today I’d like to thank both Kevin and
Dolores for inviting me here I’m gonna
present the work of our group and it’s a
real it is a village it’s a large group
of individuals couple of 3040 people at
least who have been focusing for the
past 15 or 20 years on developing a
vaccine for human malaria in fact in
particular pediatric malaria I’m often
asked you know why do I focus on malaria
why malaria and it’s usually from one of
my snarky next physician-scientist
student colleagues and they go Jake why
don’t you work on something really
important like male pattern baldness or
they remind me of those other diseases
that middle-aged men get and we have to
listen to the ads for their treatments
on Sunday football why don’t I work on
those things and as I get older I’m
starting to think maybe I should change
my focus but no no we work on malaria
and the reasons are really both simple
and compelling we worked on malaria
because it is the greatest single agent
killer of children on the planet bar
none nothing comes close we’re talking
about at the most the sort of rosy
colored estimate half a million
individuals a year at the more
pessimistic side two and a half million
individuals every single year died of
malaria the vast majority of those
deaths are in children under the age of
five and they’re concentrated in places
like sub-saharan Africa and Southeast
Asia so it’s the great calling machine
of the tropical world and so at least 8%
of all childhood deaths on the planet
for due to malaria so that’s really the
reason we focus on it again it’s the
most important single agent killer of
children so the health economist Jeffrey
Sachs has coined the phrase where
malaria has prospered people have known
and this is a map of the malarious world
and it’s color-coded the warmer colors
the Reds and orange
and yellows are aware malaria is rampant
I had what you can see is that it’s
concentrated in sub-saharan Africa to
Southeast Asia and parts of Latin
America there is no question in my mind
that the correlation between political
stability economic development
capitalizing on what might be limited
educational opportunities all three of
these social inequalities are
concentrated where malaria is doing it
it’s it’s killing it’s impossible for me
to imagine a community where you have an
under-five mortality rate of 25% that’s
one in four children not making it to
their fifth birthday it’s impossible for
me to imagine a community like that
thriving and so those are really the
reasons that we’re focused on malaria if
you’re gonna go into battle with an
adversary that has been defeating you
for millennia you best understand its
its entire strategy what are its
weaknesses it would behoove you to
understand your enemy in order to combat
it effectively and so unfortunately and
you know if there’s anyone in the room
who suffered through medical school like
we have to understand how this parasite
works and so it begins with the bite of
a female and novel a mosquito every
mosquito bite you’ve ever gotten has
been a female mosquito the females need
to take blood in order to lay their own
eggs and so it begins with the bite of a
female mosquito this parrot I mean you
guys see the movie aliens Sigourney
Weaver you know the first in the cyclone
the third by the fourth one is here
this parasite is as well a DEP that is
that Maul crusher it is so smart it has
been forged in the crucible of evolution
it knows that the first thing that
mosquito is gonna do is what when she
bites you
is it gonna suck know if it did that
blood would clot in the straw and she
would starve to death the first thing
that mosquito does is it spits it is
anti coagulating the straw the proboscis
the drinking thing where do you think
the parasite is hiding inside the
mosquito in the salivary glands isn’t
that crazy it’s in the salivary glands
she spits it in the form that she spits
in is called a sport is OE that’s Poor’s
oh it is again an amazing killing
machine it is in your bloodstream for no
more than five minutes because it knows
your immune system is ready to get it
it’s five minutes five minutes in five
minutes what it’s done is it’s sniffed
out your liver this is supposed to be an
artist’s rendition of a liver I need to
get those Holograms don’t you think this
is good so that is a liver she spits in
about thirty of these blue sporozoites
they’re tiny I’ll show you a picture of
them in a second in five minutes they
found your liver cells and each one is
infected a liver cell now I know what
you’re thinking oh my god this is gonna
be a disease of liver it’s gonna be a
liver disease no not true I tell the
students at Brown the undergraduates
especially the medical students not so
much with the undergraduate for sure
that they’ll do more damage to their
liver on the average Friday night then
will occur then will occur and all the
stuff Saharan Africa due to malaria so
in go the sporozoites each one infecting
the liver cell no disease two to four
weeks go by for the malaria that does
most of the killing of humans it’s
called falciparum malaria two to four
weeks go by completely silent during
that time the aliens are breeding each
sporozoites undergoing massive rounds of
asexual reproduction making these baby
parasites that are called Marisa lights
once or as I went in
and up to ten thousand Mara Zoe
