- Hello, everyone!
And welcome to Wednesday Nite @ the Lab ,
run 50 Wednesdays throughout the year,
supported by the Wisconsin Alumni Association,
along with partners UW-Extension,
the Biotechnology Center,
Wisconsin Public Television, and you.
I am Jordana Lenon.
I'm the Outreach Specialist
for the Wisconsin National Primate Research Center
and the Stem Cell and Regenerative Medicine Center,
and standing in for Tom Zinnen, who's on vacation.
And I'm very happy to introduce our speaker tonight,
Dr. David O'Connor.
Dr. O'Connor obtained a BS in Biology, Honors,
from the University of Illinois at Urbana-Champaign
and moved to UW-Madison, where he received his PhD
in Medical Microbiology and Immunology.
He's now a professor in the Department of
Pathology and Laboratory Medicine at UW-Madison,
and is Associate Director
of the Wisconsin National Primate Research Center.
His lab groups study the interplay between genetics,
immunology, and infectious disease pathogens.
His research has contributed to our understanding
of how HIV and AIDS undermine immune responses.
He recently developed the first non-human primate model
for studying Zika virus infection during pregnancy.
He also serves on the National Institutes of Health's
AIDS Research Advisory Committee, tasked with
making recommendations about HIV/AIDS research priorities
with the National Institutes of Allergy and Infectious Diseases.
So please let's give a warm welcome to Dr. David O'Connor.
[applause]
- Thank you, Jordana, and thank you, everyone,
for taking the time to come and listen to a presentation
about Zika virus tonight.
The first thing I want to say is that, in a sense,
I am an accidental expert on Zika virus.
So, when I say that what I mean is that a year ago,
about a year ago, this month, I was in Brazil with one
of my colleagues on vacation, because my family has worked
with our colleagues in Brazil on infectious disease issues
for nearly 10 years.
And about a year ago we were looking for somewhere to go,
and one of my friends from S?o Paulo said,
"Why don't you come down and we'll spend a week at the beach
and we'll have a good time?"
And so we said, "Sure!"
Unfortunately, the Brazilian economy is sort of in a tank
right now, so that makes it actually very cheap to go there.
And I spent an entire week down there
with people from Brazil, last year at this time,
and the word Zika didn't get mentioned even once.
So what's happened is Zika virus has come on the scene
very, very quickly.
And for reasons that I'll explain,
it's a virus that we know nearly nothing about.
So because I was studying it just a couple of months
before it hit the mainstream media here in the US,
that made me the de facto expert because I knew just a little bit
more about Zika virus than most other scientists
and most other people who are studying viruses.
So I'll share with you some of the work that we've done
at UW-Madison, as well as, hopefully,
allay some of the fears that you might have about Zika virus.
And then after we're done, I'll be able to take any questions
that you might have that I don't cover in my presentation.
So what is Zika virus?
Zika virus is a virus that was first found in 1947.
And until very recently, this was one of the many,
many viruses that scientists discover.
We're sort of like stamp collectors in this way.
We go out into the field;
we take some animal or we take some person;
we sequence all of the viruses that might be floating
around in their blood and we catalog them;
and we put them into families.
Really, just like stamp collectors.
And the vast, vast majority of these viruses,
we then do nothing with.
The reason is there's not nearly enough research funding
and not nearly enough research interest
to justify doing intensive research
on every virus that we possibly discover.
So typically what happens is
someone discovers a virus
and then does some basic research and asks:
Okay, is this virus one that is likely to make people sick?
Is it from a family of viruses
where its genetic cousins make people sick?
And then we do sort of this risk triage, this risk assessment,
and we figure out whether a virus is likely to cause disease
in humans or cause economically meaningful disease in livestock.
And then we decide whether
it should be subject to more research.
And, in fact, that happened with Zika virus in the 1950s.
[David] This Internet connection is apparently not working.
[laughter]
So, in the 1950s researchers did this sort of evaluation
for Zika virus.
And what they discovered was that
if they put the virus through enough generations of mice,
they could get a virus that, you know, if coaxed just enough,
could make mice sick.
But generally speaking, when they looked in people,
they found that a lot of people had antibodies to Zika virus,
but no one had recalled being sick.
So the conclusion was that
Zika virus was a virus that was endemic in Africa,
but wasn't capable of making people sick.
Now in terms of its genetics, Zika virus is most closely
related to another type of virus that you might've heard of,
called the dengue virus.
Dengue virus is a big deal, especially in tropical climates.
So it's thought that about 2 1/2 million people
get dengue virus each year.
And I've never had dengue, to the best of my knowledge anyway,
but I'm told it's really, really unpleasant.
And the thing that's most troublesome about dengue
is that the first time you get it, it can be pretty bad.
It'll lay you up like a bad flu.
But if you get dengue two or more times,
each subsequent time you get dengue virus,
if you get a different type of dengue virus,
you can be...
you can suffer from a hemorrhagic syndrome
called "Dengue Hemorrhagic Syndrome"
that can cause really serious,
and in some cases fatal, complications.
So when we think about the viruses that are really
closely related to Zika virus, we think about dengue virus.
