bvgh global health primer 2009

Building Biotech Solutions for Diseases of the Developing World

BVGH Global Health PrimerAugust 2009

Founded2004

SupportersBill & Melinda Gates Foundation

Biotechnology Industry Organization

The Rockefeller Foundation

Industry Leaders

Corporate Leadership CouncilAlnylam Pharmaceuticals

Anacor Pharmaceuticals

Covington & Burling LLP

Exelixis, Inc.

Genzyme Corporation

Goodwin Procter LLP

Kleiner Perkins Caufield & Byers

OSI Pharmaceuticals

Vertex Pharmaceuticals

The Winkler Foundation

AcknowledgementsBVGH thanks Anna Schoenfelder for her assistance

in writing, editing, and designing the 2009 edition

of the Global Health Primer and Joanna Lowell

for overseeing the entire project. The Primer

benefited from feedback from Jaya Banjeri

and Anna Wang of MMV; Lew Barker and Peg

Willingham of Aeras; Asmita Bavre and Anna Upton

of the TB Alliance; Lisa Beyer and Ulysee Huling III

of IAVI; Debbie Burgess of the Bill & Melinda Gates

Foundation; Esther Butler, Cynthia Roberts, and

Duncan Steele of PATH; Tim Cooke, formerly of

Avant Therapeutics; Sally Ethelston of MVI; Joan

Fahy of LSTM; Alan Fairlamb of the University of

Dundee; Beatrice Gordis of FIND; Larry Hale of

WRAIR; James Hickman and Susan Lynch of iOWH;

Clem Lewin of Novartis; Richard Mahoney of PDVI;

Curt Malloy of IDRI; Jim McKerrow of the Sandler

Center; Jean-Pierre Paccaud of DNDi; Mark Riddle

of NMRC; Holly Seltzer of IPM; Lee Schoentrup of

SBRI; Jaco Smith of Sanofi-Pasteur; Amit Srivastava

of Children’s Hospital, Boston; Richard Tidwell

of the University of North Carolina; and Irene

Thuo of SVI. Special thanks are owed to Anastasia

Semienko and Leighland Feinman for their help

with past editions of the Primer, without which

this document would have been significantly

more difficult to produce. Finally, BVGH gratefully

acknowledges the Bill & Melinda Gates Foundation

for their financial support.

Board of DirectorsRobert B. Chess, Chairman

Chairman, Nektar Therapeutics

Christopher D. Earl, PhD

President & CEO, BIO Ventures for

Global Health

Carl B. Feldbaum

President Emeritus, Biotechnology

Industry Organization (BIO)

James C. Greenwood

President, BIO

Vaughn M. Kailian

General Partner, MPM Capital

Melinda Moree, PhD

Former Director,

Malaria Vaccine Initiative

J. Leighton Read, MD

General Partner, Alloy Ventures

George Rupp, PhD

President & CEO, The

International Rescue Committee

cover photo: Julien harneis

M e s s a g e t o R e a d e R s

3 BVGH Global Health Primer

M e s s a g e t o R e a d e R s

Dear Reader:

How can biotech participate in solving the great unmet medical needs of this century?

BVGH exists, in part, to answer this question. The amazing capabilities of the biotech

industry—the financial resources, technology, and expertise—have the potential to make

a powerful impact on the diseases that primarily affect the poor in developing countries.

We seek out and define opportunities to apply those capabilities. By doing so, we can

encourage more companies to participate in global health and meet those medical needs.

This primer is focused on defining the global health needs for those in the life sciences

who want to understand the neglected diseases of the developing world. In addition,

information is provided for those in the global health community who want to

understand the progress being made in the development of new drugs, vaccines, and

diagnostics that could help them in the daily struggle against deadly and debilitating

diseases of poverty.

Our approach in this volume is scientific, yet conveys the urgency of these issues.

We have done all we can to be precise and accurate in the information we have

assembled. We quantify the emergence of an unprecedented array of candidate

vaccines, drugs, and diagnostics to treat developing world diseases, as well as

highlight increasing commitment from the public and private sectors to invent ways

to end the cycle of ill health and poverty that are prevalent in developing countries.

But research and development (R&D) for neglected diseases remains woefully

underfunded. We have the tools to create new drugs, vaccines, and diagnostics, but

the process remains difficult, lengthy, and exceedingly expensive. Even though the

investment is far greater than a decade ago, it’s far less than what’s needed. BVGH plays

two parts in this fight. We highlight the untapped scientific opportunities and we make

the argument for investment in R&D and incentives that will attract the brightest minds

and most powerful technologies. New technologies paired with an increasing investment

in health systems offer hope for defeating age-old diseases and offering better health and

well being to all.

Sincerely yours,

Melinda Moree, PhD

Interim CEO

BIO Ventures for Global Health

BVGH Global Health Primer 3

List of Abbreviations

ACT . . . . . . . . . . . . . . . . artemisinin-based.combination.therapy

Aeras . . . . . . . . . . . . . . Aeras.Global.TB.Vaccine.Foundation

AMC. . . . . . . . . . . . . . . . Advance.Market.Commitment

BCG. . . . . . . . . . . . . . . . Bacille.Calmette-Guerin.tuberculosis.vaccine

BIO. . . . . . . . . . . . . . . . . Biotechnology.Industry.Organization

BVGH. . . . . . . . . . . . . . BIO.Ventures.for.Global.Health

CDC. . . . . . . . . . . . . . . . Centers.for.Disease.Control.and.Prevention.(United.States)

CPDD. . . . . . . . . . . . . . Consortium.for.Parasitic.Drug.Development

DALY. . . . . . . . . . . . . . . Disability.Adjusted.Life.Year

DFID. . . . . . . . . . . . . . . Department.for.International.Development.(United.Kingdom)

DNDi. . . . . . . . . . . . . . . Drugs.for.Neglected.Diseases.initiative

EMEA. . . . . . . . . . . . . . European.Medicines.Agency

EPI. . . . . . . . . . . . . . . . . Expanded.Program.on.Immunization.(WHO)

ETEC. . . . . . . . . . . . . . . Enterotoxigenic.Escherichia coli

FIND. . . . . . . . . . . . . . . Foundation.for.Innovative.Diagnostics

FDA. . . . . . . . . . . . . . . . Food.and.Drug.Administration.(United.States)

FNIH. . . . . . . . . . . . . . . Foundation.for.the.National.Institutes.of.Health.(United.States)

GAVI.Alliance. . . . . . Formerly.Global.Alliance.for.Vaccines.and.Immunisation

Global.Fund. . . . . . . The.Global.Fund.to.Fight.AIDS,.TB.and.Malaria

IAVI. . . . . . . . . . . . . . . . International.AIDS.Vaccine.Initiative

ICDDR,B . . . . . . . . . . . International.Center.for.Diarrheal.Disease.Research,.Bangladesh.

IDRI. . . . . . . . . . . . . . . . Infectious.Disease.Research.Institute

IFFIm. . . . . . . . . . . . . . International.Financing.Facility.for.Immunization

iOWH. . . . . . . . . . . . . . Institute.for.OneWorld.Health

IPM. . . . . . . . . . . . . . . . International.Partnership.for.Microbicides

IVI. . . . . . . . . . . . . . . . . . International.Vaccine.Institute

MDR-TB. . . . . . . . . . . . multidrug-resistant.tuberculosis

MMV. . . . . . . . . . . . . . . Medicines.for.Malaria.Venture

MVI. . . . . . . . . . . . . . . . Malaria.Vaccine.Initiative

NGO . . . . . . . . . . . . . . . non-governmental.organization

NIAID. . . . . . . . . . . . . . National.Institute.for.Allergy.and.Infectious.Diseases.(United.States)

NIH . . . . . . . . . . . . . . . . National.Institutes.of.Health.(United.States)

OECD. . . . . . . . . . . . . . Organisation.for.Economic.Co-operation.and.Development

PAHO. . . . . . . . . . . . . . Pan.American.Health.Organization

PATH. . . . . . . . . . . . . . . Formerly.Program.for.Appropriate.Technology.in.Health

PDP. . . . . . . . . . . . . . . . product.development.partnership

PEPFAR. . . . . . . . . . . . President’s.Emergency.Plan.for.AIDS.Relief.(United.States)

PMI . . . . . . . . . . . . . . . . President’s.Malaria.Initiative.(United.States)

R&D. . . . . . . . . . . . . . . . research.and.development

SBRI. . . . . . . . . . . . . . . . Seattle.Biomedical.Research.Institute

TB.Alliance . . . . . . . . Global.Alliance.for.TB.Drug.Development

TDR. . . . . . . . . . . . . . . . Special.Programme.for.Research.and.Training.in.Tropical.Diseases

UNDP. . . . . . . . . . . . . . United.Nations.Development.Program

UNICEF. . . . . . . . . . . . United.Nations.Children’s.Fund

USAID. . . . . . . . . . . . . . United.States.Agency.for.International.Development

WHO. . . . . . . . . . . . . . . World.Health.Organization

XDR-TB . . . . . . . . . . . . extensively.drug-resistant.tuberculosis

Contents

BVGH Fact Sheet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

The Global Disease Burden . . . . . . . . . . . . . . . . . . . . 9

Bridging the Innovation Gap . . . . . . . . . . . . . . . . . 10

The Role of Biotechnology . . . . . . . . . . . . . . . . . . . 12

The Need for Incentives . . . . . . . . . . . . . . . . . . . . . 12

Why the Global Health Primer? . . . . . . . . . . . . . . 14

Key Global Health Players . . . . . . . . . . . . . . . . . . . . 16

Select Companies Working in Global Health . . . . 25

Highlights in Global Health R&D . . . . . . . . . . . . . . 26

Disease Sheets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Chagas Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Cholera . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Dengue Fever (DF) . . . . . . . . . . . . . . . . . . . . . . . . 36

Enterotoxigenic E. coli (ETEC) . . . . . . . . . . . . . . 39

Human African Trypanosomiasis (HAT) . . . . . 42

Human Hookworm Infection . . . . . . . . . . . . . . 46

Human Immunodeficiency Virus (HIV) . . . . . . 49

Japanese Encephalitis (JE) . . . . . . . . . . . . . . . . . 53

Leishmaniasis . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Lymphatic Filariasis (LF) . . . . . . . . . . . . . . . . . . 60

Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Pneumococcal Disease . . . . . . . . . . . . . . . . . . . . 68

Rotavirus Gastroenteritis . . . . . . . . . . . . . . . . . . 71

Schistosomiasis . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Shigellosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Tuberculosis (TB) . . . . . . . . . . . . . . . . . . . . . . . . 80

M E S S A G E T O R E A D E R S


BVGH Impact

Our accomplishments are measured by the growing numbers of companies who are committing their best scientists and technologies to solving pressing public health needs across the globe.

Incentives

Leading efforts to ensure successful implementation of the new Priority Review Voucher program and helping product developers take advantage of the new incentive

Worked with the G8 and multilateral organizations to help design a novel advance market commitment for pneumococcal vaccines, launched in February 2007

Innovation

Published Closing the Global Health Innovation Gap, which defines how industry-based drug discovery platforms can be applied to neglected tropical diseases

Defined a viable, untapped global market for TB vaccines, published in our report Tuberculosis Vaccines: The Case for Investment, leading to new industry investment and R&D partnerships

Partnering

Catalyzed partnerships between biotechnology companies and public-sector innovators to address diverse opportunities for drugs, vaccines, and diagnostics.

Convened meetings enabling diverse stakeholders to develop new collaborations, including the first Partnering for Global Health Forum in March, 2008, attracting over 500 attendees from all sectors of industry and global health

BIO Ventures for Global Health, a non-profit organization,

harnesses the resources of the biotechnology industry to create

new medicines for neglected diseases of the developing world.

Over the past 30 years, biotechnology has revolutionized medicine

in the developed world. In the developing world, however,

millions of patients die each year from diseases of poverty

because we don’t yet have modern medicines to prevent, treat

and diagnose deadly pathogens. Biotechnology can make major

inroads in treating neglected diseases — and offer hope for the

development of drugs, vaccines, and diagnostics in our lifetimes.

BVGH breaks down barriers that hinder industry initiatives in global

health product development. We foster collaboration among

stakeholders in industry, philanthropy, academia, and government,

and we catalyze industry investment through the creation of new

market-based incentives.

“ There are lots of interesting projects that

can be done by small biotech companies in

global health... My prediction is that we’re

right at the beginning of the global health

work by biotechnology companies.”

c l e M e n t l e W i n , h e a D , s t r a t e G i c i M M u n i z a t i o n p l a n n i n G , novartis vaccines anD DiaGnostics

W H y T H E G L O B A L H E A L T H P R I M E R ?




The Global Disease Burden

New vaccine, drug, and diagnostic technologies have helped to add almost

a decade to Americans’ average life expectancy since 1950.1 But these

innovations have yet to realize their true promise for all the world’s citizens:

life expectancy for those living in sub-Saharan Africa has actually dropped

over the past thirty years.2

The billions of people living on less than $2 per day continue to suffer from

an array of acute and chronic infectious diseases. Every year, as many as

seventeen million people — most of them children — die from such infectious

diseases as tuberculosis, malaria, and HIV/AIDS, as well as diarrheal diseases

and respiratory infections. Other, lesser-known chronic infections, including

lymphatic filariasis and schistosomiasis, debilitate rather than kill, striking

people in the prime of life, affecting entire families’ productivity and quality

of life, and trapping successive generations in poverty.

The diseases chronicled in this Global Health Primer

continue to devastate bodies, lives, communities, societies,

and governments and drastically limit the potential for

economic growth. Diseases of the developing world affect

not just individuals’ life expectancy and productivity, but

also the planet’s economic, political, and social stability.

The health of the global community depends on our

success in fighting the diseases of poverty.

We know we can conquer diseases through better medicines,

improved care, and prevention. This century’s successes in

defeating smallpox and potentially polio through universal

vaccination offer hope to impoverished millions who today

suffer from myriad pathogens unknown in the developed

world. But the fight can’t be won without a new generation

of drugs, vaccines, and diagnostics to prevent and treat neglected diseases.

Right now, however, the R&D pipeline that generates those technologies is

too meager to ensure that ten years from now, health care providers will have

the tools they need to roll back the most devastating diseases of poverty.

1.. .National.Center.for.Health.Statistics,.Health, United States, 2007.(Hyattsville,.Md .,.2007),.Table.27 ..Life.expectance.at.birth.for.men.born.in.2004.in.the.United.States.was.almost.ten.years.longer.than.men.born.in.1950 ..Life.expectancy.for.women.born.in.2004.was.more.than.nine.years.greater.than.for.women.born.in.1950 .

2. .United.Nations,.“Life.Expectancy.in.Sub-Saharan.Africa.Is.Lower.Now.Than.30.Years.Ago:.UN.Index,”.press.release,.November.9,.2006,.Accessed.online.04/01/09.at:.http://www .un .org/apps/news/storyAr .asp?NewsID=20548&Cr=human&Cr1=develop .

This century’s successes

in defeating smallpox and

potentially polio through

universal vaccination offer

hope to impoverished millions

who today suffer from myriad

pathogens unknown in the

developed world.


Bridging the Innovation Gap

Over the past decade, global health pioneers such as the Bill & Melinda

Gates Foundation have established unmistakably that global health problems

can be solved; the world can no longer turn a blind eye to the suffering

from these diseases. Tremendous progress has been made in improving

the delivery of existing drugs, vaccines, and diagnostics through programs

such as the Global Fund, the World Health Organization (WHO), the GAVI

Alliance (GAVI), and the U.S. President’s Emergency Plan for AIDS Relief

(PEPFAR). Better access to today’s drugs, vaccines, and diagnostics, however,

only accentuates the inadequacy of available treatments for such afflictions

as tuberculosis, malaria, worms, and human African trypanosomiasis.

Current investment in R&D for neglected diseases is only a fraction of

what is needed to move promising discoveries from academic laboratories

to clinical trial. According to the George Institute for International Health’s

2008 G-FINDER survey, $2.5 billion was invested in R&D to create new

products to treat diseases of poverty in 2007. While

that may seem sizeable, the majority of that funding was

dedicated to HIV/AIDS, with a lesser amount for malaria

and tuberculosis. Many other devastating neglected

diseases lack the most minimal research funding.

BVGH terms this lack of investment in R&D the

“innovation gap.” Compared to the developing world’s

staggering unmet medical needs, the funding for new

solutions is dreadfully insufficient. Today there are more compelling ideas

for R&D than there are dollars to fund them. The innovation gap is further

compounded by the near-absence of private sector innovators that have led

the field in making new medicines to treat patients in wealthy countries.

We know we can find new ways to prevent and treat diseases of poverty. The

invention of recombinant DNA technology in 1973 spurred a revolution in

the science of drug and vaccine discovery. Breakthroughs in genomics and

biochemistry have given us the tools to understand and harness the molecular

mechanisms that underlie human disease. These advances have led to the

invention of entirely new classes of drugs, vaccines, and diagnostics for

cancer, cardiovascular disease, and HIV/AIDS. There’s no scientific reason

why technological advances that have revolutionized health care for the

affluent cannot transform the course of diseases afflicting the poor.

Today there are more

compelling ideas for

R&D than there are

dollars to fund them.




If diseases could be classified as cruel and unusual, human

african trypanosomiasis, also known as “sleeping sickness,”

would be near the top of the list . spread via the bite of tsetse

flies, the disease attacks the brain, causing patients to hallucinate

and fall into a coma . according to the new York times writer Donald

Mcneil Jr ., “[patients] have been known to chase neighbors with

machetes, throw themselves into latrines, and scream with pain at

the touch of water . only at the end do they lapse into a lassitude so

great that they cannot eat, followed by coma and death .”

this scenario plays out in the poorest communities in central africa

every day . tens of thousands of people, mostly the rural poor, die

each year from the disease, while hundreds of thousands more

become infected . in some regions, sleeping sickness claims more

lives than hiv/aiDs .

african sleeping sickness is treatable if diagnosed in its early stages .

But its symptoms — headache and fever — are often overlooked .

there are no simple, point-of-care diagnostic tests that would

identify the disease before it progresses . once the disease has

advanced, diagnosis can be made only by examining the spinal fluid

extracted via lumbar puncture .

For a patient diagnosed with late-stage sleeping sickness, treatment

options are few . the drug most commonly used, melarsoprol, was

developed in 1949 . a derivative of arsenic, it kills roughly 5% of

people who are injected with it, fails to cure 1/3 of patients, and

can burn the veins of those who survive . a newer drug, eflornithine,

requires intravenous (iv) infusions four times a day for two weeks in

large volumes . since most patients live far from hospitals or nurses

able to insert an iv line, eflornithine is not an option in the remote,

rural areas where sleeping sickness takes the greatest toll .

clearly, drugs that are effective, safe, and easy to administer are

desperately needed, as are simple, point-of-care diagnostics that

detect early- and late-stage disease . Yet currently there is only

a single new drug in clinical trials for sleeping sickness . this is in

sharp contrast to the 270 drugs in development for colon cancer,

which kills roughly the same number of people in the united

states as sleeping sickness does in africa . creating important new

compounds to combat sleeping sickness is only possible with a

significant investment today in innovative drug discovery .

Sleeping Sickness: The Case for New R&D

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The Role of Biotechnology

In October 2007, BVGH published Closing the Global Health Innovation Gap,

the first in a series of reports that explore how biotechnology can solve urgent

global health problems. Our report showed that the biotechnology industry —

which today is the principal source for new therapeutics for developed world

diseases — has the means to take on the fight against neglected diseases.

A core insight from our report is that biotechnology companies organize

drug discovery around specific classes of molecular targets, some of which

underpin multiple diseases. Companies develop therapeutic technologies

to attack these targets, typically specific classes of disease-related enzymes,

molecular messengers, or cell-surface proteins.

They then apply their technology opportunistically

to the most relevant diseases. In many cases, those

targets are also present in the pathogens that cause

neglected diseases. This creates a largely untapped

opportunity to turn the biotechnology arsenal against

the problems of global health.