jam-packed in that cell until that cell
can’t keep them in anymore
and it just like on alien support
explodes an outcome ten thousand Marisa
White’s still no disease the next thing
that happens these Marisa whites infect
red blood cells I have to tell you a
little bit about red blood cells so red
blood cells are the cells in your blood
that deliver oxygen to your tissues so
their mission critical for delivering
oxygen to your favorite organ brain lung
gut placenta if you’re pregnant kidney
if you don’t have enough healthy red
blood cells you can’t get oxygen to
those tissues and those tissues die so
that’s quite bad so here’s what happens
one marries oh it goes in infects that
red blood cell and now another wave of
asexual reproduction takes place this
cycle takes about two days
marah’s oh it goes in and it becomes
something we call it a ring form doesn’t
that look like a college signet ring
becomes a ring form there’s some other
forms trophies oh it’s and shiz ons in
here it’s multiplying and at the end
there one goes in in about twenty five
baby merozoite
jam packing that red cell again and then
that red cell shatters and when that red
cell shatters twenty-five narezo aids
come out and each one infects again and
again and again if any of you are old
enough to remember that Joe Namath
commercial for Faberge organic shampoo
remember you tell two friends and then
raise your hand if you’re old enough to
remember that they tell two friends and
they tell different that’s what’s going
on here
you’ve got geometric progression of the
parasites going up but what else do you
have
geometric decline of the red cells going
down you become more and more anemic
until you can’t deliver oxygen one more
little curveball the infected red blood
cells are sticky they’re stinky like
they have velcro on and that velcro
those velcro molecules stick in the
periphery in your vasculature and so you
get clogs it’s kind of like when your
kid flushes their socks down the toilet
it clogs the drain and if the drain gets
clogged fresh blood can’t
past the clog and so the tissue
downstream that’s supposed to be getting
oxygen doesn’t get it so that’s all
going on here that’s where the disease
is every once in a while the parasite
gets sick of having all this a central
reproduction they decide to get it on
and they differentiate into male and
female gamete Oh sex only they can tell
themselves apart but if they both get
taken up by another mosquito they find
it so romantic in the belly of the beast
they can join they form a fertilized egg
and this egg mutates and grows up inside
the belly of the beast up to the guts up
through the thorax up through the chest
until it’s developed into sporozoites in
the salivary glands again so that what
completes the life cycle that’s all bad
news
some good news there are people trying
to develop vaccines that block
sporozoites from entering the liver
they’ve got five minutes in order to
stop that parasite it’s hard there are
people trying to block
marah’s Owens from infecting red blood
cells the me resides outside the red
blood cell for only 140 microseconds so
that’s a challenge our group is focusing
on trapping the me resides inside the
red blood cell so they can’t get out
it’s like being trapped in a burning
house god forbid there’s a fire in here
you’d be trapped there are people that
are trying to block the hanky-panky and
so prevent the transmission which i
think is totally cool so I’m going to
tell you about a vaccine that tries to
block the red blood cells from getting
out but first I want to tell you a
little bit about the misery of malaria
this is what a sport is oh it looks like
these are the thread-like ones that she
injects into your body this is a blood
film this is the tool we use to decide
if someone has malaria and how much
malaria do they have if we collect
enough blood films on you for enough
periods of time we can decide are you
resistant to malaria or not resistant to
malaria based on how many parasites yes
these are healthy red blood cell
that’s what delivers oxygen these are
infected red blood cells in which you
can tell immediately is some of the
parasite looks sinister and you can also
tell it took forever to find this by the
way and I’m a pathologist I usually you
know use that I’m working so but on a
serious note half of these red blood
cells are gonna burst in the next 48
hours how do you think that’s gonna feel
it’s a disaster waiting to happen so
this is actually why I got into malaria
in the first place this is a disease
that I got when I was 18 years old and
it really galvanized my interest in
malaria I was lucky enough to survive it
if your picture is up here in a slide it
means you didn’t survive it
unfortunately this is brain and this is
brain from a child who died of cerebral
malaria this is supposed to be a
capillary which is a small blood vessel
that red blood cells need to pass
through in order to deliver oxygen to
the brain and what you can see remember
I told you that the infected red cells
are sticky they’ve all of these things
are infected red blood cells and they’ve
clogged up that artery no Drano would be
able to clear it which means no good
blood can get past to deliver oxygen to
this tissue do you see this big gaping
hole here that’s dead brain this is a
child who died of something like a
massive stroke