And one of the things that I'll come back to later
is this idea that Zika virus,
because it's so closely related to dengue virus,
may be functioning in some ways like a new type of dengue virus.
This is something that we have to bear in mind.
And one of the things, as researchers,
that we did right away is we said:
Okay, Zika virus is most similar to dengue virus.
So let's take the knowledge that we've applied for dengue virus
and let's apply that to Zika virus
and let's see if we can
just generalize to Zika virus what we know about dengue.
And what I'll tell you in a little while
is that there's a lot of things about Zika
that are very similar to dengue virus,
but there are also some critical differences
that we have to be aware of when we're trying to figure out
what we're going to do next with respect to Zika.
One of the things that's similar between dengue and Zika
is that they're spread by the same types of mosquitoes.
So there's a type of mosquito you may have heard in the news:
Aedes aegypti or Aedes albopictus .
These are the same types of mosquitoes
that spread dengue.
They also are capable of spreading Zika virus.
But one of the key differences is that we now know
that Zika virus can also be spread sexually,
whereas dengue is not spread sexually.
This is really a unique feature of Zika virus because
it's really the only mosquito- borne virus that we know of
that can also be spread through sexual transmission.
So what happens if people get Zika virus?
The two main problems that have been associated with Zika virus
infection over the last couple of years are what's called
Guillain-Barr? Syndrome.
This is a disease of the peripheral nervous system
where people experience muscle weakness
that eventually can lead to paralysis.
And this happens, we think, in about 1 in 4000 people
who get Zika virus.
So not very common, but if you get it,
it can be pretty devastating.
The bigger issue by far
is this association
between Zika virus and fetal abnormalities.
We now think that approximately 30% of babies
who are born to mothers who are infected with Zika in utero
will go on to have some form of fetal abnormality.
One of the main research topics that's being pursued
by our groups and lots of others around the world right now
is trying to figure out exactly
what abnormalities can be associated Zika virus;
what percentage of pregnancies are going to be affected;
and what is it that modulates that risk.
Is the risk greatest during the first trimester of pregnancy?
Is it greater in women who
have previously had dengue virus infection?
There's a lot of unknowns right now
that go into this percentage.
In fact,
scientists who are doing studies in different countries
are coming up with different percentages
of babies who are born with fetal abnormalities,
depending on how they define fetal abnormalities,
exactly what goes into their definition.
And there also may just be differences from place to place
in terms of how severe Zika virus infection is.
Nonetheless, for a virus that a year ago
none of you in this room had probably ever have heard of,
causing something on the order of 30% of pregnancies
to have fetal abnormalities, is a big and scary deal.
So there is now a huge amount of research interest
into the Zika virus
because we need to understand how we can mitigate this risk,
especially to pregnant women
and women of childbearing age who might become pregnant.
So what sort of complications
have been associated with Zika virus infection?
Well, the one that's made the most news is microcephaly,
which is a fancy way for saying
babies who are born with unusually small heads.
And often times when you watch news reports,
you'd think that microcephaly is the only consequence
of Zika virus infection, but it's not.
Scientists have seen
in babies who are born to mothers who had Zika virus
unusual calcium deposits in the brain;
excess fluid in brain cavities
and in the areas surrounding the brain;
missing or poorly formed brain structures;
abnormal eye development;
nerve damage; club foot;
and unusually inflexible joints.
So there's really a spectrum of birth defects that have
been associated with Zika virus infection during pregnancy.
And one of the great unknowns right now
is whether babies who are born apparently normal
to Zika-virus-infected mothers
will eventually go on and have abnormalities
that don't manifest until later in development,
until the kids are one, two, five, ten years old.
So because the very first cohort of babies in Brazil
born with microcephaly were only born last year,
we really are going to have to follow these children
for a number of years before we know what the full spectrum
of possible complications will include.
So I like to contrast this in some ways to HIV/AIDS.
My background is as an HIV researcher,
so I've been studying HIV for nearly 20 years.
And in the earliest days of the HIV epidemic in the early 1980s,
what doctors saw were people who had end-stage AIDS:
their immune systems had already collapsed,
they were already being affected
by these so-called opportunistic infections that
people who have intact immune systems aren't susceptible to.
We then worked our way backwards and realized that
people who were susceptible to opportunistic infections
had likely been infected with the HIV virus,
on average about 10 years prior.
And this passing from getting HIV
to developing AIDS has been a major drag
on our healthcare system because the cost of
taking care of people with HIV has been so high.
It's estimated that the lifetime cost of care is on
the order of about one-half million dollars per person.
So when we're talking about Zika virus,
I want to emphasize that
we're right at the very beginning right now.
So what we are seeing are babies who are being born
with abnormalities now.
We don't know what other abnormalities might become
manifest over the first few years of life.
But this is going to create a lifetime commitment to care.
And in the case of babies who are severely affected,
economists have estimated that the lifetime cost of care might
be more on the order of $10 million per infected person.
So when you hear news stories where the government
is discussing whether it makes sense to spend $1 billion on
a Zika virus response right now, it's important to bear in mind
that every single excess fetal abnormality
that arises due to Zika virus infection
is probably going to incur costs on the order of $10 million.