The biotechnology industry offers strength in its

diversity. With more than 4,400 companies and

over 200 products approved by the FDA, the

biotechnology industry has the size and scope to

take on the fight against neglected diseases. Biotech

CEOs are entrepreneurs who are willing to take on

risk and who are single-minded in pursuit of their

goals. Several thousand biotechnology companies means several thousand

different approaches to solving problems, hundreds of unique technology

platforms, and a corps of scientists who know how to develop drugs, vaccines,

and diagnostics. Competition is critical when the answers aren’t clear. Solving

problems that haven’t been addressed before requires diverse ideas, different

methods, and competition to select the winning solutions.

The Need for Incentives

While the scientific and medical basis for action is clear, the financial

argument is more challenging. Establishing a clear business case is essential

if companies are to commit millions of dollars to developing products for

patients who have little or no money to pay for them. For most companies,

the reality of the marketplace and the need to turn a profit forces them to

focus on established world markets. But as this primer illustrates, where

the business case can be made, companies will follow. On pg. 25, we list

the biotechnology and pharmaceutical companies already committed to

producing medicines that address needs in the developing world.

Establishing a clear

business case is essential

if companies are to commit

millions of dollars to

developing products for

patients who have little or

no money to pay for them.


BVGH Global Health Primer 13BVGH Global Health Primer 13

Patients. that. will. benefit. from. new. products. to. treat.

neglected.diseases.live.on.less.than.two.dollars.a.day ..In.the.

developed.world,. that. is.not.enough.to.buy.a.single.bottle.

of. aspirin,. let. alone. a. regime. of. tuberculosis. treatments. lasting.

several. months .. Developing. world. patients. lack. the. purchasing.

power.of.consumers.in.the.developed.world.—.power.that.impels.

biotechnology.and.pharmaceutical.companies.to.spend.billions.on.

developing.the.next.lifestyle.drugs.to.treat.baldness.and.premature.

wrinkles ..Without.this.financial.motivation,.it.is.necessary.to.seek.

different.ways.to.spur.companies.into.action ..We.at.BVGH.believe.

companies. need. an. array. of. incentives. and. up-front. funding. to.

allow.them.to.deploy.their.scarce.resources.on.new.opportunities.

in.neglected.diseases ..

BVGH.is.active.in.the.area.of.incentives.—we.develop.and.advocate.

for.key.funding.models.like.the.priority.review.vouchers.(PRVs).and.

advanced. market. commitments. (AMCs) .. We. are. also. working. to.

develop.new.incentives.that.will.spur.industry.to.action .

The. PRV. program. awards. a. voucher. to. companies. that. develop.

drugs. for. neglected. tropical. diseases. (NTD) .. This. voucher. grants.

the.company.faster.review.of.a.future.drug.of.their.choosing.once.

the.NTD.drug.is.approved.by.the.U .S ..Food.and.Drug.Administration.

(FDA) .. The. speedier. review. process. can. shave. between. four. and.

twelve.months.off.the.standard.review,.saving.companies.millions.

by.getting.drugs. to.market. faster ..Estimates.of. the.value.of.a.PRV.

range.from.$50.million.to.$500.million.—.enough.to.offset.the.risk.

and.investment.required.for.research.and.development ..BVGH.has.a.

Web.site.—.prvinfo .org.—.dedicated.to.information.on.PRVs ..

AMCs.are.designed.to.enhance.the.value.of.insufficient.developing.

world. markets .. Under. AMCs,. donors. commit. to. guaranteed,.

preferential. prices. for. a. certain. number. of. vaccines. sold. to. the.

poorest. countries .. In. return,. manufacturers. agree. to. lower. their.

prices. substantially. after. an. agreed-upon. period .. This. ensures.

long-term. access. for. countries. with. patients. most. in. need .. BVGH.

published. a. report. in. May. of. 2006. with. recommendations. for.

AMCs ..We.worked.with.the.World.Bank.and.the.Global.Alliance.for.

Vaccines. and. Immunizations. to. incorporate. many. of. the. report’s.

recommendations.in.the.first.AMC.pilot ..This.pilot,.launched.in.2007,.

has. commitments. from. seven. donors. and. is. being. implemented ..

Donors. pledged. $1 .5. million. to. guarantee. a. market. in. developing.

countries. for. new. pneumococcal. vaccines. to. prevent. deadly.

respiratory.infections.in.children .

More. is. still. needed,. both. in. up-front. funding. and. downstream.

rewards. for. successful. developments .. Today,. BVGH. is. assessing.

novel. incentive. mechanisms. that. will. encourage. small,. early-

stage. companies. to. join. in. the. fight. against. diseases. of. the.

developing.world .

Incentives�for�Innovation



Where markets in the developing world are lacking, the most powerful

approach to stimulating innovation is to design, legislate, and fund incentives

that reward the creation of novel medicines for global health. Rewards that

are received only upon success are attractive to innovators and efficient

for donors. Effective incentive mechanisms encourage companies to invest

resources in developing products, instead of depending solely on grants

and contracts provided by the global health funders. At BVGH, we actively

advocate for novel incentives that can replicate the power of the marketplace

in driving investment in new R&D.

Why the Global Health Primer?

President Obama noted in a recent statement on global health, “We cannot

simply confront individual preventable illnesses in isolation. The world is

interconnected, and that demands an integrated approach to global health.”

BVGH’s Global Health Primer forges connections between expertise in developing

world diseases and the cutting-edge technologies that are the foundation of

new vaccines, drugs, and diagnostics. It is a resource for innovators in the

biotechnology and global health communities to learn how

best to focus efforts. The Primer lists the major global health

organizations focused on R&D, including international

non-governmental organizations, government agencies, and

academics. It highlights the companies that have committed

to global health and progress made in the past year. Using a

common framework for presenting our research, the Primer

describes the unmet needs for 16 diseases and summarizes

current pipelines for vaccines, drugs, and diagnostics, while

pointing out critical gaps that need to be addressed.

Our hope is that the Primer will foster innovative R&D to grow the pipeline

for neglected diseases. Millions in poor countries are suffering from diseases

that devastate their livelihoods. Solutions are within reach, and the time has

come to take transformative action.

At BVGH, we actively

advocate for novel incentives

that can replicate the power

of the marketplace in driving

investment in new R&D.

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K E y G L O B A L H E A L T H P L A y E R S


Key Global Health Players

P R O D U C T D E V E L O P M E N T P A R T N E R S H I P S ( P D P s )

Aeras Global TB Vaccine

Foundation — Aeras

WWW.AERAS.ORG

Focus: Vaccines for tuberculosis

n Leading the effort to develop a new vaccine for tuberculosis (TB); working on both

“prime” and “booster” candidate vaccines in prime-boost regimens with improved BCG

and several delivery systems for subunit vaccines; lead products in Phase II clinical

trials in South Africa

n Partnering with GlaxoSmithKline (GSK), Crucell, Intercell, Sanofi-Pasteur,

Oxford University, and Statens Serum Institute to develop novel TB vaccines

n Partnering with multiple research institutions to develop clinical trials sites in

South Africa, India, Uganda, and Kenya

n Has received over $300 million in funding, principally from the Bill & Melinda

Gates Foundation and also from bilateral donors such as the Netherlands

Ministry of Foreign Affairs and the Research Council of Norway

Drugs for Neglected

Diseases initiative —

DNDi

WWW.DNDI.ORG

Focus: Drugs for leishmaniasis,

human African trypanosomiasis,

Chagas disease, and malaria

n Founded in 2003 by four publicly funded research institutes from Malaysia,

India, Kenya, and Brazil along with Institut Pasteur and Médecins Sans

Frontières

n Working in partnership with industry, academia, and non-governmental

organizations (NGOs), DNDi has the largest ever R&D portfolio for the

kinetoplastid diseases and currently has two post-registration, five clinical, and

four preclinical projects, along with a wide variety of discovery activities

n In 2007-2008, delivered two new fixed-dose antimalarial products: ASAQ

(artesunate-amodiaquine) with Sanofi-Aventis, and ASMQ (artesunate-

mefloquine) with Farmanguinhos/Fiocruz

n By mid-2008, announced formation of drug discovery partnerships with GSK

and Anacor, as well as with Institute Pasteur Korea, Institut de Recherche pour

le Développement, Eskitis Institute in Brisbane, and the University of North

Carolina

n Secured over $75 million in funding from public and private sectors

Foundation for Innovative

New Diagnostics — FIND

WWW.FINDDIAGNOSTICS.ORG

Focus: Diagnostics for

tuberculosis, malaria, and human

African trypanosomiasis

n The only PDP to focus on diagnostics—initial focus on TB expanded to malaria

and human African trypanosomiasis

n Partnering with Cepheid, ImmPORT, Tyrian Diagnostics, Hain Lifesciences,

Roche Diagnostics, Becton, Dickinson and Company, Cellestis, BioMérieux,

Eiken Chemical, Zeiss, and many others

n In September 2007, announced funding of $62 million over five years for TB

diagnostics



Global Alliance for TB

Drug Development —

TB Alliance

WWW.TBALLIANCE.ORG

Focus: Drugs for tuberculosis

n Not-for-profit PDP developing new drugs for TB; founded in 2000

n Conducting Phase III trials of moxifloxacin in combination with other drugs; a

new compound, PA-824, is in Phase II trials; multiple discovery projects in early

pipeline

n Partnering with Bayer, GSK, Novartis, Sanofi-Aventis, BG Medicine, the

University of Auckland, the University of Illinois at Chicago, the University of

Pennsylvania, Texas A&M University, Yonsei University, the Infectious Disease

Research Institute (IDRI), Korea Research Institute of Chemical Technology,

Beijing Tuberculosis and Thoracic Tumor Institute, Rutgers University, and the

Institute of Materia Medica in China

n Has raised over $200 million from donors such as the Bill & Melinda Gates

Foundation, the Rockefeller Foundation, Irish Aid, UK Department for

International Development (DIFD), the Netherlands Ministry of Foreign Affairs,

and the US Agency for International Development (USAID)

Institute for OneWorld

Health — iOWH

WWW.IOWH.ORG

Focus: Drugs for neglected

diseases in developing countries

n Not-for-profit focused on drugs for neglected diseases; founded in 2000

n Paromomycin IM Injection was approved for use in India in 2006 for the

treatment of visceral leishmaniasis. In May 2007, it was designated by the WHO

for inclusion on its Model List for Essential Medicines.

n In partnership with Amyris, Sanofi-Aventis, and the University of California,

Berkeley, formed the Artemisinin Project to develop semisynthetic artemisinin,

derivatives of which are a key component in first-line malaria treatments

n Entered into a collaboration with Roche to access its proprietary compound

library to identify new diarrheal disease treatments

n Has obtained over $140 million in grants, principally from the Bill & Melinda

Gates Foundation

International AIDS

Vaccine Initiative — IAVI

WWW.IAVI.ORG

Focus: Vaccines for HIV/AIDS

n Leading global partnership for the development of an HIV/AIDS vaccine; founded

in 1996 and operational in 24 countries

n Conducted human trials with six vaccine candidates in 11 countries on four

continents—Asia, Africa, Europe, and North America

n Partnered with more than 40 academic, biotechnology, pharmaceutical, and

governmental institutions

n Received over $569 million in contributions since 1996; current annual budget

nearly $113 million

International Partnership

for Microbicides — IPM

WWW.IPM-MICROBICIDES.ORG

Focus: Microbicides for

prevention of HIV/AIDS

transmission

n Leading partnership to develop vaginal microbicides to prevent transmission of

HIV; founded in 2002

n Has one candidate product currently in clinical trials and several others in

preclinical development

n Partnering with Gilead Sciences, Merck, Imquest Biosciences, Pfizer, Tibotec,

Bristol-Myers Squibb, and Locus, among others

n Has raised over $350 million from the Bill & Melinda Gates Foundation, the

Rockefeller Foundation, DIFD, and other sources



Medicines for Malaria

Venture — MMV

WWW.MMV.ORG

Focus: Drugs for malaria

n Leading organization developing new drugs and combination therapies for

malaria; founded in 1999

n Lead products are Coartem® Dispersible, a pediatric formulation of artemether-

lumefantrine, registered with Swiss Medic in January 2009; Eurartesim®,

dihydroartemisinin-piperaquine, which has completed Phase III and now is

being prepared for filing with EMEA and US FDA; and Pyramax®, pyronaridine-

artesunate, currently in Phase III clinical trials

n Partnering with GSK, Novartis, Broad-Genzyme, Advinus, and many others on

the discovery and development of new anti-malarials

n Has received funding and pledges totaling $318 million from the Bill & Melinda

Gates Foundation, Wellcome Trust, governments, and other sources

PATH — Formerly

Program for Appropriate

Technology in Health

WWW.PATH.ORG

Focus: Sustainable, culturally

relevant solutions to improve

health and well-being in the

developing world

n Largest of the Bill & Melinda Gates-funded non-profit organizations;

founded in 1977

n Home to the PATH Malaria Vaccine Initiative, the PATH Enteric Vaccine

Initiative, and other large initiatives including the Meningitis Vaccine Project and

the PATH Rotavirus Vaccine Program

n Developing medical devices, diagnostics, and vaccines that are appropriate

for developing countries; also working to improve health care delivery and

individual and community behaviors

n Responsible for over 30 products that have helped solve global health problems,

including single-use syringes, malaria tests, and chemically active stickers that

detect heat-damaged vaccines

n Piloting introduction of cervical cancer vaccines and meningococcal vaccines into

the developing world

n Has received more than $1.4 billion in funding from foundations, the US

government, other governments, multilateral agencies, corporations, and

individuals

PATH Enteric Vaccine

Initiative — EVI

WWW.PATH.ORG/PROJECTS/ENTERIC_

VACCINE

Focus: Vaccines against leading

bacterial causes of diarrheal

disease

n Founded in 2007 as a project of PATH

n Advancing the development of safe, effective, and affordable vaccines to protect

infants and young children in the developing world against Enterotoxigenic E.

coli (ETEC) and Shigella

n In 2008, announced partnerships with Ace Biosciences and EndoBiologics

n Received $50 million start-up grant from the Bill & Melinda Gates Foundation

PATH Malaria Vaccine

Initiative — MVI

WWW.MALARIAVACCINE.ORG

Focus: Vaccines for malaria

n Created in 1999 as a global program of PATH

n RTS,S, the most clinically advanced vaccine candidate in MVI’s portfolio, has

been developed in partnership with GSK Biologicals; it is expected to enter Phase

III clinical trials soon

n Partnered with Sanaria Inc., Walter Reed Army Institute of Research (WRAIR),

GenVec Inc., Seattle Biomedical Research Institute (SBRI), and many others

n Has raised nearly $468 million in funding, chiefly from the Bill & Melinda Gates

Foundation



Pediatric Dengue Vaccine

Initiative — PDVI

WWW.PDVI.ORG

Focus: Vaccines against dengue

infection

n Mission is to accelerate the development, evaluation, and introduction of

affordable dengue vaccines; conceived in 2001 and formally established at the

International Vaccine Institute in 2003

n Current projects include supporting innovative research on diagnostics and

assays; assisting companies to develop vaccines; developing multipurpose field

sites; collaborating with partners on regulatory issues; and preparing models of

vaccine introduction and use

n Partners include seven vaccine companies in Brazil, Europe, India, and

the United States; a number of leading academic research centers; several

government agencies and the WHO

n As of mid-2008, donations of over $60 million from the Bill & Melinda Gates

Foundation, the Rockefeller Foundation, and the Government of Korea

SVI Human Hookworm

Vaccine Initiative —

SVI-HHVI

HTTP://SABIN.ORG/PROGRAMS/HHVI/

INDEx.HTML

Focus: Vaccines for hookworm

infection and schistosomiasis

n A major program of the Sabin Vaccine Institute (SVI), dedicated to accelerating

the development of safe, affordable vaccines against hookworm infection and

schistosomiasis

n The Na-ASP-2 Human Hookworm Vaccine is currently in a Phase I clinical

testing in a hookworm endemic region of Brazil

n The Sm-TSP-2 Schistosomiasis Vaccine has completed manufacturing process

development

n Partners include George Washington University, the Oswaldo Cruz Foundation,

the London School of Hygiene and Tropical Medicine (LSHTM), the Queensland

Institute of Medical Research, Instituto Butantan, and the Institute of Parasite

Diseases at the Chinese Center for Disease Control and Prevention

n Currently, grants from the Bill & Melinda Gates Foundation support the

development of the human hookworm vaccine; Private donors have provided

seed funding for the development of the schistosomiasis vaccine



I N T E R N A T I O N A L A N D M U L T I L A T E R A L O R G A N I z A T I O N S A N D I N I T I A T I V E S

Bill & Melinda Gates

Foundation

WWW.GATESFOUNDATION.ORG

Launched in 2000, the foundation supports work in the areas of global health, global development, and US public education. Current endowment is $29.7 billion, and grant commitments to date total $19.8 billion. In 2009, the foundation will disburse $3.8 billion, a figure which includes a portion of the 2006 bequest of $31 billion from Warren Buffett.

Department for

International Development

— DFID

WWW.DFID.GOV.UK

The aid and development arm of the British government. Aims to reduce world

poverty through long-term programs that tackle its underlying causes. A major

supporter of Advanced Market Commitments (AMCs) and other programs to

improve health in the developing world. Its annual budget is roughly $6 billion.

Foundation for the

National Institutes

of Health — FNIH

WWW.FNIH.ORG

Founded in 1996, FNIH was established by the NIH as a flexible funding

organization to support pioneering biomedical research. In partnership with the

Bill & Melinda Gates Foundation, the Wellcome Trust, and the Canadian Institutes

of Health Research, FNIH administers the Grand Challenges in Global Health

initiative, a $436.6 million program to develop cost-effective, simple-to-use,

inexpensive, health tools for the developing world.

International Center

for Diarrheal Disease

Research, Bangladesh —

ICDDR,B

WWW.ICDDRB.ORG

ICDDR,B is an international health research institution that conducts research,

training, and program-based activities in collaboration with partners from academic

and research institutions throughout the world. In 2007, the organization received

almost $29 million, with large portions from USAID, DFID, and the government of

Bangladesh.

International Finance

Facility

for Immunisation

Company — IFFIm

WWW.IFFIM.COM

IFFIm is a financing facility backed by a coalition of governments to finance

vaccine commitments. These commitments are floated on the international

bond market in order to “front-load” predictable funding to GAVI for enhanced

vaccination programs. IFFIm provided $800 million, or 90 percent, of GAVI’s 2007

expenditures.

International Vaccine

Institute

(UN Program hosted by

Korea) — IVI

WWW.IVI.ORG

The IVI, established by the United Nations Development Program with the support

of 35 countries and the WHO, supports collaborative research to accelerate the

introduction of new vaccines into developing countries. The IVI’s focus includes

basic and applied laboratory research, product development, training, and technical

assistance. The Pediatric Dengue Vaccine Initiative (PDVI) is hosted by the IVI.

GAVI Alliance —

Formerly Global Alliance

for Vaccines and

Immunisation

WWW.GAVIALLIANCE.ORG

An alliance between the public and private sector, GAVI has raised more than $3.5

billion for the purchase and distribution of vaccines to children in the developing

world. GAVI’s funding comes from national governments and a 15-year, $1.5

billion grant from the Gates Foundation. GAVI estimates its efforts have prevented

2.9 million deaths since 2000.

The Global Fund to Fight

AIDS, TB and Malaria —

Global Fund

WWW.THEGLOBALFUND.ORG

Since 2002, the Global Fund has directed global financing for the prevention and

treatment of HIV/AIDS, tuberculosis, and malaria. As of April 2009, the Global

Fund has approved $15.6 billion to support programs in 136 countries and

disbursed $7.3 billion.



National Institute for

Allergy and Infectious

Diseases — NIAID

WWW.NIAID.NIH.GOV

Part of the National Institutes of Health (NIH), NIAID provides support for research

into infectious, immunologic, and allergic diseases. NIAID is the leading arm of the

US government that promotes research into preventions and cures for HIV/AIDS,

influenza, and infectious diseases of the developing world.

Pan American Health

Organization — PAHO

WWW.PAHO.ORG

PAHO is an international public health agency working to improve health and

living standards of the countries of the Americas. It serves as the WHO’s Latin

America regional office and is the main purchaser of vaccines in Latin America.

