DYANN WIRTH: In the final section, we're going
to talk about malaria elimination and eradication
through this lens of biology that we've learned about.
OK so here are some of the challenges to eradicating an organism.
This is from a biological standpoint pretty tough.
So we've already talked about this a bit, but let's think about some
of the challenges from a biology perspective.
This is a highly evolved interacting system.
The parasite, the human host, the mosquito.
Adaptations have been made in all of these organisms,
in order to have this life cycle be successful.
It's a longstanding relationship.
The biology is complex and certainly not fully understood.
There is a dynamic adaptation of the host, the vector, and the parasite.
I just talked about drug resistance.
The adaptation of the parasite to a human intervention.
There's a strong selective force and there's
an evolutionary response in the parasite for a mutation
to occur and become prevalent in the population.
And something which is very important is that this disease
has a very high reproductive capacity or R not.
That means that from a single case of malaria,
you can get dozens to hundreds of new cases.
Partly because of this amplification due to the mosquito vector.
It's also I think a challenge to eradication.
It's a paradigm shift for those people who think about malaria.
It's a paradigm shift from population biology, and ecology.
That's what you need to do, versus controlling disease
or treating disease.
And for the last 100 years, we have been focused on disease.
And now you have to make a shift to actually focus on transmission,
as being the largest single factor in determining the outcome of elimination
and eradication.
I also think it's very important to keep in mind
that if you perturb complex systems, you may get unexpected consequences.
Remember, there is an &quot;arms race&quot; between survival of the organism
and whatever you're introducing to eliminate it.
And it's not clear--
or if you take history, in fact, the parasite has won the last several times
we've tried this.
So it's something that I think it's important to keep in mind.
I think another important conceptual piece of this
is that if you think about this kind of pyramid or triangular
form of the infection, in fact the parasites we can see with microscopy
or RDTs, or maybe even the current PCR methodologies,
are really just the tip of the iceberg.
There are many people that are asymptomatic,
who carry lower numbers of parasites, but may in fact be perfectly
capable of transmitting the disease.
We just don't know the answer to this.
But in fact, it's something to keep in mind
I also think this is something that people forget about.
But if you think about the parasite itself,
you think about where are the parasites today.
99% of the parasites are in people that can circle the globe,
they can be infected, particularly for Plasmodium vivax, for many years,
and they live a long time.
People are a reservoir for this for a very long time.
Whereas mosquitoes, live usually two to three weeks.
They don't have parasitemia, they're not infectious for very long.
They don't travel, unless they happen to get on an airplane, which is probably
not that frequent compared to people.
And they have very little of the parasite biomass.
So important in keeping in mind, if you get rid
of all the mosquitoes, or 99% of the mosquitoes,
you're still going to have parasites in people.
Now we come to this population biology concept of population bottlenecks.
And I think this is also something that's very important to keep in mind
as we think about intervening in the parasite life cycle.
So this is just the life cycle in a different way.
Here's the passage through time, starting with infection in the liver
schizonts to the liver infected cells.
And then, as this goes into the bloodstream, you get up to 10
of the 11th parasites.
Remember, I told you it's a huge biomass.
A subset of these form the sexual stages,
but when the mosquito takes a blood meal it only takes up
a very small number of parasites.
So despite the fact that there are potentially say, 10 to the 10th,
or 10 to the 9th gametes, 1% to 10% of the asexual,
the red cells stage parasites or gametocytes.
Only a very small number of these get taken up.
We don't know how this is determined.
And then in the mosquito again, there is a expansion.
A large number, 10 to the 3rd, 10 to the 4th sporozoites.
But again, when these go into humans, a very small number get in,
and even a smaller number get into the liver.
So this means if we think about where we're going to attack the parasite,
if we're thinking about reducing transmission,
it's very clear that the focus should be on these bottlenecks.
And both of them are at that interface between the mosquito
and the human host.
And I think that's really a paradigm shift.
So we need to think about transmission blocking strategies.
Now there are many ways to block transmission.
You could directly block it with a vaccine or a drug.
Or you can reduce the number of asexual parasites
or reduce the replication in mosquitoes.
So I'm not saying that everything has to be focused on those stages.
But you have to think about the bottlenecks as places where you in fact
can have the greatest impact, because you're targeting
the smallest number of genomes.
And another way to look at that is how can we
bend the curve of malaria transmission.
And this is a slide from the Bill &amp; Melinda Gates Foundation,
from their strategy for malaria.
So if you simply look at the current progress, that
is the increased use of bed nets and the increased use of RDTs,
if this just continues, we suspect that things will continue to go down,
and may eventually plateau.
If you have something like drug resistance,
you may actually have this resurgence.
This is what has happened in many places where disease has been reduced
to a low level, but then either a resistance to drug,
or resistance to insecticides, or lack of continued commitment
to malaria prevention and control, you've gotten resurgence.
And the goal here really, I think, in the new strategy
is to bend this curve to try to accelerate to zero,
such that we get really to zero transmission
by focusing on elimination as the strategy.
And just to give you a sense that this isn't all theoretical,
here is just data from real situations.
This was published in 2014.
And this is comparing 2000 to 2010.
And I just show you in fact, Senegal going from about 20%
prevalence to about 5% prevalence, simply
with the increased use of the current tools.
Now clearly, this isn't zero.
That's where we'd like to be.
But I think it tells us that by concentrating on transmission
and focusing on elimination as the goal, you can have dramatic effects.
Whether or not we get to full limitation, I think remains to be seen.
And I think it's important, as we think about malaria elimination
and eradication, to recognize it's not just the biological factors.
We've been talking about those in some detail.
But there are also human related factors,
including socioeconomic status, migration, whether or not
the mosquitoes that transmit the particular malaria also
are involved in feeding on animals or livestock.
So there are many factors that are going to contribute.
Social and behavioral issues of humans.
Once malaria transmission gets to a low enough level,
will people continue to use bed nets, use RDTs, get treated,
as the disease becomes less and less prevalent.
So the challenge, I think, to elimination and eradication
is not just biology.
But it is in fact, these broader issues.
So with that, I think we'll conclude.