So it doesn't really take very many $10 million-infections
to get to the sort of billion-dollar price tag
that we're currently debating in terms of whether it's worthwhile
to have a really robust response to the Zika virus
here in the US.
So, now I've talked a little bit about the problems that can
occur with Zika virus and about how often they occur.
And so the big question that I want to know the answer to,
and many of you probably want to know the answer to,
is what happens next?
Where do we go from here?
First, I think it's instructive to look at
where we have what's called
active Zika virus transmission.
This means that the virus
is going from mosquitoes into people,
back into mosquitoes, back into people.
What you see here on this map in purple are countries where we
have so-called active transmission.
What you can see is that, with the exception of Chile,
United States, and Canada, Zika virus transmission is occurring
throughout South and Central America as well as throughout
the Caribbean, which is shown in the inset.
So the mosquitoes that can transmit the virus
are transmitting the virus in all of these different countries
shown in purple.
This is going to be a problem
that's going to be with us for a little while.
Among the locations in the Caribbean that are experiencing
a Zika virus outbreak, I think it does make sense
to pay special attention to Puerto Rico
because Puerto Rico is a US territory,
and there is a major outbreak of Zika virus going on
in Puerto Rico right now.
The way that they're assessing how bad the Zika virus outbreak
is in Puerto Rico is by monitoring blood donors.
We knew that six months or so ago, if you were to sample
100 blood donors who came in to give blood in San Juan,
none of them would have had Zika virus.
But over the course of the last couple of months,
the incidence of Zika virus in blood donors in Puerto Rico
has gone up and up and up.
And if you extrapolate through the rest of the summer,
the people who work in the blood banks think that approximately
25% of all the people in Puerto Rico are likely going to be
infected with Zika this summer, based on the prevalence and
incidence of Zika virus among blood donors right now.
What is that going to mean for people living on the island?
For the vast majority of people living on the island it's going
to be nothing at all because, again,
remember that Guillain-Barr? is a very rare complication.
And so if you are an otherwise healthy adult male or female
and you're not pregnant or planning on becoming pregnant,
your risk of getting Zika virus is very, very low.
Ninety percent of people who get Zika virus
don't even know that they've been infected.
And the remaining 10% might have a very mild itchy,
inconvenient rash for about a week.
So if you get it and you don't have Guillain-Barr? and you
don't have the concerns of pregnancy,
the fact that a large number of Puerto Rico are going to get
infected this summer shouldn't be too scary.
In fact, it might actually be good news
for reason that I will come back to a little bit later.
Nonetheless, with 32,000 or so pregnancies in Puerto Rico
each year, this still leaves open the possibility that
thousands of babies are going to be born with abnormalities
either later this year or early in 2017.
In addition to the health costs associated with Zika virus,
there are going to be secondary costs
that impact tourism, blood transfusion,
securing the safety of organ and tissue transplant programs.
And there's going to need to be an investment
in mental and emotional health
for women who are pregnant and don't have Zika virus,
but have to carry this anxiety throughout their pregnancies.
Additionally, and it's an uncomfortable subject,
but abortion politics, contraception politics
are going to feature
in the dialogue about what's going to happen in Puerto Rico
with Zika virus later this year.
In fact, I got a little bit of a preview of that last week.
I was asked to speak before a Senate committee hearing
on Zika virus and you could see very much
the alignment of the different political parties
with respect to how they viewed the most essential ways
of combating Zika virus, both in Puerto Rico and
if the threat reaches the US.
I think that some of these thorny issues
are going to come to the forefront
and with this coinciding with an election year,
it's entirely possible that this is going to be
a major driver of some news cycles between now and November.
Now what about in the United States?
You've probably heard on the news
people have talked about the Zika virus in the US.
And it's important to emphasize that right now...
well, actually these slides are as of about two weeks ago...
there are a bunch of what we call travel-associated cases
in the US.
These are people who were traveling
in Central or South America or the Caribbean,
they came back, and they were diagnosed as having Zika virus
upon their return.
None of these cases indicate
transmission from mosquitoes in the United States,
but among these 755 cases
are more than 200 cases in pregnant women.
Now this is a bit of over-reporting because
doctors are largely only sending at-risk women's samples off for
definitive diagnosis because if you don't have Guillain-Barr?
and you're not pregnant or at risk of becoming pregnant,
the fact that you come back with the Zika virus infection
as a souvenir from your trip to Central or South America
really isn't that big of a problem.
And so given the limited resources available for testing,
people who come back and are just curious whether or not they
have Zika aren't having their samples sent off.
So there is an over- representation of pregnant women
in these statistics.
But in the territories, which include Puerto Rico,
we have the converse.
There is a very small number of travel-associated cases, but
a larger number of cases where there is local transmission
from mosquitoes into people.
And again, a sizable fraction of these cases
are in pregnant women.
This is a slide that I originally gave when I presented
a version of this talk a couple of weeks ago.
I think it was two weeks ago yesterday.
So this morning I went back
and I actually pulled the updated numbers.
And I'm going to show them here just to illustrate that
this is a problem that continues to grow.
So, 755 became 934; 234 became 287.
The number of cases transmitted by mosquitoes has grown
from 1,436 to 2,020.
The number of cases in pregnant women has grown to 250.
