Malaria Drugs Vaccine 2010

8/13/2019 Malaria Drugs Vaccine 2010

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I never found the order I searched for

But always a sinister

And well-planned disorder

That increases in the hands

Of those who hold power

While the others who clamor for

A more kindly world

A world with less hunger and more hopefulness

Die of torture in the prisons

Claribel Alegria, Nicaraguan poet


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Leading causes of death in Sub-Saharan Africa, South Asia, and Southeast Asia for persons age

0-44 (World Health Organization)

How can we defeat this disease?


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First, how does your body strike back?


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Can you say antibodies and T cells?


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Antibodies work at all stages

but T cells are only effectivewhen the parasite is in the liver


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Red blood cells do NOT express MHC proteins

and thus infected cells cannot

generate a T cell response!


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In adults the immune system does

a pretty good job,but in kids its a different story


9/113www.columbia.edu/itc/hs/medical/pathophys/parasitology/2006/PAR-05Color .pdf

Young kids are hit much harder by malaria

Because of differences in their immune response


10/113www.columbia.edu/itc/hs/medical/pathophys/parasitology/2006/PAR-05Color .pdf

How does the malaria parasite respond to

the natural selection produced by immune attack?


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generate a T cell response

One clue comes from the fact that malaria makes

Red blood cells sticky so they lodge in capillaries


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This allows them to prevent their host cells from

Going through the spleen where they can be killed


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Infected red blood cells can be recognized by a change

In shape--the cells get knobs

www3.niaid.nih.gov/.../ malariaGeneticsSection/

parasite


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The knobs and the stickiness result from

Plasmodium proteins that are put on the plasma membrane

of the red blood cellincluding the PfEMP proteins



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PfEMP-1 proteins are encoded by the var(for variable) genes.

individual parasite genomes contain 50-150var genes

but only oneis expressed at any one time.


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PfEMP-1 proteins are very antigenic and thus we mount

a strong and effective response


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Parasites fight back: they switch on different var genes

during asexual reproduction allowing them

to evade the initial immune response!

Nature 415: 673 (2002)


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Variation also allows the parasiteto re-infect previously exposed hosts

Nature 415: 673 (2002)


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www.columbia.edu/itc/hs/medical/pathophys/parasitology/2006/PAR-05Color .pdf

Despite this, as we have seen, most adults

fight off the infection over time


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How can we speed up this process, protect children

and the elderly, and reduce the death rate?

H d hi hild


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How can we speed up this process, protect children

and the elderly, and reduce the death rate?

We need drugs


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Well focus on the deadliest parasite


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http://drnelson.utmem.edu/Woods.Hole/slide5.png

But there is a problem that takes us

back to the family tree

You and memushrooms

plants

Plasmodium

W lik di t t l ti


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http://drnelson.utmem.edu/Woods.Hole/slide5.png

We seem like distant relatives

but this is only partof the tree of life

You and me

mushrooms

plantsPlasmodium

H th bi i t t ll


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Heres the bigger picture--we are actually

relatively closely related to Plasmodium

E. coli

Staph. aureus

TB bug

Genome Research 12, 1080-1090 (2002)

Plasmodium and me!

W h h f ll l hi


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We share much more of our cellular machinery

Than we do with bacteria.

E. coli

Staph. aureus

TB bug

Genome Research 12, 1080-1090 (2002)

Plasmodium and me!


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We need to find drug targets

that Plasmodium have

And people do not share


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The first insight goes back >400 years


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Following their arrivalin the New World,Spanish Jesuit missionaries

in Peru learned of a medicinal barkThat the native Quechuaused to treat fever.

web1.caryacademy.org/.../ Quinine/history.htm


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Legend suggests thatthe Countess of Chinchn, wife ofthe Viceroy of Peru, was cured

of her fever with the bark.The tree was namedCinchona after the countess.

The Quechua called itQuinquina = bark of barks


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In 1820 J.B. Caventouand P.J. Pelletierisolated the active chemicaland named it quinine


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A synthesis approach wasdiscovered in the 1940sBut most is still purifiedFrom Cinchona bark


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Quinine remains an effective drugand was dominant through 1950.

But chemists soughtmore effective derivativesthat had less side effectsHans Andersag at Bayer

discovered chloroquine in 1934and by the 1950s itbecame the drug of choice

H d i i


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How do quinineAnd its derivatives

kill Plasmodium?


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Most current drugs target the red blood cell stage


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Plasmodium eats blood!(actually really hemoglobin)


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Plasmodium eats blood!