President’s Emergency

Plan for AIDS Relief —

PEPFAR

WWW.PEPFAR.GOV

PEPFAR aims to dramatically scale up HIV/AIDS prevention, diagnosis, and

treatment in 15 target countries. Currently the program supports the treatment

of 1.7 million patients, most of whom live in sub-Saharan Africa. President Bush

signed a bill to reauthorize PEPFAR in 2008, pledging up to $48 billion in funding

over five years, more than tripling the $15 billion spent from 2003-2008. The

reauthorization includes over $9 billion to fight malaria and tuberculosis.

President’s Malaria

Initiative — PMI

WWW.PMI.GOV

Begun in 2005, the PMI was reauthorized in 2008 to increase malaria funding to $5

billion over five years through bilateral programs worldwide. The PMI is working

with multiple public and private sector partners in programs to distribute bed nets,

drugs, and insecticides.

The Rockefeller

Foundation

WWW.ROCKFOUND.ORG

Established in 1913, the foundation has more than $4 billion in assets that support

programs in health, globalization, arts and culture, agriculture, housing, and

education. Many of today’s largest product development partnerships (PDPs) were

founded with seed financing from the foundation.

Special Programme for

Research and Training

in Tropical Diseases —

TDR

WWW.WHO.INT/TDR

TDR, an independent program established by the WHO, supports R&D through

grants and partnerships to combat 10 of the most devastating tropical diseases.

It coordinates worldwide efforts in discovery research for neglected diseases,

emphasizing support for research in developing countries.

United Nations

Development Program —

UNDP

WWW.UNDP.ORG

The UNDP is the United Nation’s principal provider of advice, advocacy, and grant

support to foster development initiatives.

United Nations Children’s

Fund — UNICEF

WWW.UNICEF.ORG

UNICEF provides long-term humanitarian and developmental assistance to children

and mothers in developing countries. UNICEF is the global leader in vaccine

procurement, reaching 40 percent of the world’s children. In 2008, UNICEF

vaccinated 700,000 women to prevent neonatal tetanus.

United States Agency for

International Development

— USAID

WWW.USAID.GOV

USAID is the US government’s foreign aid and development organization. With field

offices all over the world, USAID strives to advance US foreign policy objectives by

supporting economic growth, agriculture, trade, democracy, conflict prevention,

humanitarian assistance, and global health. USAID administers PEPFAR, PMI, and

other disease-targeted programs.



The Wellcome Trust

WWW.WELLCOME.AC.UK

The Wellcome Trust is the largest funder of biomedical research in the United

Kingdom, investing £600 million annually. The Trust has a strong interest in

infectious disease and has devoted significant resources to neglected diseases. The

Trust is increasingly funding “translational” efforts to invent new therapeutics based

on fundamental discoveries made in academic laboratories—the organization is

unusual in its willingness to fund private sector R&D. The Trust helped pioneer the

use of the antimalarial artemisinin outside of China.

World Health Organization

— WHO

WWW.WHO.INT/EN

The WHO is the agency of the United Nations that acts as a coordinating authority

on international public health. Its major aim is to combat disease, especially

infectious diseases, and to promote the general health of the peoples of the world.



N O T A B L E R E S E A R C H I N S T I T U T I O N S A N D A C A D E M I C C O N S O R T I U M S

The Broad Institute of MIT

and Harvard

WWW.BROAD.MIT.EDU

Focus: Malaria and tuberculosis

n A biomedical research institute investigating all aspects of human disease; launched in 2004

n Collaborating with MMV, Genzyme, and Advinus to identify new malaria therapeutics

n Helped decode the extensively drug resistant (XDR) form of the M. tuberculosis genome in 2007

n Received $600 million in gifts from Eli and Edythe Broad

Infectious Disease

Research Institute — IDRI

WWW.IDRI.ORG

Focus: Vaccines, diagnostics,

and drugs for leishmaniasis,

tuberculosis, malaria, leprosy, and

other infectious diseases

n A non-profit biotechnology organization committed to developing products to

prevent, detect, and treat infectious diseases of poverty; founded in 1993

n Lead product is a vaccine against leishmaniasis, currently in Phase I & II clinical

trials in India, Latin America, and Africa

n World-class platforms in antigen discovery and development, adjuvant

formulation and delivery, therapeutic molecule target discovery, and biomarker

discovery for diagnostics

n Funded by the Bill & Melinda Gates Foundation, the NIH, the American Leprosy

Missions, and the M.J. Murdock Charitable Trust; IDRI also engages in public-

private partnerships with such companies as Eli Lilly & Company and GSK

Sabin Vaccine Institute

WWW.SABIN.ORG

Focus: Vaccine research,

development, and advocacy

n Working to develop and deliver vaccines to the developing world for nearly

two decades

n Home to the Human Hookworm Vaccine Initiative, the Global Network for

Neglected Tropical Disease Control, and several other advocacy efforts

n Has supported symposia for rotavirus, pneumococcal diseases, and other global

health threats

n Funded by the Gates Foundation, Geneva Global, GSK, Wyeth, Merck, and

other private donors

Seattle Biomedical

Research Institute — SBRI

WWW.SBRI.ORG

Focus: Malaria, tuberculosis, HIV/

AIDS, trypanosomal diseases,

toxoplasmosis, candida, and

other infectious diseases

n Independent research institute focused on infectious diseases, particularly

malaria, HIV/AIDS, tuberculosis, human African trypanosomiasis, leishmaniasis,

and Chagas disease; founded in 1976

n Currently establishing, in collaboration with MVI, the Malaria Clinical Trials

Center, devoted to testing the safety and efficacy of malaria vaccines

n Annual budget of approximately $40 million

n $30.6 million awarded by NIH to fund Seattle Structural Genomics Center for

Infectious Disease



University of California,

San Francisco Sandler

Center

WWW.SANDLER.UCSF.EDU

Focus: Parasitic diseases

n A simulated pharmaceutical R&D division in which academic groups are

combined with managers from industry

n Maintains open-access “Low Hanging Fruit” Web site; a database of

FDA-approved drugs that have shown activity against T. brucei, L. donovani, and

S. mansoni

n Developed high throughput anti-parasitic screens; partnered with over 20

companies to identify drug leads for neglected tropical diseases

n One candidate for Chagas disease in IND-enabling studies and three in lead

optimization

n Supported by $20 million from the Sandler Foundation

University of Dundee

Tropical Disease Initiative

WWW.DRUGDISCOVERy.DUNDEE.

AC.UK/TROPICAL/OVERVIEW

Focus: Parasitic diseases

n A translational research and drug discovery center targeting human African trypanosomiasis and other neglected diseases

n Phenotypic and target-based screening capabilities; multiple projects in hit validation and hits-to-leads phase

n Aims to have at least one drug candidate ready for entry in formal preclinical development by 2011

n £15 million in funding over five years from the Wellcome Trust, the Wolfson Foundation, and other agencies

University of North

Carolina Consortium for

Parasitic Drug

Development — CPDD

Focus: Human African

trypanosomiasis, leishmaniasis,

and malaria

n Developed pafuramidine, an oral drug for early-stage human African

trypanosomiasis that failed in Phase III clinical trials in 2008; new compounds

for late-stage human African trypanosomiasis and visceral leishmaniasis are in

preclinical stage

n Consortium members include the University of North Carolina, Georgia State

University, the Swiss Tropical Institute, the London School of Hygiene and

Tropical Medicine, Ohio State University, the University of South Florida, the

University of Glasgow, Gorgas Memorial Institute (Panama), Kenya Agricultural

Research Institute, and Immtech Pharmaceuticals

n Has received over $60 million in funding from the Gates Foundation


Select Companies Working in Global Health


Highlights in Global Health R&D: New Incentives and Initiatives

Market Incentives n Priority Review Vouchers (PRVs): In September 2008, the FDA’s new PRV program went

into full effect. Sponsors obtaining FDA approval for a new biologic or chemical entity for

a neglected tropical disease are awarded a transferable PRV that reduces the FDA review

period for any other subsequent application to approximately six months. In April 2009,

Coartem®, an antimalarial drug launched by Novartis and MMV, received the first PRV.

n Advanced Market Commitment (AMC): In June 2009, the governments of Italy,

the United Kingdom, Canada, Russia, Norway, the Bill & Melinda Gates Foundation, and

GAVI Alliance partners World Bank, UNICEF, and the World Health Organization formally

launched the first AMC program. $1.5 million was pledged in October 2007 to encourage

industry investment in much-needed vaccines for the developing world. The first project

will focus on pneumococcal disease, which effects 1.6 million people each year.

US Government Initiatives

n National Institutes for Health’s Therapeutics for Rare Diseases Program:

In May 2009, the National Institutes for Health (NIH) announced a $120 million, five-year

program to advance pre-clinical research for rare and neglected diseases. The program

will enhance the drug development pipeline by absorbing some of the risk of early stage

development and encouraging new public-private partnerships.

n New Funding for NTDs: In February 2008, President Bush announced the formation of

a new, five-year, $350 million initiative to fund the control of seven key neglected tropical

diseases (six parasitic worm infections and trachoma).

n PEPFAR: In July 2008, the President’s Emergency Program for AIDS relief (PEPFAR) was

reauthorized by Congress for $48 billion over five years.

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New Financial Support for R&D

n Grand�Challenges�Explorations: In October 2007, the Gates Foundation announced

the new five-year, $100 million initiative to spur innovation in global health research.

$100,000 grants are awarded on the basis of a 2-page application; successful projects have

the opportunity to receive additional funding of $1 million or more. 104 Round 1 winners

were announced in October 2008. In May 2009, an additional 81 grants were announced.

Among the awardees were three biotech firms: Cupron, Inc., Osel and Sangamo BioSciences.

n Enteric�Vaccine�Initiative�(EVI): In October 2007, PATH received $50 million from the

Gates Foundation to form EVI, a public-private partnership aimed at developing new anti-

diarrheal vaccines.

New Private Sector Initiatives

n GlaxoSmithKline�Patent�Pool: In March 2009, GSK announced the creation of a

“patent pool” to provide third parties with access to GSK Intellectual Property. To catalyze

new efforts in R&D, GSK is providing access to small molecule pharmaceuticals to treat the

16 neglected diseases identified by the FDA.

n Celgene�Global�Health: In February 2009, Celgene announced the creation of Celgene

Global Health, a new group formed to apply Celgene’s science, technology, resources and

expertise towards developing solutions for major health problems in underdeveloped

countries.

n Vertex�Global�TB�Network: In mid-2008, Vertex Pharmaceuticals announced the

formation of a global collaboration aimed at advancing early-stage research into new

approaches for the treatment of tuberculosis. To date, Vertex has engaged the commitment

of multiple TB research organizations and over 60 researchers around the globe.

n Novartis�Vaccines�Institute�for�Global�Health: In February 2008, the non-profit

initiative was launched in Siena, Italy with the goal of discovering and developing vaccines

for the developing world. The institute’s initial focus will be on diarrheal diseases. Novartis

will pay for staff and running costs, and will seek additional external funding to cover

project costs.

New Research Centers

n HIV�Neutralizing�Antibody�Center: In September 2008, IAVI and the Scripps Research

Institute announced the establishment of a $30 million research center to develop

neutralizing antibodies, seen as a key component of an effective HIV preventative vaccine.

n Human�Challenge�Center: In March 2008, SBRI and MVI announced that they will open a

new $4.8 million center devoted to testing the safety and efficacy of malaria vaccine candidates

in humans. The first trial at the center is expected to take place in the summer of 2009.

n Seattle�Structural�Genomics�Center�for�Infectious�Disease: In December

2007, SBRI received a $30 million federal contract to house the bioinformatics center

aimed at determining the structure of significant pathogen proteins in vaccine, drug and

diagnostic design.

D I S E A S E B A C K G R O U N D E R S


Disease Sheets


Chagas Disease

BACKGRouND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

What Is Chagas Disease?Chagas disease, also called American trypanosomiasis, is a parasitic disease that through chronic infection causes damage to the nervous system, digestive tract, and the heart . Humans contract the disease when the infected feces of the insect vector enter the body, typically by scratching the insect bite .

Global BurdenIt is estimated that 8 million to 9 million people are currently infected, with 750,000 new cases and 14,000 deaths occurring each year . An additional 25 million people are at risk of infection .

Geographic DistributionChagas disease is prevalent in 18 countries within the Americas, ranging from Mexico to Argentina .

Causative Agent/TransmissionChagas disease is caused by the protozoan parasite Trypanosoma cruzi. It is transmitted to humans through the feces of blood-sucking insects known as triatomine bugs (also called “assassin” or “kissing” bugs) .

Transmission may also occur congenitally or via breast milk or blood transfusion . In its human host, the parasites invade and replicate inside many cell types . Pet dogs are an alternate mammalian host, whose proximity to humans thwarts efforts to break the chain of transmission . Chagas disease is most prevalent in rural areas and is linked to substandard housing . Thatched roofs and mud walls are especially prone to infestation by the insect vector . T. cruzi is related to the trypanosomes that cause human African trypanosomiasis and leishmaniasis .

PresentationChagas disease can be classified as acute or chronic .

The acute phase of the disease begins several days after infection . Most acute infections are asymptomatic, but some produce fever and swelling of the lymph nodes, spleen, liver, and the site of infection . The hallmark of the acute phase of Chagas disease is the swelling of the eyelids or the side of the face near the bite wound (Romaña’s sign) .

The chronic phase can last from months to decades and may also remain asymptomatic for long periods of time . Damage can eventually occur to the nervous system, the digestive system, and the heart . Cardiomyopathy, or damage to the heart’s muscle structure, is the leading cause of death .

TrendsThe number of deaths per year has decreased slightly in recent years . The WHO launched an eradication campaign in 2007 .

Countries endemic for Chagas disease (WHO, 2008)

Triatomine bugs often infest rural, substandard

housing (photo: CDC/WHO)

C H A G A S D I S E A S E


ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Drugs Vaccines DiagnosticsThere is no treatment for chronic

infections.n NIFuRTIMox�&�BENzNIDAzolE

– Cures at least 50 percent of

acute and short-term chronic

infections principally in children,

but has little to no impact on

long-term chronic infections

– Frequently causes side effects,

which can be severe

– Limited access

– High cost of treatment

– Shows signs of resistance

n None Current diagnostics cannot reliably detect

chronic disease or monitor effects of

treatment. n TcF-ElISA

– Sensitive and specific

– Low occurrence of leishmaniasis

cross-reactionsn uBI�MAGIWEl™�ElISA

– Detects antibodies (IgG) to T. cruzi

in human serum or plasman CHEMBIo�CHAGAS�STAT-PAK™

– Detects antibodies to T. cruzi

– Rapid test, no refrigeration required

NEW� PRoDuCT � NEEDS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Drugs Vaccines Diagnostics

n Effective against chronic diseasen Oral formulationn Short course of therapyn Pediatric formulations

n Preventive: long-term protection

against infectionn Therapeutic: treat the chronic phase

n Able to differentially diagnose the

presence and stage of diseasen Test of cure

PIPElINE nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

� Pre-� Clinical-�� Clinical-� Clinical-�Drugs� Discovery� Clinical� Phase�I� Phase�II� �Phase�III

DNDi/LAFEPE/University of Liverpool (pediatric benznidazole) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

DNDi/Eisai/Federal University of Ouro Preto (ravuconazole) nnnnnnnnnnnnnnnnnnnn

Sandler Center/NIAID/SRI International (cysteine protease inhibitors) nnnnnnnnnnnnnnnnnnnn

Schering-Plough Research Institute (posaconazole) nnnnnnnnnnnnnnnnnnnn

DNDi/GSK/STI (4[1H] pyridones and cysteine protease inhibitors) nnnnnnn

DNDi/CDCO/Epichem/Murdoch University (Chagas lead optimization consortium) nnnnnnn

DNDi/STI/Fiocruz and many others (nitroimidazoles) nnnnnnn

DNDi/Institut de Recherche pour le Développement (canthin-6-one alkaloids ) nnnnnnn

Genzyme/Fiocruz (target identification and screening) nnnnnnn

MARKET � oPPoRTuNIT IES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

n This is primarily a disease of the poor and will require donor support to encourage innovation .

C H A G A S D I S E A S E


DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn


n Clinical trials are likely to

be complicated by the slow

progression of the disease n In the chronic stage, organisms are

difficult to detect and damage occurs

over many (more than 15) years

n Clinical trials are likely to

be complicated by the slow

progression of the disease

n No biomarkers exist to

detect chronic diseasen Troponin, a marker for cardiac

damage that is elevated in late-

chronic-stage disease, cannot

differentiate between “no disease”

and the early chronic stage

ADDIT IoNAl � INFoRMATIoN nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

General Disease Linksn World Health Organization (WHO) ~ www .who .int/topics/chagas_disease/enn Centers for Disease Control and Prevention (CDC) ~ www .cdc .gov/ncidod/dpd/parasites/chagasdisease

Key Organizationsn Drugs for Neglected Diseases initiative (DNDi) ~ www .dndi .orgn Special Programme for Research and Training in Tropical Diseases (TDR) ~ www .who .int/tdr

Important Papersn Bustamante, JM, et al . Drug-induced cure drives conversion to a stable and protective CD8+ T central memory

response in chronic Chagas disease . Nature Med 14:542-50 (2008)n De Souza, W . From the cell biology to the development of new chemotherapeutic approaches against

trypanosomatids: Dreams and reality . Kinetoplastid Biol Dis 1:3 (2002) n El-Sayed, NM, et al . The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease . Science

309:409-15 (2005) n El-Sayed, NM, et al . Comparative genomics of trypanosomatid parasitic protozoa . Science 309:404-9 (2005) n Hucke, O, et al . The protein farnesyltransferase inhibitor Tipifarnib as a new lead for the development of drugs

against Chagas disease . J Med Chem 48:5415-18 (2005) n Tarleton, RL, et al . The challenges of Chagas disease—grim outlook or glimmer of hope? PLoS Med 4:e332 (2007)


Cholera


What Is Cholera?Cholera is an acute bacterial intestinal infection with a short incubation period, typically one to five days . Cholera causes watery diarrhea and vomiting that can lead to severe dehydration and death in less than 24 hours if not treated promptly . In areas where cholera is endemic, the disease mainly affects children .

Global BurdenIn 2004, the WHO reported that 101,383 cases of cholera occurred in 56 countries resulting in 2,345 deaths . Case-fatality rates in epidemic conditions can exceed 40 percent, making cholera prevention a major public health objective .

Geographic DistributionThe majority of cases currently occur in sub-Saharan Africa and Southeast Asia, but distribution varies . During 2004, major outbreaks occurred in Cameroon, Chad, Guinea, Mali, Niger, Senegal, and Zambia .

Causative Agent/TransmissionCholera is caused by ingestion of food or water contaminated with the bacterium Vibrio cholerae . Most sudden, large outbreaks are linked to a contaminated water supply . Rarely, cholera can be transmitted by direct person-to-person contact . Until 1992, the only known cholera agent was Vibrio cholerae O1, but in that year a new serogroup, O139, was observed and found to be the cause of several epidemics in Asia .

PresentationV. cholerae produces an enterotoxin that induces the intestine to release fluid, causing abundant, watery diarrhea that can quickly lead to severe dehydration . Frequent vomiting can exacerbate dehydration . If the dehydration is not addressed, cholera can be fatal . Most healthy people have the ability to fight a cholera infection without manifesting symptoms; however, about 10 percent of those infected develop severe disease .

Trends Cholera remains a global threat and one of the key indicators of low development level . It is a particularly dangerous problem in places with limited access to clean water . Most developing countries are at risk for cholera outbreaks .

Current vaccines do not protect against O139 . The Institut Pasteur cautioned in 2003 that this new strain “may well become the origin of an eighth cholera pandemic .”