because they couldn’t oxygenate their
brain so very serious disease if you are
lucky enough to survive it like I was
you may be left with neuropsychiatric
sin coli which I think I actually do
have but it can be a quite significant
event so this is all bad news right why
isn’t malaria uniformly fatal well it
turns out that after years of exposure
some children some lucky few to
paraphrase the st. Crispin’s Day speech
some lucky few develop protective
antibodies what’s an antibody this is a
picture of one it’s a y-shaped molecule
that your immune system makes and if you
look at where my hands are
it attacks invaders with its two arms
and it’s extremely
– what it will bind to here’s the
problem if you go into a village the
vast majority of kids make antibodies
against malaria but the vast majority of
those antibodies are irrelevant
they won’t protect that child it’s very
few antibodies that are protective and
so that’s a major challenge if we could
figure out what it is that the very few
who are protected are recognizing
uniquely on the parasite we would have a
great leg up to developing a vaccine
because if we had that knowledge we
could mimic those antibodies in the
susceptible kids and that’s really been
the focus of our work honestly for the
past almost 20 years so here’s our
approach we go into it endemic area the
place we work in Tanzania is one of the
most endemic places on planet earth the
children in that community get more than
one infectious mosquito bite per person
per day that’s not one mosquito bite per
day which is a drag at your picnic right
this is one infectious mosquito bite per
person per day
it’s unbelievable pressure malaria so we
go there and we follow children
longitudinally over time collecting
blood films to see who is resistant and
who is not resistant and then we have to
do what I call DNA gymnastics or
molecular biology wizardry and here’s a
cartoon of it that will help me explain
it to you this red thing is a parasite
the Golden Triangle is a piece of the
parasite a parasite protein that is
being recognized by member the antibody
by an antibody in a resistant child that
child is resistant they make this
antibody it sees the Golden Triangle I
want to find the Golden Triangle the
problem is the vast majority of kids are
susceptible they also make antibodies
against the parasite but they’re seeing
blue squares there is a sea of blue
squares you are all blue squares and I’m
to find one golden triangle so that’s
you yes that’s the challenge that’s
absolutely the challenge if we can find
the golden triangle the rest the
biotechnology to turn that into a
buckets of vaccine is fairly
straightforward if I can immunize
susceptible kids with golden triangle
they’ll make this antibody and they’ll
be protected so that’s the goal is to
find the golden triangles let me tell
you about the study this was conducted
beginning in the 2000s was actually
funded by gates to my postdoctoral
mentors at Pat Duffy and without food
you are down at NIH
this is Tanzania that’s the Indian Ocean
that’s Lake Victoria
that’s Daraa Salam Mombasa there that’s
the village we work in like I said the
you know really is a an unbelievable
transmission of malaria there we
enrolled almost a thousand children at
birth and we followed them every two
weeks with a blood film to measure Paris
at emia in the first year life and then
every month in years two three and four
so intensive follow-up looking for
malaria in these kids we have active
surveillance we went to every child and
this is spread out over a 60 kilometre
square grid we went to every child’s
village every three to five days to
ascertain their health status with a
health wagon with a clinical officer and
despite that intense observation we
still had an under-five mortality rate
of 8% which sounds horrific right in
comparison to the children who are not
in our study the under-five mortality
rate is 25 percent so it really it’s one
in four children not making it to their
fifth birthday it really emphasizes why
malaria is public enemy number one we’re
able to collect almost 50 blood films on
these kids and we used these to decide
who was resistant and who is susceptible
this slide is here just to remind me to
tell you that there’s lots of molecular
biology hocus-pocus in order to figure
out the difference product between
resistant and susceptible and I had
anything
PhD student who was on vacation for the
summer and he decided to come back into
the lab and he went through 1.25 million
blue squares in order to find three
golden triangles so yeah here for him
and he never complain and in fact I told
him the story of Madame Curie you know
when she had six tons of pitchblende
delivered to her lab and after umpteen
years she found a microgram of radio I
told her he got no solace with that
story so he needs to sing in order to
get the healing power he needs to sing
so we got we got three I’m gonna tell
you about one of them today and it was
brand new
never been described before so we got to
name it sort of like our child se a PFS
eh isn’t egress energy memory the shy
slant is that form just before it
ruptures just before it ruptures so we
clone this thing the first thing you
want to do if you’re making a vaccine
for a parasite is make sure that the
parasite needs that protein you don’t
want to attacks a parasite hair right