These stats are current as of about the last week of June.
So what this means is that as we get into the height of summer
and the height of mosquito season,
we are going to see a major surge in the number of Zika
virus cases both in US states and in US territories.
The million-dollar question that I don't know the answer to
and I don't think anyone knows the answer to is:
How much mosquito spread can we anticipate
happening in the continental United States?
So the first question is: Do we have the mosquitoes?
Answer to that is, unequivocally, yes.
As you see here on the left,
we have the host range of the Aedes aegypti mosquito
and on the right we have the Aedes albopictus mosquito.
What you can see is that these mosquitoes are
widely distributed throughout the Southern United States,
and they're particularly common
in Florida and along the Gulf Coast.
Now if you look at the map, don't squint too much because if
you squint hard enough you'll see that there is a little bit
of an extension into the southern tip of Wisconsin.
But remember that when they do these sorts of surveys,
they will take the identification of a single
mosquito in a tire as evidence that a particular type of
mosquito is in a state.
So we really don't have significant numbers of these
mosquitoes in Wisconsin.
So we really don't have to worry very much about local
transmission here in Wisconsin.
We do, however, need to worry quite a bit about it
on the Gulf Coast in Florida and in Texas because there
there are a lot of these mosquitoes.
And we also know from the dengue virus history that it
is possible for these viruses to be spread in the continental US.
Now, one possibly reassuring feature
of our history of studying dengue virus is that
in recent times, dengue virus outbreaks in the US
have been relatively small and self-contained.
There was an outbreak on the big Island of Hawaii last December,
but really outbreaks of dengue are sporadic
and typically brought under control
through intensive mosquito-control measures.
That's probably because
we do have better infrastructure
than other places that are reporting
significant mosquito-borne Zika virus transmission.
We have screens on many to most of our windows,
we have access to air-conditioning.
We do have pretty good mosquito-control programs,
though I'm learning more and more,
that there's lots of room for improvement there.
There are some reasons to think that because of our
infrastructure we are going to be better protected from local
transmission of Zika virus than, say, Puerto Rico will be,
but we really don't know.
We also don't know whether Zika virus is transmitted more
efficiently than dengue virus by mosquitoes.
So we don't know how much we should be reassured by the fact
that dengue hasn't spread very much in the continental US.
But clearly, if Zika virus does start spreading in the
continental US, it will have similar secondary impacts not
only on pregnant women who are going to have serious anxiety,
but also tourism, blood supply security,
organ transplant systems.
It really is going to take only a very small number of cases to
have Zika punching above its weight with respect to
how it's going to be perceived.
For those of you who remember the small number of Ebola cases
two years ago, you can see and you can imagine how a very small
number of Zika virus cases could lead to outsized public anxiety.
With that said, I think it's quite likely
that there will be at least some local spread.
We don't know how much, as I said,
but I think that we can expect
that there's probably going to be at least some.
And as I said,
even a small number of these cases
can incur major costs.
This is going to be something that we're going to have to
watch closely over the summer.
That's kind of a background on Zika virus and
where we are as of right now.
So what I'm going to do is spend the next bit of my talk talking
about what we've been doing at Wisconsin to study Zika virus
and why researchers in Wisconsin,
who are nowhere near these mosquitoes,
have managed to be very involved
in the public health response to Zika virus.
The story starts with me and some of my colleagues
who have been studying HIV for a really long time.
And as part of our work on HIV we've been working
internationally with partners in South America and Africa
for a long time.
These are sustainable, long-term partnerships.
Here's a picture of me with my colleague Tom Friedrich,
with our colleague, Denis Nansera,
who's a pediatrician in Mbarara, Uganda, back in a hut in 2010.
We've been really involved in trying to take this technology
that we discover in our labs here in Wisconsin and use it to
help our colleagues who are studying HIV around the world.
In addition to our work in Africa,
my longest-standing collaboration internationally
is with this gentleman, in the middle, Esper Kallas.
Esper is a clinician researcher
at the University of S?o Paulo in Brazil.
This picture was taken in 2005.
You can tell I'm younger because I had more hair.
[laughter]
I'm shown here with my wife, who you can tell,
is smiling because she's been married to me for 10 fewer years
in this picture than she has been now.
[laughter]
We have worked with Esper and his team on HIV,
on dengue virus, and on hepatitis C virus projects
going back to 2005.
We have exchanges between scientists from our labs.
So we go down there a couple times a year and show their
scientists how to use the newest and latest and greatest tools
that we developed in our lab.
They bring their scientists and clinicians up to Madison
and receive on-site training.
And we learn a lot from them
about how these infectious diseases
are impacting their groups in Brazil.
In addition to our work in S?o Paulo,
we also have collaborators in Rio de Janeiro.
Here once again is my wife, shown here with Renato Santana.
He is a professor from
the Federal University of Rio de Janeiro.
Here he was actually giving a Skype lecture
with my undergrad class on HIV.
We were in Florian?polis, Brazil,
and he was talking about the Brazilian response to HIV
to 100 or so undergraduate students
who take a class that Tom and I run every fall.
And you can see our son looking bored,
doing his reading in the corner.
This same day, as we were doing the Skype lecture,
Renato came up to us and said,
"You know what, guys? I need your help"
because we have heard that there are
a bunch of babies being born in the north of Brazil
with really small heads.
And one of the things that Tom and I have done
in collaboration with Tony Goldberg in the Vet School
over a number of years is we've collected those postage stamps.
We've gone out into the African jungle,
and we've sampled different types of monkeys,
and we've looked for new viruses
that haven't been discovered before.
So, Renato asked us if we could
look in some of these babies to see if they had a new virus
that was causing them to be born with really small heads.
And within a couple of weeks, it was pretty clear that Zika virus
was the leading candidate for
what was causing these babies to be born with small heads.
So we turned our attention from trying to figure out
what virus was making the babies be born this way
to trying to figure out
how we could understand more about this virus.
Because as soon as we realized it was Zika virus,
our next thought was: Oh, my gosh,
we know nothing about Zika virus!
And this isn't just us like,
"I didn't know anything about Zika virus," but I didn't.
This was as a community.
If you looked in the databases that have papers,
all the papers of all the scientific programs
from around the world,
there was something like
15 Zika virus papers over the last 50 years.
There really was not very much known at all about Zika virus.
However, it did make it pretty easy to get up to speed
because you didn't have to read a whole lot.
[laughter]
At the same time as we were learning about Zika virus
from our colleagues in Brazil,
Jorge Osorio, who's a professor in the Vet School,
who also has had a long-standing research program in Colombia,
where he is from, came back from Colombia and said,
"Oh, my God, we're seeing cases of Zika virus in Colombia!"
So Jorge's lab was actually the first
to describe Zika virus in Colombia.
So early in November, Tom Friedrich,
who had been talking to Jorge
because he worked with him as a colleague in the Vet School
and had been talking to me
because we were talking about Zika in Brazil,
put this together and said,
"You guys really need to talk to each other."
So we did and we decided
that one of the things that was going to be really important
in learning about Zika virus was trying to develop animal models
that we could use to ask very focused questions
about Zika virus
very rapidly
so that we could inform the sorts of studies
that were going to be done in people,
but that are going to require very large cohorts
and are going to play out
over a much larger period of time.
After Jorge and I decided
that we were going to start working on this together,
we realized that we were missing some critical buy-in.
So fortunately, I was able to convince Jon Levine,
who's the Director of the Wisconsin Primate Center
and is shown in the center here, and Buddy Capuano,
who's the Attending Veterinarian and the Associate Director
for Animal Services at the Primate Center,
that we really needed to start thinking about
doing Zika virus studies
with experimentally-infected macaque monkeys,
where we would give macaque monkeys
a defined dose and strain of Zika virus,
and then follow what happens to those animals
throughout infection.
Fortunately, they both immediately understood
the potential implications of this
and offered the full support of the Primate Center.
And, finally,
this was sort of an embarrassing admission that we all had.
We realized that
if we're studying a virus during pregnancy,
we need to know something about pregnancy.
And short of the fact that I have a son,
that was about the extent of my knowledge
of reproductive biology and obstetrics.??????[laughter]
So we needed to get specific expertise
that could help understand the many dimensions
of studying an infectious disease
that infects pregnant women and infects the fetus in utero .
So Ted Golos, who has been studying
reproductive biology, reproductive health,
and infectious diseases during pregnancy
for decades at the WNPRC,
joined our team in early December
as the obstetrics component.
And so we really have a multi-disciplinary team
that spans all of campus working on this.
And over the course of the next couple of months,
our team has grown to encompass even more dimensions.
Here is Dawn Dudley, she's on the right,
she's a senior scientist in my lab.
Here we are down in Rio de Janeiro
trying to help them process some of the first Zika virus samples
that they got in their lab back in February
to try to characterize
what sort of tissues have Zika virus in them.
Sallie Permar is a colleague of mine from the HIV community.
She's at Duke University.
She contacted me in late December and said,
"I've been studying congenital cytomegalovirus infections
in women for the last several years.
Have you heard about this Zika thing?"
And so she's been part of our team,
bringing more expertise
studying congenital infections that can affect fetuses.
Jorge has an extended team shown here down in Colombia
studying Zika virus and other mosquito-borne viruses.
And as time's gone on,
one of the things that's just been really awesome
has been how much expertise we have on this campus
that I had no idea about, to be honest.
It's kind of embarrassing
because I've been here since 1997.
We have people like Christina Newman,
whose job for a long time was to go set mosquito traps
down in Chicago to capture mosquitoes.
She'd bring them up here to try to grow them in the insectary.
But mosquitoes don't like growing inside--
outside of their natural environment--
so what she would do, because
they wouldn't eat the synthetic food that she gave them,
she'd give her arm out and they would feed on her arm.
They'd take a blood meal.
So they established the insectary
using mosquitoes that were feeding on Christina.
But she has become one of our local mosquito experts.
And we've also drawn on
a lot of the expertise that exists in the medical school.
One of the things that we want to do during pregnancy
is look at how animals develop during pregnancy.
And to do that the most sensitive technique is MRI.
Here you have Kevin Johnson, who is a medical physicist, whom
we recruited along with several maternal fetal specialists,
to help us look at the MRIs of developing fetuses.
