Building Biotech Solutions for Diseases of the Developing World
BVGH Global Health PrimerAugust 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
7 BVGH Global Health Primer
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 ?
9 BVGH Global Health Primer
W H y T H E G L O B A L H E A L T H P R I M E R ?
BVGH Global Health Primer 9
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.
10 BVGH Global Health Primer
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.
W H y T H E G L O B A L H E A L T H P R I M E R ?
W H y T H E G L O B A L H E A L T H P R I M E R ?
BVGH Global Health Primer 11
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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12 BVGH Global Health Primer
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 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.
W H y T H E G L O B A L H E A L T H P R I M E R ?
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
W H y T H E G L O B A L H E A L T H P R I M E R ?
14 BVGH Global Health Primer
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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16 BVGH Global Health Primer
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
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BVGH Global Health Primer 17BVGH Global Health Primer 17
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
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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
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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
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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.
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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.
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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.
K E y G L O B A L H E A L T H P L A y E R S
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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
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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
BVGH Global Health Primer 25
Select Companies Working in Global Health
26 BVGH Global Health Primer
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
29 BVGH Global Health Primer
Disease Sheets
30 BVGH Global Health Primer
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
BVGH Global Health Primer 31BVGH Global Health Primer 31
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
32 BVGH Global Health Primer
DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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)
BVGH Global Health Primer 33
Cholera
BACKGRouND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
34 BVGH Global Health Primer
ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
NEW� PRoDuCT � NEEDS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
PIPElINE nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
� 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
MARKET � oPPoRTuNIT IES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n Potential commercial opportunities for vaccines through military and travelers’ applications .
DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
BVGH Global Health Primer 35BVGH Global Health Primer 35
ADDIT IoNAl � INFoRMATIoN nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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)
36 BVGH Global Health Primer
Dengue Fever (DF)
BACKGRouND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
BVGH Global Health Primer 37BVGH Global Health Primer 37
ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn�
Drugs Vaccines Diagnostics
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)
NEW� PRoDuCT � NEEDS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
PIPElINE nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
� Pre-� Clinical-�� Clinical-� Clinical-�Drugs� Discovery� Clinical� Phase�I� Phase�II� �Phase�III
Novartis Institute for Tropical Diseases (inhibitors of viral and host targets) nnnnnnn
SIGA (ST 981, ST 610, ST 689, and ST 562) nnnnnnn
� Pre-� Clinical-�� Clinical-� Clinical-�Vaccines� Discovery� Clinical� Phase�I� Phase�II� �Phase�III
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
MARKET � oPPoRTuNIT IES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
38 BVGH Global Health Primer
DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
ADDIT IoNAl � INFoRMATIoN nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 )
BVGH Global Health Primer 39
Enterotoxigenic E. coli (ETEC)
BACKGRouND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
40 BVGH Global Health Primer
ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n PAllIATIVE�CARE
− Oral rehydration therapy can
be used to treat symptoms
− Antibiotics and intravenous fluids
are sometimes given in severe cases
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
NEW� PRoDuCT � NEEDS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n High-potency antibiotic n Oral deliveryn Multivalentn Provide extended protection to
infants and young children
n Ability to differentiate between
ETEC and other causes of
diarrhea, including protozoa
PIPElINE nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn��
� Pre-� Clinical-�� Clinical-� Clinical-�Vaccines� Discovery� Clinical� Phase�I� Phase�II� �Phase�III
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)
MARKET � oPPoRTuNIT IES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
BVGH Global Health Primer 41BVGH Global Health Primer 41
DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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’
and military markets may differ
from endemic markets
n None
ADDIT IoNAl � INFoRMATIoN nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 )
42 BVGH Global Health Primer
Human African Trypanosomiasis (HAT)
BACKGRouND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
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43 BVGH Global Health Primer
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
43 BVGH Global Health Primer
ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
NEW� PRoDuCT � NEEDS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
BVGH Global Health Primer 43
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 )
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44 BVGH Global Health Primer
PIPElINE nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
MARKET � oPPoRTuNIT IES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n Primarily a disease of impoverished rural communities and will require donor support to encourage innovation .
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 )
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
BVGH Global Health Primer 45
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DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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)
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 )
46 BVGH Global Health Primer
Human Hookworm Infection
BACKGRouND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
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ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
NEW� PRoDuCT � NEEDS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
PIPElINE nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
MARKET � oPPoRTuNIT IES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 .
DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
48 BVGH Global Health Primer
ADDIT IoNAl � INFoRMATIoN nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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)
BVGH Global Health Primer 49
Human Immunodeficiency Virus (HIV)
BACKGRouND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 )
50 BVGH Global Health Primer
ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
NEW� PRoDuCT � NEEDS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
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PIPElINE* nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
� Pre-� Clinical-�� Clinical-� Clinical-�Vaccines� Discovery� Clinical� Phase�I� Phase�II� �Phase�III
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 .
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 )
52 BVGH Global Health Primer
MARKET � oPPoRTuNIT IES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 .
DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
ADDIT IoNAl � INFoRMATIoN nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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)
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 )
BVGH Global Health Primer 53
Japanese Encephalitis (JE)
BACKGRouND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
54 BVGH Global Health Primer
ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
NEW� PRoDuCT � NEEDS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
PIPElINE nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Discovery� Pre-� Clinical-�� Clinical-� Clinical-�Vaccines� � Clinical� Phase�I� Phase�II� �Phase�III
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
MARKET � oPPoRTuNIT IES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n Significant opportunity in travelers’ and military markets . n One company estimates a global market of over $300 million .
DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
BVGH Global Health Primer 55BVGH Global Health Primer 55
ADDIT IoNAl � INFoRMATIoN nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 )
56 BVGH Global Health Primer
Leishmaniasis
BACKGRouND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
BVGH Global Health Primer 57
L E I S H M A N I A S I S
BVGH Global Health Primer 57
ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
NEW� PRoDuCT � NEEDS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
L E I S H M A N I A S I S
58 BVGH Global Health Primer
PIPElINE nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
� Pre-� Clinical-�� Clinical-� Clinical-�Drugs� Discovery� Clinical� Phase�I� Phase�II� �Phase�III
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
� Pre-� Clinical-�� Clinical-� Clinical-�Vaccines� Discovery� Clinical� Phase�I� Phase�II� �Phase�III
IDRI/GSK (leish-111f + MPL-SE) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
MARKET � oPPoRTuNIT IES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 .
DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
L E I S H M A N I A S I S
BVGH Global Health Primer 59
L E I S H M A N I A S I S
BVGH Global Health Primer 59
ADDIT IoNAl � INFoRMATIoN nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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)
60 BVGH Global Health Primer
Lymphatic Filariasis (LF)
BACKGRouND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 )
BVGH Global Health Primer 61BVGH Global Health Primer 61
ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
NEW� PRoDuCT � NEEDS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
L y M P H A T I C F I L A R I A S I S ( L F )
62 BVGH Global Health Primer
PIPElINE nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
� Pre-� Clinical-�� Clinical-� Clinical-�Drugs� Discovery� Clinical� Phase�I� Phase�II� �Phase�III
Anti-Wolbachia Consortium: Liverpool School of Tropical Medicine/ nnnnnnn
CombinatoRx/New England Biolabs, and others (anti-Wolbachia treatments)
MARKET � oPPoRTuNIT IES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 .
DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
ADDIT IoNAl � INFoRMATIoN nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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)
L y M P H A T I C F I L A R I A S I S ( L F )
BVGH Global Health Primer 63
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
64 BVGH Global Health Primer
ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
NEW� PRoDuCT � NEEDS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
BVGH Global Health Primer 65
M A L A R I A
BVGH Global Health Primer 65
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
66 BVGH Global Health Primer
Discovery� Pre-� Clinical-�� Clinical-� Clinical-�Vaccines� � Clinical� Phase�I� Phase�II� �Phase�III
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
MARKET � oPPoRTuNIT IES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 .
DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
BVGH Global Health Primer 67
M A L A R I A
BVGH Global Health Primer 67
ADDIT IoNAl � INFoRMATIoN nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
68 BVGH Global Health Primer
Pneumococcal Disease
BACKGRouND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 .
ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn�
Drugs Vaccines Diagnostics
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
BVGH Global Health Primer 69BVGH Global Health Primer 69
NEW� PRoDuCT � NEEDS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
PIPElINE nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
� Pre-� Clinical-�� Clinical-� Clinical-�Vaccines� Discovery� Clinical� Phase�I� Phase�II� �Phase�III
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
MARKET � oPPoRTuNIT IES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 .
DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
P N E U M O C O C C A L D I S E A S E
70 BVGH Global Health Primer
ADDIT IoNAl � INFoRMATIoN nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
P N E U M O C O C C A L D I S E A S E
BVGH Global Health Primer 71
Rotavirus Gastroenteritis
BACKGRouND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
72 BVGH Global Health Primer
ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn�
Drugs Vaccines Diagnostics
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
NEW� PRoDuCT � NEEDS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
PIPElINE nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
�� 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 .
MARKET � oPPoRTuNIT IES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 .
DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n None n No increased risk of intussusceptionn EPI schedule-compatible
n None
R O T A V I R U S G A S T R O E N T E R I T I S
BVGH Global Health Primer 73
R O T A V I R U S G A S T R O E N T E R I T I S
BVGH Global Health Primer 73
ADDIT IoNAl � INFoRMATIoN nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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)
74 BVGH Global Health Primer
Schistosomiasis
BACKGRouND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
BVGH Global Health Primer 75
S C H I S T O S O M I A S I S
BVGH Global Health Primer 75
ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
NEW� PRoDuCT � NEEDS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
PIPElINE nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Discovery� Pre-� Clinical-�� Clinical-� Clinical-�Drugs� � Clinical� Phase�I� Phase�II� �Phase�III
UCSF Sandler Center (K11777 cysteine protease inhibitor) nnnnnnnnnnnnnnnnnnnn
Illinois State University/NIH (oxadiazoles) nnnnnnn
Discovery� Pre-� Clinical-�� Clinical-� Clinical-�Vaccines� � Clinical� Phase�I� Phase�II� �Phase�III
Fiocruz (S. mansoni Sm14) nnnnnnnnnnnnnnnnnnnn
SVI-HHVI (Sm-TSP-2) nnnnnnnnnnnnnnnnnnnn
MARKET � oPPoRTuNIT IES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n This is primarily a disease of the very poor . Donor support will be required to encourage innovation .
DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
S C H I S T O S O M I A S I S
76 BVGH Global Health Primer
ADDIT IoNAl � INFoRMATIoN nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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)
S C H I S T O S O M I A S I S
BVGH Global Health Primer 77
Shigellosis
BACKGRouND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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
78 BVGH Global Health Primer
ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n PAllIATIVE�CARE
− Oral rehydration therapy can
be used to treat symptoms
− Antibiotics and intravenous fluids
are sometimes given in severe cases
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
NEW� PRoDuCT � NEEDS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n High-potency antibiotic n Single- or 2-dose productn Oral deliveryn Effective for at least two yearsn Multivalent
n Ability to differentiate between
shigellosis and other gut infections
such as those caused by ETEC
and diarrhea-causing protozoa
PIPElINE nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Discovery� Pre-� Clinical-�� Clinical-� Clinical-�Vaccines� � Clinical� Phase�I� Phase�II� �Phase�III
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
S H I G E L L O S I S
BVGH Global Health Primer 79
S H I G E L L O S I S
BVGH Global Health Primer 79
MARKET � oPPoRTuNIT IES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n Potential opportunity in travelers’ and military markets may improve global market opportunity .
DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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’
and military markets may differ
from endemic markets
n Key issue is the rapid identification
of all serotypes from fecal material
ADDIT IoNAl � INFoRMATIoN nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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)
80 BVGH Global Health Primer
Tuberculosis (TB)
BACKGRouND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 )
BVGH Global Health Primer 81
T U B E R C U L O S I S ( T B )
BVGH Global Health Primer 81
ExIST ING � PRoDuCTS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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.
NEW� PRoDuCT � NEEDS nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
T U B E R C U L O S I S ( T B )
82 BVGH Global Health Primer
PIPElINE � (SElECT � ITEMS � oNly)nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Discovery� Pre-� Clinical-�� Clinical-� Clinical-�Drugs� � Clinical� Phase�I� Phase�II� �Phase�III
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
T U B E R C U L O S I S ( T B )
BVGH Global Health Primer 83
T U B E R C U L O S I S ( T B )
BVGH Global Health Primer 83
Discovery� Pre-� Clinical-�� Clinical-� Clinical-�Vaccines� � Clinical� Phase�I� Phase�II� �Phase�III
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
T U B E R C U L O S I S ( T B )
84 BVGH Global Health Primer
MARKET � oPPoRTuNIT IES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 .
DEVEloPMENT � ISSuES nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
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
ADDIT IoNAl � INFoRMATIoN nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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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