because what’s the parasite gonna do
it’s gonna go bald and then attacking
the hair won’t help you want to attack
the parasites heart and so we can grow
parasites and culture this is parasite
emia and days and culture if we grow
regular wild-type unaltered parasites
they grow great if we knock out our gene
which we can do from the parasite they
don’t grow well at all and so it’s
mission critical it’s a vital protein
for the parasite to grow that’s really
good you want to attack something that’s
vital you want to know where it is so
this is micrographs of parasites the
early stages and the late stages
that’s just marking their DNA this is
marking our protein is our protein in
them Arizona
no and the Rings no in the tropes no
it’s in the late science just before
they rupture we want to know a little
bit more I thought this was pretty cool
this is a transmission electron
micrograph this is a red blood cell and
it has been entirely consumed on the
inside this is all parasite it’s eating
the red blood cell from the inside out
that’s its digestive that’s like the
waste product that’s the parasite poop
these are the developing parasites right
there now I’m gonna take you out to this
membrane that’s the outer membrane of
the red blood cell and that’s marking it
with these big black dots the little
black dots are marking our protein so
our protein is right underneath on the
Shazahn – this is the parasite membrane
and right up on the inner leaflet of the
red cell so it clearly is a parasite
protein and it’s a cool picture all
right first thing we immunize months
with our protein we take the Syrah from
the mice and ask the question does it
kill parasites growing in culture and
that’s what this experiment is these are
parasites growing in culture more
parasites go up three different
conditions if we incubate those
parasites with nothing they grow great
if we incubate them with mouse serum
before we vaccinated the mouse they grow
great if we incubate them with mouse
Syrah after we vaccinated the mouse the
parasites grow much worse 60% reduction
in parasite growth which got us very
excited what if we vaccinate the mice
and then challenge them with parasites
and watch what happens
so here’s parasite emia on the vertical
axis days after challenge these are two
control groups what happens is the mice
get high paris ET meais and then they
die if the mouse got vaccinated they
control their paris ET mia’s they go up
a bit but then they stay they mice don’t
die and I’m a huge fan of not dead this
is a survival huge fan huge fan this is
a I’m a pathologist so I’m supposed to
be a doctor of the dead but I’m a funny
one I’m a doctor of the
be dead like the Billy and I’m feeling
great about it’s not bad yeah survival
survival so they’re all surviving the
control groups die on date ten eight ten
twelve the vaccinated group goes at
least twice as long this is clinically
relevant if I can keep a child living
for another four or five days they can
get effective drug treatment so the
magic is to extend the survival window
this is the home run I think we go back
to that cohort of children 700 children
and we measure antibodies to our protein
in all seven hundred over seven hundred
and eighty and we ask the question if
you are lucky enough to have made an
antibody against our Golden Triangle
were you protected from severe malaria
we’re you protected from all cause
mortality were you protected from
malaria specific mortality this is the
number of cases adjusted for 1,500 child
weeks of observation in the black bars
are what happened to you if you did not
have antibody against our Golden
Triangle and you can see lots of severe
malaria a fair amount of mortality and a
fair amount of malaria specific
mortality what’s really hard to see cuz
I had to fake it is that little bar
there turns out if you had antibodies
against our Golden Triangle there was
zero cases of severe malaria absolutely
zero there were zero cases of malaria
specific and all cause mortality this is
really excited if we could immunize
these kids with our golden triangles and
make them look like these kids we would
have a phenomenal impact on under-five
mortality in malarious areas the
take-home messages are one I should tell
you we’ve moved this on to non-human
primate trials and it looks very
exciting and so we really are getting
ready for Phase one human trials malaria
is going to be the great killing machine
for the next decade no question
multidisciplinary approaches I didn’t
even get to talk about the social
interventions drug interventions that
are possible but they’re all very
helpful and very valid bed nets for
instance just to sleep under a bed
you don’t get bitten as much would be
really helpful but until we have new
drugs because the drugs we have are
getting less effective until we have new
drugs and maybe a vaccine we don’t have
any vaccines yet from malaria it’s going
to kill for the foreseeable future until
we get new tools my hope my dream really
is that this vaccine or the ones that
are being developed by other groups I
don’t want to sound like ours is the
only one in town it’s not but I hope
that our vaccine or those being produced
by other groups will in fact represent
at least the beginning and if not the
beginning the beginning of the beginning
of the end of malaria thank you very
much
