,
basic research, follow the idea.
[00:19:27.846]
This is very mission oriented group and self
contain means that we cover a broad array
[00:19:34.766]
of activities all the way from
atomic structure of the proteins
[00:19:39.376]
to clinical trials in a relatively small group.
[00:19:44.336]
So these are some of the
principal investigators of the VRC.
[00:19:47.626]
We work out of Building 40 on the NIH campus,
[00:19:51.426]
but now the program also includes
what we call the pilot plan,
[00:19:55.556]
which is a GNP production facility in
Frederick about 20 miles north of campus.
[00:20:00.406]
It is a state of the art facility that is every
bit like you would see at a Merck or a Glaxo.
[00:20:09.396]
There is a clinic here now in this building.
[00:20:13.696]
This is the new Building 10, so we
can do phase one clinical trials.
[00:20:18.156]
This is the clinical trials group and we
also have a processing cite in Gaithersburg,
[00:20:24.256]
a few miles away that processes
our clinical samples
[00:20:27.036]
and does good laboratory
practice end point analysis.
[00:20:32.136]
We also can do small animal work and we have a
primate colony spread out throughout the world
[00:20:38.386]
of about 500 Indian (inaudible) that
allow us to do the studies we need
[00:20:44.046]
to do pre-clinically before
we get into clinical trials.
[00:20:47.586]
And because the gates are imposing
and the fence around NIH is imposing,
[00:20:52.316]
we now have a mobile clinic
to see if we can reach
[00:20:54.706]
out beyond the gates to do
these clinical trials.
[00:21:00.356]
And since 9/11 in 2001, our mission has
expanded somewhat and I won't say anything
[00:21:05.826]
about these other programs, but in
addition to HIV, we now have a programs
[00:21:10.726]
or have done programs on Ebola Marburg,
smallpox vaccine, alternative smallpox vaccine,
[00:21:19.146]
West Nile Virus, SARS caronavirus,
and influenza viruses.
[00:21:23.836]
[00:21:24.846]
So the story of HIV vaccine development has been
kind of staggered and it has its ups and downs.
[00:21:34.766]
Pat Thomas has written a book about some
of these ups and downs, some of the peaks
[00:21:38.646]
and valleys that she has witnessed, but
there has been a clinical trials program
[00:21:44.056]
for HIV vaccine evaluation since 1987.
[00:21:47.756]
Vanderbilt was one of the
founding sites and since that time,
[00:21:51.586]
a number of different vaccine
products have been developed and may be
[00:21:57.156]
as many as 60 different concepts.
[00:22:00.296]
And but those have only resulted in
a small number of efficacy trials
[00:22:04.636]
where you actually test to see
whether a vaccine works or not
[00:22:07.266]
and the first one was this Vac Gen GP 120,
which was based on a purified protein.
[00:22:12.906]
It was based on the same thing that
the Hepatitis B vaccine was based on
[00:22:18.026]
and the problem is because we
weren't inducing antibodies
[00:22:23.796]
that could neutralize the
common virus, it did not work.
[00:22:27.226]
So that trial ended in 2003.
[00:22:30.136]
A purified protein can induce antibodies
in CD4 T cells, but it cannot CD8 T cells,
[00:22:36.926]
the ones that can clear the
virus infected cells.
[00:22:40.096]
And so from that time, even before
that time, studies were being done
[00:22:46.086]
with vectors, vector based vaccine delivery.
[00:22:48.446]
So this RV 144 is a trial using a canary
post vector boosted with this GP 120.
[00:22:57.846]
It is in 16,000 people in Thailand.
[00:23:00.636]
They had an interim analysis in 2007 and
8, the trial is continuing and we will hear
[00:23:06.586]
about the results of that study,
I think this year in October.
[00:23:11.666]
And then there was the Merck studies, where
they took an ad nil virus based vaccine
[00:23:17.496]
and add 5 vector, I will tell you more about
that and did something called the step study.
[00:23:22.996]
That is where the title of my talk came
from, because the step study was a good idea.