Again, we really were shameless in going out throughout campus
and getting expertise from anywhere we could find it
to help us answer some of these key questions.
I think there might be only one more of these.
These are two neonatal specialists
who spend most of their time
looking at ultrasounds from human babies.
But they got trained--
They went through all the rigmarole necessary
so that they could come back and also use their expertise
to look at monkey babies and try to assess whether
there were any developmental issues in the monkeys.
It really has taken a huge team to get where we are right now.
What we've been able to do as part of this team is
develop the first monkey model for understanding Zika virus.
In summary, what we found is that macaque monkeys,
which are the kind of monkeys
that get used in most biomedical research,
can be infected with Zika virus and exhibit similar symptoms
to people who are infected with Zika virus.
That is to say most of them don't get sick at all.
But they have a very similar trajectory
of viral response and immune response
as has been observed in people.
We see that the virus is detected in the same fluids
for about the same amount of time
and, critically, macaques have been used
to study reproductive biology for decades.
So unlike other animal models
like mice and rodents and guinea pigs, macaque pregnancies
are generally very similar to human pregnancies.
They can be broadly subdivided into three trimesters;
each trimester has key developmental milestones
that track very closely with those in humans.
So this actually makes it
a very good model for trying to understand
how a virus like Zika could cause fetal abnormalities.
I'm just going to show you
a couple pieces of data from our studies.
I have one piece of really good news
and one piece of not-so-good news.
Let's start with the good news first.
The good news is that
all the data that our group is generating
and that others are generating points to the fact
that a Zika vaccine should be successful.
So as someone who studies HIV
and has studied it for a long time,
I'm very gun-shy about saying things like,
"a vaccine should be successful" because, of course,
we said that about HIV back in 1984
and here we are 35 years later
and we still don't have an HIV vaccine.
But there's good reasons to think that
making a vaccine for Zika should be conceptually easier
than making a vaccine for HIV or other more thorny viruses.
The reason we think that is because we infected a number of-
and these are non-pregnant animals--
we infected these animals with Zika virus.
And what we did is we
measured the amount of virus in the blood.
What you can see is that within one day of infection
there was some Zika virus in the blood,
but that by about a week after infection
the animals had pretty much controlled their infections.
They had cleared their virus, there wasn't any virus left.
There were occasional very low-level blips
out to about 20 days,
but, for all intents and purposes,
the animals had cleared their virus within a week to 10 days.
We then waited another about eight weeks, so 70 days total,
or 10 weeks from the first infection.
Then we gave them the same virus again.
The question we were trying to test is whether the immune
response that was elicited by this initial infection,
when the virus was replicating, would be sufficient
to protect the animals from being re-infected
if they were exposed to the same virus again.
And as you can see from the arrow where it says Rechallenge ,
we saw no evidence of any virus replication after the animals
were re-challenged with the same virus.
So this suggests that the antibody response and that the
immune response that got made against the first virus
protects them from re-challenge.
Let's think about the implications are for this in a
place like Puerto Rico.
It means that if you're a woman of childbearing age who's not
pregnant right now, arguably the best thing that could happen for
you would be to get Zika virus, develop protective immunity,
and then if you get pregnant, you should be at significantly
reduced, if not zero risk, for having Zika virus-related
complications during pregnancy.
It also means that if you are scared about Zika virus,
the best thing that could happen would be for there to be a wave
of Zika virus that comes through a community,
leaves the entire community immune,
such that the mosquitoes won't have vectors
that they can use to continuously transmit the virus
back and forth between people and more mosquitoes.
Indeed, in some of the outbreaks that we've been going back
and looking at that happened in French Polynesia
and other parts of the Pacific in the last 10 years,
that's what we've seen.
We've seen huge numbers of people being infected
in places like Yap Island,
and then the virus goes away and isn't heard from again.
Again, this is consistent with the idea
that people have immunity.
We don't know how long it lasts, but that they have immunity
that protects them from being re-infected.
That's the good news.
The bad news is that some of our data also suggests
that the risk to pregnant women might be even higher
than was previously appreciated.
Our reason for thinking that is because,
in contrast to non-pregnant animals,
whose amount of virus in the blood is shown here again.
So, this is the same data that you saw in the last slide.
When we look at two animals that were infected with Zika virus
in the first trimester of pregnancy
and two animals that were infected
in the third trimester of pregnancy,
we saw that in three of the four animals
there was a dramatically-prolonged detection of virus
in the blood, relative to what we see in non-pregnant animals.
So this suggests that the risk to the fetus
might be much higher than currently thought,
in part, because the virus sticks around a lot longer.
That provides a lot longer time
for the virus to infect the fetus.
Now we do not know why the virus persists for so long-- yet.
But one of our leading hypotheses is that the situation
is actually even a bit more dire than that,
and that what we're actually seeing here in red
are fetuses that are infected with Zika virus.
The mom infects the fetus.
The mom clears her infection
because she has good immune responses,
just like we see in the other animals,
but the fetus doesn't.
What the fetus is doing
is shedding virus back into the mom.
What we are detecting here
is fetal virus that's detectable
because the fetus and the mom are sharing the blood stream.
If this is true, it suggests
that you have a duration of infection in the fetus
that can vary from about a month to two months
and possibly be associated
with adverse outcomes.
What we're trying to do right now is to figure out
what the impact of these virus infections is going to be
on the newborn brains and other tissues.
So this is always the part of the talk where I have to say,
"It's to be continued."
Because we're just now at the point
where we're delivering these babies by C-section
and then we're dissecting them
to look comprehensively at whether or not
there are any abnormalities in the newborn,
and, if so, where they're located.
What tissues and organ systems are affected?
How were they affected?
And, unfortunately, for the purposes of presentation anyway,
it's about a 2 to 3 week process to get the tissues stabilized
and prepared for analysis.
We're still in the midst of that 2 to 3 week process right now.
So I don't have any information on whether the newborn babies
born to mothers who had this prolonged viremia
have any adverse outcomes yet.
But we should be getting that data over the next 4 to 6 weeks.
We're also very interested in this idea that there might be
interactions between dengue virus and Zika virus
because the viruses are in the same place.
Some people have speculated that
if you have previously had a dengue virus infection,
you might be at a higher risk
of having a severe Zika virus infection.
This is something that we can model in animals
much better than you can study it in people.
People don't know what their dengue virus history was.
They don't know when they were infected,
they don't know how many times they've been infected.
We can control that precisely by having animals that are
challenged with dengue virus and then go on to receive Zika virus
to see if Zika virus is worse
than in animals that haven't had dengue before.
Additionally, just in the last couple of years,
the very first dengue vaccines have been licensed.
So Mexico has licensed the vaccine,
other countries have licensed the vaccine,
and there are advanced clinical trials going on
in a number of countries right now.
If natural dengue virus infection does change the risk
of having adverse outcomes following Zika virus,
what about dengue vaccines?
If we vaccinate an entire population against dengue virus,
are we going to modulate in some way
what their future susceptibility to Zika virus is?
Again, for the vast majority of the population,
I think I'd go ahead and vaccinate for dengue.
But this is going to be something that we're going
to have to think about when it comes to vaccinating women
who could be potentially at risk of Zika virus in the future.
It also gives currency to the idea
that we should really be focusing
on trying to develop combined Zika and dengue vaccines.
But developing vaccines that target all the dengue subtypes
and Zika at the same time, is a much bigger ask
than making a vaccine just against Zika
or just against one of the dengue serotypes.
The third thing that we're looking at right now
is whether or not the virus persists
in a replication-competent form for longer periods of time
in tissues than it does in the blood.
I told you that within about a week to 10 days,
the virus is pretty much gone from the blood.
But almost by accident, we looked at one of the mothers
who had an enlarged lymph node
at the time the baby was delivered by C-section,
and we found that, much to our surprise,
there was still detectable viral nucleic acid in the lymph node
about two months after the animal have been infected.
Now, we don't know whether that virus is replication-competent
or represents sort of a viral fossil of an earlier infection.
You can imagine that especially for people
who are trying to secure the tissue and organ supply,
it's vital to know whether or not tissues and organs that are
going to be transplanted could be harboring the Zika virus,
because while the risk to the general population is low,
the same might not be true for people who are immuno-suppressed
because they're receiving immunosuppressant drugs
to tolerize them to tissue or organ transplant.
So it's really important to figure out
whether this virus that we're detecting is
actually capable of replicating and being infectious.
So...
The last thing I want to talk about
is something that I'm particularly proud of because
it represented a bit of a change in how we do science and
it really required the buy-in from our entire team to do this.
This is the idea of real-time data sharing.
This has been a concept that's been kicked around in science
for the last several years, in light of
some of the last major infectious disease outbreaks.
It began right around the SARS outbreak in 2000, 2001.
In 2009 when we had the H1N1 pandemic flu,
a lot of people were talking about
the need to share data more quickly.
And then some of the investigators who were
studying West African Ebola really put this into action
and made a lot of their data available in close to real-time
through public repositories
so others could go in and analyze it.
In fact, one of the things my lab did
was we took some data from West African Ebola patients,
and we asked a question that was totally different
from the questions that the study authors had asked.
And we eventually got into contact with them and
put together our own manuscript that basically looked at
whether or not someone who is co-infected
with the second virus had reduced susceptibility to Ebola.
That was really
an eye-opening experience for me
because it showed that the data that we're collecting
and the data that we're generating,
other people might want to use
in ways that we could never imagine.
Other funding and people who pay for the research
and the journals that publish the research
all fortuitously agreed, in principle, to this statement
on data sharing and public health emergencies
back in February.
The idea was that we should try to make Zika virus research
as available as possible,
as quickly as possible.
This goes to one of the real problems
with scientific knowledge communication in general,
which is the long time from when data is collected
until it's made available to the public
and the rest of the scientific community
through published papers.
So the general process for doing a study was kind of like this:
you start the study; you do some experiments;
you finish collecting the data; you analyze the data;
you write up a manuscript; you submitted to a journal;
the journal submits it to a series of peer reviewers
who rake you over the coals and tell you your work is terrible,
but that they are willing to publish it
if you make the following 36 suggestions;
you respond to these individual comments one at a time;
Hopefully, eventually, the reviewers are satisfied
and the manuscript appears as a published paper.