[Applause]
Dolores for inviting me here I’m gonna
present the work of our group and it’s a
real it is a village it’s a large group
of individuals couple of 3040 people at
least who have been focusing for the
past 15 or 20 years on developing a
vaccine for human malaria in fact in
particular pediatric malaria I’m often
asked you know why do I focus on malaria
why malaria and it’s usually from one of
my snarky next physician-scientist
student colleagues and they go Jake why
don’t you work on something really
important like male pattern baldness or
they remind me of those other diseases
that middle-aged men get and we have to
listen to the ads for their treatments
on Sunday football why don’t I work on
those things and as I get older I’m
starting to think maybe I should change
my focus but no no we work on malaria
and the reasons are really both simple
and compelling we worked on malaria
because it is the greatest single agent
killer of children on the planet bar
none nothing comes close we’re talking
about at the most the sort of rosy
colored estimate half a million
individuals a year at the more
pessimistic side two and a half million
individuals every single year died of
malaria the vast majority of those
deaths are in children under the age of
five and they’re concentrated in places
like sub-saharan Africa and Southeast
Asia so it’s the great calling machine
of the tropical world and so at least 8%
of all childhood deaths on the planet
for due to malaria so that’s really the
reason we focus on it again it’s the
most important single agent killer of
children so the health economist Jeffrey
Sachs has coined the phrase where
malaria has prospered people have known
and this is a map of the malarious world
and it’s color-coded the warmer colors
the Reds and orange
and yellows are aware malaria is rampant
I had what you can see is that it’s
concentrated in sub-saharan Africa to
Southeast Asia and parts of Latin
America there is no question in my mind
that the correlation between political
stability economic development
capitalizing on what might be limited
educational opportunities all three of
these social inequalities are
concentrated where malaria is doing it
it’s it’s killing it’s impossible for me
to imagine a community where you have an
under-five mortality rate of 25% that’s
one in four children not making it to
their fifth birthday it’s impossible for
me to imagine a community like that
thriving and so those are really the
reasons that we’re focused on malaria if
you’re gonna go into battle with an
adversary that has been defeating you
for millennia you best understand its
its entire strategy what are its
weaknesses it would behoove you to
understand your enemy in order to combat
it effectively and so unfortunately and
you know if there’s anyone in the room
who suffered through medical school like
we have to understand how this parasite
works and so it begins with the bite of
a female and novel a mosquito every
mosquito bite you’ve ever gotten has
been a female mosquito the females need
to take blood in order to lay their own
eggs and so it begins with the bite of a
female mosquito this parrot I mean you
guys see the movie aliens Sigourney
Weaver you know the first in the cyclone
the third by the fourth one is here
this parasite is as well a DEP that is
that Maul crusher it is so smart it has
been forged in the crucible of evolution
it knows that the first thing that
mosquito is gonna do is what when she
bites you
is it gonna suck know if it did that
blood would clot in the straw and she
would starve to death the first thing
that mosquito does is it spits it is
anti coagulating the straw the proboscis
the drinking thing where do you think
the parasite is hiding inside the
mosquito in the salivary glands isn’t
that crazy it’s in the salivary glands
she spits it in the form that she spits
in is called a sport is OE that’s Poor’s
oh it is again an amazing killing
machine it is in your bloodstream for no
more than five minutes because it knows
your immune system is ready to get it
it’s five minutes five minutes in five
minutes what it’s done is it’s sniffed
out your liver this is supposed to be an
artist’s rendition of a liver I need to
get those Holograms don’t you think this
is good so that is a liver she spits in
about thirty of these blue sporozoites
they’re tiny I’ll show you a picture of
them in a second in five minutes they
found your liver cells and each one is
infected a liver cell now I know what
you’re thinking oh my god this is gonna
be a disease of liver it’s gonna be a
liver disease no not true I tell the
students at Brown the undergraduates
especially the medical students not so
much with the undergraduate for sure
that they’ll do more damage to their
liver on the average Friday night then
will occur then will occur and all the
stuff Saharan Africa due to malaria so
in go the sporozoites each one infecting
the liver cell no disease two to four
weeks go by for the malaria that does
most of the killing of humans it’s
called falciparum malaria two to four
weeks go by completely silent during
that time the aliens are breeding each
sporozoites undergoing massive rounds of
asexual reproduction making these baby
parasites that are called Marisa lights
once or as I went in
and up to ten thousand Mara Zoe
jam-packed in that cell until that cell