When living in red blood cellsIt survives by digestingHemoglobin in its food vacuole(the parasite lysosome).

However, the leftoverheme, the metal complex

that actually carries oxygen,Is quite toxic.

Wikipedia.com


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Plasmodium eats blood!

The parasites

heme polymerase converts

the toxic heme intonon-toxic hemazoin

Which then crystalizes


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Chloroquine accumulates in the food vacoule

Where it inhibits conversion of heme to hemazoin

Either by directly binding heme and/orBy inhibiting heme polymerase

http://www.tulane.edu/~wiser/protozoology/notes/drugs.html


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Chloroquine accumulates in the food vacoule

Where it inhibits conversion of heme to hemazoin

Either by directly binding heme and/orBy inhibiting heme polymerase


No, not chloroquine!

Ahhhhhhhhh..


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Chloroquine allowed major progress against malaria--

What do you think happened next?


No, not chloroquine!

Ahhhhhhhhh..


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What cellular changes underline resistance?

Chl i i i li k d i i


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Chloroquine resistance is linked to a mutation in amembrane-located food vacuolardrug-metabolite transporter protein

Mutant PfCRT is thought to move Chloroquineout of the food vacuole


Choroquine resistance set back


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www.uhhg.org/mcrh/resources/video/malariappt.pdf

Choroquine resistance set back

the fight against malaria


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www.uhhg.org/mcrh/resources/video/malariappt.pdf

Option 1: make more derivatives of quinine or use quinine again


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p q q g


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Option 2: new drug targets


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Pyrimethamine (DHFR) + sulfadoxine or dapsone (DHPS)

attack enzymes involved in making nucleotides

(wecan take in folate from our diet- theycannot)



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One of the newest medicines has one of the longest histories


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Artemisiahas been used by Chinese herbalists

for >1000years to treat many illnesses including malaria

Med Trop (Mars). 1998;58(3 Suppl):13-7. Int J Parasitol.2002 Dec 4;32(13):1655-60.


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The active compound was found to be Artemisinin



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Artemisinin is not toxic until it is cleavedinside the parasite by exposure to heme-iron

A resulting free radical intermediate maykill the parasite by poisoningone or more essential malarial protein(s).



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Whats another rule to prevent resistance

we learned from treating TB?


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When you use new drugs, use

them in combination!

C t CDC id li


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Current CDC guidelines are:

If malaria was acquired in areas without

chloroquine resistance

Then Treat with chloroquine

C t CDC id li


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If from area with resistance :

1. quinine plus doxycycline or tetracycline

or

2. Atovaquone + proguanil (Malarone)

C t CDC id li


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If P. vivax or P. Ovale

Chloroquine plusPRIMAQUINEto hit liver stage

Plasmodium is also evolving


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g

resistance to other drugs

Research continues to identify new drugs


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Research continues to identify new drugs

Nature 415: 686 (2002)

Scientists also sequenced the genome of P falciparum


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Scientists also sequenced the genome of P. falciparum

In 2002 looking for new drug targets

Nature 415: 686 (2002)

23 million base pairs

5,300 proteins encoded

60% are not similar

to known proteins!

The genome of P vivax was completed this past month


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The genome of P. vivax was completed this past month

(October 2008)

More similar to P. falciparum than expected

Only 150 unique proteins

H it i t t


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pathmicro.med.sc.edu/ppt-vir/vaccine.ppt

Hey wait a minute, arent you

forgetting something?


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pathmicro.med.sc.edu/ppt-vir/vaccine.ppt

What about a vaccine

against malaria?


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(Program for Appropriate Technology in Health)


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Genetically attenuatedP. falc iparum

sporozoites.Developmentally arrested at an early stage

following liver cell invasion,

or

Radiation attenuated sporozoite

Of all malaria vaccines GlaxoSmithKlines


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Of all malaria vaccines, GlaxoSmithKline s

RTS,S/AS02A is the furthest along

in clinical testing, "at least by four to five years,"

Zarifah Reed at the WHO Initiative for Vaccine Research

RTS S/AS02A is generated against CSP


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RTS,S/AS02A is generated against CSP,the most abundant cell surface protein

during the malaria parasite's infectious sporozoite stage

The RTS S/AS02A antigen is a fusion of CSP


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The RTS,S/AS02A antigen is a fusion of CSPwith a surface protein from hepatitis B,

to stimulate a more effective immune response

CS is attached to the plasma membrane


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CS is attached to the plasma membrane

and contains a large immunodominant domain

that consists of repeats of a short, species-specific peptide.