[00:23:30.226]
It was testing a very important vector that
can induce CD8 T cells that could have a chance
[00:23:37.266]
of clearing the virus early and it was conducted
first in North America and then in people
[00:23:45.976]
who are adnel virus naive, add 5,0 negative
and then extended to add 5 immune people
[00:23:53.316]
and then it was extended to a sister trial in
South Africa called Pambilly (assumed spelling),
[00:23:59.416]
so these 6,000 people were studied with the
Merck vaccine and you see these big red Xs.
[00:24:05.676]
There was something that happened in this
trial and that was at the interim analysis
[00:24:10.996]
when they were evaluating this first
trial that was primarily in North America,
[00:24:15.386]
they found that among the
vaccinees there was a higher rate
[00:24:18.896]
of infection then among the placebo recipients.
[00:24:21.816]
So the vaccine was causing an increased rate of
infection at least among some of the sub groups
[00:24:28.536]
and we will talk about those sub groups
later, but the consequence of that was
[00:24:32.666]
that the Pambilly trial was immediately
stopped and this pay 100 trial
[00:24:38.546]
which we had been planning for the last 7
years, which was slated to start on September 28
[00:24:46.646]
of 2007, 10 days after this
Merck announcement never started.
[00:24:52.306]
So this pay 100 study that was going to evaluate
a different gene based vector concept did not
[00:24:58.536]
start, so I will tell you the
basis for that vaccine product.
[00:25:04.996]
I will tell you the differences
between it and the Merck product
[00:25:08.146]
and then I will ask you what you
think about starting the 505 study
[00:25:12.796]
and you can help me decide
whether it should go forward.
[00:25:16.656]
[00:25:17.766]
So the VRC vaccine candidate was multi-valient.
[00:25:21.866]
It included envelope genes from plates
A, B and C that covered about 85 percent
[00:25:27.566]
of the incident stains in the
global epidemic, attempting at least
[00:25:31.686]
to have broader coverage of
a greater number of viruses.
[00:25:36.806]
And it included multiple genes,
not only the gag and paul genes,
[00:25:42.176]
but the nef gene and these envelope genes.
[00:25:45.046]
So it included a lot of genes and a
lot of plates to cover a lot of viruses
[00:25:50.366]
and it used two different types of platforms,
a DNA vaccine platform to prime the response
[00:25:58.636]
and an antinal virus based platform to
boost the response, the DNA was delivered
[00:26:03.616]
by this needle free injection system and
the boost had a set of matching genes.
[00:26:08.336]
And so what we knew about that
vaccine is that in non-human primates,
[00:26:13.676]
among the vaccinated animals, you could lower
the peak virania relative to the controls
[00:26:20.426]
and you could lower the early set point
virania in animals who had been vaccinated
[00:26:26.086]
with a similar type of vaccine and challenged
with SIV, a simulated immune deficiency virus.
[00:26:33.286]
We also knew that vaccinated
animals had a survival advantage
[00:26:37.436]
in this very stringent SIV challenge model and
so that DNA ad combination had better protection
[00:26:46.896]
in monkeys then the adnil virus
alone product from the Merck studies.
[00:26:51.926]
We also know that in this example where compared
to the sham or the mock vaccinated animals,
[00:27:00.886]
animals immunize just with the
DNA add (inaudible) gag and paul,
[00:27:05.686]
which had a relatively small
reduction in the set point virania,
[00:27:09.756]
had a much larger reduction
in the semen viral load.
[00:27:14.506]
So the amount of virus in the
mecak (assumed spelling) semen
[00:27:19.686]
that could be detected was even greater,
[00:27:23.356]
more reduced in the vaccinees
then you would have guessed
[00:27:27.276]
from just looking at the plasma virus.
[00:27:30.756]
We also know from early phase one clinical
trials that giving either DNA alone
[00:27:35.756]
or adnil virus alone compared to the
combination of DNA and adnil virus
[00:27:40.086]
that the heterologist (assumed spelling) gene
based combination gave a much higher antibody
[00:27:44.236]
response, more than 100 fold higher antibody
response and if you measure T cell responses
[00:27:50.416]
and this is an ell-(inaudible)
essay, but it is a measure
[00:27:54.266]
of these CD8 T cells that
I have been talking about.