In the case of our initial Zika virus model work,
that timeline looked like this.
And this is actually a very, very fast timeline,
as research goes.
We started our study on February 15.
By March 15, we had collected data
from the first four weeks of infection.
We wrote the paper over a process of about two weeks
and submitted it to a journal.
We responded to comments,
once we got them back in the middle of May.
Then, eventually, the paper was finally published last week.
You're looking here at a time window of more than four months
between the time when we started the study
and the time that we ended up publishing it.
For a virus whose trajectory is changing as quickly as Zika,
that has such public health importance,
this is simply too long.
We can't afford to let data sit siloed in individual labs
and at journal editors
while people are continuing to get infected,
especially when we have the greatest opportunity
to intervene and try to mitigate the threat.
I would argue that it's actually not particularly ethical
to delay the distribution of research results for months
during a public health emergency.
We asked: What could we do differently?
One thing that people in science have been doing is they've
been publishing to what are called these "preprint servers."
So at the same time that they submit a manuscript
for publication in a conventional journal,
they put a PDF of it online in these indexed preprint servers.
This is good because it saves considerable amount of time.
We posted our data in a preprint server
the same day that we submitted it, which was March 31.
But this was still quite a while after we started the study,
so we took it one step further.
What we did is we decided
to put all of our data online in real-time.
This takes advantage of the fact that my lab actually has
pretty good computing expertise and bioinformatics expertise.
This model wouldn't necessarily work for everyone,
but we were in a position where
we were already going to be storing our data
and making it available
to the really large team of UW investigators
I talked about earlier.
So we decided, well,
rather than restrict it by password or user ID
to the people who would want to see it here at UW,
we'll just open it up to the public and see what happens.
It was quite the experiment.
But it turns out that it's been really quite successful.
So all the data is available,
and information on all of our participants is online,
along with how we've done the studies,
the raw data that people can go in and re-analyze,
as well as annotated data.
One of the things that we learned pretty quickly
is that a lot of people who are interested in this data
didn't really have the stomach to go and analyze it themselves.
We took to writing brief summaries
that kind of guide people through what the data means.
One of the people in my lab,
who actually just returned from giving a--
to being a social media outreach expert
at the Juno orbiter this weekend
took over the lab's Twitter account
when she realized I had no idea how to really use Twitter--
which is absolutely true.
She started putting some of that information on Twitter
and we actually started getting a lot of feedback.
One of the really neat things that's happened is
other people have interacted with us about our studies
in real-time.
In some cases they've taken what we've put up online
and given us suggestions about how we can do things better.
So in the top example here,
we had tweeted that there was some data that suggested
that a number of the viruses that were called one thing,
one of them wasn't like the others.
And this researcher from the University of Birmingham in England
immediately wrote back within a few hours and said,
"Yes, we also noticed that that sequence was wrong,
"but we actually have already taken it one step further,
"and shown that it was a mosquito virus
"that was incorrectly labeled in the database of viruses,
not an actual Zika virus from a primate or a person."
On the bottom, you see an example
where a woman who has led studies
in human pregnancies affected by Zika,
who's also seen this idea of extended viremia,
or prolonged detection of virus in the blood,
saw some of our data and suggested that we do
some additional experiments that she wanted to do in people,
but she wasn't able to do.
This has turned out to be really good,
and if you're curious at looking,
the URL is there zika.labkey.com
I'm just going to close by saying that I think, in a way,
this is what Wisconsin and the University of Wisconsin
is all about.
Because if you think of what the Wisconsin Idea is,
it's the idea that
we take knowledge that's generated at the University
and share it with the community for the greater good of all
and really have knowledge
that transcends the boundaries of the classroom,
or in this case, the research lab.
So it's been really great to have the University of Wisconsin
be at the forefront of this type of data sharing
and have a team of people who are so willing to try something
that's pretty far outside the orthodoxy
for scientific research.
With that, I'm going to close by acknowledging just
a small number of the people who have helped with this.
In blue, you have the people who have been the project leaders
in various parts of this: Dawn Dudley.
Emma Mohr is a pediatrician who is a Fellow in my lab
and has brought a valuable clinical perspective.
Tom Friedrich, who I've worked with for nearly 20 years on HIV.
And we're somewhat inseparable
when it comes to doing this sort of work together.
Jorge Osorio and Matt,
who brought the mosquito virus expertise.
My wife and colleague, Shelby,
who did some of the virus sequencing in our projects.
Sallie Permar from Duke and her team.
Buddy Capuano, the attending vet at the Primate Center.
Ted Golos, who led the obstetrics.
NIAID,
which is a part of the National Institutes of Health,
that when they learned that
we were about ready to start the Zika projects were
able to use some unconventional funding mechanisms
to provide support for these studies,
as well as the Wisconsin National Primate Research Center
who galvanized the studies by providing seed grant support.
And then, our colleagues in Brazil:
Amilcar Tanari and Renato Santana
at the University of Rio de Janeiro
and Esper Kallas and his team at the University of S?o Paulo.
So with that, I will stop and take any questions.
Thank you. [applause]