It is important for invasion of liver cells

Membrane anchor

Since RTS S incorporates a hepatitis B antigen


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Since RTS,S incorporates a hepatitis B antigen,

it "will also be a hepatitis B vaccine," she adds.

An estimated one million people die annually worldwide

from hepatitis B and ensuing liver complications.

After Phase I trials demonstrated safety


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After Phase I trials demonstrated safety,

the vaccine entered Phase II trials in children in Africa

Heres the data--did it work?


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Here s the data did it work?


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It continues to look good after a longer follow up


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It continues to look good after a longer follow up

The Lancet 36610 December 2005, pp. 2012-2018

Other vaccines are following this
http://www.sciencedirect.com/science?_ob=PublicationURL&_tockey=%23TOC%234886%232005%23996330497%23613325%23FLA%23&_cdi=4886&_pubType=J&view=c&_auth=y&_acct=C000004198&_version=1&_urlVersion=0&_userid=130907&md5=8873990152a32414e1313d1a51ab1902http://www.sciencedirect.com/science?_ob=PublicationURL&_tockey=%23TOC%234886%232005%23996330497%23613325%23FLA%23&_cdi=4886&_pubType=J&view=c&_auth=y&_acct=C000004198&_version=1&_urlVersion=0&_userid=130907&md5=8873990152a32414e1313d1a51ab1902


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Other vaccines are following this

though trials are less far along

Th t hi h t h h


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Thats high techhow

about low tech

R d C t t B t


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Reduce Contact Between

Humans And Mosquitoes Personal protective measures

DEET

PERMETHRIN

Bed nets

I ti id t t d b d t


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Insecticide treated bednets

can reduce infection by 63%

F l 20 illi B d t


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UNICEF Ethiopia

For example, 20 million Bednets

have been distributed in Ethiopia

Legend: PSI - Population Services International;

WB -World Bank.

GFATM 2, 5 - Global Fund for AIDS, TB and Malaria

Cum nets: Cumulative number of nets distributed.

WHO UNICEF the World Bank and


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WHO, UNICEF, the World Bank and

the UN Development Program formed a

new partnership in 1998


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Its goal: eliminate malaria as a major

disease by 2015


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Accessible drugs

Nets and Insecticide

Rapid diagnostic tests

More Artemesia


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A U.S. government initiative designed tocut malaria deaths in half in sub-Saharan Africa.

Announced by President Bush on June 30, 2005.


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Pledges to increase U.S. funding of malaria preventionand treatment in sub-Saharan Africa

by > $1.2 billion over 5 years.

Before we end, lets consider one other cool aspect of malaria


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This brings us back to blood and how it carries oxygen


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J. Mol. Biol., 235, 657

Hemoglobin is a finely tuned machine crafted by natural selection


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J. Mol. Biol., 235, 657

to deliver oxygen and remove CO2

A single amino acid change alters hemoglobin structure

A d ll th t i t f l d


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And allows the protein to form long rods

A single amino acid change alters hemoglobin structure

A d ll th t i t f l d


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And allows the protein to form long rods

These protein rods change the shape of the Red blood cell


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and this change occurs when hemoglobin is not bound to oxygen

Sickled cell block capillaries and trigger


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lower oxygen and more sickling

The disease is treatable in the developed world


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But still shortens life expectancy

Untreated, as in much of the developing world,


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the disease is fatal in childhood

The mutation responsible for sickle cell anemia


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is surprisingly common in parts of the world

anthro.palomar.edu/synthetic/synth_4.htm

Why hasnt natural selection eliminated this allele?
http://anthro.palomar.edu/synthetic/synth_4.htmhttp://anthro.palomar.edu/synthetic/synth_4.htm


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Does this map look familiar?


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Does this map look familiar?


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Malaria distribution

Heterozygotes have an advantage!


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While red blood cells from heterozygotes are usually normal,

h i kl d b d d if i f d b Pl di


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they are prone to sickle and be destroyed if infected by Plasmodium,

eliminating the blood stage of the parasite before it can reproduce

And this is not the only such example!


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y p

Glucose-6-phosphate dehydrogenase plays a key role


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Protects red blood cells

Against oxidative stress

in glucose metabolism but also generates glutathione

200 million people are deficient in this process


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p p p

Complete loss of function can


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lead to episodes of anemia

Milder reductions can provide partial resistance

i i i f


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to malaria as malaria-infected red cells

are susceptible to more rapid death

However, these individuals are also

hypersensitive to certain antimalarials


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hypersensitive to certain antimalarials

like primaquine that affect oxidative stress

Documents

Malaria Drugs Vaccine 2010