[00:27:57.466]
If you combine the DNA and adnil virus, you
can see about a 5 to 7 fold higher response
[00:28:04.036]
of T cells in the combination than you can
in either of the modalities by themselves.
[00:28:10.586]
And the response was also
qualitatively different.
[00:28:13.756]
One of the big features of this new center is
all the ways we can measure T cell responses
[00:28:19.906]
and Mario Roater and Rick Kelp
there have pioneered this use
[00:28:24.736]
of poly functional T cell analysis using flow
based methods where we can pheno type cells
[00:28:32.236]
and then define whether they are making these
degranulation markers or putting out the things
[00:28:37.926]
that can kill the target cell or making
these various (inaudible) that are a measure
[00:28:43.626]
of the CD8 T Cell function and we
can measure all of these things
[00:28:47.316]
at the same time on a single cell basis.
[00:28:49.866]
So there is really a large number of phenol
types in these cells, but we condense them
[00:28:56.636]
down into just how many functions
are present and we can ask
[00:29:01.806]
in the HIV response is it poly
functional or relatively oligal functional
[00:29:08.446]
and what you can see in both CD 4 and CD 8 T
cells compared to just adnil virus by itself,
[00:29:16.026]
the DNA ad combination is
much more poly functional.
[00:29:19.086]
There are many more cells that are making
3, 4, or 5 functions instead of 1 or 2.
[00:29:26.906]
And so in the DNA ad heterologist prime boost
combination, we are seeing more T cell response
[00:29:33.486]
and a more functional T cell response.
[00:29:37.106]
So this product was moved in to phase 2
studies and this was done on three continents
[00:29:42.616]
and three major regions by three major
networks, so we had network partners, the HVTN,
[00:29:49.716]
which was domestic and also in South
Africa, US Military Research Program,
[00:29:55.296]
the International AIDS Vaccine Initiative, a
nonprofit and a military program work together
[00:30:01.306]
in East Africa with a very
diverse group of investigators
[00:30:05.336]
and we accomplished a 920 person
study that we called the Triad
[00:30:11.606]
and in that I will just show you this one table
and bottom line that either at our facility
[00:30:18.776]
in Gaithersburg, the HVTN labs in Seattle, the
IOVI labs in London or the military field sight
[00:30:25.696]
in Tanzania, if you measured T cell responses
in the field in these vaccines in populations
[00:30:32.026]
at risk, you could see about a
70 to 80 percent response rate,
[00:30:36.446]
which was considered good at the time.
[00:30:40.596]
But then on September 18th, our September 18
was worse than September 11th, in some way,
[00:30:49.306]
but this report from the Merck study
showed that there was increased rate
[00:30:55.446]
of infection among vaccinees compared to
placebos and it was even more profound in people
[00:31:01.586]
who were prior, previously exposed to adnil
virus 5, so ad 5 zero positive people,
[00:31:08.706]
there was a risk rate, odds
ratio of some place of around 3
[00:31:13.976]
to 1 vaccinees to placebos getting affected.
[00:31:17.586]
So the question is first of all what is
going on there and second of all is it safe
[00:31:23.136]
to do any more gene based vaccine studies?
[00:31:26.266]
So the next analysis broke it down into whether
a person's ad 5s were all negative or positive
[00:31:34.286]
and whether they are circumcised
or uncircumcised
[00:31:38.126]
and what you see here is the greatest risk
among vaccinees was among the uncircumcised men
[00:31:45.856]
and this entire analysis was done in men.
[00:31:49.266]
So of the 83 infections in that first
analysis, 82 of those analysis were in men.
[00:31:55.746]
This analysis is only evaluating
gay men in North America.
[00:32:02.376]
[00:32:03.456]
And so, the odds ratio is highest in
uncircumcised whether they are ad 5, 0 positive
[00:32:09.846]
or not, but there also appeared to
be some risk among circumcised men
[00:32:15.616]
if they were add 5, 0 positive.
[00:32:18.796]
So the question is if you just focus in on this
group of circumcised ad 5 naive individuals
[00:32:30.316]
where the relative risk of
vaccination was less than 1,
[00:32:35.936]
could you do a safe vaccine
study in that population?
[00:32:41.346]
The other piece of data that came out
of the Merck study was that among people
[00:32:45.816]
who had a low ad 5 antibody before vaccination,
if you looked at their LE spot response compared
[00:32:56.656]
to the viral load after they were
infected, there appeared to be a correlation
[00:33:01.686]
in those people who are ad 5 naive, ad 5, 0
negative, as opposed to the people who are ad 5,
[00:33:08.526]
0 positive prior to vaccination where
there was no correlation at all.
[00:33:12.136]
So the question became was it safe
to do a vaccine trial in ad 5,
[00:33:17.736]
0 negative circumcised men and ask the
question can we identify a T cell measurement
[00:33:25.756]
that correlates with reduce viral load
[00:33:28.096]
and at least take another step
toward finding an HIV vaccine.
[00:33:34.146]
So that is one piece of information
that you need.
[00:33:37.606]
Now I am going to compare the
VRC vaccine to the Merck vaccine
[00:33:42.346]
and you can then judge if
it is different enough.
[00:33:47.226]
So the VRC vaccine includes these
plasma primes with an adnil virus boost.
[00:33:52.226]
It is an ad 5 based vector.
[00:33:55.036]
It has some differences, but the gag paul
included in ours is represented here.
[00:34:00.346]
In the Merck vector, there was a gag paul naf
adnil (assumed spellings) given repeatedly
[00:34:05.566]
at 0, 1 and 6 months.
[00:34:08.116]
[00:34:09.156]
So the genes differed somewhat, our
product included gag and paul and nef,
[00:34:16.086]
as did the Merck product, but
we also included envelope genes,
[00:34:21.916]
so there was a little bit difference in
antigenic content and then this is a nuance
[00:34:28.416]
to some people, but it may be one of the most
important differences in these two vectors.
[00:34:34.066]
There is different ways of making adnil virus
vectors, the Merck vector used the E1 region
[00:34:40.076]
to put the trans-genes, so the gag
and paul and nef were put here,
[00:34:45.296]
so that when the adnil virus was used to
deliver the gene, those genes were expressed
[00:34:50.366]
out of this site, but that means
the rest of the genome backbone
[00:34:54.326]
for the adnil virus was also making
RNA and making adnil virus proteins.
[00:35:00.586]
In our construct that was made by Gen
Vec, not only was the E1 region used
[00:35:06.396]
for expressing the trans gene, but the E3 region
was deleted, partially deleted that is a region
[00:35:13.856]
that adnil virus uses to
modify immune responses.
[00:35:16.826]
It has analogs to different cemokin
(assumed spelling) receptor genes.
[00:35:21.166]
It has proteins that will down regulate the
MHC molecules and so this contains a lot
[00:35:28.086]
of immune avoidance genes that was deleted.
[00:35:31.016]
And importantly, this E4 region was
deleted and E4 region has a set of genes
[00:35:35.796]
that allows the other adnil genes to
be expressed and so if you just look
[00:35:41.826]
at the blots here of the kinds of
proteins in adnil virus that are made
[00:35:47.036]
by either an E1 deleted or E1, E3, E4
deleted vector, what you see is the hexon
[00:35:51.536]
and the panton based in the fiber that
makes up the capsule of the adnil virus
[00:35:58.816]
or made from the E1 deleted
vector, but not made,
[00:36:02.576]
so there may be a lot more adnil virus proteins
being made if you don't believe the E4 regions,
[00:36:09.136]
so that is the other difference
in these vector systems.
[00:36:12.856]
So in the field studies, we saw that not only in
the phase one studies, but in the field studies,
[00:36:19.666]
six months after the adnil virus boost, you
were able to maintain a fairly high level
[00:36:24.816]
of T cell response to the different envelope A,
B and C proteins or peptide pools and the gag,
[00:36:34.256]
not so much against Paul and nef.
[00:36:36.946]
But against the envelope and gag
proteins, even after six months,
[00:36:40.776]
there was a good T cell response.
[00:36:42.926]
[00:36:43.946]
So the question is and this is what we
believe and I would like to hear comments
[00:36:48.906]
from the audience on whether
I have made the case to you.
[00:36:52.806]
That is that we think it is safe to
proceed with this type of product,
[00:36:56.576]
an ad 5 antibody negative circumcised
MSN because of the partial protection
[00:37:03.506]
in SIV challenged monkeys, we think we have a
slightly different possibility for efficacy,
[00:37:09.896]
because there are differences in the antigenic
content and the pattern of immune responses
[00:37:14.656]
with a more balanced CD4 and CD8 and
more envelope and gag rather than paul
[00:37:19.996]
and gag response and because importantly we have
the opportunity to identify T cell responses
[00:37:26.766]
that could correlate with reducing virus load,
[00:37:29.736]
which were made to take the next
step in vaccine development.
[00:37:33.226]
We think there is a good scientific basis
and ethical basis for moving forward.
[00:37:38.756]
So there is a trial called HVTN 505, it is
much smaller than that original pay 100 study.
[00:37:46.246]
It is designed to study this vaccine in this
group that I just described and it would enroll
[00:37:54.436]
about 1,350 people, half of who would receive
this vaccine and half of who would not
[00:38:00.216]
and the major end point would be able to see if
they could reduce viral load by at least a log
[00:38:05.546]
in those people that became
infected despite being vaccinated.
[00:38:11.206]
So if we were able to start that study
and it has now been submitted to the FDA
[00:38:15.316]
as of just a few days ago, the crew would
again around July and that means that sometime
[00:38:24.726]
in 2012, we would know if this vaccine was
having the affect that we thought it was.
[00:38:31.916]
So I am going to stop there for just a moment
and I would like to take a few questions
[00:38:36.896]
and I want to go on to finish what
alternative strategies there may be.
[00:38:42.586]
So if anybody has a question or would like
to make a comment here, let me hear it?
[00:38:47.756]
>> The Merck study was done just in
(inaudible) is that correct and if so, what?
[00:38:54.876]
>> Well the Merck study was done initially
in people who are ad 5, 0 negative in 1,500
[00:39:03.726]
and then it was extended to ad 5, 0
positives in North America and the Caribbean.
[00:39:09.376]
It turns out that about 1,200 of those
3,000 were women, 1,800 were men,
[00:39:17.456]
but almost all of the infections were in men.
[00:39:23.336]
It says a couple of things.
[00:39:24.826]
One it says that we aren't very good
[00:39:27.386]
at identifying high-risk cohorts
of women in the United States.
[00:39:31.926]
It also probably says that women
follow directions better than men.
[00:39:37.476]
You can interpret it either way.
[00:39:40.666]
[00:39:43.146]
>> In terms of phase twos for something
like this, how much does putting
[00:39:49.506]
on the trial change behavior, I mean.
[00:39:56.946]
>> Well when you go into start
preparing sites for a vaccine trial,
[00:40:00.696]
the question is how much does preparation change
the dynamic of where you can do the trial.
[00:40:06.946]
So when you start preparing sites like
this for vaccine work, it often takes years
[00:40:13.236]
of preparation of cohort development,
education, testing and treatment,
[00:40:20.436]
exercises and so generally if you go
into a place with a zero incidence of 3
[00:40:26.496]
to 4 percent a year, after a year or
two that incidence will be halved.
[00:40:32.076]
It will go down to 1 to 1 1/2 percent per year.
[00:40:36.536]
So in general, it will go down about 50 percent.
[00:40:41.956]
It is hard to get it to go below 50
percent with just educational intervention,
[00:40:47.456]
but it does start making a big
difference in the number of infections
[00:40:51.546]
that you might expect from a given cohort.
[00:40:56.796]
>> Bernie, you didn't make it completely
clear in my mind, are you testing them
[00:41:04.596]
or us that you have refined it and
(inaudible) more at this time (inaudible)
[00:41:13.986]
and what is your deadline going to be,
failures do you figure okay no more.
[00:41:26.026]
>> So, the question is where are
we going to do the trial, I think.