Countries with reported endemic cholera cases,

2004-2007 (WHO, 2008)

Vibrio cholerae serogroup O1

(photo: CDC/Janice Carr)

C H O L E R A




n PAllIATIVE�CARE

− Oral rehydration therapy is

used to treat symptoms

− Antibiotics and intravenous fluids

are sometimes given in severe cases

n FIRST-GENERATIoN�VACCINES��

(INCluDING�DuKoRAl®)

− Oral delivery

− Protection ranges from three

months to two years

− Some require multiple doses for

efficacy; efficacy can be as low as

61 percent

− Licensed in some countries but

mainly available to travelers

− Ineffective against O139 strain

n RAPID�DIAGNoSTIC�DIPSTICK�TEST

− Relies on immunochromatography

to detect the presence of O1 and

O139 lipopolysaccharides



n High-potency antibiotic n Single-dose, oral vaccinen Bivalent against O1 and O139 choleran Provides long-term protection

(more than 2 years) to infants

and young children

n Ability to differentiate between

cholera and other diarrheal pathogensn Rapid test to ensure quick

response in an epidemic


� Pre-� Clinical-�� Clinical-� Clinical-�Vaccines� Discovery� Clinical� Phase�I� Phase�II� �Phase�III

IVI/National Institute of Cholera & Enteric Diseases, India/ nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Shantha Biotechnics/VaBiotech (ORC-Vax®: oral, killed, bivalent)

Celldex/IVI (CholeraGarde®: oral, live, attenuated) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Finlay Institute, Cuba (strain 638: oral, live, attenuated) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Celldex/NIAID (oral, cholera-ETEC combination vaccine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn


n Potential commercial opportunities for vaccines through military and travelers’ applications .



n Need to overcome antibiotic resistance n Difficulties in conjugate developmentn Specifications for travelers’

and military markets may differ

from endemic markets

n None

C H O L E R A



General Disease Linksn World Health Organization (WHO) ~ www .who .int/topics/cholera/enn Centers for Disease Control and Prevention (CDC) ~ www .cdc .gov/ncidod/dbmd/diseaseinfo/cholera_g .htm

Key Organizationsn International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) ~ www .icddrb .org/pubn WHO Initiative for Vaccine Research (IVR) ~ www .who .int/vaccine_research/en

Important Papersn Lucas, MES, et al . Effectiveness of mass oral cholera vaccination in Beria, Mozambique . NEJM 352:757-67 (2005)n Mahalanabis, D, et al . A randomized, placebo-controlled trial of the bivalent killed, whole-cell, oral cholera

vaccine in adults and children in a cholera endemic area in Kolkata, India . PLoS One 3:e2323 (2008)n Sack, DA, et al . Cholera . Lancet 363:223-33 (2004)


Dengue Fever (DF)


What Is Dengue Fever?Dengue fever (DF) is a viral, mosquito-borne disease that can cause severe, flu-like symptoms with high fever and extreme muscle and joint pain . Dengue hemorrhagic fever (DHF), a more dangerous form of the disease associated with increased blood vessel permeability, can be fatal .

Global BurdenThere are an estimated 50 million new dengue infections each year, and more than 2 .5 billion people are at risk for the disease . Approximately 500,000 cases of DHF require hospitalization each year, the majority of whom are children, resulting in more than 20,000 deaths . Without proper treatment, DHF case fatality rates can exceed 20 percent .

Geographic DistributionDF is endemic in 100 countries throughout the Americas, Southeast Asia, the Western Pacific Islands, Africa, and the eastern Mediterranean . Southeast Asia and the Western Pacific are most seriously affected . Dengue cases have also been reported in Hawaii, Texas, and Puerto Rico .

Causative Agent/TransmissionThe dengue virus is a member of the family Flaviviridae, which includes the viruses that cause yellow fever, Japanese encephalitis, and West Nile disease . There are four known serotypes . The viruses are transmitted by Aedes aegypti mosquitoes, subgenus Stegomyi.

PresentationDF is a severe, incapacitating, flu-like illness that affects infants, young children, and adults, but seldom causes death . In older children and adults, DF symptoms include sudden onset of high fever, severe headache, muscle and joint pain, and rash . With palliative care, these symptoms typically resolve within weeks, but complete convalescence may require additional time .

Less than 1 percent of patients infected with dengue develop DHF, which is characterized by low platelet counts and blood iron imbalance that may be accompanied by bleeding, enlarged liver, and circulatory failure . Without proper treatment, DHF case fatality rates can exceed 20 percent . However, modern intensive supportive therapy such as intravenous fluid

replacement can reduce case fatality rates to less than 1 percent .

Exposure to one dengue serotype provides permanent immunity against that serotype, but subsequent infections by a different serotype increase the likelihood that the patient will develop DHF .

TrendsDue to the deforestation, development, and urbanization of tropical regions, breeding grounds for A. aegypti have expanded . As a result, human-vector contact has increased, and infection rates are on the rise .

The A. aegypti habitat is not limited to the developing world, and dengue cases have recently occurred in Puerto Rico, Singapore, Hawaii, and the southern United States .

A dengue epidemic in Brazil that started in early 2008 caused over 55,000 infections over four months in Rio de Janeiro alone .

Countries with areas of dengue risk (WHO, 2007)

Aedes aegypti, the vector for dengue fever

(photo: CDC/James Gathany/Frank Collins)

D E N G U E F E V E R


ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn�


n PAllIATIVE�CARE

– Intravenous fluid replacement

can be used for rehydration

− Acetaminophen can be used

to manage pain and fever

n None n PANBIo�RAPID�TESTS

− Dengue Duo Cassette and Dengue

Duo IgM and IgG Rapid Strip Test

(For differentiation between primary

and secondary dengue infection)n PANBIo�ElISAS

− Dengue IgG Indirect ELISA (For

detecting past/active dengue infection)

− Dengue IgM and IgG Capture

ELISAs (For diagnosis of

primary and secondary dengue

infection, respectively)



n Oral formulationn Rapid-actingn Ameliorates symptoms n Prevents DHF

n Single- or two-dose tetravalentn Provides extended protectionn Safe and effective in young childrenn Effective against all four serotypes

n Ability to diagnose initial

stage of disease, to distinguish

between serotypes, and to

distinguish from other fevers



Novartis Institute for Tropical Diseases (inhibitors of viral and host targets) nnnnnnn

SIGA (ST 981, ST 610, ST 689, and ST 562) nnnnnnn


Acambis/Sanofi-Pasteur (ChimeriVax™-Dengue: live, chimeric tetravalent) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

GSK/WRAIR (live, attenuated tetravalent) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

NIAID/JHU/Biologics(E)/Panacea/Butantan nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(monovalent, live, attenuated intertypic chimeric)

GenPhar/NMRC (flavivirus-based recombinant DNA vaccine, tetravalent) nnnnnnnnnnnnnnnnnnnn

InViragen/Shantha Biotechnics/CDC/PDVI nnnnnnnnnnnnnnnnnnnn

(DENVax: live, attenuated chimeric tetravalent)

Hawaii Biotech/PDVI (recombinant protein, tetravalent) nnnnnnnnnnnnnnnnnnnn

WRAIR (whole virus, inactivated) nnnnnnnnnnnnnnnnnnnn


n Potential markets for travelers to endemic regions and for people living in developed world areas where A. aegypti can be found . The range of dengue is expanding into areas such as Singapore and the southern United States .

n Military market; biodefense vaccines can qualify for FDA fast-track approval .n Largest market for dengue vaccines is in the endemic areas of the tropics (over 4 billion people at risk in Latin

America, Asia, and perhaps Middle East/Africa) .

D E N G U E F E V E R ( D F )

D E N G U E F E V E R




n Developing an antiviral that is

effective once infection has occurred

n Developing a tetravalent vaccine

effective against all four serotypes

n Serologic tests only detect antibodies

to dengue late in infection


General Disease Linksn World Health Organization (WHO) ~ www .who .int/topics/dengue/enn Centers for Disease Control and Prevention (CDC) ~ www .cdc .gov/ncidod/dvbid/dengue

Key Organizationsn Genome Institute of Singapore and Novartis Institute for Tropical Diseases ~ http://dengueinfo .org/NITD/ n Pediatric Dengue Vaccine Initiative (PDVI) ~ www .pdvi .orgn Special Programme for Research and Training in Tropical Diseases (TDR) ~ www .who .int/tdrn WHO Initiative for Vaccine Research (IVR) ~ www .who .int/vaccine_research/en

Important Papersn Blaney, JE, Jr ., et al . Recombinant, live-attenuated tetravalent dengue virus vaccine formulations induce a

balanced, broad, and protective neutralizing antibody response against each of the four serotypes in rhesus monkeys . J Virol 79:5516-28 (2005)

n Edelman, R . Dengue and dengue vaccines . J Infect Dis 191:650-3 (2005)n Guirakhoo, F, et al . Live attenuated chimeric yellow fever dengue type 2 (ChimeriVax™-DEN2) vaccine:

Phase I clinical trial for safety and immunogenicity: Effect of yellow fever pre-immunity in induction of broad neutralizing antibody responses to all 4 dengue serotypes . Human Vaccines 2:60-7 (2006)

n Monath, TP . Dengue and yellow fever—challenges for the development and use of vaccines . NEJM 357:2222-5 (2007)

n Wilder-Smith, A, and Schwartz, E . Dengue in travelers . NEJM 353:924-32 (2005)

D E N G U E F E V E R ( D F )


Enterotoxigenic E. coli (ETEC)


What Is Enterotoxigenic E. coli?Enterotoxigenic E. coli (ETEC), a virulent strain of the bacterium Escherichia coli, is a major cause of severe diarrhea leading to hospitalization . Infection by this bacterium is a leading killer of children in the developing world .

Global BurdenEach year an estimated 300 million to 400 million new infections of ETEC result in 400,000 to 500,000 deaths . Ninety percent of these deaths occur in lower income countries . ETEC is a major cause of childhood diarrhea; most fatal cases occur in children under the age of two . ETEC is also the leading cause of travelers’ diarrhea .

Geographic DistributionETEC cases are reported worldwide; incidence rates are highest in Central and South America, Africa, and Southeast Asia .

Causative Agent/TransmissionE. coli is a bacterium with numerous serotypes, most of which normally inhabit the human intestinal tract with little ill effect . Several strains,

however, secrete toxins that act on the intestinal lining and cause disease . E. coli that cause diarrheal illness can be broken down into four categories based on virulence mechanism: enterotoxigenic (ETEC), enteropathogenic (EPEC), enteroinvasive (EIEC), and enteroaggregative (EAggEC) . ETEC is transmitted through food or water contaminated with human or animal feces .

PresentationToxins released by gut-colonizing ETEC cause water and salts to be lost into the intestine, resulting in watery diarrhea, abdominal cramping, fever, and vomiting . Death is caused by extreme dehydration .

TrendsThe disease burden associated with ETEC and other diarrheal infections remains enormous across all developing countries . ETEC is also a concern for travelers visiting the developing world .

Although ETEC can be treated with antibiotics, the most effective drugs are prohibitively expensive . Misuse of antibiotics has led to drug-resistant ETEC strains .

Countries at high risk for travelers’ diarrhea

(CDC, 2007)

One strain of E. coli (photo: CDC/Janice Carr)

E N T E R O T O x I G E N I C E . C O L I




n PAllIATIVE�CARE

− Oral rehydration therapy can

be used to treat symptoms



n Dukoral® is a cholera vaccine that

has shown 60 percent short-term

efficacy against travelers’ diarrhea n No product exists to vaccinate

people in endemic regions

n None



n High-potency antibiotic n Oral deliveryn Multivalentn Provide extended protection to

infants and young children


ETEC and other causes of

diarrhea, including protozoa

PIPElINE nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn��


Intercell (LT transcutaneous patch) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Center for Vaccine Development at University of Maryland nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(CVD 1208: oral, attenuated Shigella expressing ETEC antigens)

Ace BioSciences/PATH Enteric Vaccine Initiative nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(Ace527: live, attenuated recombinant E. coli expressing LTB)

Celldex/NIAID (attenuated cholera expressing CTB and ETEC antigen CFA/I) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

MIDRP (SC608: attenuated S. flexneri w/ETEC Cfab component of CFA/I and LTB) nnnnnnnnnnnnnnnnnnnn

NICHD/Robbins (O-LT/ST: LT-ST toxoid conjugated to O antigen) nnnnnnnnnnnnnnnnnnnn

Göteborg University (killed, whole-cell ETEC expressing CFA/I, CS1-5, and rCTB-LTB) nnnnnnnnnnnnnnnnnnnn

MIDRP (fimbrial tip adhesion antigens) nnnnnnnnnnnnnnnnnnnn

Emergent Europe (Spi-VEC ETEC: S. typhi vector expressing LTB nnnnnnnnnnnnnnnnnnnn

and other ETEC antigens)


n Surveys indicate that individuals across low- and middle-income countries would be willing to pay one-half to one day’s wage for a vaccine on the private market .

n Moderate financial case for investment: – Market may be sufficient to attract innovators (nearly $400 million peak annual) – Market driven by travelers, military, and middle-income populations – More robust travelers’ market could boost revenue an additional $200 million per year

E N T E R O T O x I G E N I C E . C O L I ( E T E C )

E N T E R O T O x I G E N I C E . C O L I




n Need to overcome antibiotic resistance n Multiple strains make it difficult

to design a multivalent vaccine

with sufficient coveragen Certain major cell-surface markers

are not immunogenic, making them

poor candidates for vaccinesn Specifications for travelers’



n None


General Disease Linksn World Health Organization (WHO) ~ www .who .int/vaccine_research/diseases/e_e_coli/enn Centers for Disease Control and Prevention (CDC) ~ www .cdc .gov/ncidod/dbmd/diseaseinfo/etec_g .htm

Key Organizationsn International Centre for Diarrheal Disease Research, Bangladesh (ICDDR,B) ~ www .icddrb .org/pubn PATH Enteric Vaccine Initiative (EVI) ~ www .path .org/projects/enteric_vaccine

Important Papersn Qadri, F, et al . Enterotoxigenic Escherichia coli in developing countries: Epidemiology, microbiology, clinical

features, treatment, and prevention . Clin Microbiol Rev 18:46-83 (2005)n Qadri, F, et al . Reduced doses of oral killed enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine is

safe and immunogenic in Bangladeshi infants 6-17 months of age: Dosing studies in different age groups . Vaccine 24:1726-33 (2006)

n Walker, RI . Considerations for development of whole-cell bacterial vaccines to prevent diarrheal diseases in children in developing countries . Vaccine 23:3369-85 (2005)

E N T E R O T O x I G E N I C E . C O L I ( E T E C )


Human African Trypanosomiasis (HAT)


What Is Human African Trypanosomiasis?Human African trypanosomiasis (HAT), also known as sleeping sickness, is caused by a single-celled parasitic protozoan called a trypanosome and is transmitted by tsetse flies . The disease progresses from fever and fatigue to severe neurological conditions . Untreated HAT results in death .

Global BurdenThere are 60 million people at risk worldwide . Each year, there are an estimated 10,000 to 50,000 deaths .

Geographic DistributionHAT is found in 36 countries in sub-Saharan Africa, but the vast majority of cases occur in just three countries: Angola, the Democratic Republic of the Congo, and Sudan .

Causative Agent/TransmissionHAT is caused by Trypanosoma brucei, a protozoan parasite transmitted to humans by the bite of an infected tsetse fly . There are several subspecies of T. brucei; T.b. gambiense, found in Central and West Africa, causes

chronic disease, and T.b. rhodesiense, present in South and East Africa, causes acute disease . The cattle reservoir for T.b. rhodiense has proved to be a barrier for disease control . T. brucei is related to the trypanosomes that cause Chagas disease and leishmaniasis .

PresentationT. brucei parasites first develop in the blood, lymph, and peripheral organs (stage 1) and then cross the blood-brain barrier and enter the central nervous system (stage 2) . Stage 2 is characterized by severe neurological disorders

including extreme fatigue, major disturbances to patients’ sleep cycle (hence “sleeping sickness”), and coma . Without treatment, the disease is always fatal .

TrendsBy the 1960s, aggressive surveillance and programs to eradicate tsetse flies resulted in the near disappearance of the disease . Subsequently, control measures were relaxed, tsetse populations recovered, and HAT rebounded . Since the WHO made HAT a priority in 1995, improved HAT control has caused a 68 percent reduction in cases, as of 2006 .

(Simarro et al. PLoS NTD5:e55 [2008])

T. brucei parasites in a patient’s blood smear

(photo: CDC/Myron Schultz)

H U M A N A F R I C A N T R y P A N O S O M I A S I S








Current treatments have variable efficacy,

are prohibitive to deliver (pentamidine

is delivered by parenteral injection; all

others are administered intravenously),

and can be highly toxic.n PENTAMIDINE

– Treats stage 1 T.b. gambiense infection

(ineffective against stage 2 HAT)

– Side effects are raren SuRAMIN

– Treats stage 1 T.b. rhodesiense

infection (ineffective

against stage 2 HAT)

– Side effects can be severen MElARSoPRol�(ARSENIC�DERIVATIVE)

– Treats stage 2 HAT

– Side effects are frequent and severe;

results in reactive encephalopathies

in 5 to 10 percent of treated cases

– Showing evidence of resistancen EFloRNITHINE�(DFMo)

– Treats stage 2 HAT; effective only

against T.b. gambiense infection

– Side effects are numerous

and can be severe

– Requires hospital administration

– Highly effective, but costs are

high and supply is unreliable

n None There are no rapid, easy-to-use, serological

point-of-care diagnostic tests available.

As a result, patients are not typically

diagnosed until the late stage of the

disease. n CASE�DETECTIoN

– Blood smear for T.b. rhodesiense

(sensitive) or T.b. gambiense

(less sensitive)

– Card indirect agglutination test

(CATT) for T.b. gambiensen STAGING

– Microscopy on cerebral spinal

fluid following lumbar puncture



n Reduced toxicityn Efficacy against T. gambiense

and T. rhodesiensen Efficacy against stage 1

and stage 2 diseasen Must cross blood-brain barrier in

order to eliminate central nervous

system infection in stage 2 disease

n Vaccines not targeted n Distinguishes between stage 1 and

stage 2 disease (treatment choice

depends on whether or not there is

central nervous system involvement)n Test of cure


H U M A N A F R I C A N T R y P A N O S O M I A S I S ( H A T )




Discovery� Pre-� Clinical-� Clinical-� Clinical-�Drugs� � Clinical� Phase�I� Phase�II� Phase�III

DNDi/Epicentre/MSF/Democratic Rep. of the Congo/Rep. of the Congo/STI nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(nifurtimox-eflornithine) (completed 11/2008)

DNDi/Accelera/STI/Axyntis/Covance/Aptuit/KARI (fexinidazole) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Consortium for Parasitic Drug Development (DB series) nnnnnnnnnnnnnnnnnnnn

Dafra Pharma (DF-051) nnnnnnn

DNDi/Scynexis/Pace University (HAT consortium for lead optimization) nnnnnnn

DNDi/STI/Fiocruz and many others (nitroimidazoles) nnnnnnn

DNDi/Epichem/Murdoch University (microtubule inhibitors) nnnnnnn

DNDi/GSK/STI (4(1H) pyridones and cysteine protease inhibitors) nnnnnnn

DNDi/Kitasato Institute (screening: natural products) nnnnnnn

DNDi/Central Drug Research Institute (screening) nnnnnnn

DNDi/Eskitis Institute (screening: natural products) nnnnnnn

University of Dundee Tropical Disease Initiative (screening) nnnnnnn

Sandler Center (kinase inhibitors) nnnnnnn

Discovery� � Preclinical�� Clinical�Diagnostics� � � � � �

Nucleic�acid�detection

FIND/Murdoch University/Obihiro University/Eiken Chemical Corp nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(loop-mediated isothermal amplification of DNA)

Antibody�or�antigen�detection

FIND/MicroCoat (serologic dx: T. b. gambiense) nnnnnnn

FIND/University of Technology (Germany) (RNA aptamers) nnnnnnn

FIND/SBRI (optimized antibody probes) nnnnnnn

FIND/University of Brussels (nanobodies) nnnnnnn

Disease�staging

FIND/Inst. of Tropical Medicine/Royal Tropical Institute nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(IgM quantification; ‘dri-dot’ single format test)

FIND/Aberdeen University (blood markers) nnnnnnn

FIND/University of Geneva/Inst. of Tropical Medicine/Makerere Univ. (biomarkers) nnnnnnn


n Primarily a disease of impoverished rural communities and will require donor support to encourage innovation .








n Eradication of central nervous system

infection is difficult to confirm

(only a few residual organisms are

needed for infection to recur)

n T. brucei undergo extensive antigenic

variation, which presents significant

obstacles to vaccine development

n Serum biomarkers that correlate

with stage 2 disease have only

recently been identified

� ADDIT IoNAl � INFoRMATIoN nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

General Disease Linksn World Health Organization (WHO) ~ www .who .int/topics/trypanosomiasis_african/enn Centers for Disease Control and Prevention (CDC) ~ www .cdc .gov/ncidod/dpd/parasites/trypanosomiasis

Key Organizationsn Drugs for Neglected Diseases Initiative (DNDi) ~ www .dndi .orgn Foundation for Innovative New Diagnostics (FIND) ~ www .finddiagnostics .orgn Special Programme for Research and Training in Tropical Diseases (TDR) ~ www .who .int/tdrn University of Dundee, Tropical Disease Initiative ~ www .drugdiscovery .dundee .ac .uk/tropical/overview/

Important Papersn Berriman, M, et al . The genome of the African trypanosome Trypanosoma brucei . Science 309:416-22 (2005) n El-Sayed, NM, et al . Comparative genomics of trypanosomatid parasitic protozoa . Science 309:404-9 (2005) n Legros, D, et al . Treatment of human African trypanosomiasis—present situation and needs for research and

development . Lancet Infect Dis 2:437-40 (2002) n Njiru, ZK, et al . Loop mediated isothermal amplification (LAMP) method for rapid detection of Trypanosoma brucei

rhodesiense . PLoS NTD. 2:e147 (2008) n Renslo, AR, and McKerrow, JH . Drug discovery and development for neglected parasitic diseases . Nature Chemical

Biology 2:701-10 (2006) n Simarro, P, et al . Eliminating human African trypanosomiasis: Where do we stand and what comes next? PLoS

Med 5:e55 (2008)



Human Hookworm Infection


What Is Human Hookworm Infection?Human hookworm infection is a parasitic disease caused by soil-dwelling nematodes . Whereas light infections may be asymptomatic, heavy infections may cause anemia, diarrhea, abdominal pain, weight loss, and loss of appetite .

Global BurdenAn estimated 576 million people are infected with hookworm, and approximately 3 billion people are at risk for acquiring the infection .

Geographic DistributionThe largest number of cases occurs in impoverished rural areas of sub-Saharan Africa (198 million cases), Southeast Asia (59 million), India (71 million), and tropical regions of the Americas (50 million) .

Causative Agent/TransmissionHookworm infection is caused by the parasitic nematodes Necator americanus and Ancylostoma duodenale. N. americanus is found in the Americas, sub-Saharan Africa, Southeast Asia, China, and Indonesia and is the more prevalent cause of infection; A. duodenale is geographically

restricted to the Middle East, North Africa, and India . Hookworms hatch in soil and mature through three larval stages . Upon contact with humans, larvae penetrate the skin, enter the blood stream, and eventually migrate into the lung trachea, where they are swallowed into the stomach . They then travel through the digestive tract to the small intestine where, over five to nine weeks, they feed on blood components and mature into adult worms that are approximately one centimeter in length . Adult females lay eggs, which are released in feces into the environment, reinitiating the cycle of infection .

PresentationTo feed, hookworms attach to the walls of the small intestine, resulting in host blood loss and injury to the mucosa . In children, chronic disease causes iron-deficiency anemia, which impairs physical and cognitive development . In expectant mothers, severe infection results in adverse outcomes for both mother and child, including low birth weight, impaired milk production, and increased risk of death .

TrendsCurrently, human hookworm infection is treated by deworming with the drugs, and deworming programs are a crucial component of hookworm control programs . Many control programs, however, are school-based, which limits their ability to reach adults and the elderly . Also, drug

treatment has variable efficacy, and with frequent and repeated use, there are concerns that drug resistance may develop . Moreover, re-infection occurs rapidly post-treatment, especially in areas of high transmission where it can occur within four to 12 months .

Countries with areas endemic for hookworm

infection (SVI, 2005)

A hookworm in its immature, noninfectious stage

(photo: CDC)

H U M A N H O O K W O R M I N F E C T I O N

BVGH Global Health Primer 4747 BVGH Global Health Primer BVGH Global Health Primer 47


Drugs Vaccines Diagnosticsn AlBENDAzolE,�MEBENDAzolE,�

oR�PyRANTEl�PAMoATE

– Low efficacy (mebendazole),

rapid reintroduction,

resistance, limited access

n None commercially available n Microscopic examination

of feces for eggs



n New class of drugs to counter

inevitable rise of resistancen Drugs that offer long-lasting

protection in order to break

the chain of transmission

n Prevent hookworm disease due to

infection with Necator americanus, the

most prevalent hookworm worldwide

n Low-cost, simple test on feces to

diagnose hookworm infection


Discovery� Pre-� Clinical-�� Clinical-� Clinical-�Vaccines� � Clinical� Phase�I� Phase�II� �Phase�III

SVI-HHVI (Na-ASP-2 hookworm vaccine: recombinant antigen) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

SVI-HHVI (Na-APR-1 hookworm vaccine: recombinant antigen) nnnnnnnnnnnnnnnnnnnn


n Because hookworm occurs almost exclusively among the estimated 2 .7 billion people who survive on incomes of less than $2 per day, there is no commercial market for a vaccine targeting hookworm . To be effective, such a vaccine must be manufactured and distributed for less than $1 a dose, and possibly even much less . The SVI-HHVI has developed a unique Global Access Strategy to ensure that an eventual vaccine is made available to those affected at extremely low cost .



n New targets have not been defined n A highly efficacious vaccine that

protects against a multicellular

organism has never before been maden Access to adjuvants to

increase immunogenicity

n Potential cross-reactivity with

other helminth infections

H U M A N H O O K W O R M I N F E C T I O N



General Disease Linksn World Health Organization (WHO) ~ www .who .int/vaccine_research/diseases/soa_parasitic/en/index2 .htmln Centers for Disease Control and Prevention (CDC) ~ www .cdc .gov/ncidod/dpd/parasites/hookworm

Key Organizationsn SVI-Human Hookworm Vaccine Initiative (SVI-HHVI) ~ http://sabin .org/programs/hhvi/index .html

Important Papersn Asojo, OA, et al . X-ray structures of Na-GST-1 and Na-GST-2 two glutathione s-transferase from the human

hookworm Necator americanus . BMC Structural Biology 7:42 (2007)n Bethony, J, et al . Antibodies against a secreted protein from hookworm larvae reduce the intensity of hookworm

infection in humans and vaccinated laboratory animals . FASEB J 19:1743-5 (2005)n Bethony, JM, et al . Randomized, placebo-controlled, double-blind trial of the Na-ASP-2 hookworm vaccine in

unexposed adults . Vaccine 26:2408-17 (2008)n Diemert, DJ, et al . Vaccines: Hookworm vaccines . Clin Infect Dis 46:282-8 (2008) n Loukas, A, et al . Vaccination with recombinant aspartic hemoglobinase reduces parasite load and blood loss after

hookworm infection in dogs . PLoS Med 2:e295 (2005)n Loukas, A, et al . Hookworm vaccines: Past, present, and future . Lancet Infect Dis 6:733-41 (2006)


Human Immunodeficiency Virus (HIV)


What Is HIV?HIV is a retrovirus that causes acquired immunodeficiency syndrome (AIDS), a syndrome characterized by progressive deterioration of the immune system . HIV/AIDS patients are at risk for opportunistic infections because of their diminished immune function, which may eventually lead to their death .

Global BurdenAt the end of 2007, it was estimated that 33 .2 million people worldwide were infected with HIV . There were approximately 2 .1 million AIDS deaths, and another 2 .5 million people were newly infected with HIV . Young people between the ages of 15 and 24 now account for almost half of all the new infections . Young women are especially vulnerable, with prevalence rates being as high as four times those for young men of the same age .

Geographic DistributionHIV/AIDS is a worldwide pandemic . Nearly two-thirds of those living with HIV/AIDS are located in sub-Saharan Africa . Southern Africa has

been hardest hit; in several countries, the prevalence of HIV exceeds 30 percent of the adult population . Although the prevalence of HIV in South and Southeast Asia is much lower than in Africa, its huge population makes it second to Africa in terms of the total number of individuals infected .

Causative Agent/TransmissionHIV is spread by exposure to infected body fluids including blood, semen, and breast milk . The major routes of transmission are by sexual contact, through contaminated needles, and from infected mother to child in utero, at birth, or through breastfeeding .

HIV mutates rapidly, and today patients are infected by many different strains . Most broadly, HIV can be classified as HIV-1 or HIV-2 . HIV-1 is more virulent than HIV-2, causes the majority of infections, and can be divided into several distinct groups, which are themselves divided into subtypes, or clades, that display distinct geographic infection patterns . Treatment is more complicated in regions where more than one clade is circulating because hybrid strains can arise .

PresentationClinical diagnosis of HIV infection is complicated by the lack of specific symptoms . Two to four weeks after infection, patients may display flu-like symptoms accompanied by a rash and fever . However, many patients are initially asymptomatic . Although the incubation period between infection and onset of AIDS is often cited as seven to 10 years,

disease course is accelerated in low- and middle-income countries due to environmental factors including burden of disease and nutrition . Once a patient develops AIDS (as defined as a CD4 lymphocyte count of <200 cells/µL), the disease is characterized by decreased immune functioning and an extreme susceptibility to opportunistic infections .

TrendsThe HIV/AIDS epidemic has spread rapidly and is now considered a global pandemic . More than 95 percent of all new infections occur in people living in low- and middle-income countries . There is some good news—since 2000, worldwide, the percentage of people living with HIV/AIDS has stabilized . Due to the success of antiretroviral (ARV) treatment programs in prolonging life combined with new infections, however, the total number of individuals infected with HIV continues to rise . Resistance to ARVs is common and transmission of HIV strains resistant to one or multiple drugs has been documented and appears to be increasing .

HIV affects countries all over the world (WHO)

The tiny spheres in this micrograph are the HIV

virus budding from the surface of a lymphocyte

(photo: CDC/C. Goldsmith)

H U M A N I M M U N O D E F I C I E N C y V I R U S ( H I V )




n CoMBINATIoN�AND�HIGHly�ACTIVE�

ANTIRETRoVIRAl�THERAPy�(HAART)

− Composed of a combination

of anti-HIV drugs

− There are three major groups of

anti-HIV drugs, consisting of more

than 20 approved medications

− Side effects and drug resistance

can be significant issues

− Although older, less expensive

antiretrovirals are increasingly

available, the latest treatments

remain out of reach for many

in the developing world

− Current drugs reduce viral load,

but do not cure the disease and

must be taken indefinitely

n None Current technologies do not provide an

inexpensive point-of-care test by which

to direct treatment.n HIV�ENzyME�IMMuNoASSAy�

&�WESTERN�BloT�ASSAy

− Detects antibodies to HIV in serum,

plasma, oral fluid, dried blood, or urinen oRAQuICK®�ADVANCE™�

HIV-1/2�ANTIBoDy�TEST

− First oral fluid rapid HIV test

− Can be used on oral fluid, plasma,

fingerstick, and venipuncture

whole blood specimensn CHEMBIo�STAT-PAK™�&�SuRE�CHECK®�

ASSAyS�AND�DIPSTICK�TESTS

− Simple, sensitive, and specific

− Room-temperature storage



n New fixed-dose combinationsn Specific pediatric formulationsn Low-cost, effective, easy-to-use

first- and second-line treatmentsn Combinations that could be used

for pre-exposure prophylaxis

n Preventative vaccine that offers long-

term protection against multiple clades

n Test to diagnose infection in infants

less than 18 months of agen Point-of-care test that quantifies

viral load and CD4 count and

indicates when to start treatment

and when to switch treatment

in children and adults



PIPElINE* nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn


Sanofi-Pasteur/ANRS (ALVAC-vCP1521: canary pox vector) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

GeoVax/NIAID (prime: Gag, Pol, Env DNA, boost: MVA expressing Gag, Pol, Env) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Bavarian Nordic (MVA-BN® multiantigen) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

EuroVacc Foundation/GENEART (DNA-C + NyVAC-C) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Muhimbili University/Karolinska Institute/Swedish Institute for Infectious nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Disease Control/Vecura/USMHRP (prime: HIVIS DNA, boost: MVA-CMDR)

Aaron Diamond AIDS Research Center/IAVI and others (ADVAx and TBC-M4) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

GSK (recombinant prophylaxis) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

St. Jude’s/NIH (PolyEnv1, EnvDNA, EnvPro) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

GenVec/NIH (VRC-HIVADV014-00-VP) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Crucell/NIAID (Ad26.ENVA.01) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

WRAIR (MVA-CDMR) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

South African AIDS Vaccine Initiative (DNA C-2) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

St. George’s University, London, and others (HIV gp140 + adjuvants) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

University of Pennsylvania (PENNVAx-B; DNA plasmids) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

University of South Wales (prime: pHIS-HIV-AE; boost: rFPV-HIV-AE ) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Moscow Institute of Immunology (VICHREPOL with adjuvant) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Wyeth/NIAID (various DNA and peptide vaccines) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Guangxi CDC (multiclade HIV-1 DNA vaccine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

AlphaVax/NIAID (multigene) nnnnnnnnnnnnnnnnnnnn

Novavax (VLP HIV-1) nnnnnnnnnnnnnnnnnnnn

Novartis/NIH (preventive vaccine) nnnnnnnnnnnnnnnnnnnn

� Pre-� Clinical-�� Clinical-� Clinical-�Microbicides� Discovery� Clinical� Phase�I� Phase�II� �Phase�III

Indevus/MRC/DFID (PRO 2000) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

CAPRISA/USAID/LIFElab/Gilead/FHI/CONRAD (tenofovir gel) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

NIAID/Indevus/ReProtect (PRO 2000 and BufferGel®) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

StarPharma/NIAID/NICHD (VivaGel®) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

IPM (TMC120: dapivirine gel) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

NIAID (ethanol in emollient gel) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

CONRAD/NIAID/UCLA/CDC/Thailand Ministry of Health (UC-781) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

*This is not an exhaustive listing of all HIV vaccines and microbicides currently in development or clinical trials and excludes HIV drugs and

preclinical microbicides .




n The worldwide market for HIV/AIDS products is rising because of several factors, including increasing HIV prevalence, drug resistance, and poor patient compliance with existing regimens .

n Efficacious HIV drugs and vaccines, especially if affordable, will find markets in both the developed and developing worlds . By one estimate, annual sales of HIV/AIDS drugs are expected to grow from $7 .1 billion in 2005 to more than $10 .6 billion by 2015 .

n Donor commitment to fighting HIV/AIDS includes the President’s Emergency Plan for AIDS Relief (PEPFAR), funded at $15 billion for 2003-2008 and reauthorized for $48 billion for 2008-2013 .



n Continued need for high-

potency, less-costly drugsn Resistance is a growing issue

n Vaccines need to overcome wide

variability of virus strains, both in

single patients and across populationsn The development of a vaccine

that induces humoral, cell-

mediated, and mucosal immunity

has proven challenging

n CD4�AND�VIRAl�loAD�DIAGNoSTICS

In infants, it is difficult to obtain

sample volume adequate for

detection; also presence of maternal

antibodies can complicate diagnosis


General Disease Linksn World Health Organization (WHO) ~ www .who .int/topics/hiv_infections/enn Centers for Disease Control and Prevention (CDC) ~ www .cdc .gov/hivn National Institute for Allergy and Infectious Diseases (NIAID) ~ www .niaid .nih .gov/factsheets/hivinf .htm

Key Organizationsn AIDS Vaccine Advocacy Coalition (AVAC) ~ www .avac .orgn Alliance for Microbicide Development ~ www .microbicide .orgn Global Fund to Fight AIDS, Tuberculosis and Malaria ~ www .theglobalfund .org/enn HIV InSite ~ http://hivinsite .ucsf .edun HIV Vaccine Trials Network (HVTN) ~ www .hvtn .orgn International AIDS Vaccine Initiative (IAVI) ~ www .iavi .orgn International Partnership for Microbicides (IPM) ~ www .ipm-microbicides .org

Important Papersn AIDS Epidemic Update 2007 ~ http://data .unaids .org/pub/EPISlides/2007/2007_epiupdate_en .pdfn Aledort, JE . Reducing the burden of HIV/AIDS in infants: The contribution of improved diagnostics . Nature S1,

19-28 (2006)n Barouch, DH . Challenges in the development of an HIV vaccine . Nature 455:613-9 (2008)n Duerr, A, et al . HIV vaccines: New frontiers in vaccine development . Clin Infect Dis 43:500-11 (2006) n Gallo, RC . The end or the beginning of the drive to an HIV-preventive vaccine: A view from over 20 years . Lancet

366:1894-8 (2005) n Lederman, MM, et al . Microbicides and other topical strategies to prevent vaginal transmission of HIV . Nat Rev

Immunol 6:371-82 (2006)n Markel, H . The search for effective HIV vaccines . NEJM 353:753-7 (2005)



Japanese Encephalitis (JE)


What Is Japanese Encephalitis?Japanese encephalitis (JE) is a viral disease transmitted by mosquitoes that causes fever and flu-like symptoms . In severe cases, JE results in inflammation of the brain (encephalitis) . Death may result if the symptoms are not treated .

Global BurdenJE is the leading cause of viral encephalitis and neurological infection in Asia . Annually, 50,000 new cases are recorded, resulting in 15,000 deaths and a 75 percent JE-related disability rate; however, these numbers may not reflect the true disease burden due to underreporting . Over 3 billion people live in areas endemic for JE .

Geographic DistributionJE is endemic in Asia, ranging from the islands of the Western Pacific in the east to the Pakistani border in the west, and from Korea in the north to Papua New Guinea in the south . JE distribution is linked to irrigated rice production combined with pig rearing .

Causative Agent/TransmissionThe JE virus belongs to the family Flaviviridae, along with the viruses responsible for dengue fever, yellow fever, and West Nile disease . Mosquitoes belonging to the Culex tritaeniorhynchus and Culex vishnui groups, which breed in flooded rice fields, transmit JE . Because Culex mosquitoes prefer to feed on animals, the virus circulates in birds and pigs, spilling into human populations only when Culex populations increase dramatically over a short period of time .

PresentationMost JE virus infections are mild (fever and headache) or asymptomatic . Approximately one in 300 infections results in severe disease characterized by rapid onset of high fever, headache, neck stiffness, disorientation, coma, seizures, spastic paralysis, and death . In these cases, JE affects the brain or the membranes around the brain (meninges) . Of

those who survive severe JE, 30 percent suffer lasting damage to the central nervous system . In areas where the JE virus is common, encephalitis occurs mainly in young children because older children and adults have acquired immunity through prior exposure .

TrendsLarge outbreaks of JE in India and Nepal have highlighted the continuing expansion of the geographic range of the disease in recent years .

Countries with seasonal or year-round transmis-

sion of Japanese encephalitis in 2003 (WHO, 2008)

JE virus particles (photo: picture library of

Sanofi Pasteur)

J A P A N E S E E N C E P H A L I T I S




n PAllIATIVE�CARE

− Intravenous fluid replacement

can be used for rehydration

− Acetaminophen can be used

to manage pain and fever

n INACTIVATED�VACCINE�(JE-VAx®)

− Derived from infected mouse brain

− Expensive

− Requires three doses

− Offers short-term protection

− Reports of neurological and

hypersensitivity reactions

following vaccinationn lIVE,�ATTENuATED�VACCINE

− Inexpensive

− Used in China, but not widely available

− Currently being developed under

improved GMP conditions

An inexpensive, field-ready technology

(MAC DOT) has been developed but not

commercialized.n PlAQuE�REDuCTIoN�

NEuTRAlIzATIoN�ASSAy�(PRNT)

− Time intensive and costly

− High biosafety-level requirements n HEMAGGluTINATIoN�INHIBITIoN�(HI)

− Low specificity

− High level of cross-reactivity

with other flavivirusesn ElISA

− Simple and sensitive

− Some cross-reactivity with

other flaviviruses

− Not currently suitable for

point-of-care testing



n Drug therapy not targeted n SECoND-GENERATIoN�VACCINE

− Safer

− Requires fewer doses

− Should be compatible with

the WHO EPI schedule

n No cross-reactivity with other

flaviviruses



Intercell/Novartis/Biologics E (Ixiaro®) FDA approved 03/2009 nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(IC51: inactivated Vero cell-grown SA14-14-2 strain)

Acambis/Sanofi Pasteur nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(ChimeriVax-JE: live, chimeric derived from SA14-14-2 strain)

Biken/Kaketsuken (inactivated Vero cell-grown Beijing strain) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn


n Significant opportunity in travelers’ and military markets . n One company estimates a global market of over $300 million .



n Difficult to develop therapeutic

antivirals

n Evaluation of efficacy of JE

vaccines against virus strains for

different geographic regions

n Important to detect disease in

early stages of infection, when

intervention may be beneficial

J A P A N E S E E N C E P H A L I T I S ( J E )

J A P A N E S E E N C E P H A L I T I S



General Disease Linksn World Health Organization (WHO) ~ www .who .int/vaccine_research/diseases/japanese_encephalitis/enn Centers for Disease Control and Prevention (CDC) ~ www .cdc .gov/ncidod/dvbid/jencephalitis

Key Organizationsn International Vaccine Institute, Japanese Encephalitis Program ~ http://www .ivi .org/program/tr_je_program .html

Important Papersn Anonymous . RNA sequence restrains fatal encephalitis . Focus Online (2006) n Konstantin, V, et al . Chimeric vaccines against Japanese encephalitis, dengue and West Nile . New Generation

Vaccines, 3rd ed . Chapter 47 . Eds . M Levine, JB Kapper, R Rappuoli, MA Liu, and MF Good . New York and Basel: Marcel Dekker (2004)

n Monath, TP, et al . Chimeric live, attenuated vaccine against Japanese encephalitis (ChimeriVax-JE): Phase II clinical trials for safety and immunogenicity, effect of vaccine dose and schedule, and memory response to challenge with inactivated Japanese encephalitis antigen . J Infect Dis 188:1213-30 (2003)

n Solomon, T. Flavivirus encephalitis. NEJM 351:370-78 (2004)n Tauber, E, et al . Safety and immunogenicity of a Vero-cell-derived, inactivated Japanese encephalitis vaccine: A

non-inferiority, phase III, randomised controlled trial . Lancet 370:1847-53 (2007)

J A P A N E S E E N C E P H A L I T I S ( J E )


Leishmaniasis


What Is Leishmaniasis?Leishmaniasis is a widespread parasitic disease that affects the skin, mucosa, and internal organs, resulting in severe disfigurement, disability, or death .

Global BurdenWorldwide there are 12 million people infected with Leishmania parasites. An estimated 350 million people are at risk for infection . There are approximately 1 .7 million new cases and 45,000 deaths each year .

Geographic DistributionLeishmaniasis is found in 88 countries, 72 of which are low-income countries .

More than 90 percent of all cases of cutaneous leishmaniasis, the most common form of the disease, are found in Afghanistan, Brazil, Iran, Peru, Saudi Arabia, and Syria . Approximately 90 percent of all cases of visceral leishmaniasis, a less common but deadlier form of the disease, occur in Bangladesh, India, Nepal, Sudan, and Brazil .

Causative Agent/TransmissionThe leishmaniases are caused by approximately 20 different species of protozoa that belong to the genus Leishmania. The parasites are transmitted by the bite of the female phlebotomine sandfly . Within the vertebrate host, parasites invade and replicate inside white blood cells such as macrophages and inside dendritic cells . Leishmania are related

to the trypanosomes that cause human African trypanosomiasis and Chagas disease .

PresentationLeishmania diseases can be classified into one of four forms: (1) visceral leishmaniasis (VL), commonly known as Kala-azar, which is fatal if left untreated; (2) cutaneous leishmaniasis (CL), the most common form, which is marked by a proliferation of self-healing skin lesions that produce significant scarring; (3) mucocutaneous leishmaniasis (MCL), which is an ulcerative Leishmania infection that results in destruction of the mucosal membranes of the nose and mouth; and (4) diffuse cutaneous leishmaniasis (DCL), the most difficult Leishmania manifestation to treat, which causes chronic ulcers and skin lesions resulting in severe disfigurement .

TrendsThere is a profound need for safe, effective therapeutics and vaccines to combat the leishmaniases . Indeed, over the last 10 years, regions endemic for leishmaniasis have been growing, and there has been a sharp increase in the number of recorded cases of the disease . It is likely that a substantial number of cases are never recorded because declaration is compulsory in only 32 of the 88 countries affected by the disease .

Countries with areas of visceral and cutaneous

leishmaniasis risk. Leishmaniasis epidemiological

information has serious gaps. (WHO, 2003)

Protozoan parasites cause leishmaniasis (CDC)

L E I S H M A N I A S I S






n MIlTEFoSINE�(IMPAVIDo®)

− Approved in 2003 for use in India for VL

and in 2005 for use in Colombia for CL

− Has shown a 95 percent response

rate when used against VL

− Currently the only effective

oral treatment

− Contraindicated in pregnancyn PARoMoMyCIN�(AMINoSIDINE,�

HuMATIN®)

− Approved in 2006 for use in India for VL

− Granted “orphan drug” status

− Injectedn AMPHoTERICIN�B

− Liposomal amphotericin B

(AmBisome®) is first-line treatment

of VL in United States.

− Severe side effects associated

with non-liposomal forms

− Injectedn PENTAVAlENT�ANTIMoNIAlS:��

SoDIuM�STIBoGluCoNATE�(PENToSAM®),�

MEGluMINE�ANTIMoNIATE�(GluCANTIME)�

− Predictable, but reversible side effects

− Resistance has emerged

in certain areas

− Injectedn PENTAMIDINE,�KEToCoNAzolE

There are no modern vaccines against

leishmaniasis. n In some endemic regions, to protect

against CL, a controlled lesion is

created in an area of the skin normally

covered by clothing, via inoculation of

live parasite. While this lesion is active,

the individual is protected from lesions

on more visible parts of the body. This

process is called leishmanization.

n DIRECT�AGGluTINATIoN�TEST�(DAT)�

WITH�FREEzE-DRIED�ANTIGEN

− First-line diagnostic

− Highly sensitive and specific

− Does not require special equipmentn DIPSTICKS�RK39/RK26

− rK39 for serological diagnosis

− Based on a recombinant

antigen of L. chagasi

− Requires cold storage

− Reduced sensitivity in

HIV-positive patients and in

certain genetic backgroundsn KATEx�(lATEx�AGGluTINATIoN�TEST)

− Used to detect L. donovani

antigen in urine samples

− Requires cold storagen SKIN�SNIP

− Test of cure



n Oral formulationn Shorter course of treatmentn Safer than current treatmentsn High efficacy against all

leishmania species

n High-efficacy recombinant

subunit vaccine n Prophylactic and therapeuticn Effective against multiple

leishmania species

n Detection of early-stage,

systemic diseasen Perform satisfactorily in East African Less invasive test of cure





DNDi/iOWH/multiple East African partners (paromomycin) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

DNDi and multiple Indian partners (combination therapies) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

DNDi and multiple East African partners (Ambisome®) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Banaras Hindu University (amphomul) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

DNDi/BioDelivery Sciences International (Bioral™: amphotericin B) nnnnnnnnnnnnnnnnnnnn

DNDi/Advinus/Drugabilis/University Seins Malaysia, LSHTM (buparvaquone) nnnnnnnnnnnnnnnnnnnn

DNDi/Imperial College/London School of Pharmacy/LSHTM nnnnnnnnnnnnnnnnnnnn

(amphotericin B polymer)

ICO Therapeutics (iCo-009: oral reformulation of amphotericin B) nnnnnnnnnnnnnnnnnnnn

Consortium for Parasitic Drug Development (DB series) nnnnnnnnnnnnnnnnnnnn

Dafra Pharma/Max Planck Institute (oleylphosphocholine) nnnnnnn

DNDi/Advinus/CDRI (VL consortium for lead optimization) nnnnnnn

DNDi/STI/Fiocruz and others (nitroimidazoles) nnnnnnn

DNDi/GSK/STI (4[1H] pyridones and cysteine protease inhibitors) nnnnnnn

DNDi/Institute Pasteur Korea (visual high-throughput screening) nnnnnnn


IDRI/GSK (leish-111f + MPL-SE) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn


n Potential military market; CL has been reported in hundreds of troops stationed in Iraq . The problem has become widespread enough that the CDC has advised soldiers returning from Iraq to wait a year before donating blood to prevent the spread of the parasite .



n None n Leishmanization (see existing

products, above) suggests

vaccination is possible but long-

lasting immunity may be difficult to

achieve with a recombinant vaccine

n Regional differences in population

can influence the strength of

the immune response to certain

diagnostic test antigens






General Disease Linksn World Health Organization (WHO) ~ www .who .int/topics/leishmaniasis/enn Centers for Disease Control and Prevention (CDC) ~ www .cdc .gov/ncidod/dpd/parasites/leishmania

Key Organizationsn Drugs for Neglected Diseases initiative (DNDi) ~ www .dndi .orgn Institute for OneWorld Health (IOWH) ~ www .oneworldhealth .orgn Infectious Disease Research Institute (IDRI) ~ www .idri .orgn Special Programme for Research and Training in Tropical Diseases (TDR) ~ www .who .int/tdr

Important Papersn Coler, RN, and Reed, SG . Second-generation vaccines against leishmaniasis . Trends in Parasitol 21:244-9 (2005)n Davies, CR, et al . Leishmaniasis: New approaches to disease control . BMJ 326:377-82 (2003)n El-Sayed, NM, et al . Comparative genomics of trypanosomatid parasitic protozoa . Science 309:404-9 (2005)n Hailu, A, et al . Visceral leishmaniasis: New health tools are needed . PLoS Med 2:e211 (2005)n Ivens, AC, et al . The genome of the kinetoplastid parasite, Leishmania major. Science 309:436-42 (2005) n Peacock, CS, et al . Comparative genomic analysis of three Leishmania species that cause diverse human disease .

Nature Genetics 39:839-47 (2007)


Lymphatic Filariasis (LF)


What Is Lymphatic Filariasis?Lymphatic filariasis (LF), also known as elephantiasis, is caused by parasitic worms and leads to severe disfigurement of the extremities . While not directly life-threatening, LF is among the world’s leading causes of permanent and long-term disability . Those infected are disabled in their most productive stage of life, resulting in an economic and psychosocial burden on afflicted individuals, families, and communities .

Global BurdenMore than 120 million people are infected with LF; over 40 million are seriously disfigured by the disease . It is estimated that 1 .3 billion people are at risk for the disease .

Geographic DistributionLF is endemic in 83 countries . One-third of the people infected with LF live in India, and one-third live in Africa . Most of the remaining cases are distributed throughout South Asia, the Pacific, and the Americas .

Causative Agent/TransmissionThe thread-like, parasitic worms Wuchereria bancrofti and Brugia malayi cause lymphatic filariasis . Adult worms lodge in the lymphatic system,

where they live for four to six years and produce millions of immature microfilariae (minute larvae) that circulate in the blood . The parasites are transmitted to a mosquito vector when its blood meal includes microfilariae . Inside the mosquito, over the course of one to thee weeks, the larvae mature to the infective stage and are transmitted to a new human host during a subsequent blood meal .

PresentationThe worst symptoms of the chronic disease generally appear in adults . Elephantiasis of an entire leg, arm, the vulva, or the breast—swelling up to several times normal size—is common . In endemic communities, some 10 to 50 percent of men suffer from genital damage, especially formation of hydrocoeles (fluid-filled balloon-like

enlargements of the sacs around the testes) and elephantiasis of the penis and scrotum . Once hydrocoele formation has begun, the most effective way to deal with it is generally surgery, but this solution is too expensive for the majority of people affected by the disease .

TrendsThe Global Programme to Eliminate Lymphatic Filariasis has targeted elimination of LF by 2020 . Results from the program’s first eight years (2000-2007) are encouraging . Yearly, single-dose mass drug adminstration has reached 570 million individuals in 48 LF-endemic countries, protecting an estimated 9 .5 million people with subclinical disease from progressing to clinical disease and preventing disease in 6 .6 million newborns .

Countries endemic for lymphatic filariasis

(WHO, 2006)

LF pathogen Wuchereria bancrofti in a blood smear.

The worm is in the microfilariae stage

(CDC/Mae Melvin)

L y M P H A T I C F I L A R I A S I S ( L F )




n CoMBINATIoN�TREATMENT—

AlBENDAzolE�WITH�

DIETHylCARBAMAzINE�(DEC)��

oR�IVERMECTIN

− Use of single doses of two drugs

administered concurrently is 99

percent effective in removing

microfilariae from the blood for

a full year after treatment

− Does not kill adult worms

− Current standard of care is to

treat children annually for five

years to prevent disease and

break the chain of infection

− Treatment with DEC can cause serious

side effects if onchocerciasis is also

present, as occurs in certain African

countries; ivermectin is used as an

alternative in these regions

n None n MICRoSCoPy

− Difficult because the parasites often

have a “nocturnal periodicity” that

restricts their appearance in the blood

to the hours between 10 p.m. and 2 a.m.

− Inexpensive reagentsn BINAx�NoW®�FIlARIASIS�TEST

− Antigen detection test

− Rapid; requires 10 minutes

− Detects antigens of W. bancrofti in

whole blood, serum, or plasma

− Simple, very sensitive, and specific

− Expensive to use; generally used

to identify populations at risk

rather than individual diagnosis



n Kills adult worms (macrofilaricidal)

and reduces swellingn Decreases necessity of repeated,

annual treatment; inhibits

microfilariae production

n Prevents establishment of

infection by microfilariae

n Further development of diagnostics

for B. malayin Adapt existing serologic assays to

work with oral fluids or urine





Anti-Wolbachia Consortium: Liverpool School of Tropical Medicine/ nnnnnnn

CombinatoRx/New England Biolabs, and others (anti-Wolbachia treatments)


n The critical issues for LF are delivery into remote, endemic areas and maintenance of treatment over many years to reduce adult disease and break the chain of transmission . Currently, all drugs used to treat LF are donated .

n Many current LF treatments are also effective against other diseases common in the developing world; new drugs might likewise have multiple markets .



n Recent evidence (June 2007) suggests

that ivermectin resistance is emerging

in onchocerciasis (a filarial worm

disease); this observation reinforces

the need for new drugs in the

event resistance appears in LF

n Lack of an in vitro culture

system for filariaen Absence of tools for easy

genetic manipulationn Need for improved animal models

n The major challenge is to reduce

cost of each diagnostic to below $1


General Disease Linksn World Health Organization (WHO) ~ www .who .int/topics/filariasis/enn Centers for Disease Control and Prevention (CDC) ~ www .cdc .gov/ncidod/dpd/parasites/lymphaticfilariasis

Key Organizationsn Anti-Wolbachia Consortium ~ www .a-wol .netn The Carter Center ~ www .cartercenter .orgn The Global Alliance to Eliminate Lymphatic Filariasis ~ www .filariasis .orgn Special Programme for Research and Training in Tropical Diseases (TDR) ~ www .who .int/tdr

Important Papersn Galvez Tan, JZ . The elimination of lymphatic filariasis: A strategy for poverty alleviation and sustainable

development—perspectives from the Philippines . Filaria Journal 2:12 (2003)n Johnston, KL, and Taylor, MJ . Wolbachia in filarial parasites: Targets for filarial infection and disease control . Curr

Infect Dis Rep 9:55-9 (2007)n Molyneux, D . Lymphatic filariasis (elephantiasis) elimination: A public health success and development

opportunity . Filaria Journal 2:13 (2003)n Ottesen, EA, et al . The global program to eliminate lymphatic filariasis: Health impact after 8 years . PLoS NTD

2:e317 (2008)n Perera, M, et al . Neglected patients with a neglected disease? A qualitative study of lymphatic filariasis . PLoS NTD

1:e128 (2007)n Towards a strategic plan for research to support the global program to eliminate lymphatic filariasis: Summary

of immediate needs and opportunities for research on lymphatic filariasis . Supplement 5 to AJTMH 71 (2004)



Malaria

BACKGRouND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

What Is Malaria?Malaria is a parasitic disease transmitted by infected mosquitoes . It can be categorized as either uncomplicated or severe . Symptoms of uncomplicated malaria include fever, chills, body aches, nausea, headache, vomiting, and diarrhea . Severe disease can cause anemia, acute respiratory distress syndrome, coma, and death .

Global BurdenHalf of the world’s population is at risk for malaria . In 2006, there were an estimated 246 million malaria cases and nearly 1 million deaths . Over 90 percent of malaria deaths occur in Africa; 85 percent of deaths were in children under the age of five . In Africa, malaria has been estimated to result in more than $12 billion in lost annual gross domestic profit; malaria control would cost a fraction of this sum .

Geographic DistributionMalaria is endemic in more than 100 countries in tropical and subtropical regions of Africa, Asia, and Central and South America .

Causative Agent/TransmissionMalaria is caused by four species of protozoa of the genus Plasmodium: P. falciparum, P. vivax, P. ovale, and P. malariae. P. falciparum causes the most severe and deadly form of the disease . P. vivax is less deadly, but worldwide, is the most prevalent Plasmodium parasite and is the cause of the most morbidity . Transmission of all species occurs via the bite of an infected female Anopheles mosquito .

PresentationOnce in the bloodstream, parasites migrate to the liver, invade hepatocytes, and undergo multiple rounds of replication . Following this asymptomatic period (which lasts anywhere from a week to months depending on the species of Plasmodium), parasites are released from the hepatocyte and infect red blood cells (RBCs) . During this blood or erythrocytic stage, parasites replicate several times inside the RBCs, eventually causing them to burst and thereby freeing the parasites to infect new RBCs . The symptoms of uncomplicated disease are associated with the erythrocytic stage . The destruction of RBCs may also cause jaundice and anemia . Severe disease may result in kidney failure, seizures, or coma .

TrendsIncreasingly, Plasmodium are resistant to existing antimalarials . Use of combination therapies and the development of new drugs and vaccines are strategies being pursued to guard against drug resistance .

Several Anopheles vector species are exhibiting pesticide resistance, even to the powerful pesticide DDT .

Countries with areas of malaria transmission

(WHO, 2003)

A red blood cell harboring many P. vivax parasites

(photo: CDC/Mae Melvin)

M A L A R I A




The leading drugs used in the developing

world, chloroquine and sulfadoxine-

pyrimethamine (SP/Fansidar®), are

increasingly ineffective across wide

areas because of resistant parasites. New

artemisinin-based combination therapies

(ACTs) are currently the best treatments

but are up to ten times as costly. n CHloRoQuINE

− Affordable and widely available

− Now ineffective in most malaria

endemic areas due to resistance n SulFADoxINE-PyRIMETHAMINE��

(SP/FANSIDAR®)

− Resistance increasing rapidly n ARTEMISININ-BASED�CoMBINATIoN�

THERAPIES�(ACTS)

− Currently the best treatment

− Only one ACT (Coartem®) is licensed

for use in the United States; many

other ACTs are available overseas

− More expensive than chloroquine or SP

Other, more expensive drugs are available

in the developed world and are used

prophylactically

n None n lIGHT�MICRoSCoPy

− High sensitivity and specificity when

performed under optimal conditions

− Labor-intensive and requires

skill to read slidesn RAPID�DIAGNoSTIC�TESTS�(RDTS)

− More expensive than microscopy

− Vulnerable to high temperatures

and humidity

− Can be highly sensitive and specific

− Cannot distinguish severe disease,

active disease, and background

parasitemia from one another

− Binax NOW® test is the only rapid

test approved in the United States



n Inexpensive (in tens of cents)n Easy to manufacturen Significant shelf lifen Simple, regular, and short dosing

regimen (one to three days)n Effective against malaria caused by

all major species of Plasmodium

n Vaccine for infants with delivery

tied to EPI schedulesn Effective for at least two yearsn Demonstrated non-interference

with EPI vaccines

n Requires minimal trainingn Distinguishes between severe

and uncomplicated malaria n Distinguishes malaria from other

causes of acute febrile illness

M A L A R I A


M A L A R I A


PIPElINE � (SElECT � ITEMS � oNly)nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Discovery� Pre-� Clinical-�� Clinical-� Clinical-�Drugs� � Clinical� Phase�I� Phase�II� �Phase�III

MMV/Novartis (Coartem® Dispersible) (launched 01/2009) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Sigma-Tau/WRAIR (Nuartez®: intravenous artesunate for adults) (in registration) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

MMV/Sigma-Tau/Chongqing Holley (Eurartesim®: dihydroartemisinin piperaquine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

MMV/U. of Iowa/Shin Poong Pharma, Korea (Pyramax®: pyronaridine-artesunate) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Pfizer Inc. (zithromax®-chloroquine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Ranbaxy (RBx 11160: arterolane malate-piperaquine phosphate) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Sanofi-Aventis (artesunate-ferroquine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

MMV/University of Tübingen (intravenous artesunate for children) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Sanofi-Aventis (SAR 97276: choline uptake inhibitor) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

MMV/GSK (tafenoquine for P. vivax) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

MMV/GSK (GSK 932121A and prodrug: 4-pyridones) nnnnnnnnnnnnnnnnnnnn

Sanofi-Aventis (SAR 116242: trioxaquine) nnnnnnnnnnnnnnnnnnnn

MMV/Univ. Nebraska/Monash Univ./STI nnnnnnnnnnnnnnnnnnnn

(Oz439: next-generation synthetic peroxide)

MMV/Merck (MK4815) nnnnnnnnnnnnnnnnnnnn

MMV/Treague (non-racemic RS(+) mefloquine: AD 452) nnnnnnnnnnnnnnnnnnnn

MMV/WRAIR (mirincamycin) nnnnnnnnnnnnnnnnnnnn

MMV/Biotec/LSHTM/Monash University (DHFR inhibitors) nnnnnnn

MMV/Novartis Institute for Tropical Diseases (quinazoline derivatives) nnnnnnn

MMV/Novartis Institute for Tropical Diseases (natural product) nnnnnnn

MMV/UT Southwestern/U. Washington/Monash University nnnnnnn

(dihydroorotate dehydrogenase (DHODH) inhibitors)

MMV/Novartis Institute for Tropical Diseases (screening and lead optimization) nnnnnnn

MMV/Broad Institute/Genzyme/Advinus (screening and lead optimization) nnnnnnn

MMV/GSK (screening and lead optimization) nnnnnnn

MMV/Eskitis Institute (screening: natural products) nnnnnnn

M A L A R I A



MVI/GSK/WRAIR (Mosquirix; RTS,S AS01/AS02) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Oxford University (FP9/MVA, ME-TRAP) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Mymetics/Pevion Biotech (PeviPRO™ - PEV3a) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

NIAID/Univ. of Bamako/Univ. of Maryland/GSK/USAID/WRAIR (AMA1/ASO2A) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

NMRC/USAID/MIDRP/CDMRP (M3V-Ad-PfCA) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Sinobiomed/WHO (PfCP2.9) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

MVI/LaTrobe University (MSP2-C1 ISA720) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Crucell/NIAID (AdHu35: adenovirus vector+CSP) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

MVI/MVDB/NIAID/NIH (AMA1-C1 ISA720) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Oxford University/Okairòs/Wellcome Trust (PlaMaVax: adenovirus vector) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

WRAIR/GSK/USAID (FMP010 ASO1B) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

SSI/EMVI (GMz2: Glurp and MSP3) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

MVI/Sanaria (radiation-attenuated sporozoites) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

MVI/ICGEB (P. vivax; PvRII) nnnnnnnnnnnnnnnnnnnn

Pharmexa/NIH (EP1300) nnnnnnnnnnnnnnnnnnnn

MVI/Monash University (MSP4) nnnnnnnnnnnnnnnnnnnn

MVI/GenVec/NMRC (multivalent: adenovirus vector) nnnnnnnnnnnnnnnnnnnn


n A highly efficacious vaccine, marketed to travelers and the military as well as to the developing world, could yield a positive return on investment for its developer, provided the public sector is willing to support the purchase for resource-poor countries .

n Because malaria is such an overwhelming burden to African societies, donor funding for malaria prevention and treatment is expected to be a priority for many years to come and is likely to support the development, manufacture, and delivery of a highly efficacious vaccine .



n Resistance may make new drugs

obsolete quickly

n No correlates of protectionn No predictive animal modelsn A highly efficacious vaccine that

protects against a eukaryote

has never before been made

n In areas highly endemic for

P. falciparum malaria, due to

acquired immunity, not all people

infected with parasites will be

sick with malaria disease

M A L A R I A


M A L A R I A



General Disease Linksn World Health Organization (WHO) ~ www .who .int/topics/malaria/enn Centers for Disease Control and Prevention (CDC) ~ www .cdc .gov/malaria/

Key Organizationsn Foundation for Innovative New Diagnostics (FIND) ~ www .finddiagnostics .orgn Global Fund to Fight AIDS, Tuberculosis and Malaria ~ www .theglobalfund .org/enn Medicines for Malaria Venture (MMV) ~ www .mmv .orgn Multilateral Initiative on Malaria (MIM) ~ www .mimalaria .orgn PATH Malaria Vaccine Initiative (MVI) ~ www .malariavaccine .orgn Roll Back Malaria ~ www .rbm .who .intn Special Programme for Research and Training in Tropical Diseases (TDR) ~ www .who .int/tdr

Important Papersn Águas R, et al . Prospects for malaria eradication in Sub-Saharan Africa . PLoS ONE 3:e1767 (2008)n Alonso, PL, et al . Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in

young African children: Randomised controlled trial . Lancet 364:1411-20 (2004)n Alonso, PL, et al . Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum

disease in Mozambican children: Single-blind extended follow-up of a randomised controlled trial . Lancet 366:2012-8 (2005)

n Anonymous . Disease watch – focus: Malaria . Nature Rev: Microbiol 2:276-7 (2004)n Carlton, JM, et al . Comparative genomics of the neglected human malaria parasite Plasmodium Vivax . Nature

455:757-63 (2008)n Defining and defeating the intolerable burden of malaria III: Progress and perspectives . Supplement 6 to AJTMH

77 (2007)n Gardner, MJ, et al . Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419:498-511

(2002)n Greenwood, BM, et al . Malaria . Lancet 365:1487-98 (2005)n Moody, A . Rapid diagnostic tests for malaria parasites . Clin Microbiol Rev. 15:66-78 (2002)n Rafael, ME, et al . Reducing the burden of childhood malaria in Africa: The role of improved diagnostics . Nature

S1, 39-48 (2006)n WHO-FIND report: Malaria RDT Performance: Results of WHO product testing of malaria RDTs: Round 1 (2008)n World Malaria Report (2008) ~ www .who .int/malaria/wmr2008/malaria2008 .pdf


Pneumococcal Disease


What Is Pneumococcal Disease?Pneumococcal disease is a collection of maladies caused by the bacterium Streptococcus pneumoniae . The infection commonly manifests as pneumonia, meningitis, sepsis, and middle ear infection . S. pneumoniae is one of the most important pathogens of infants in the developing world; the elderly and the immunocompromised are also at high risk .

Global BurdenPneumococcal disease is estimated to be responsible for the deaths of nearly 1 million children under the age of five, 90 percent of whom live in the developing world .

Geographic DistributionPandemic; pneumococcal disease is found in all countries .

Causative Agent/TransmissionStreptococcus pneumoniae (“pneumococcus”), the cause of pneumococcal disease, is a Gram-positive, encapsulated bacterium . Due to differences in composition of its polysaccharide capsule, there are at least 90 S. pneumoniae serotypes; 11 common serotypes account for 75 percent of invasive disease globally . The nasopharynx of young children is the major reservoir of the bacterium; infection is transmitted person-to-person by inhalation of respiratory droplets .

PresentationThe onset of pneumonia, a potentially fatal form of pneumococcal disease, begins with fever, chills, and headache . Other symptoms include cough and difficulty breathing due to the buildup of liquid in the lung alveoli .Two other invasive S. pneumonia infections are prevalent: 1) infection of the bloodstream may lead to sepsis, an overwhelming inflammatory response resulting in death; and 2) infection of the outer layer of the brain and spinal cord (meningitis) may result in paralysis, neurological effects, and death .

TrendsIn the United States, the introduction in 2000 of the seven-valent

pneumococcal conjugate vaccine (Prevnar®) has been remarkably effective at reducing pneumococcal disease in young children . Moreover, due to herd immunity, vaccination of children reduces pneumonia in adults . Prevnar®, however, does not protect against serotypes 1 and 5, both of which are highly prevalent in the developing world . Because of the twin issues of serotype coverage and replacement, there is growing interest in protein vaccines and protein-polysaccharide combination vaccines .



n ANTIBIoTICS

– Penicillin, amoxicillin, cephalosporins,

erythromycin, azithromycin,

clarithromycin, fluoroquinolones

n Prevnar® (PCV7): 7-valent

pneumococcal conjugate vaccine

(for children under age five)n PPV23, a 23-valent polysaccharide

vaccine (for adults over 65 and

other high-risk persons)

n BinaxNOW pneumococcal

urinary antigen (PNAG) test

Pneumococcal disease is pandemic (WHO)

Scanning electron micrograph of S. pneumoniae

(CDC/Janice Carr/Richard Facklam)

P N E U M O C O C C A L D I S E A S E




n Overcome antibiotic resistance n Efficacy in children under fiven Efficacy against regionally

prevalent serotypesn Efficacy that is independent

of capsular serotype, ensuring

widest possible coverage

n Differentially diagnose the cause

of a fever of unknown origin (e.g.

bacterial pneumonia or malaria)n Distinguish bacterial and

viral pneumonias to aid in

treatment decisions



GSK (Synflorix®: 10-valent conjugated vaccine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(EDMA approval in 01/2009)

Wyeth (13vPnC: 13-valent conjugated vaccine) (in registration) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

GSK (S. pneumoniae adult recombinant conjugated vaccine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Sanofi-Pasteur (single antigen; meningitis & pneumonia in infants) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Intercell/PATH (protein subunit vaccine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Ace BioSciences/SSI (S. pneumoniae vaccine) nnnnnnnnnnnnnnnnnnnn

Sanofi-Pasteur (multivalent meningitis & pneumonia in infants) nnnnnnnnnnnnnnnnnnnn

PATH/Children’s Hospital Boston (killed whole cell vaccine) nnnnnnnnnnnnnnnnnnnn

PATH/Genocea/Children’s Hospital Boston (Geno 002: protein subunit vaccine) nnnnnnn


n A significant market for pneumococcal vaccines exists in the developed world . Additionally, a $1 .5 billion Advanced Market Commitment (AMC) has been established to create a market for pneumococcal vaccines in the developing world .



n Antibiotic resistance n At least 90 serotypes existn Non-conjugated polysaccharide

vaccines exhibit poor immune

response in children under age two

and in immunocompromised peoplen Protein subunit vaccines—identifying

an efficacious cocktail

n Many children are nasopharyngeal

carriers of S. pneumoniae, hampering

the ability to use polysaccharides

excreted in urine as diagnostic of

infection as can be done for adults




General Disease Linksn World Health Organization (WHO) ~ www .who .int/topics/pneumococcal_infections/en/n Centers for Disease Control and Prevention ~ http://www .cdc .gov/ncidod/dbmd/diseaseinfo/streppneum_t .htm

Key Organizationsn GAVI Alliance ~ www .gavialliance .orgn PATH ~ www .path .org/projects/pneumococcal_protein_vaccine_project .phpn PneumoADIP ~ www .preventpneumo .org/index .cfm

Important Papersn Briles, DE, et al . Pneumococcal diversity: Considerations for new vaccine strategies with emphasis on

pneumococcal surface protein A (PspA) . Clin Micro Reviews 11:645-57 (1998)n Lim, YW, et al . Reducing the global burden of acute lower respiratory infections in children: The contribution of

new diagnostics . Nature S1:9-18 (2006)n Malley, R, et al . Intranasal immunization with killed unencapsulated whole cells prevents colonization and

invasive disease by capsulated pneumococci . Infect Immun. 69:4870-3 (2001)n Scott, JAG, et al . Pneumonia research to reduce childhood mortality in the developing world . J Clin Invest

118:1292-300 (2008)n UNICEF, Pneumonia: The forgotten killer of children (2006) ~ www .unicef .org/publications/files/Pneumonia_The_

Forgotten_Killer_of_Children .pdf



Rotavirus Gastroenteritis


What Is Rotavirus Gastroenteritis?Rotavirus gastroenteritis is a viral infection predominantly affecting infants and young children that causes severe diarrhea, vomiting, and fever . Because of the rapid dehydration that results from the combination of diarrhea and vomiting, the disease can be fatal .

Global BurdenRotavirus is the most common form of severe diarrhea in infants and children . Each year, rotavirus is responsible for an estimated 527,000 deaths (85 percent of deaths occur in developing countries) and over 2 million hospitalizations .

Geographic DistributionPandemic; rotavirus is found in all countries .

Causative Agent/TransmissionRotavirus is a non-enveloped, double-stranded RNA virus that is transmitted by the fecal-oral route via person-to-person contact or, less frequently, via contaminated food, water, or objects . Upon ingestion, the virus infects epithelial cells lining the small intestine, inside of which it replicates manyfold, causing cells to excrete fluids, which results in profuse, watery diarrhea . Once released, virus particles can infect neighboring cells, reinitiating the cycle of infection . Rotavirus exists in multiple serotypes, is stable in the environment and is highly contagious; improved sanitation has little effect on disease control .

PresentationSymptoms include fever, vomiting, and severe diarrhea leading to rapid dehydration . Symptoms appear two to three days after exposure and last three to eight days .

TrendsBy age three, nearly all children have been exposed to rotavirus . In developing countries, 75 percent or more of children have their first infection by 12 months of age . The availability of highly efficacious vaccines is expected to have a major impact on diarrheal disease in infants and young children .

Rotavirus infects nearly all young children and in-

fants worldwide, but mortality rates vary widely.

Scanning electron micrograph of rotavirus virions

and a number of smaller, unknown 29 nm virion

particles (CDC/Erskine Palmer)

R O T A V I R U S G A S T R O E N T E R I T I S




n Palliative caren Oral rehydration therapy

Currently, there are two FDA-approved

rotavirus vaccines on the market:n RotaTeq™: oral, 3-dose, live,

pentavalent human-bovine

reassortant vaccine (Merck)n Rotarix®: oral, 2-dose, live,

attenuated vaccine (GSK)

In addition, the Chinese government has

licensed LLR, a lamb-derived monovalent,

live, attenuated, 1-dose oral vaccine

There are several commercially available

diagnostic assays to detect rotavirus in

patient stooln ELISA, Latex agglutination,

immunochromatographic strips



n Not currently targeted n Must provide protection to infantsn Must act on relevant serotypes

n Robust, reliable, and simple “bedside”

diagnostics for point-of-care use


�� Pre-� Clinical-�� Clinical-� Clinical-�Vaccines� Discovery� Clinical� Phase�I� Phase�II� �Phase�III

Bharat Biotech International* (ORV 116E: live, natural reassortant vaccine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Bhutantan (Brazil), Serum Institute of India (India), Shantha Biotechnics* (India), nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

and Wuhan Institute* (China) (human bovine (UK) reassortant vaccine)

Murdoch Children’s Research Institute* (Australia) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(RV3: naturally attenuated neonate strain)

International Medica Foundation/Biovirx (rhesus assortant oral vaccine) nnnnnnnnnnnnnnnnnnnn

Lanzhou Institute of BioMedical Products (multivalent lamb rotavirus vaccine) nnnnnnnnnnnnnnnnnnnn

*Supported by PATH .


n The market in the developed world for a rotavirus vaccine is estimated to be up to $1 billion annually . The GAVI Alliance is committed to purchasing rotavirus vaccines for the developing world .



n None n No increased risk of intussusceptionn EPI schedule-compatible

n None






General Disease Linksn World Health Organization (WHO) ~ www .who .int/topics/rotavirus_infections/en/n Centers for Disease Control and Prevention (CDC) ~ www .cdc .gov/rotavirus/

Key Organizationsn GAVI Alliance ~ http://www .gavialliance .org/n PATH Rotavirus Vaccine Program ~ http://www .path .org/projects/rvp .php

Important Papersn Glass, RI . New hope for defeating rotavirus . Sci Am 294:46-55 (2006)n Ruiz-Palacios G, et al . Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis . NEJM

354:11-22 (2006)n Vesikari, T, et al . Safety and efficacy of a pentavalent human–bovine (WC3) reassortant rotavirus vaccine . NEJM

354:23-33 (2006)


Schistosomiasis


What Is Schistosomiasis?Parasitic worms that infect blood vessels cause schistosomiasis . Symptoms of early infection include blood in urine or stool, and over time the infection leads to urinary tract or liver damage . Death can result from bladder cancer or from an internal hemorrhage .

Global BurdenSchistosomiasis is endemic in 74 developing countries, infecting more than 200 million people in rural agricultural and peri-urban areas . Twenty million may suffer from severe disease, while approximately 120 million are thought to experience chronic debilitating symptoms such as anemia and impaired cognitive development . An estimated 779 million people worldwide are at risk for the disease .

Geographic DistributionMore than 80 percent of people infected with schistosomiasis live in sub-Saharan Africa . The disease is also prevalent in the Middle East and can be found in parts of Southeast Asia and Latin America .

Causative Agent/TransmissionSchistosomiasis is caused by trematode flatworms of the genus Schistosoma. Schistosoma eggs are expelled in the feces or urine of infected individuals . When humans come in contact with contaminated water, schistosome larvae, which initially develop in freshwater snails, penetrate the skin and enter the bloodstream . The parasites migrate

through the lungs to the liver where they mature, mate, and migrate together to blood vessels near either the intestine (S. mansoni) or bladder (S. haematobium). Over the next five years, a female worm lays 200 to 2,000 eggs daily . About half the eggs produced are excreted in the feces or urine; the remainder become trapped in body tissues and organs, where they can cause severe damage, particularly to the liver . The parasite itself causes little damage to the human body .

PresentationSchistosomiasis can take two forms—urinary and intestinal . In urinary schistosomiasis, urination becomes painful and urine turns blood red . There is progressive damage to the bladder, urine ducts, and then kidneys . In intestinal schistosomiasis, there is progressive enlargement of the liver and spleen and hypertension of the abdominal blood vessels . Eggs breaking through from blood vessels into the intestine leads to

blood in stools . In advanced cases, the functioning of organs such as liver, spleen, and kidneys becomes impaired . Death can result from bladder cancer or renal failure (S. haematobium) or bleeding from varicose veins in the esophagus or gastrointestinal tract (S. mansoni) .

TrendsOlder estimates of the burden of schistosomiasis failed to adequately take into account the full range of symptoms, sequelae, and chronic nature of the disease . More recent analysis has revealed that it is among the most serious tropical diseases . Schistosomiasis often goes undiagnosed in children and is associated with stunting, vitamin deficiency, and developmental and cognitive problems . Children under 14 are especially vulnerable to severe infection leading to progressive disease and early death .

Countries endemic for schistosomiasis (WHO, 2007)

Schistosoma are named for their split (schisto)

body. In this photo, a pair is shown on the left,

while the separate male and female are shown to

the center and right, respectively (photo: CDC)

S C H I S T O S O M I A S I S






n PRAzIQuANTEl�(DISToCID®,�BIlTRICIDE®)

− Standard of care

− Safe and highly effective in

curing an infected patient

− Does not prevent reinfection

− Off patent and inexpensive;

costs as low as $0.20/dosen oTHERS�-�oxAMNIQuINE,�METRIFoNATE�

− Difficult to obtain

− Do not work on all forms of the disease

n None n DIPSTICK (S. haematobium)

− Detection of blood in urine n MICRoSCoPy�(S. manSoni)

− Examine stool for eggs

− Most practical method for diagnosis

− Inefficient; requires laboratory,

multiple analyses

− Poor sensitivity; does not

catch early infectionsn ANTIBoDy�DETECTIoN

− Sensitivity and specificity vary widelyn ElISA

− Highly sensitive; species can be

determined by immunoblot



n Effective against multiple speciesn Long-lasting

n Requires few dosesn Extended protectionn High immunogenicity

n For S. mansoni, control programs

need more sensitive diagnostics



UCSF Sandler Center (K11777 cysteine protease inhibitor) nnnnnnnnnnnnnnnnnnnn

Illinois State University/NIH (oxadiazoles) nnnnnnn


Fiocruz (S. mansoni Sm14) nnnnnnnnnnnnnnnnnnnn

SVI-HHVI (Sm-TSP-2) nnnnnnnnnnnnnnnnnnnn


n This is primarily a disease of the very poor . Donor support will be required to encourage innovation .



n None n Need for further research

into target antigensn A highly efficacious vaccine that

protects against a multicellular

organism has never before been made

n Diagnostic tests need to be

adapted to point-of-care formats




General Disease Linksn World Health Organization (WHO) ~ www .who .int/topics/schistosomiasis/enn Centers for Disease Control and Prevention (CDC) ~ www .cdc .gov/ncidod/dpd/parasites/schistosomiasis

Key Organizationsn Sabin Vaccine Institute (SVI) ~ http://sabin .org/indexn Schistosomiasis Control Initiative (SCI) ~ www .schisto .orgn Special Programme for Research and Training in Tropical Diseases (TDR) ~ www .who .int/tdr

Important Papersn Chitsulo, L, et al . Disease watch – focus: Schistosomiasis . Nature Rev: Microbiol 12:12-3 (2004)n Fenwick, A . New initiatives against Africa’s worms . Trans . Royal Soc Trop Med Hyg 100:200-7 (2006)n Pearce, EJ . Progress towards a vaccine for schistosomiasis . Acta Tropica 86:309-13 (2003)n Sayed AA, et al . Identification of oxadiazoles as new drug leads for the control of schistosomiasis . Nature Med

14:407-12 (2008)



Shigellosis


What Is Shigellosis?Shigellosis is an infection by bacteria of the genus Shigella that causes severe abdominal symptoms, including diarrhea, dysentery, abdominal cramps, fever, and rectal pain . Shigellosis can result in death . The disease is more dangerous than other gut pathogens because it can penetrate the lining of the intestine and cause severe inflammation of the intestine and systemic complications .

Global BurdenWorldwide there are approximately 165 million cases of shigellosis annually, causing over 1 .1 million deaths . Nearly 70 percent of all episodes and approximately 60 percent of all deaths attributable to shigellosis involve children under five years old .

Geographic DistributionS. sonnei is the most common species in the United States and other industrialized countries . S. flexneri is endemic to the developing world . S. boydii is common only in India . S. dysenteriae type 1 is associated with epidemic outbreaks of shigellosis in confined populations such as can occur following natural disaster or political unrest .

Causative Agent/TransmissionShigellosis is caused by bacterial infection by one of four species of Shigella: S. dysenteriae, S. flexneri, S. boydii, and S. sonnei . Transmission occurs via consumption of food and water contaminated by human waste .

PresentationShigella bacteria multiply within the epithelial cells of the colon, cause cell death, and spread laterally to infect and kill adjacent epithelial cells, resulting in mucosal ulceration, inflammation, and bleeding . Shigella dysenteriae serotype 1 produces severe disease and may be associated with life-threatening complications . Symptoms of shigellosis

include diarrhea and/or dysentery with frequent mucoid bloody stools, abdominal cramps, and tenesmus . In some children, shigellosis causes seizure . Adults can experience Reiter’s Syndrome as a result of the disease, leading to eye and joint inflammation and reactive arthritis .

TrendsDiarrheal diseases including shigellosis represent an enormous disease burden across all developing countries . Shigellosis is also a concern for travelers .

Although shigellosis can be treated with antibiotics, the most effective drugs are expensive . Antibiotic misuse has led to the emergence of drug-resistant Shigella strains .

Prevalent Shigella species vary by geographic area

(WHO)

Shigella bacteria may penetrate the intestinal

mucosum (CDC/Eugene Gangarosa/Sam Formal,

WRAIR)

S H I G E L L O S I S




n PAllIATIVE�CARE

− Oral rehydration therapy can

be used to treat symptoms



n No FDA-approved vaccine existsn In China, a recombinant, live,

oral Bivalent FS (S. flexneri, S.

sonnei) vaccine, which has shown

60 percent efficacy in adults, is

available (Lanzhou Institute of

Vaccines and Biological Products)

n Standard clinical microbiologyn No commercially available

molecular tests



n High-potency antibiotic n Single- or 2-dose productn Oral deliveryn Effective for at least two yearsn Multivalent


shigellosis and other gut infections

such as those caused by ETEC

and diarrhea-causing protozoa



NICHD/Robbins (O-specific polysaccharide conjugate) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

WRAIR (Invaplex 50: S. flexneri 2a) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Institut Pasteur (SC599: live, attenuated S. dysenteriae 1a) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

CVD at University of Maryland (CVD 1208: Shigella) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

CVD at University of Maryland (CVD 1208S: Shigella) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

CVD at University of Maryland (Hybrid CVD 1208S: Shigella + ETEC) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

MIDRP/Venkatesan (WR Ss1: live, attenuated S. sonnei) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

MIDRP/Venkatesan (WR Ss2 & Ss3: live, attenuated S. sonnei) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

MIDRP/Venkatesan (WR Sd2: live, attenuated S. dysenteriae) nnnnnnnnnnnnnnnnnnnn

MIDRP/Venkatesan (WR Sf2 & Sf3: live, attenuated S. flexneri) nnnnnnnnnnnnnnnnnnnn

Aridis (live, attenuated typhoid vector expressing nnnnnnnnnnnnnnnnnnnn

S. sonnei, S. dysenteriae, and S. flexneri 2a O-PS)

Celldex (live, attenuated cholera vector [Peru 15] expressing S. sonnei O-PS) nnnnnnnnnnnnnnnnnnnn

Endobiologics/PATH Enteric Vaccine Initiative (O-specific polysaccharide) nnnnnnnnnnnnnnnnnnnn

Bird-C (bacterial ghosts; S. flexneri 2a) nnnnnnnnnnnnnnnnnnnn

GlycoVaxyn AG (O-specific biconjugate) nnnnnnnnnnnnnnnnnnnn






n Potential opportunity in travelers’ and military markets may improve global market opportunity .



n Antibiotic resistance n Multiple strains make it difficult

to design a multivalent vaccine

with sufficient coveragen Certain major cell-surface markers

are not immunogenic, making them

poor candidates for vaccinesn Specifications for travelers’



n Key issue is the rapid identification

of all serotypes from fecal material


General Disease Linksn World Health Organization (WHO) ~ http://www .who .int/vaccine_research/diseases/diarrhoeal/en/index6 .htmln Centers for Disease Control and Prevention (CDC) ~ http://www .cdc .gov/ncidod/dbmd/diseaseinfo/

shigellosis_g .htm

Key Organizationsn International Center for Diarrheal Disease Research, Bangladesh (ICDDR,B) ~ www .icddrb .org/pubn PATH Enteric Vaccine Initiative (EVI) ~ www .path .org/projects/enteric_vaccine

Important Papersn Von Seidlein, L, et al . A multicentre study of Shigella diarrhoea in six Asian countries: Disease burden, clinical

manifestations, and microbiology . PLoS Med 3:e359 (2006)n Walker, RI . Considerations for development of whole cell bacterial vaccines to prevent diarrheal diseases in

children in developing countries . Vaccine 23:3369-85 (2005)


Tuberculosis (TB)


What Is Tuberculosis?Tuberculosis (TB) is a pandemic bacterial disease that most commonly affects the lungs (pulmonary TB) . In otherwise healthy individuals, most infections are latent and therefore asymptomatic . About 10 percent of people infected with TB will develop disease . In immunocompromised patients such as those with HIV, active TB disease is

extremely common .

Global BurdenOne-third of the global population—2 billion people—is infected with the mycobacterium that causes TB; between 5 and 10 percent of those infected will develop active TB disease . In 2006, the WHO estimated that 9 .2 million people became sick with TB and 1 .7 million died . TB is the leading killer of HIV-positive patients .

Geographic DistributionTB is a worldwide problem, but 80 percent of the global burden is borne by only 22 countries . One-third of those infected live in India and China .

TB incidence in 2006, by WHO region, were as follows: Africa (2,807,688), the Americas (330,724), Eastern Mediterranean (569,703), Europe (433,261), Southeast Asia (3,100,355), and the Western Pacific (1,915,285) .

Causative Agent/TransmissionTB is caused by Mycobacterium tuberculosis (MTB) and is spread via an aerosol route; when people with active pulmonary TB exhale, cough, sneeze, or even talk, they release tiny droplets containing bacteria that can be inhaled by others . Once inside the lung, MTB invades and replicates within macrophages . The host’s immune response may result in the formation of granulomas that contain the infection . Alternatively, MTB may escape control by the granuloma and replicate within the lung and/or disseminate to tissues throughout the body . In contrast to many

bacteria, MTB is extremely slow-growing (~20- to 24-hour doubling time in log phase), a fact that has important implications on the course of treatment .

PresentationSymptoms of active pulmonary TB include a cough lasting more than two weeks, coughing up blood, fatigue, fever, chills, night sweats, and weight and appetite loss . Latent TB is neither contagious nor symptomatic . If a carrier’s immune system is compromised, the chance that he or she will develop active TB increases dramatically .

TrendsTB is a leading cause of death in the developing world . The recent increase in TB deaths stems from a multitude of factors including

pandemic HIV, drug resistance, war, and increasing poverty (which reduce treatment compliance) . The incidence of multidrug-resistant TB (MDR-TB) is rising at an alarming rate (an estimated 500,000 cases in 2006) and is not restricted to the developing world . Moreover, recent WHO data has revealed the existence of “super strains” of MDR-TB: 79 percent of such MDR-TB strains are resistant to three of the four first-line drugs . MDR-TB that is also resistant to certain second-line drugs is known as extensively drug-resistant TB (XDR-TB) and has recently been identified in HIV-positive populations and others . Active TB is the primary cause of HIV-related death in Africa .

Tuberculosis is a global threat

Micrograph of M. tuberculosis under a magnifica-

tion of over 15000x (CDC/Janice Carr/Ray Butler)

T U B E R C U L O S I S ( T B )






Current TB therapies are delivered as

combinations of antibiotics over six

to nine months. Serious problems of

efficacy and toxicity reduce compliance

and increase the generation of resistant

bacteria.n RIFAMPICIN

− Introduced in 1963 n ISoNIAzID,�PyRAzINAMIDE,�

STREPToMyCIN�&�ETHAMBuTol

− Introduced in 1940s–60s

− Most frequently used in three-

and four-drug combinations

− Treatment often causes

toxic side effectsn ETHIoNAMIDE,�PARA-AMINo�SAlICylATE�

(PAS),�CyCloSERINE,�AMIKACIN,�

KANAMyCIN,�FluoRoQuINoloNES

− Second-line drugs

− Generally less potent and more

toxic (except fluoroquinolones)

− Used to treat drug-resistant TB

n BCG�(BACIllE�CAlMETTE-GuERIN)

− Most widely administered

vaccine in the world

− Safe and inexpensive

− Targeted at newborn

infants only, per WHO

− Not used in the United States,

Canada, or parts of Europe, but

common in the developing world

− Variable and limited efficacy

− Appears to reduce risk of severe

childhood TB disease, but,

provides limited or no long-term

protection against pulmonary TB in

adolescents or adults; this subject

is controversial with numerous

studies providing conflicting results

Diagnostics for active case detection:n STAINED�SPuTuM�SMEAR

− Microscopic first indicator of the

presence of mycobacteria

− Provides physician with a preliminary

confirmation of the diagnosis

− Only 50 percent sensitivity; less

in HIV-positive patients

− Difficult to perform in childrenn CulTuRE

− Gold standard for diagnosis

− Common in reference labs only

− Needed for drug susceptibility testing

to diagnose MDR- and xDR-TBn NuClEIC�ACID�AMPlIFICATIoN�

− Rapid, sensitive

− Used mainly in research

− Too expensive for use in

developing countriesn QuANTIFERoN-TB�GolD�&�

T-SPoT.TB�ANTIGEN�TESTS

− Detects immune response

(interferon) to antigens unique to MTB

Diagnostics to detect latent TB:n PuRIFIED�PRoTEIN�DERIVATIVE�(PPD)�

SKIN�TEST,�A.K.A.�MANToux�TEST

− Nonspecific; can be misleading

due to prior BCG vaccination

− Does not work in HIV-positive patients

There are no rapid, point-of-care

diagnostics to distinguish latent from

active disease.



n Rapid acting (courses of two months

or less) n Can be co-administered with

antiretroviralsn Safer than existing treatmentsn Effective against MDR-TB and xDR-TBn Highly potent

n Safe to administer to HIV-positive

infants and to adolescentsn At least 70 percent efficacy

against TB diseasen At least as safe as BCG

New products for active case detection:n Rapid and easily performedn Specific and sensitive n Able to distinguish latent

TB from active diseasen Effective in HIV-positive

patients and in childrenn Unaffected by prior BCG vaccination



PIPElINE � (SElECT � ITEMS � oNly)nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn


OFLOTUB consortium/EU/TDR/IRD/Lupin (gatifloxacin) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

TB Alliance/Bayer/University College London/British MRC (moxifloxacin) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Tibotec/Johnson & Johnson (TMC 207: diarylquinolines) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

TB Alliance (PA-824: nitroimidazole) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Otsuka (OPC-67683: nitroimidazole) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Sequella/NIH (SQ-109: diamine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Lupin Pharmaceuticals (LL-3858: pyrrole) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

TB Alliance/KRICT/yonsei University (TBK-613: quinolone) nnnnnnnnnnnnnnnnnnnn

Sequella (SQ-609: dipiperidine) nnnnnnnnnnnnnnnnnnnn

Eli Lilly drug discovery partnership/ nnnnnnnnnnnnnnnnnnnn

Microbial Chemistry Research Foundation (CPzEN-45)

Eli Lilly drug discovery partnership/Summit plc. (anti-TB compounds) nnnnnnn

Dafra Pharma (DF-152) nnnnnnn

FASgen (FAS20013: synthase inhibitor) nnnnnnn

Sequella (SQ-641: capuromycin) nnnnnnn

Vertex (kinase inhibitors) nnnnnnn

TB Alliance/University of Auckland/University of Illinois, Chicago nnnnnnn

(nitroimidazole analogs)

TB Alliance/University of Auckland/Colorado State University nnnnnnn

(multifunctional molecules)

TB Alliance/GSK (mycobacterial gyrase inhibitor) nnnnnnn

TB Alliance/GSK (InhA inhibitors) nnnnnnn

TB Alliance/GSK/Texas A&M (malate synthase inhibitor) nnnnnnn

TB Alliance/Institute of Materia Medica/BTTTRI (riminophenazines) nnnnnnn

TB Alliance/University of Pennsylvania/University of Illinois, Chicago nnnnnnn

(energy metabolism inhibitors)

TB Alliance/University of Illinois, Chicago (phenotypic screening) nnnnnnn

TB Alliance/IDRI (protease inhibitors) nnnnnnn

TB Alliance/Novartis Institute for Tropical Disease (various projects) nnnnnnn

TB Alliance/Rutgers (RNA pol inhibitors) nnnnnnn

TB Alliance/IMCAS (natural product screening) nnnnnnn

Astrazeneca (screening and target identification) nnnnnnn






Oxford University/Emergent BioSolutions/Aeras (MVA-85A/AERAS-485) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

GSK/Aeras (GSK M72) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Crucell/Aeras (Crucell Ad35/AERAS-402) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

SSI/Intercell/Sanofi-Pasteur/Aeras (HyVac 4/AERAS-404) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

SSI/Intercell/TBVAC (Hybrid 1: 85B-ESAT-6) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Aeras (AERAS-405: double stranded RNA nucleocapsids encoding Mtb antigens) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Aeras (AERAS-407: rBCG) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Vakzine Projekt Management/Max Planck Institute (VPM1002: rBCG: ΔureC-Hly) nnnnnnnnnnnnnnnnnnnn

Albert Einstein College of Medicine (live, attenuated Mtb derivatives) nnnnnnnnnnnnnnnnnnnn

Institut Pasteur/University of zaragoza (live, attenuated Mtb ΔphoP/R) nnnnnnnnnnnnnnnnnnnn

UCLA/NIAID (rBCG30ARMF, rBCG(MtbB)30, rBCG-hIFN-g) nnnnnnnnnnnnnnnnnnnn

Karolinska Institute (Nas L3/Htk BCG) nnnnnnnnnnnnnnnnnnnn

Karolinska Institute (Nas L3/AM85B conjugate) nnnnnnnnnnnnnnnnnnnn

Institut Pasteur/INSERM/TB-VAC (heparin-binding haemagglutin protein nnnnnnnnnnnnnnnnnnnn

purified from M. bovis BCG)

ImmunoBiology/Aeras (HspC™ TB vaccine) nnnnnnnnnnnnnnnnnnnn

Discovery� � Preclinical�� Clinical�Diagnostics� � � � � �

Nucleic�acid�detection

FIND/Cepheid/UMDMJ (Genexpert System TB) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

FIND/Eiken Chemical (LAMP-based dx) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

FIND and partners (urinary NAAT) nnnnnnn

Antibody�or�antigen�detection

FIND/Tauns Co. Ltd. (Capilia TB test) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Sequella (transdermal TB patch) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Tyrian Diagnostics/Becton-Dickinson/FIND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(TB DiagnosticIQ™: rapid antigen-based)

FIND and partners (Mycobacterial lipoarabinomannan [LAM] nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

antigen detection in urine)

ChemBio/IDRI (serologic rapid TB test using Dual Path Platform [DPP™]) nnnnnnn

FIND and partners (dipstick antibody test) nnnnnnn




n According to the Global Alliance for TB Drug Development (TB Alliance), the current TB drug market is estimated at $450 million and is projected to reach $700 million by 2010 .

n With 9 million new cases each year, and manyfold greater new latent infections, there is a very large target patient population .

n BVGH estimates the peak annual market for a TB vaccine is over $750 million for a booster vaccine and over $400 million for a BCG replacement vaccine, with most of these revenues coming from developed and emerging economies .

n Despite potentially profitable developed and emerging country markets, donor support will still be needed for delivery to the neediest patients .



n Latent infection is difficult to

clear with standard antibioticsn Non-replicating, persistent MTB

are often minimally affected

by standard antibiotics

n Lack of immune correlates of

protection or surrogate markers that

predict clinical efficacy of a vaccinen Development and maintenance

of clinical trial site capacity

n New diagnostics will require

the discovery of TB-specific

serum biomarkers


General Disease Linksn World Health Organization (WHO) ~ www .who .int/tb/enn Centers for Disease Control and Prevention (CDC) ~ www .cdc .gov/nchstp/tb/default .htm

Key Organizationsn Aeras Global TB Vaccine Foundation ~ www .aeras .orgn Foundation for Innovative New Diagnostics (FIND) ~ www .finddiagnostics .orgn Global Alliance for TB Drug Development ~ www .tballiance .orgn Global Fund to Fight AIDS, Tuberculosis and Malaria ~ www .theglobalfund .org/enn Special Programme for Research and Training in Tropical Diseases (TDR) ~ www .who .int/tdrn Stop TB Partnership ~ www .stoptb .org

Important Papersn Andries, K, et al . A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis.

Science 307:223-7 (2005)n Gandhi, NR, et al . Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with

tuberculosis and HIV in a rural area of South Africa . Lancet 368:1575-80 (2006)n Keeler, E, et al . Reducing the global burden of tuberculosis: The contribution of improved diagnostics . Nature S1,

49-57 (2006)n Reichman, LB, and Tanne, JH . Timebomb: The Global Epidemic of Multi-drug Resistant Tuberculosis. New York:

McGraw-Hill (2002)n Skeiky, YAW, and Sadoff, JC . Advances in tuberculosis vaccine strategies . Nature Rev: Microbiol 4:469-76 (2006) n The Stop TB Strategy ~ www .who .int/tb/publications/2006/who_htm_tb_2006_368 .pdfn Tuberculosis Vaccines: The Case for Investment ~ www .bvgh .org/documents/

BVGHTBVaccineReport10-6FINAL .pdfn WHO Report 2008: Global Tuberculosis Control ~ www .who .int/tb/publications/global_report/2008/

pdf/fullreport .pdf

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Phone: +1 202-312-9260

Fax: +1 443-320-4430

www.bvgh.org

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bvgh global health primer 2009

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