can’t keep them in anymore
and it just like on alien support
explodes an outcome ten thousand Marisa
White’s still no disease the next thing
that happens these Marisa whites infect
red blood cells I have to tell you a
little bit about red blood cells so red
blood cells are the cells in your blood
that deliver oxygen to your tissues so
their mission critical for delivering
oxygen to your favorite organ brain lung
gut placenta if you’re pregnant kidney
if you don’t have enough healthy red
blood cells you can’t get oxygen to
those tissues and those tissues die so
that’s quite bad so here’s what happens
one marries oh it goes in infects that
red blood cell and now another wave of
asexual reproduction takes place this
cycle takes about two days
marah’s oh it goes in and it becomes
something we call it a ring form doesn’t
that look like a college signet ring
becomes a ring form there’s some other
forms trophies oh it’s and shiz ons in
here it’s multiplying and at the end
there one goes in in about twenty five
baby merozoite
jam packing that red cell again and then
that red cell shatters and when that red
cell shatters twenty-five narezo aids
come out and each one infects again and
again and again if any of you are old
enough to remember that Joe Namath
commercial for Faberge organic shampoo
remember you tell two friends and then
raise your hand if you’re old enough to
remember that they tell two friends and
they tell different that’s what’s going
on here
you’ve got geometric progression of the
parasites going up but what else do you
have
geometric decline of the red cells going
down you become more and more anemic
until you can’t deliver oxygen one more
little curveball the infected red blood
cells are sticky they’re stinky like
they have velcro on and that velcro
those velcro molecules stick in the
periphery in your vasculature and so you
get clogs it’s kind of like when your
kid flushes their socks down the toilet
it clogs the drain and if the drain gets
clogged fresh blood can’t
past the clog and so the tissue
downstream that’s supposed to be getting
oxygen doesn’t get it so that’s all
going on here that’s where the disease
is every once in a while the parasite
gets sick of having all this a central
reproduction they decide to get it on
and they differentiate into male and
female gamete Oh sex only they can tell
themselves apart but if they both get
taken up by another mosquito they find
it so romantic in the belly of the beast
they can join they form a fertilized egg
and this egg mutates and grows up inside
the belly of the beast up to the guts up
through the thorax up through the chest
until it’s developed into sporozoites in
the salivary glands again so that what
completes the life cycle that’s all bad
news
some good news there are people trying
to develop vaccines that block
sporozoites from entering the liver
they’ve got five minutes in order to
stop that parasite it’s hard there are
people trying to block
marah’s Owens from infecting red blood
cells the me resides outside the red
blood cell for only 140 microseconds so
that’s a challenge our group is focusing
on trapping the me resides inside the
red blood cell so they can’t get out
it’s like being trapped in a burning
house god forbid there’s a fire in here
you’d be trapped there are people that
are trying to block the hanky-panky and
so prevent the transmission which i
think is totally cool so I’m going to
tell you about a vaccine that tries to
block the red blood cells from getting
out but first I want to tell you a
little bit about the misery of malaria
this is what a sport is oh it looks like
these are the thread-like ones that she
injects into your body this is a blood
film this is the tool we use to decide
if someone has malaria and how much
malaria do they have if we collect
enough blood films on you for enough
periods of time we can decide are you
resistant to malaria or not resistant to
malaria based on how many parasites yes
these are healthy red blood cell
that’s what delivers oxygen these are
infected red blood cells in which you
can tell immediately is some of the
parasite looks sinister and you can also
tell it took forever to find this by the
way and I’m a pathologist I usually you
know use that I’m working so but on a
serious note half of these red blood
cells are gonna burst in the next 48
hours how do you think that’s gonna feel
it’s a disaster waiting to happen so
this is actually why I got into malaria
in the first place this is a disease
that I got when I was 18 years old and
it really galvanized my interest in
malaria I was lucky enough to survive it
if your picture is up here in a slide it
means you didn’t survive it
unfortunately this is brain and this is
brain from a child who died of cerebral
malaria this is supposed to be a
capillary which is a small blood vessel
that red blood cells need to pass
through in order to deliver oxygen to
the brain and what you can see remember
I told you that the infected red cells
are sticky they’ve all of these things
are infected red blood cells and they’ve
clogged up that artery no Drano would be
able to clear it which means no good
blood can get past to deliver oxygen to
this tissue do you see this big gaping
hole here that’s dead brain this is a
child who died of something like a
massive stroke
because they couldn’t oxygenate their