[00:41:31.666]
The trial as it is planned right now, originally
it was going to be planned in those same reasons
[00:41:37.696]
where we did the phase 2, but because of
the zero prevalence of ad 5 is so high,
[00:41:45.826]
especially in Eastern Africa, it is about
95 percent, recruiting a population of ad 5,
[00:41:52.216]
0 negative people there was
untenable and because
[00:41:56.836]
of the issues involving safety the trial is
going to be done in North America where at least
[00:42:05.456]
to ad 0 prevalence range is at
50 percent instead of 95 percent,
[00:42:10.656]
so we at least have a chance
of enrolling people.
[00:42:14.036]
So this trial would be planned for North
American MSM, men having sex with men, ad 5,
[00:42:21.006]
0 negative circumcised men, but
the subgroup in the Merck study
[00:42:24.976]
that actually may have had
a benefit from the vaccine
[00:42:29.106]
at least had a lower odds ratio
for infection with the vaccine.
[00:42:35.886]
The second question is how
many times will we fail
[00:42:39.876]
with an HIV vaccine approach before we
stop testing and developing HIV vaccines.
[00:42:48.136]
Well if I tell you that there is 7,000
new infections every day with HIV,
[00:42:54.936]
do you think we should stop trying?
[00:43:01.016]
>> Oh no (inaudible).
[00:43:03.086]
>> So our goal is to never stop trying
and either we are going to find a vaccine
[00:43:11.796]
or we are going to change the dynamic of HIV
in the world by trying to develop a vaccine
[00:43:17.576]
and the question is you know what is
it going to take to develop a vaccine
[00:43:24.896]
and I am going give you a few additional
slides about some of the new approaches
[00:43:28.976]
that are being taking and some of the
technology that is being applied to this problem
[00:43:32.496]
and hopefully to get us to the point that
we can have a more effective AIDS vaccine,
[00:43:37.806]
but you know if you look at the malaria
field, there have been at least 20
[00:43:42.376]
to 30 failed efficacy trials
for malaria vaccines.
[00:43:46.306]
If you look at the development process
of almost any other vaccine product,
[00:43:50.956]
you have to go through a lot of failure
to ever achieve something that is working.
[00:43:55.406]
We are still working to improve the influenza
vaccine, something that is already licensed.
[00:44:00.126]
So I think that in vaccine
development in general,
[00:44:04.826]
there is a lot of failure
before success typically.
[00:44:10.536]
[00:44:14.166]
So one of the problems for achieving the
kind of breadth we need, not only the breadth
[00:44:22.166]
of response in an individual, but the breadth
and response in the population to cover all
[00:44:27.056]
of the possible incoming HIV viruses is
being addressed and an informatics approach
[00:44:34.396]
and Betty Corber (assumed spelling) at
Los Alamos is a brilliant mathematician
[00:44:38.926]
who also is a trained immunologist
and she has brought a lot
[00:44:43.596]
of innovation to HIV vaccine concepts.
[00:44:48.376]
So one of the things she has done is
using bioinformatics, she takes sequences
[00:44:54.666]
from a large population of individuals.
[00:44:59.006]
So for instance, all these different
lines might represent a population,
[00:45:05.496]
well these would be the different viruses
within a population and then she puts it
[00:45:12.036]
through her computer algorithm and asks
if I start recombining these sequences
[00:45:18.596]
at natural recombination break sites,
because HIV does a lot of recombination
[00:45:24.096]
and I keep remaking recombinations
of viruses and then I ask
[00:45:30.276]
within those new virus recombinants, how many
of the T cell epitomes that have been mapped
[00:45:36.476]
within these viruses have been retained
and can I achieve a virus sequence
[00:45:41.366]
that is relatively natural with the normal break
points, but that has achieved a higher level
[00:45:48.866]
of epitome coverage for the
different virus possibilities.
[00:45:53.026]
And what she has found by doing that,
she can find winning sequences from each
[00:46:01.116]
of these recombination experiences and
then by using a combination of these,
[00:46:09.116]
in silica recombined sequences, she can
achieve about a 20 to 30 percent higher level
[00:46:16.676]
of coverage with new epitomes above any given
single natural isolate or even a combination
[00:46:24.306]
of natural isolates and that is now
proving to be true in animal experiences.
[00:46:28.526]
So if you use a cocktail of two or three
mosaics or four mosaics compared to a cocktail
[00:46:35.426]
of three natural isolate sequences, you can
achieve a much broader range of response
[00:46:41.176]
and so instead of having the
three or four epitope response
[00:46:45.126]
in a normal setting you might achieve
in some of the monkey studies,
[00:46:50.176]
they have gotten up to 12
to 20 epitope responses.
[00:46:53.676]
So the thought is especially in T cells,
if you can achieve multiple responses
[00:46:57.676]
to multiple epitopes, it will be much harder for
that virus to escape, just like three drugs is
[00:47:04.086]
when we really started making a big impact
on HIV instead of just single treatment
[00:47:10.126]
where the virus can serially escape.
[00:47:12.856]
So this new concept of mosaic inserts is
now being combined with a whole variety
[00:47:18.666]
of new vector choices which are
being developed, not as DNA and ad 5,
[00:47:25.356]
but there is a whole variety of gene based
vectors that are being used and combined
[00:47:30.306]
in different ways using these new insert designs
to see if we can really maximize the breadth
[00:47:36.256]
and the magnitude of the T cell response.
[00:47:39.036]
[00:47:40.306]
But the real problem is antibodies, so I am
going to end with a brief series of slides
[00:47:46.746]
on the antibody problem and most vaccines
have worked because we introduce an antibody
[00:47:52.076]
and it turns out for various reasons, because
this protein, this GP 160 protein on the surface
[00:48:00.536]
of HIV is so highly cligoscualted,
it is hard for antibodies
[00:48:05.546]
to reach the most vulnerable sites.
[00:48:07.176]
It is very flexible and so there is a lot of
different forms that it takes before it locks
[00:48:13.756]
into the sector making it hard for an antibody
to ever lock in on a single confirmation
[00:48:20.256]
and the sites that are most
vulnerable are hidden in these places.
[00:48:24.896]
If you were looking at the top
of this molecule even in a groove
[00:48:29.196]
that requires an antibody coming
in at just the right angle,
[00:48:33.236]
just the right specificity to neutralize.
[00:48:36.396]
So over all these years, there has only been
a handful of antibodies that have been found
[00:48:41.796]
to broadly neutralize the commonly
transmitted strains of virus.
[00:48:46.846]
Two of them are against this
membrane proximal region in the GP 41
[00:48:51.916]
that is anchoring the protein to the
viral membrane and then two of them are
[00:48:58.416]
in this GP 120 head, one of them is where
the CD4 binding site is for main receptor
[00:49:06.826]
of the virus, that is the B12 antibody.
[00:49:09.346]
The other one is 2G12, which recognizes
a combination of glocisolation sites
[00:49:15.806]
that is not particularly well understood.
[00:49:18.536]
So the question is if you
apply structural biology
[00:49:21.686]
to understanding exactly the atomic structure of
these GP 120 molecules in their different forms,
[00:49:29.476]
can you use structure based
vaccine design to find something
[00:49:34.726]
that might actually work
for neutralizing antibodies.
[00:49:38.146]
So one of the big findings early on
using this structure based approach is
[00:49:43.776]
that if you compare this core structure
over here, which Peter Cong solved in 1998,
[00:49:50.186]
this is taking off a lot of the GP 120 just
looking at the core molecule and asking
[00:49:57.136]
in the CD4 bound confirmation, bound to
its receptor, what is the GP 120 look like
[00:50:03.306]
and this domain right here, which
is called the bridging sheet.
[00:50:08.086]
This is where the CD4 binds, this is
the inner domain and the outer domain.
[00:50:13.316]
This is the place that binds the co
receptor for HIV, the CCR5 or CCR4,
[00:50:19.026]
so this is one of the early important
vaccine targets thinking that we could use
[00:50:24.856]
that as a target for vaccine development.
[00:50:27.576]
Well it turns out a few years later when
Harrison solved the unbound, unleaded structure,
[00:50:34.736]
if you look at GP 120 before it is bound to
its structure, these two regions that make
[00:50:40.246]
up the bridging sheet are not even together and
so that region doesn't even exists in the virus,
[00:50:46.446]
before it is already bound to its receptor.
[00:50:49.306]
So using this kind of structure information,
[00:50:52.486]
we can have a much better idea
of what the targets are for HIV.
[00:50:56.886]
So making antibodies to the bridging sheet
is obviously not an option based on this and
[00:51:05.226]
but in contrast if you focus not on the
inner domain and its changing position,
[00:51:11.406]
but the outer domain, the outer
domain in both the unliganded
[00:51:15.386]
and liganded position is very constant,
[00:51:18.796]
so this region of the GP 120
molecule remains very constant.
[00:51:24.566]
So Peter and his group at the VRC
have used a series of experiments
[00:51:31.136]
where they co crystallize these antibodies,
these broadly neutralizing antibodies the GP 120
[00:51:37.026]
or the GP 41 and they determine exactly
what the structure of the binding stuff is
[00:51:42.836]
for neutralization and one of the
more important papers was this one
[00:51:47.156]
where they used the B12 antibody pictured here
interacting with the CD 4 binding site here
[00:51:53.686]
and then they mapped the region of the antibody
foot print to the CD 4 foot print to try
[00:52:00.306]
to really show how the antibody was
binding to neutralize the virus.
[00:52:05.336]
So if you have that information,
what do you do with it?
[00:52:10.106]
So the different approaches now that
are being taken with the proteins,
[00:52:14.986]
based on this structural
information is the following.
[00:52:18.266]
First of all one of the problems
with HIV is this reason here
[00:52:23.206]
where CD 4 binds is somewhat blocked by the
other primers and these regions in here,
[00:52:32.446]
if you just present the single monomer, if you
just present one of these to the immune system,
[00:52:36.866]
all of the antibodies response
is happening to this
[00:52:39.976]
which is not even present in the natural virus.
[00:52:43.326]
So one option is to make the more native primer
as a vaccine hoping that the antibody will find
[00:52:49.956]
that little groove right there to go into.
[00:52:52.956]
The other approach is to make an artificial
protein in which you try to single
[00:52:58.376]
out that one area where you want the
antibody to bind by cloaking the rest
[00:53:04.086]
of the protein in glacosolation sites.
[00:53:06.506]
So you can build these glacusolation sites
into your protein so that this now is covered
[00:53:12.166]
with sugar and you are hoping that it will
make the antibody focus on that one green spot.
[00:53:18.616]
Another approach is just simply
presenting the outer domain of the protein
[00:53:23.126]
to the immune system hoping that
it will see that CD 4 binding site
[00:53:27.476]
and an even more elegant approach is
scaffolding where that exact structure
[00:53:33.516]
for neutralization is preserved
and a guy at Washington University,
[00:53:39.576]
University of Washington Seattle, Bill Sheaf
(assumed spelling) takes that structure
[00:53:44.296]
and he does a threading program
and so he threads that structure
[00:53:47.946]
through the entire protein database and he finds
other proteins that can hold that structure
[00:53:54.376]
in the right conformation, so then he can
then lift that exact determinate and put it
[00:54:00.566]
in 10 different proteins that are
irrelevant of themselves other than the fact
[00:54:06.906]
that they can hold that one little
structure in just the right shape.
[00:54:11.006]
And so all these approaches
are being taken and some
[00:54:15.056]
of the more successful approaches
have been the trimer in which some
[00:54:19.816]
of the pieces have been locked into place
with disulfide bonding so that it won't be
[00:54:27.136]
such a flexible molecule and
it will have less entropy.
[00:54:31.796]
That approach is starting to have some
promise and this scaffolding approach
[00:54:36.476]
and the outer domain approach
are starting to have some promise
[00:54:39.436]
that we can start directing more of these
antibodies at the right angle to the right spot,
[00:54:45.286]
but the question is still whether we can ever
develop that into a real manufactured vaccine,
[00:54:51.666]
which is still several years away.
[00:54:55.756]
So that is what is happening
in HIV vaccine research.
[00:54:59.116]
We still have a long way to go, but we
will believe that somewhere over here
[00:55:05.046]
after we finishing walking on this
path that we will get there eventually
[00:55:10.656]
and I will stop there and
take any more questions.
[00:55:15.516]
( Applause )
[00:55:32.370]
[00:55:32.870]