brain so very serious disease if you are
lucky enough to survive it like I was
you may be left with neuropsychiatric
sin coli which I think I actually do
have but it can be a quite significant
event so this is all bad news right why
isn’t malaria uniformly fatal well it
turns out that after years of exposure
some children some lucky few to
paraphrase the st. Crispin’s Day speech
some lucky few develop protective
antibodies what’s an antibody this is a
picture of one it’s a y-shaped molecule
that your immune system makes and if you
look at where my hands are
it attacks invaders with its two arms
and it’s extremely
– what it will bind to here’s the
problem if you go into a village the
vast majority of kids make antibodies
against malaria but the vast majority of
those antibodies are irrelevant
they won’t protect that child it’s very
few antibodies that are protective and
so that’s a major challenge if we could
figure out what it is that the very few
who are protected are recognizing
uniquely on the parasite we would have a
great leg up to developing a vaccine
because if we had that knowledge we
could mimic those antibodies in the
susceptible kids and that’s really been
the focus of our work honestly for the
past almost 20 years so here’s our
approach we go into it endemic area the
place we work in Tanzania is one of the
most endemic places on planet earth the
children in that community get more than
one infectious mosquito bite per person
per day that’s not one mosquito bite per
day which is a drag at your picnic right
this is one infectious mosquito bite per
person per day
it’s unbelievable pressure malaria so we
go there and we follow children
longitudinally over time collecting
blood films to see who is resistant and
who is not resistant and then we have to
do what I call DNA gymnastics or
molecular biology wizardry and here’s a
cartoon of it that will help me explain
it to you this red thing is a parasite
the Golden Triangle is a piece of the
parasite a parasite protein that is
being recognized by member the antibody
by an antibody in a resistant child that
child is resistant they make this
antibody it sees the Golden Triangle I
want to find the Golden Triangle the
problem is the vast majority of kids are
susceptible they also make antibodies
against the parasite but they’re seeing
blue squares there is a sea of blue
squares you are all blue squares and I’m
to find one golden triangle so that’s
you yes that’s the challenge that’s
absolutely the challenge if we can find
the golden triangle the rest the
biotechnology to turn that into a
buckets of vaccine is fairly
straightforward if I can immunize
susceptible kids with golden triangle
they’ll make this antibody and they’ll
be protected so that’s the goal is to
find the golden triangles let me tell
you about the study this was conducted
beginning in the 2000s was actually
funded by gates to my postdoctoral
mentors at Pat Duffy and without food
you are down at NIH
this is Tanzania that’s the Indian Ocean
that’s Lake Victoria
that’s Daraa Salam Mombasa there that’s
the village we work in like I said the
you know really is a an unbelievable
transmission of malaria there we
enrolled almost a thousand children at
birth and we followed them every two
weeks with a blood film to measure Paris
at emia in the first year life and then
every month in years two three and four
so intensive follow-up looking for
malaria in these kids we have active
surveillance we went to every child and
this is spread out over a 60 kilometre
square grid we went to every child’s
village every three to five days to
ascertain their health status with a
health wagon with a clinical officer and
despite that intense observation we
still had an under-five mortality rate
of 8% which sounds horrific right in
comparison to the children who are not
in our study the under-five mortality
rate is 25 percent so it really it’s one
in four children not making it to their
fifth birthday it really emphasizes why
malaria is public enemy number one we’re
able to collect almost 50 blood films on
these kids and we used these to decide
who was resistant and who is susceptible
this slide is here just to remind me to
tell you that there’s lots of molecular
biology hocus-pocus in order to figure
out the difference product between
resistant and susceptible and I had
anything
PhD student who was on vacation for the
summer and he decided to come back into
the lab and he went through 1.25 million
blue squares in order to find three
golden triangles so yeah here for him
and he never complain and in fact I told
him the story of Madame Curie you know
when she had six tons of pitchblende
delivered to her lab and after umpteen
years she found a microgram of radio I
told her he got no solace with that
story so he needs to sing in order to
get the healing power he needs to sing
so we got we got three I’m gonna tell
you about one of them today and it was
brand new
never been described before so we got to
name it sort of like our child se a PFS
eh isn’t egress energy memory the shy
slant is that form just before it
ruptures just before it ruptures so we
clone this thing the first thing you
want to do if you’re making a vaccine
for a parasite is make sure that the
parasite needs that protein you don’t
want to attacks a parasite hair right
because what’s the parasite gonna do
it’s gonna go bald and then attacking
the hair won’t help you want to attack
the parasites heart and so we can grow
parasites and culture this is parasite
emia and days and culture if we grow
regular wild-type unaltered parasites
they grow great if we knock out our gene
which we can do from the parasite they
don’t grow well at all and so it’s
mission critical it’s a vital protein
for the parasite to grow that’s really
good you want to attack something that’s
vital you want to know where it is so
this is micrographs of parasites the
early stages and the late stages
that’s just marking their DNA this is
marking our protein is our protein in
them Arizona
no and the Rings no in the tropes no
it’s in the late science just before
they rupture we want to know a little
bit more I thought this was pretty cool
this is a transmission electron
micrograph this is a red blood cell and
it has been entirely consumed on the
inside this is all parasite it’s eating
the red blood cell from the inside out
that’s its digestive that’s like the
waste product that’s the parasite poop
these are the developing parasites right
there now I’m gonna take you out to this
membrane that’s the outer membrane of
the red blood cell and that’s marking it
with these big black dots the little
black dots are marking our protein so
our protein is right underneath on the
Shazahn – this is the parasite membrane
and right up on the inner leaflet of the
red cell so it clearly is a parasite
protein and it’s a cool picture all
right first thing we immunize months
with our protein we take the Syrah from
the mice and ask the question does it
kill parasites growing in culture and
that’s what this experiment is these are
parasites growing in culture more
parasites go up three different
conditions if we incubate those
parasites with nothing they grow great
if we incubate them with mouse serum
before we vaccinated the mouse they grow
great if we incubate them with mouse
Syrah after we vaccinated the mouse the
parasites grow much worse 60% reduction
in parasite growth which got us very
excited what if we vaccinate the mice
and then challenge them with parasites
and watch what happens
so here’s parasite emia on the vertical
axis days after challenge these are two
control groups what happens is the mice
get high paris ET meais and then they
die if the mouse got vaccinated they
control their paris ET mia’s they go up
a bit but then they stay they mice don’t
die and I’m a huge fan of not dead this
is a survival huge fan huge fan this is
a I’m a pathologist so I’m supposed to
be a doctor of the dead but I’m a funny
one I’m a doctor of the
be dead like the Billy and I’m feeling
great about it’s not bad yeah survival
survival so they’re all surviving the
control groups die on date ten eight ten
twelve the vaccinated group goes at
least twice as long this is clinically
relevant if I can keep a child living
for another four or five days they can
get effective drug treatment so the
magic is to extend the survival window
this is the home run I think we go back
to that cohort of children 700 children
and we measure antibodies to our protein
in all seven hundred over seven hundred
and eighty and we ask the question if
you are lucky enough to have made an
antibody against our Golden Triangle
were you protected from severe malaria
we’re you protected from all cause
mortality were you protected from
malaria specific mortality this is the
number of cases adjusted for 1,500 child
weeks of observation in the black bars
are what happened to you if you did not
have antibody against our Golden
Triangle and you can see lots of severe
malaria a fair amount of mortality and a
fair amount of malaria specific
mortality what’s really hard to see cuz
I had to fake it is that little bar
there turns out if you had antibodies
against our Golden Triangle there was
zero cases of severe malaria absolutely
zero there were zero cases of malaria
specific and all cause mortality this is
really excited if we could immunize
these kids with our golden triangles and
make them look like these kids we would
have a phenomenal impact on under-five
mortality in malarious areas the
take-home messages are one I should tell
you we’ve moved this on to non-human
primate trials and it looks very
exciting and so we really are getting
ready for Phase one human trials malaria
is going to be the great killing machine
for the next decade no question
multidisciplinary approaches I didn’t
even get to talk about the social
interventions drug interventions that
are possible but they’re all very
helpful and very valid bed nets for
instance just to sleep under a bed
you don’t get bitten as much would be
really helpful but until we have new
drugs because the drugs we have are
getting less effective until we have new
drugs and maybe a vaccine we don’t have
any vaccines yet from malaria it’s going
to kill for the foreseeable future until
we get new tools my hope my dream really
is that this vaccine or the ones that
are being developed by other groups I
don’t want to sound like ours is the
only one in town it’s not but I hope
that our vaccine or those being produced
by other groups will in fact represent
at least the beginning and if not the
beginning the beginning of the beginning
of the end of malaria thank you very
much
[Applause]
Please follow and like us: