Professional Documents
Culture Documents
October 2007
List of Abbreviations. . . . . . . . . . . . . . . . . . . . . . . . . . 6
Biotech Solutions. . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Disease Sheets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
African Trypanosomiasis. . . . . . . . . . . . . . . . . . . 24
Chagas Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Cholera. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Leishmaniasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Malaria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Schistosomiasis. . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Shigellosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Tuberculosis (TB) . . . . . . . . . . . . . . . . . . . . . . . . . 62
About BVGH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Founded
2004
Supporters
Bill & Melinda Gates Foundation
Biotechnology Industry
Organization
The Rockefeller Foundation
Industry Leaders
Management
Christopher D. Earl, PhD
President & CEO
Wendy Taylor
Founder, Vice President,
Strategy & Operations
Julie S. Klim
Vice President,
Business Development
Board of Directors
Robert 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
M e ss a g e t o R e a d e rs
Dear Reader:
As our knowledge expands, our world becomes smaller. We are increasingly aware of the
challenges faced by the world’s poorest citizens. Each year infectious diseases—many of them
potentially preventable or treatable—ravage families throughout the developing world. Some
lose their ability to work, many lose their loved ones, and others lose their lives.
However, to ensure that the next generation of products enters the development pipeline,
it is essential that we commit an unprecedented investment in new product discovery.
Otherwise we may never see the day when poor families, particularly children, can escape
the effects of disease.
We have created this primer to serve as a reference tool for those interested in understanding
the major challenges and opportunities in global health. It summarizes the infectious diseases
that cause the greatest burden of disease, outlines the technologies currently available, and
points out gaps in our armamentarium. It also describes the existing pipelines of emerging
medicines and highlights areas where innovation is required. Finally, it identifies many of
the major players in global health, including international non-governmental organizations,
governments, academia and industry, who are working together to accelerate global health
research and development.
The information contained in this document was compiled from various sources including, but
not limited to, the World Health Organization, the Centers for Disease Control and Prevention,
product development partnerships, and biopharmaceutical companies. We have highlighted
additional references throughout the document where you can obtain further information.
BIO Ventures for Global Health fosters collaboration among groups and individuals working
to ensure that new medicines are introduced in the developing world. We are working to
build incentives that will draw the best of biopharmaceutical industry resources and expertise
to this fight. We hope this document will motivate many to seek innovative solutions for the
devastating diseases described in the following pages. Collectively, we have the ability to create
a better world for millions of people.
Sincerely yours,
Leading Causes of Mortality and Disease Burden from Infectious Diseases (2002)
* DALYs – Disability adjusted life years: The sum of the years of life lost due to premature mortality and disability.
180
160
140
(In US Dollars)
120
$102
100 $93
80
$63
60
40
$24
20 $11 $6
0
cer es gue ar S TB lari
a
Can bet Den cul /AID Ma
Dia i o vas HIV
a r d
C
Source: Lewison, G, et al. Outputs and expenditures on health research in
eight disease areas, 1996-2001. Global Forum for Health Research Forum 8,
Mexico City, November 2004
Funding Source Funds Available (in US $billions) Advance Market Commitments (AMCs)
The Bill & Melinda Gates $1.5 per year, with $900 n An AMC is an innovative financing mechanism in
Foundation million for global health
which major donors guarantee a market as incentive for
Warren Buffett’s contribution to $1.6 per year by 2009
the Gates Foundation
industry to supply the developing world’s demand for
Global Alliance for Vaccines and vaccines targeting neglected diseases.
$1.7 since inception
Immunization (GAVI Alliance)
n A pilot $1.5 billion AMC program for pneumococcal
International Financing Facility for $4.0 over 10 years
Immunization (IFFIm) through 2015
vaccines was launched in February 2007 funded by
President’s Emergency Plan for $15.0 from 2003-2008 Italy, the United Kingdom, Canada, Russia, Norway,
AIDS Relief (PEPFAR) $30.0 from 2008-2013 and the Gates Foundation.
Global Fund for AIDS, TB & Malaria $7.7 spent to date
(Global Fund) n The AMC will supplement the vaccine market in target
President’s Malaria Initiative (PMI) $1.2 over 5 years countries by subsidizing the purchase of vaccines at an
agreed-upon price that makes them affordable to the
world’s poorest countries.
Important Papers
n BIO Ventures for Global Health. Advance Market Commitments to Stimulate Industry Investment in Global Health
Product Development (2006) ~ http://bvgh.org/documents/BVGH_AMCReport_Complete_000.pdf
n Center for Global Development. Making Markets for Vaccines–Ideas to Action (2005) ~ www.cgdev.org/section/initiatives/_active/vaccinedevelopment
n Ridley, DB, et al. Developing Drugs for Developing Countries. Health Affairs 25:313-324 (2006)
n Tremonti, G. Ministero dell’Economia e delle Finanze. Advanced Market Commitments for vaccines–A new
tool in the fight against disease and poverty. Report to the G8 Finance Ministers (2005)
n More than any other cancer, cervical cancer reflects n Drug discovery platforms focused on targets such as
striking global health inequity. More than 80 proteases, kinases, and cell motility factors that control
percent of the 300,000 worldwide deaths from this diseases such as cancer and cardiovascular disease can
devastating disease occur in developing countries. be applied to analogous targets in neglected diseases.
Human papillomavirus (HPV) vaccines produced by
Merck and GSK, using MedImmune technology, stand Select companies investing in neglected disease R&D
to substantially reduce this burden and efforts are
AstraZeneca: Tuberculosis
under way to make these vaccines affordable in the AVANT Immunotherapeutics and IOMAI: ETEC
developing world. Genzyme: Malaria, African trypanosomiasis
Market Incentives
n In February 2007, five countries belonging to the Organisation for Economic Co-operation
and Development (OECD) and the Gates Foundation launched a $1.5 billion pilot Advance
Market Commitment to fund the purchase of novel vaccines against pneumococcal disease
for developing countries.
n In September 2007, the United States enacted the FDA Amendments Act with an amendment
that creates a transferable priority review voucher for companies that obtain approval for
drugs or vaccines targeting neglected diseases.
Aeras Global TB Vaccine n Leads the effort to develop a new vaccine for tuberculosis; working on both improved
Foundation — Aeras live attenuated vaccines and subunit vaccines; lead products entering Phase I
www.aeras.org n Partnering with GlaxoSmithKline, Crucell, Intercell and Statens Serum Institute
Focus: Vaccines for tuberculosis for both second-generation BCG and novel TB vaccines
n Working with the University of Cape Town and St. John’s Medical College,
Bangalore, to develop clinical trials facilities in South Africa and southern India,
respectively
n Has received over $100 million in funding, principally from the Gates
Foundation with a new $200 million grant announced in September 2007
n In 2006, opened a new vaccine research and production facility in Rockville, MD
Drugs for Neglected n Formed in 2003 by leaders from Medecins Sans Frontieres (MSF) with support
Diseases Initiative — from multiple NGOs and governments
DNDi n Focuses primarily on trypanosomal diseases and malaria; portfolio includes a
www.dndi.org range of discovery, preclinical, and clinical projects
Focus: Drugs for leishmaniasis, n Launched its first product in March 2007, a new antimalaria formulation,
African trypanosomiasis, Chagas artesunate-amodiaquine (ASAQ), in collaboration with Sanofi-Aventis
disease, and malaria n Has received $48.2 million in funding from MSF and the British and French
governments
Foundation for Innovative n The only PDP to focus on diagnostics—initial focus on TB expanded to malaria
New Diagnostics — FIND and human African trypanosomiasis
www.finddiagnostics.org n Partnering with Cepheid, ImmPORT, Proteome Systems, Hain Lifesciences,
Focus: Diagnostics for Roche Diagnostics, Becton, Dickinson and Company (BD), Cellestis, and the
tuberculosis and other diseases government of Lesotho
n In September 2007, announced funding of $62 million over five years for TB
diagnostics
Global Alliance for TB n Leading developer of new drugs for TB; founded in 2000
Drug Development — n Announced Phase III trials of moxifloxacin in combination with other drugs; a
TB Alliance new compound, PA-824, has completed Phase I trials; several discovery projects
www.tballiance.org in early pipeline
Focus: Drugs for tuberculosis n Partnering with Bayer, GlaxoSmithKline, Novartis, BG Medicine, Cumbre, and
the Institute of Materia Medica in China
n Has raised over $193 million, principally from the Gates Foundation and
European governments
International AIDS n Leading global partnership for developing an HIV/AIDS vaccine; founded in 1996
Vaccine Initiative — IAVI n Pipeline includes six vaccine candidates currently in clinical trials
www.iavi.org n Partnering with Targeted Genetics, Biosciences UK, and Becton, Dickinson and
Focus: Vaccines for HIV/AIDS Company.
n Has received $340 million in contributions since 1997; current annual budget
nearly $100 million
Medicines for Malaria n Leading organization developing new drugs and combination treatments
Venture — MMV for malaria
www.mmv.org n Lead product is PYRAMAX®, pyronaridine-artesunate, currently in Phase III
Focus: Drugs for malaria trials; has a broad portfolio of projects from discovery through Phase III trials
n Partnering with GlaxoSmithKline and Novartis on the discovery of new
antimalarials
n Has received $113 million in funding from the Gates Foundation and other
sources, with an additional $30 million of “in-kind” contributions
Malaria Vaccine n An independent unit of PATH created in 1999; leader in malaria vaccine
Initiative — MVI development
www.malariavaccine.org n The most advanced candidate, RTS,S, partnered with GlaxoSmithKline, is
Focus: Vaccines for malaria entering Phase III clinical trials; also partnering with Sanaria, Shanghai Wanxing
Bio-Pharmaceuticals Co., Walter Reed Army Institute of Research (WRAIR), and
GenVec, among others
n Has raised nearly $260 million in funding, principally from the Gates
Foundation
I n t e rn a t ion a l a nd M u l t il a t e r a l O rg a ni z a t ions a nd I ni t i a t iv e s
Bill & Melinda Gates Launched in 2000 with an endowment of $29.1 billion, the foundation supports
Foundation
work in the areas of global health, global development, and improving public
schools in the United States. Grant commitments to date total $13.6 billion with
www.gatesfoundation.org
average annual commitments of $1.5 billion. By 2009, the foundation will begin
to disburse an additional $1.6 billion a year from the 2006 bequest of $31 billion
from Warren Buffett.
Department for The government of the United Kingdom aid and development arm, DFID aims
International Development to reduce world poverty through long-term programs that tackle its underlying
— DFID causes. DFID is a major supporter of Advanced Market Commitments (AMCs)
www.dfid.gov.uk and other programs to improve health in the developing world. Its annual budget
is roughly $6 billion.
Foundation for the Founded in 1996, FNIH was established by the NIH as a flexible funding
National Institutes organization to support pioneering biomedical research. Along with the Gates
of Health — FNIH Foundation, FNIH administers the Gates Grand Challenges within the Global
www.fnih.org Health Program.
International Center ICDDR,B is an international health research institution that conducts research,
for Diarrheal Disease training, and program-based activities in collaboration with partners from
Research, Bangladesh academic and research institutions throughout the world. In 2006, the
— ICDDR,B organization received almost $24 million with large portions from USAID,
www.icddrb.org the United Kingdom’s Department for International Development, and the
government of Bangladesh.
International Financing IFFIm is a financing facility backed by several European governments to finance
Facility vaccine commitments. These commitments will be floated on the international
for Immunization — IFFIm bond market in order to “front-load” predictable funding to GAVI for enhanced
www.iffim.com vaccination programs. IFFIm provided $800 million, or 90 percent, of GAVI’s
2007 expenditures.
International Vaccine The IVI, established by the United Nations Development Program with the
Institute support of 35 countries and the WHO, supports collaborative research to
(UN Program hosted by accelerate the introduction of new vaccines into developing countries. IVI’s focus
Korea) — IVI includes basic and applied laboratory research, product development, training,
www.ivi.org and technical assistance.
Formerly Global Alliance An alliance between the public and private sector, GAVI has raised more than
for Vaccines and $3.3 billion for the purchase and distribution of vaccines to children in the
Immunisation — developing world. GAVI’s funding comes from national governments and a 15-
GAVI Alliance year, $1.5 billion grant from the Gates Foundation. GAVI estimates its efforts
www.vaccinealliance.org have saved the lives of 2.3 million children.
The Global Fund to Fight Since 2002, the Global Fund has directed global financing of interventions
AIDS, TB and Malaria against HIV, tuberculosis, and malaria. The Global Fund has committed $7.7
— Global Fund billion in 136 countries to prevention and treatment, and has developed
www.theglobalfund.org innovative systems to measure its success.
National Institute for Part of the NIH, NIAID provides support for research into infectious,
Allergy and Infectious immunologic, and allergic diseases. NIAID is the leading arm of the United
Diseases — NIAID States government promoting research into preventions and cures for HIV/AIDS,
www.niaid.nih.gov influenza, and infectious diseases of the developing world.
Pan American Health PAHO is an international public health agency working to improve health and
Organization — PAHO living standards of the countries of the Americas. It serves as the WHO’s Latin
www.paho.org America regional office and is the main purchaser of vaccines in Latin America.
President’s Emergency A $15 billion, five-year plan announced by President Bush in 2003, PEPFAR
Plan for AIDS Relief — aims to dramatically scale up HIV/AIDS prevention, diagnosis and treatment in
PEPFAR 15 target countries. The president recently announced a plan to renew PEPFAR
www.pepfar.gov and double its funding to $30 billion for 2008-2013.
President’s Malaria Begun in 2005, the PMI will increase malaria funding by $1.2 billion over five
Initiative — PMI years with the goal of reducing deaths from malaria by 50 percent in 15 African
www.pmi.gov countries. The PMI is working with multiple public and private sector partners in
programs to distribute bed nets, drugs and insecticides.
The Rockefeller Established in 1913, the foundation has $3.4 billion in assets that support
Foundation programs in health, globalization, arts and culture, agriculture, housing, and
www.rockfound.org education. Many of today’s largest product development partnerships (PDPs)
were founded with seed financing from the foundation.
Special Programme for TDR, an independent program established by WHO, supports research and
Research and Training development to combat 10 of the most devastating tropical diseases through
in Tropical Diseases grants and partnerships. It coordinates worldwide efforts in discovery research
— TDR for neglected diseases.
www.who.int/tdr
United Nations The UNDP is the United Nation’s principal provider of advice, advocacy, and
Development Program grant support to foster development initiatives.
— UNDP
www.undp.org
United Nations Children’s UNICEF provides long-term humanitarian and developmental assistance to
Fund — UNICEF children and mothers in developing countries. UNICEF is the global leader in
www.unicef.org vaccine supply, reaching 40 percent of the world’s children. In 2002, UNICEF
procured two billion vaccine doses.
United States Agency for USAID is the United States government’s foreign aid and development
International Development organization. The population, health, and nutrition sector works to stabilize
— USAID world population and protect human health. USAID administers PEPFAR and
www.usaid.gov other disease-targeted programs.
The Wellcome Trust The Wellcome Trust is the largest funder of biomedical research in the United
www.wellcome.ac.uk Kingdom. The Trust has a strong interest in infectious disease and has focused
significant funding in 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. Wellcome Trust funding helped to
produce the malaria treatment artemisinin.
World Health Organization WHO is the agency of the United Nations that acts as a coordinating authority
— WHO on international public health. WHO’s major aim is to combat disease, especially
www.who.int/en infectious diseases, and to promote the general health of the peoples of the world.
The Broad Institute of MIT n A biomedical research institute researching all aspects of human disease;
and Harvard
founded with $100 million from Eli and Edythe Broad
n Collaborating with MMV and Genzyme to identify new malaria therapeutics
www.broad.mit.edu
Infectious Disease n Leading independent research institute focused on developing treatments and
Research Institute — IDRI vaccines for infectious diseases
www.idri.org n Lead program is a vaccine for leishmaniasis
Focus: Leishmaniasis, n Funded by the Gates Foundation, GlaxoSmithKline, the NIH, and American
tuberculosis, leprosy, Chagas Leprosy Missions; actively seeks industrial partnerships
disease, chlamydia, Buruli ulcer
Sabin Vaccine Institute n Funds the Hookworm Vaccine Initiative and the Center for Neglected
www.sabin.org Tropical Disease Control and Elimination
Focus: Neglected diseases n Budget of $14 million in 2007
Seattle Biomedical n Leading independent research institution, funded by grants, with a strong
Research Institute — SBRI focus on neglected diseases, particularly malaria and tuberculosis
www.sbri.org n Created a genetically attenuated whole-organism malaria vaccine that
Focus: Malaria, tuberculosis, conferred protection in a rodent model
HIV/AIDS, trypanosomal diseases, n Annual budget of approximately $25 million
toxoplasmosis, and H. influenzae
associated diseases
UCSF Sandler Center n Combines academic groups and resources to simulate a pharmaceutical R&D
www.ucsf.edu/mckerrow/ division
slide.html n Maintains open-access “Low Hanging Fruit” database; a set of FDA-approved
Focus: Parasitic diseases drugs that have shown promise against T. brucei and Leishmania
n Building compound libraries for drug screening
University of North n Developing pafuramidine, an oral drug currently in Phase III clinical trials, for
Carolina Consortium for the treatment of sleeping sickness
Parasitic Drug n Consortium members include the University of North Carolina, Georgia State
Development — CPDD University, Swiss Tropical Institute, London School of Hygiene and Tropical
Focus: Human African Medicine, Ohio State University, University of South Florida, University of
trypanosomiasis (sleeping Glasgow, Gorgas Memorial Institute (Panama), Kenya Agricultural Research
sickness) and leishmaniasis Institute, and Immtech Pharmaceuticals
n Has received grant funding of $15.1 million from the Gates Foundation
Recent Examples of Companies and PDPs Working Together on Global Health R&D
S m a ll M ol e c u l e Th e r a p e u t ics
V a ccin e s
Problem: Biotech companies can improve existing vaccines and create new vaccines
Vaccines are the most sought-after against infectious agents:
intervention in the developing world because n Genetically engineered “live attenuated” vaccines with greater
they provide long-term protection in areas safety, specificity, and efficacy
where patients’ access to medical treatment n Recombinant bacterial or viral vectors incorporating multiple
may be infrequent or inadequate. immunogens in a single vaccine
n Recombinant subunit vaccines engineered to maximize both T-
Vaccines protecting against smallpox and polio
and B- cell responses
have been among the most important public
n Molecular identification of the most immunogenic and
health success stories in both industrialized
conserved antigens that can be used in new vaccines
and developing countries. Vaccines are
still needed for the infectious diseases that Innovative vaccine approaches include:
primarily affect the developing world, n Rotarix®, a live attenuated oral vaccine for rotavirus, developed
including HIV/AIDS and other sexually- by AVANT Immunotherapeutics/GlaxoSmithKline and approved
transmitted diseases, malaria, TB, enteric in 90 worldwide markets, including the European Union
pathogens, trypanosomes, and nematodes. n Japanese encephalitis vaccine, a purified, inactivated vaccine in
Phase III development by Intercell in partnership with Novartis;
the vaccine is planned for a 2008 release
n ChimeriVax™-Dengue, a live attenuated vaccine for all serotypes
of dengue fever, in Phase II development by Acambis and its
partner Sanofi Pasteur
n DNA/MVA prophylactic vaccine for HIV, in Phase II
development by Oxford BioMedica in conjunction with IAVI
M ol e c u l a r D i a gnos t ics
V a ccin e a nd D r u g D e liv e r y
R e s e a rch P rod u c t s
Global Burden
There are 60 million people at risk worldwide, with an estimated 300,000 new cases and 50,000 deaths annually.
Geographic Distribution
HAT is found in 36 countries in sub-Saharan Africa.
Causative Agent/Transmission
HAT 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.
Presentation
T. brucei parasites first develop in the blood, lymph, and peripheral organs (Stage One) and then cross the blood-
brain barrier and enter the central nervous system (Stage Two). Stage Two 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.
Trends
By 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.
E x i s t i n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
Current treatments are only minimally None Typically patients are not diagnosed until
effective, are prohibitive to deliver (all are the late stage of the disease. There are no
delivered intravenously), and can be highly molecular diagnostic methods currently
toxic. available.
n Pentamidine n Case Detection
– Treats early-stage T.b. gambiense – Blood smear for T.b.
(ineffective against late-stage disease) rhodesiense (sensitive) or T.b.
– Side effects are rare gambiense (less sensitive)
n Suramin – Card indirect agglutination test
– Treats early-stage T.b. rhodesiense (CATT) for T.b. gambiense
(ineffective against late-stage disease) n Staging
– Side effects can be severe – Microscopy on cerebral spinal fluid
n Melarsoprol (arsenic derivative)
– Treats late-stage disease
(first-line treatment)
– Side effects are frequent and severe;
results in reactive encephalopathies
in five to ten percent of treated cases
– Showing evidence of resistance
n Eflornithine (DFMO)
– Treats late-stage T.b. gambiense
(first- or second-line treatment)
– Side effects are numerous
and can be severe
– Requires hospital administration
– Highly effective, but costs are
high and supply is unreliable
T a r g e t P r o d u c t P r o f i l e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Less toxic n Offers long-term protection n Molecular diagnostic capable of
n Oral or injectable treatments against infection early detection for prevention
can be effective; injectable is of severe disease
preferable for patients in coma n Detects disease stage (treatment
n Crosses blood-brain barrier in choice depends on whether
order to eliminate CNS infection there is CNS involvement)
in late-stage disease n Less invasive methods for staging
(current method is lumbar puncture)
n Affordable
P ipe l i n e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Research & Pre- Clinical- Clinical- Clinical-
Drugs Discovery Clinical Phase I Phase II Phase III
Immtech Pharmaceuticals/University of North Carolina (DB 289; pafuramidine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
M a r k e t Opp o r t u n i t ie s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n Primarily a disease of impoverished rural communities and will require donor support to encourage innovation.
De v e l o p m e n t I s s u e s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
Eradication of CNS infection is difficult to T. brucei undergo extensive antigenic No serum biomarkers yet identified to
confirm (only a few residual organisms are variation, which presents significant diagnose late-stage disease
needed for infection to recur) obstacles to vaccine development
A d d i t i o n a l I n f o r m a t i o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n World Health Organization (WHO) ~ www.who.int/topics/trypanosomiasis_african/en
n Centers for Disease Control & Prevention (CDC) ~ www.cdc.gov/ncidod/dpd/parasites/trypanosomiasis
Key Organizations
n Drugs for Neglected Diseases Initiative (DNDi) ~ www.dndi.org
n University of Dundee, Tropical Disease Initiative ~ www.drugdiscovery.dundee.ac.uk/tropical/overview/
n Special Programme for Research and Training in Tropical Diseases (TDR) ~ www.who.int/tdr
Important Papers
n Berriman, M et al. The genome of the African trypanosome Trypanosoma brucei. Science 309:416-422 (2005)
n El-Sayed, NM et al. Comparative genomics of trypanosomatid parasitic protozoa. Science 309:404-409 (2005)
n Legros, D et al. Treatment of human African trypanosomiasis–present situation and needs for research and
development. Lancet Infectious Diseases 2:437-440 (2002)
n Renslo, AR, and McKerrow, JH. Drug discovery and development for neglected parasitic diseases. Nature Chemical
Biology 2:701-710 (2006)
Global Burden
It is estimated that eight million to nine 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 Distribution
Chagas disease is prevalent in 18 countries within the Americas, ranging from Mexico to Argentina.
Causative Agent/Transmission
Chagas 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 known as “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 types of cells. Pet dogs are an alternate mammalian host, a situation that has impeded 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.
Presentation
Both phases of Chagas disease, acute and chronic, can be either asymptomatic or life-threatening.
The acute phase of the disease begins several days after infection. Most acute infections are asymptomatic.
However, this phase can have fever and swelling of the lymph nodes, spleen, liver, and the site of infection. The
hallmark of acute Chagas disease is the swelling of the eyelids or the side of the face near the bite wound. This is
called 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.
Trends
The number of deaths per year has decreased slightly in recent years. The WHO launched a major campaign in 2007
to seek eradication of the disease.
E x i s t i n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
There is no treatment for long-term, n None There are no diagnostics that can reliably
chronic infections. detect chronic disease.
n Nifurtimox & Benznidazole n TcF-ELISA
– Cures at least 50 percent of acute – Sensitive and specific
and short-term chronic infections – Low occurrence of leishmaniasis
principally in children, but little to no cross-reactions
impact on long-term chronic infections n UBI MAGIWEL™ ELISA
– Frequently causes side effects, – Detects T. cruzi antibodies (IgG)
which can be severe in human serum or plasma
– Limited access n Chembio Chagas STAT-PAK™
– High cost of treatment – Detects T. cruzi antibodies
– Shows signs of resistance – Rapid test and does not require
special equipment or refrigeration
T a r g e t P r o d u c t P r o f i l e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Effective against chronic disease n Preventive: long-term protection n Molecular diagnostic
n Oral formulation against infection n Able to differentially diagnose the
n Short course of therapy n Therapeutic: treat the chronic phase presence and stage of disease
n Affordable n Affordable
P ipe l i n e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Research & Pre- Clinical- Clinical- Clinical-
Drugs Discovery Clinical Phase I Phase II Phase III
DNDi (Ravucnazole) nnnnnnnnnnnnnnnnnnnnn
M a r k e t Opp o r t u n i t ie s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n This is primarily a disease of the very poor and will require donor support to encourage innovation.
De v e l o p m e n t I s s u e s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Clinical trials are likely to n Clinical trials are likely to n No biomarkers exist to
be complicated by the slow be complicated by the slow detect chronic disease
progression of the disease progression of the disease n Troponin, a marker for cardiac
n In the chronic stage, organisms damage that is elevated in late-
are difficult to detect and damage chronic stage disease, cannot
occurs over many (>15) years differentiate between “no disease”
and the early chronic stage
A d d i t i o n a l I n f o r m a t i o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n World Health Organization (WHO) ~ www.who.int/topics/chagas_disease/en
n Centers for Disease Control & Prevention (CDC) ~ www.cdc.gov/ncidod/dpd/parasites/chagasdisease
Key Organizations
n Drugs for Neglected Diseases Initiative (DNDi) ~ www.dndi.org
n Special Programme for Research and Training in Tropical Diseases (TDR) ~ www.who.int/tdr
Important Papers
n De Souza, W. From the cell biology to the development of new chemotherapeutic approaches against
trypanosomatids: dreams and reality. Kinetoplastid Biology and Disease 1:3 (2002)
n El-Sayed, NM, et al. The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease. Science
309:409-415 (2005)
n El-Sayed, NM, et al. Comparative genomics of trypanosomatid parasitic protozoa. Science 309:404-409 (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 48:5415-5418 (2005)
Global Burden
In 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 Distribution
The 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/Transmission
Cholera 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.
Presentation
V. 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
The number of cholera deaths and the case-fatality rate have increased significantly in high-risk areas such as sub-
Saharan Africa.
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. Institut Pasteur cautioned in 2003 that this new strain “may well
become the origin of an eighth cholera pandemic.”
E x i s t i n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Palliative Care n First-Generation Vaccines n Rapid diagnostic dipstick test
− Oral rehydration therapy can (including Dukoral®) − Uses immunochromatography
be used to treat symptoms − Oral delivery to detect the presence of O1 and
− Antibiotics and intravenous (IV) − Protection ranges from three O139 lipopolysaccharides
fluids are sometimes given in months to two years
severe cases, where available − 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
T a r g e t P r o d u c t P r o f i l e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n High-potency antibiotic n Live attenuated, or killed bacterial n Ability to differentiate between
n Affordable (the latter for use in areas with other diarrheal pathogens
high HIV-positive populations) n Rapid test to ensure quick
n Single, oral dose response in an epidemic
n Thermostable
n Bivalent against O1 and O139 cholera
n Long-term protection (>2 years)
to infants and young children
P ipe l i n e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Research & Pre- Clinical- Clinical- Clinical-
Vaccines Discovery Clinical Phase I Phase II Phase III
National Institute of Cholera & Enteric Diseases/IVI (VAI-3; oral, killed, bivalent) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
M a r k e t Opp o r t u n i t ie s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n Potential commercial opportunities for vaccines through military and travelers’ applications.
De v e l o p m e n t I s s u e s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Need to overcome antibiotic resistance n Single-dose oral vaccine
n Difficulties in conjugate development
n Specifications for travelers’
and military markets may differ
from endemic markets
A d d i t i o n a l I n f o r m a t i o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n World Health Organization (WHO) ~ www.who.int/topics/cholera/en
n Centers for Disease Control & Prevention (CDC) ~ www.cdc.gov/ncidod/dbmd/diseaseinfo/cholera_g.htm
Key Organizations
n WHO Initiative for Vaccine Research (IVR) ~ www.who.int/vaccine_research/en
n ICDDR,B: Centre for Health and Population Research ~ www.icddrb.org/pub
Important Papers
n Lucas, MES, et al. Effectiveness of mass oral cholera vaccination in Beria, Mozambique. NEJM 352:757-767 (2005)
n Sack, DA, et al. Cholera. The Lancet 363:223-233 (2004)
Global Burden
There 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 Distribution
DF 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 and Puerto Rico.
Causative Agent/Transmission
The 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.
Presentation
DF 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 one 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, with modern intensive supportive
therapy such as intravenous fluid replacement, case fatality rates can be reduced to less than one 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.
Trends
Due 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 Paraguay that started in early 2007 is ongoing and has spread to both Argentina and Brazil,
with an estimated number of cases above 100,000. Cases are on the rise in India as well.
E x i s t i n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Palliative Care n None n PanBio Rapid Tests
– Intravenous fluid replacement − Dengue Duo Cassette and Dengue
can be used for rehydration Duo IgM and IgG Rapid Strip Test
− Acetaminophen can be used (For differentiation between primary
to manage pain and fever 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 active and secondary
dengue infection, respectively)
T a r g e t P r o d u c t P r o f i l e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Oral formulation n Single or two-dose tetravalent n Rapid test
n Rapid-acting n Provides extended protection n Ability to diagnose in initial
n Ameliorates symptoms n Safe and effective in small children stage of disease, to distinguish
n Prevents DHF n Effective against all four serotypes between serotypes and to
distinguish from other fevers
P ipe l i n e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Research & Pre- Clinical- Clinical- Clinical-
Drugs Discovery Clinical Phase I Phase II Phase III
United Therapeutics (UT-231B) nnnnnnnnnnnnnnnnnnnnn
Novartis nnnnnnnn
M a r k e t Opp o r t u n i t ie s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 four billion people at risk in Latin
America, Asia, and perhaps Middle East/Africa).
De v e l o p m e n t I s s u e s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Developing an antiviral that is n Developing a tetravalent vaccine n Current tests only detect antibodies
effective once infection has occurred effective against all four serotypes to dengue late in infection
A d d i t i o n a l I n f o r m a t i o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n World Health Organization (WHO) ~ www.who.int/topics/dengue/en
n Centers for Disease Control & Prevention (CDC) ~ www.cdc.gov/ncidod/dvbid/dengue
Key Organizations
n Genome Institute of Singapore and Novartis Institute for Tropical Diseases ~ www.dengueinfo.org/NITD
n Pediatric Dengue Vaccine Initiative (PDVI) ~ www.pdvi.org
n WHO Initiative for Vaccine Research (IVR) ~ www.who.int/vaccine_research/en
n Special Programme for Research and Training in Tropical Diseases (TDR) ~ www.who.int/tdr
Important Papers
n 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 79:5516-5528 (2005)
n Edelman, R. Dengue and dengue vaccines. J Infect Dis 191:650-653 (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 2:60-67 (2006)
n Wilder-Smith, A, and Schwartz, E. Dengue in travelers. NEJM 353:924-932 (2005)
Global Burden
Each year an estimated 300 million to 400 million new infections of ETEC result in between 400,000 and 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 Distribution
ETEC cases are reported worldwide; incidence rates are highest in Central and South America, Africa, and Southeast
Asia.
Causative Agent/Transmission
E. 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.
Presentation
Toxins 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.
Trends
The disease burden associated with 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.
E x i s t i n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Palliative Care n Dukoral® is a cholera vaccine that n None
− Oral rehydration therapy can has shown 60 percent short-term
be used to treat symptoms efficacy against travelers’ diarrhea
− Antibiotics and IV fluids are sometimes n No product exists to vaccinate
given in severe cases, where available people in endemic regions
T a r g e t P r o d u c t P r o f i l e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n High potency antibiotic n Oral delivery n Ability to differentiate between
n Affordable n Extended protection ETEC and other gut infections
n Multivalent such as other diarrheagenic E.
n Acceptable side effects coli and protozoan diseases
P ipe l i n e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Research & Pre- Clinical- Clinical- Clinical-
Vaccines Discovery Clinical Phase I Phase II Phase III
IOMAI (LT+CS6 Transcutaneous patch) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
MIDRP (SC608: Attenuated S. flex w/ETEC Cfab component of CFA/i and LTb) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Göteborg University
(Killed, whole cell ETEC expressing CFA/I, CS1-5 and rCTB-CF) nnnnnnnnnnnnnnnnnnnnn
AVANT (Attenuated cholera expressing CTB and ETEC antigen CFA/I) nnnnnnnnnnnnnnnnnnnnn
M a r k e t Opp o r t u n i t ie s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 > $200 million/year
De v e l o p m e n t I s s u e s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Need to overcome antibiotic resistance n Multiple strains make it difficult
to design a multivalent vaccine
with sufficient coverage
n Certain major cell-surface markers
are not immunogenic, making them
poor candidates for vaccines
n Specifications for travelers’
and military markets may differ
from endemic markets
n Implementation in field
conditions must be easy
n Cost must be low in comparison to
alternative therapies/other vaccines
A d d i t i o n a l I n f o r m a t i o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n World Health Organization (WHO) ~ www.who.int/vaccine_research/diseases/e_e_coli/en
n Centers for Disease Control & Prevention (CDC) ~ www.cdc.gov/ncidod/dbmd/diseaseinfo/etec_g.htm
Key Organizations
n International Centre for Diarrheal Disease Research, Bangladesh (ICDDR,B): ~ www.icddrb.org/pub
Important Papers
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 24:1726-1733 (2006)
n Qadri, F, et al. Enterotoxigenic Escherichia coli in developing countries: epidemiology, microbiology, clinical
features, treatment, and prevention. Clin Microbiol Rev 18:465-483 (2005)
n Walker, RI. Considerations for development of whole cell bacterial vaccines to prevent diarrheal diseases in
children in developing countries. Vaccine 23:3369-3385 (2005)
Global Burden
In 2006, it was estimated that 39.4 million people worldwide were infected with HIV. There were approximately 2.9
million AIDS deaths, and another 4.3 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 much as four times those found in young men of the same age.
Geographic Distribution
HIV/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, the
huge population of this region makes it second to Africa in terms of the total number of individuals infected.
Causative Agent/Transmission
HIV is spread by exposure to infected body fluids including blood, semen, and breast milk. The major routes of
transmission are sexual contact, 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 of virus. Most broadly, HIV can
be divided into two types: HIV-1 and HIV-2. HIV-1 is more virulent than HIV-2 and causes the majority of human
infections. HIV-1 itself can be divided into several distinct groups, which are themselves divided into subtypes, or
clades, which display distinct geographic infection patterns. Treatment is more complicated in regions where more
than one clade is circulating because hybrids of multiple clades can appear.
Presentation
Clinical diagnosis of HIV infection is complicated by the lack of specific symptoms. Two to four weeks after
becoming infected, patients may display flu-like symptoms, accompanied by a rash and fever. However, many
patients are asymptomatic upon initial infection. Although the incubation period between infection and onset of
AIDS is often cited at seven to ten 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.
Trends
The HIV/AIDS epidemic has spread rapidly and is now considered a pandemic. While a majority of current and
new HIV infections occur in sub-Saharan Africa, emerging crises are developing in Eastern Europe, Central Asia and
East Asia. More than 95 percent of all new infections occur in people living in low- and middle-income countries.
Resistance to antiretrovirals (ARV) is common and develops against all classes of ARVs, usually after prolonged use.
Transmission of HIV strains resistant to one or multiple drugs has been documented and appears to be increasing.
E x i s t i n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Combination and Highly Active n None Current technologies do not provide an
Antiretroviral Therapy (HAART) inexpensive point-of-care test by which
− Composed of a combination to direct treatment.
of anti-HIV drugs n HIV Enzyme Immunoassay
− There are three major groups of & Western Blot Assay
anti-HIV drugs, consisting of more − Detects HIV antibodies in serum,
than 20 approved medications plasma, oral fluid, dried blood, or urine
− Side effects and drug resistance n OraQuick® ADVANCE™ HIV-
can be significant issues 1/2 Antibody Test
− Although older, less expensive − First oral fluid rapid HIV test
antiretrovirals are increasingly − Can be used on oral fluid, plasma,
available, the latest treatments fingerstick, and venipuncture
remain out of reach for many whole blood specimens
in the developing world n Chembio STAT-PAK™ & SURE CHECK®
− Current drugs reduce viral load, Assays and Dipstick Tests
but do not cure the disease and − Simple, sensitive and specific
must be taken indefinitely − Room-temperature storage
T a r g e t P r o d u c t P r o f i l e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Fixed-dose combinations n Induce several types of immunity: n Point-of-care test that quantifies
n Specific pediatric formulations humoral, cell-mediated, mucosal viral load and CD4 count
n Low-cost, effective, easy-to-use n Offer long-term protection n Able to indicate when to start
first- and second-line treatments against multiple clades treatment and when to switch
n Combinations that could be used n Formulation and cost suitable treatment in children and adults
for pre-exposure prophylaxis for developing world use
P ipe l i n e * nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Research & Pre- Clinical- Clinical- Clinical-
Vaccines Discovery Clinical Phase I Phase II Phase III
Sanofi-Aventis (LIPO-5/ALVAC-canary pox vector) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
* This is not an exhaustive listing of all HIV vaccines and microbicides currently in development or clinical trials and excludes HIV drugs.
M a r k e t Opp o r t u n i t ie s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 $30 billion for 2008-2015.
De v e l o p m e n t I s s u e s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Continued need for high- n Vaccines need to overcome wide n CD4 and Viral Load Diagnostics
potency, less-costly drugs variability of virus strains, both in − Need to be accessible to
n Resistance is a growing issue single patients and across populations developing world
− Need to develop a rapid,
quantitative test
A d d i t i o n a l I n f o r m a t i o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n World Health Organization (WHO) ~ www.who.int/topics/hiv_infections/en
n Centers for Disease Control & Prevention (CDC) ~ www.cdc.gov/hiv
n National Institute for Allergy and Infectious Diseases (NIAID) ~ www.niaid.nih.gov/factsheets/hivinf.htm
Key Organizations
n AIDS Vaccine Advocacy Coalition (AVAC) ~ www.avac.org
n Alliance for Microbicide Development ~ www.microbicide.org
n Global Fund to Fight AIDS, Tuberculosis & Malaria ~ www.theglobalfund.org/en
n HIV Vaccine Trials Network (HVTN) ~ www.hvtn.org
n HIV InSite ~ www.hivinsite.ucsf.edu/InSite
n International AIDS Vaccine Initiative (IAVI) ~ www.iavi.org
n International Partnership for Microbicides ~ www.ipm-microbicides.org
Important Papers
n AIDS Epidemic Update 2006 ~ http://data.unaids.org/pub/EpiReport/2006/2006_EpiUpdate_en.pdf
n Duerr, A, et al. HIV vaccines: new frontiers in vaccine development. Clin Infect Dis 43:500-511 (2006)
n Gallo, RC. The end or the beginning of the drive to an HIV-preventive vaccine: a view from over 20 years. Lancet
366:1894-1898 (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 353:753-757 (2005)
Global Burden
JE is the leading cause of viral encephalitis and neurological infection in Asia. The disease is severely unreported;
50,000 new cases are recorded annually that result in 15,000 deaths and a 75 percent JE-related disability rate. Over
three billion people live in areas endemic for JE.
Geographic Distribution
JE 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/Transmission
The JE virus belongs to the family Flaviviridae. The viruses responsible for dengue fever, yellow fever, and West Nile
disease are also flaviviruses. Mosquitoes belonging to the Culex tritaeniorhynchus and Culex vishnui groups, which
breed in flooded rice fields, transmit JE. The virus circulates in birds and pigs, and tends to spill over into human
populations only when Culex populations increase dramatically over a short period of time, as Culex mosquitoes
prefer to feed on animals.
Presentation
Most JE virus infections are mild (fever and headache) or lack apparent symptoms. Approximately 1 in 200 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.
Trends
Large outbreaks of JE in India and Nepal have highlighted the continuing expansion of the geographic range of the
disease in recent years.
E x i s t i n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Palliative Care n Killed Vaccine (JE-VAX) An inexpensive, field-ready technology
− Intravenous fluid replacement − Expensive (Mac Dot) has been developed but not
can be used for rehydration − Requires three doses commercialized.
− Acetaminophen can be used − Offers short-term protection n Plaque Reduction
to manage pain and fever − Reports of neurological and Neutralization Assay (PRNT)
hypersensitivity reactions − Time intensive and costly
after vaccination − High biosafety-level requirements
n Live-Attenuated Vaccine n Hemagglutination Inhibition (HI)
− Inexpensive − Low specificity
− Used in China, but not available − High level of cross-reactivity
elsewhere with other flaviviruses
− Currently being developed under n ELISA
improved GMP conditions − Simple and sensitive
− Some cross-reactivity with
other flaviviruses
− Not suitable for point-of-care testing
T a r g e t P r o d u c t P r o f i l e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Drug therapy not targeted n Second-Generation Vaccine n Simple
− Safer n Sensitive
− Requires fewer doses n Low cross-reactivity with other
− Should be compatible with the flaviviruses
WHO Expanded Program on
Immunization (EPI) schedule
P ipe l i n e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Research & Pre- Clinical- Clinical- Clinical-
Vaccines Discovery Clinical Phase I Phase II Phase III
Intercell/Novartis (Inactivated Vero cell-grown SA14-14-2 strain) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
M a r k e t Opp o r t u n i t ie s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n Significant opportunity in travelers’ and military markets.
n One company estimates a global market of over $300 million.
De v e l o p m e n t I s s u e s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Difficult to develop therapeutic n Evaluation of efficacy of JE vaccines n Important to detect disease in
antivirals against all four virus strains early stages of infection, when
n Immunity to fewer strains intervention may be beneficial
could increase susceptibility
to DHF in the vaccinated when
exposed to a new strain
A d d i t i o n a l I n f o r m a t i o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n World Health Organization (WHO) ~ www.who.int/vaccine_research/diseases/japanese_encephalitis/en
n Centers for Disease Control & Prevention (CDC) ~ www.cdc.gov/ncidod/dvbid/jencephalitis
Key Organizations
n WHO Initiative for Vaccine Research (IVR) ~ www.who.int/vaccine_research/en
Important Papers
n 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. JID 188:1213-1230 (2003)
n Solomon, T. Flavivirus encephalitis. NEJM 351:370-378 (2004)
Global Burden
Worldwide there are 12 million people infected with Leishmania. An estimated 350 million people are at risk for
infection. There are an estimated 1.7 million new cases and 45,000 deaths each year.
Geographic Distribution
Leishmaniasis is found in 88 countries, 72 of which are low-income countries.
More than 90 percent of all cutaneous leishmaniasis cases, the most common form of the disease, are found in
Afghanistan, Brazil, Iran, Peru, Saudi Arabia, and Syria. Approximately 90 percent of all visceral leishmaniasis cases,
a less common but deadlier form of the disease, occur in Bangladesh, India, Nepal, Sudan, and Brazil.
Causative Agent/Transmission
The 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 dendritic cells.
Presentation
Leishmania diseases can be classified into one of four forms: (1) visceral leishmaniasis (VL), commonly known
as Kala-azar, is fatal if left untreated; (2) cutaneous leishmaniasis (CL), the most common form, is marked by a
proliferation of self-healing skin lesions that produce significant scarring; (3) mucocutaneous leishmaniasis (MCL) 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, causes chronic ulcers
and skin lesions resulting in severe disfigurement.
Trends
There 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.
E x i s t i n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Miltefosine (Impavido®) There are no modern vaccines against n Direct Agglutination Test (DAT)
− Approved in 2003 for use in India for VL, leishmaniasis. with freeze-dried antigen
and in 2005 for use in Colombia for CL n In some endemic areas, a controlled − First-line diagnostic
− Has shown a 95 percent response lesion is created in an area of the − Highly sensitive and specific
rate when used against VL skin normally covered by clothing, − Does not require special equipment
− Currently the only effective via inoculation of live parasite. While n Dipsticks K39/K26
oral treatment this lesion is active, the individual − K39 for serological diagnosis
− Contraindicated in pregnancy is protected from lesions on more − Based on a recombinant
n Paromomycin (aminosidine, visible parts of the body. This process, antigen of L. chagasi
Humatin®) called leishmanization, is used to − Requires cold storage
− Approved in 2006 for use in India for VL protect children from future lesions n Katex (Latex Agglutination Test)
− Granted “orphan drug” status on the exposed parts of the body. − Used to detect L. donovani
− Injected This only protects against CL. antigen in urine samples
n Pentosam (SSG), Amphotericin − Requires cold storage
B, KetoconAzole, Pentamidine,
and antimony
− Shows up to 60 percent
resistance rates
− Frequently have severe adverse events
(up to nine percent of patients have
fatal adverse reactions to antimony)
T a r g e t P r o d u c t P r o f i l e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Oral formulation n Highly efficacious subunit vaccine n Detection of early-stage,
n Short course of treatment with lasting protection systemic disease
n Safer than current treatments n Effective in preventing n Thermostable
n High efficacy against all forms of the establishment of new infections,
parasite, including drug-resistant ones particularly on the face
P ipe l i n e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Research & Pre- Clinical- Clinical- Clinical-
Drugs Discovery Clinical Phase I Phase II Phase III
DNDi (Paromomycin) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
M a r k e t Opp o r t u n i t ie s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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.
De v e l o p m e n t I s s u e s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Scientific feasibility not an issue n Leishmanization suggests n Thermostability may be difficult to
vaccination is possible but long- achieve using antibody-based
lasting immunity may be difficult to diagnostics
achieve with a recombinant vaccine
A d d i t i o n a l I n f o r m a t i o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n World Health Organization (WHO) ~ www.who.int/topics/leishmaniasis/en
n Centers for Disease Control & Prevention (CDC) ~ www.cdc.gov/ncidod/dpd/parasites/leishmania
Key Organizations
n Drugs for Neglected Diseases Initiative (DNDi) ~ www.dndi.org
n Institute for OneWorld Health (IOWH) ~ www.oneworldhealth.org
n WHO Initiative for Vaccine Research (IVR) ~ www.who.int/vaccine_research/en
n Special Programme for Research and Training in Tropical Diseases (TDR) ~ www.who.int/tdr
Important Papers
n Coler, RN, and Reed, SG. Second-generation vaccines against leishmaniasis. Trends in Parasitol 21:244-249 (2005)
n Davies, CR, et al. Leishmaniasis: new approaches to disease control. BMJ 2003;v326:377-382
n El-Sayed, NM, et al. Comparative genomics of trypanosomatid parasitic protozoa. Science 309:404-409 (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 309:436-442 (2005)
n Peacock, CS, et al. Comparative genomic analysis of three Leishmania species that cause diverse human disease.
Nature Genetics 39:839-47 (2007)
Global Burden
More 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 Distribution
LF 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/Transmission
Thread-like, parasitic filarial worms Wuchereria bancrofti and Brugia malayi cause lymphatic filariasis. These 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. Mosquitoes transmit the disease.
Presentation
The 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 hydrocoele (fluid-filled balloon-like enlargement 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.
Trends
In tropical and subtropical areas where lymphatic filariasis is well established, the prevalence of infection is
continuing to increase. A primary cause of this increase is the rapid and unplanned growth of cities, which creates
numerous breeding sites for the mosquitoes that transmit the disease.
E x i s t i n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Combination Treatment— n None n Microscopy
Albendazole with − Difficult because the parasites have a
Diethylcarbamazine (DEC) “nocturnal periodicity” that restricts
or Ivermectin their appearance in the blood to
− Use of single doses of two drugs only the hours around midnight
administered concurrently is 99 − Inexpensive reagents
percent effective in removing n Antigen-Detection “ICT” Test
microfilariae from the blood for − Simple, very sensitive, and specific
a full year after treatment − Detects circulating parasite antigens
− Current standard of care is to treat without the need for laboratory
children annually to prevent disease facilities
and break the chain of infection − Uses only finger-prick blood
− Treatment with DEC can cause serious droplets taken anytime of the day
side effects if certain other diseases n NOW® Filariasis Test
are co-endemic to the region, as occurs − Rapid immunodiagnostic test
in Africa; ivermectin is used as an − Detects antigens in whole
alternative in these regions blood, serum, or plasma
− Expensive to use except to
identify populations at risk
T a r g e t P r o d u c t P r o f i l e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Kills adult worms (macrofilaricidal) n Prevents establishment of n Further development of diagnostics
and reduces swelling infection by microfilariae for Brugia malayi
n Decreases necessity of repeated, n Less expensive point-of-care
annual treatment; inhibits diagnostics would allow assessment
microfilariae production of more at-risk individuals
n Increased monitoring and
surveillance ability
n Adapt existing serologic assays to
work with oral fluids or urine
P ipe l i n e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Research & Pre- Clinical- Clinical- Clinical-
Drugs Discovery Clinical Phase I Phase II Phase III
Regimens of tetracyclines, rifampicin, and combinations of
antibiotics and conventional antifilarial drugs nnnnnnnn
Moxidectin nnnnnnnn
M a r k e t Opp o r t u n i t ie s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 infection. 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.
De v e l o p m e n t I s s u e s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Drugs and drug combinations n Lack of an in vitro culture n The major challenge is to reduce
should avoid interactions with system for filariae cost of diagnostics below $1
other tropical diseases n Absence of tools for easy n Maintain the current standard
n Recent evidence suggests (June genetic manipulation of tests that can be done at
2007) that ivermectin resistance n Need for advances in animal any time, day or night
is emerging in other diseases; this model development n High sensitivity
emphasizes the need for new drugs
in the event resistance appears
A d d i t i o n a l I n f o r m a t i o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n World Health Organization (WHO) ~ www.who.int/topics/filariasis/en
n Centers for Disease Control & Prevention (CDC) ~ www.cdc.gov/ncidod/dpd/parasites/lymphaticfilariasis
Key Organizations
n The Global Alliance to Eliminate Lymphatic Filariasis ~ www.filariasis.org
Important Papers
n Summary of immediate needs and opportunities for research on lymphatic filariasis. Supplement to AJTMH 71
(2004)
n Molyneaux, D. Lymphatic filariasis (elephantiasis) elimination: a public health success and development
opportunity. Filaria Journal 2:13 (2003)
n Tan, JZG. The elimination of lymphatic filariasis: a strategy for poverty alleviation and sustainable development
– perspectives from the Philippines. Filaria Journal 2:12 (2003)
Global Burden
Over 40 percent of the world’s population is estimated to be at risk for malaria. Each year, there are between 300
million and 500 million new cases and one million deaths. Over 70 percent of malaria deaths occur in children
under the age of five. In Africa, malaria has been estimated to result in more than $12 billion in lost annual GDP;
malaria control would cost a fraction of this sum.
Geographic Distribution
Malaria is endemic in more than 100 countries in tropical and subtropical regions of Africa, Asia, and Central and
South America. An estimated 90 percent of deaths occur in sub-Saharan Africa.
Causative Agent/Transmission
Malaria 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.
Presentation
Once 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 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.
Trends
Increasingly, 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 of the 10 significant Anopheles vector species are exhibiting pesticide resistance, even to the powerful
pesticide DDT.
E x i s t i n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
The leading drugs used in the developing n None n Light Microscopy
world, chloroquine and Fansidar®, are − Labor-intensive and requires
increasingly ineffective across wide skill to read slides
areas because of resistant parasites. New − High sensitivity and specificity
artemisinin-based combination therapies when used by well-trained staff,
(ACTs) are currently the best treatments but this is rare in the field
but are ten times as costly. n Rapid Diagnostic Tests (RDTs)
− More expensive than microscopy
Other more expensive drugs are available
− Vulnerable to high temperatures
in the developed world.
and humidity
n Chloroquine
− Can be highly sensitive and specific
− Affordable and widely available
− Cannot distinguish severe disease,
− Now ineffective in most endemic
active disease, and background
areas due to resistance
parasite from one another
n Sulfadoxine-pyrimethamine
− Binax NOW® test is the only rapid
(SP/Fansidar®)
test approved in the United States
− Resistance increasing rapidly
n Artemisinin-based Combination
Therapies (ACTs)
− Currently the best treatment
− Not licensed for use in the United
States but often found overseas
− More expensive than chloroquine or SP
T a r g e t P r o d u c t P r o f i l e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Inexpensive (in tens of cents) n Vaccine for infants with delivery n Quick and non-invasive
n Easy to manufacture tied to EPI schedules n Field appropriate
n Significant shelf life n Effective for at least two years n Affordable
n Simple, regular, and short dosing n Demonstrated non-interference n Requires minimal training
regimen (one to three days) with EPI vaccines n Distinguishes severe disease
n Effective against all four n Thermostable from uncomplicated disease
species of Plasmodium n Need to boost immunogenicity
and duration of effect
P ipe l i n e ( Se l e c t i t e m s o n l y ) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Research & Pre- Clinical- Clinical- Clinical-
Drugs Discovery Clinical Phase I Phase II Phase III
Sanofi-Aventis/DNDi (Artesunate-amodiaquine) Registered 3/07 nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
UT Southwestern/University of Washington/MMV
(Dihydroorotate dehydrogenase inhibitor) nnnnnnnn
M a r k e t Opp o r t u n i t ie s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 (ROI) 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 can be 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.
De v e l o p m e n t I s s u e s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Resistance may make new drugs n Needs to overcome antigenic variation n Differentially diagnose malaria
obsolete quickly n No correlates of protection from acute febrile illness
n No predictive animal models
A d d i t i o n a l I n f o r m a t i o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n World Health Organization (WHO) ~ www.who.int/topics/malaria/en
Key Organizations
n Medicines for Malaria Venture (MMV) ~ www.mmv.org
n PATH Malaria Vaccine Initiative (MVI) ~ www.malariavaccine.org
n Multilateral Initiative on Malaria (MIM) ~ www.who.int/tdr/diseases/malaria
n Special Programme for Research and Training in Tropical Diseases (TDR) ~ www.who.int/tdr
n Roll Back Malaria ~ www.rbm.who.int
n Global Fund to Fight AIDS, Tuberculosis & Malaria ~ www.theglobalfund.org/en
Important Papers
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 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 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 365:1487-1498 (2005)
n Touré, YT, et al. Disease watch – focus: malaria. Nature Rev: Microbiol 2:276-277 (2004)
Global Burden
The disease is endemic in 74 developing countries, infecting more than 200 million people in rural agricultural and
peri-urban areas. Approximately 120 million are thought to experience chronic debilitating symptoms. Twenty
million suffer more severe consequences from the disease. An estimated 779 million people worldwide are at risk
for the disease. Children under 14 are especially vulnerable to infection leading to progressive disease and early
death.
Geographic Distribution
More 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/Transmission
Schistosomiasis is caused by trematode flatworms of the genus Schistosoma. Infected individuals expel Schistosoma
eggs in their feces or urine. 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, the female lays anywhere from 200 to 2,000 eggs per
day. About half the eggs produced are excreted in the feces or urine; the remainder becomes 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; it is the eggs that bring about harmful symptoms.
Presentation
Schistosomiasis 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, ureters 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
(urinary schistosomiasis) or to bleeding from varicose veins in the esophagus or gastrointestinal tract.
Trends
Original estimates of the burden of schistosomiasis failed to adequately take into account the symptoms, sequelae,
and chronic nature of the disease. Subsequent analysis revealed that it is among the most serious tropical diseases.
Countries such as Nigeria are concerned that the unrecognized schistosomiasis problem may come to the forefront
of their health-care issues.
E x i s t i n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Praziquantel (Distocid®, Biltricide®) n None n Dipstick
− Standard of care − Detection of blood in urine
− Safe and highly effective in n Microscopy
curing an infected patient − Most practical method for diagnosis
− Does not prevent reinfection − Inefficient; requires laboratory,
− Off patent and inexpensive; multiple analyses
costs as low as $0.20/dose − Does not catch early infections
n Others - Oxamniquine, Metrifonate n Antibody Detection
− Difficult to obtain − Sensitivity and specificity vary widely
− Do not work on all forms of the disease n ELISA
− Highly sensitive; species can be
determined by immunoblot
T a r g e t P r o d u c t P r o f i l e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Affordable n Requires few doses n Simple; appropriate for field-use
n Effective against multiple species n Extended protection n Sensitive
n Long-lasting n Thermostable n Detects all stages of disease
n High immunogenicity
P ipe l i n e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Research & Pre- Clinical- Clinical- Clinical-
Drugs Discovery Clinical Phase I Phase II Phase III
UCSF Sandler Center (K11777 cysteine protease inhibitor) nnnnnnnnnnnnnnnnnnnnn
Research & Pre- Clinical- Clinical- Clinical-
Vaccines Discovery Clinical Phase I Phase II Phase III
Institute Pasteur (S. Haematobium 28kD GST subunit) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
M a r k e t Opp o r t u n i t ie s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n This is primarily a disease of the very poor. Donor support will be required to encourage innovation.
De v e l o p m e n t I s s u e s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Current therapy is adequate −n Need for further research n Diagnostic tests need to be adapted
into target antigens to affordable, point-of-care formats
A d d i t i o n a l I n f o r m a t i o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n World Health Organization (WHO) ~ www.who.int/topics/schistosomiasis/en
n Centers for Disease Control & Prevention (CDC) ~ www.cdc.gov/ncidod/dpd/parasites/schistosomiasis
Key Organizations
n Schistosomiasis Control Initiative (SCI) ~ www.schisto.org
n Special Programme for Research and Training in Tropical Diseases (TDR) ~ www.who.int/tdr
n WHO Initiative for Vaccine Research (IVR) ~ www.who.int/vaccine_research/en
Important Papers
n Chitsulo, L, et al. Disease watch – focus: schistosomiasis. Nature Rev: Microbiol 12:12-13 (2004)
n Fenwick, A. New initiatives against Africa’s worms. Trans. Royal Soc Trop Med Hyg 100: 200-207 (2006)
n Pearce, EJ. Progress towards a vaccine for schistosomiasis. Acta Tropica 86:309-313 (2003)
Global Burden
Worldwide 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 Distribution
Distribution of Shigella serotypes varies by geography: S. sonnei and S. flexneri are prevalent in the United States, S.
boydii in Middle East, Africa, and South Asia. The most severe form, S. dysenteriae, is primarily found in South Asia
and sub-Saharan Africa.
Causative Agent/Transmission
Shigellosis 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 water contaminated by human waste.
Presentation
Shigella multiply within the epithelial cells of the colon, cause cell death, and spread laterally to infect and kill
adjacent epithelial cells, causing mucosal ulceration, inflammation and bleeding. Shigella dysenteriae type 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.
Trends
Diarrheal diseases 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 antibiotics are expensive. Their misuse has
led to the emergence of drug-resistant Shigella strains.
E x i s t i n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Palliative Care n None There is no way to differentiate, at the
− Oral rehydration therapy can diarrheal stage, between shigellosis
be used to treat symptoms and several other parasitic or bacterial
− Antibiotics and IV fluids are sometimes infections.
given in severe cases, where available n Standard clinical microbiology
n No molecular tests available
T a r g e t P r o d u c t P r o f i l e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Affordable, high-potency antibiotic n Single or two-dose n Ability to differentiate between
n Improved oral rehydration therapy n Oral delivery Shigella and other gut infections
n Effective for at least two years such as ETEC and protozoa
n Multivalent
n Acceptable side effects
P ipe l i n e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Research & Pre- Clinical- Clinical- Clinical-
Vaccines Discovery Clinical Phase I Phase II Phase III
NICHD/Robbins (O-specific polysaccharide conjugate) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
MIDRP/Hale (WR Ss1, Sd1; live attenuated S. sonnei and S. dysenteriae) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
AVANT (Live attenuated cholera vector (Peru 15) expressing S. sonnei O-PS) nnnnnnnnnnnnnnnnnnnnn
MIDRP (Hybrid SC 608; live attenuated S. flexneri 2a expressing ETEC CfaB andLTB) nnnnnnnnnnnnnnnnnnnnn
M a r k e t Opp o r t u n i t ie s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n Potential opportunity in travelers’ and military markets may improve global market opportunity.
De v e l o p m e n t I s s u e s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Antibiotic resistance n Multiple strains make it difficult n Key issue is the rapid
to design a multivalent vaccine identification of all serotypes
with sufficient coverage
n Certain major cell-surface markers
are not immunogenic, making them
poor candidates for vaccines
n Specifications for travelers’
and military markets may differ
from endemic markets
A d d i t i o n a l I n f o r m a t i o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n World Health Organization (WHO) ~ http://www.who.int/vaccine_research/diseases/diarrhoeal/en/index6.html
n Centers for Disease Control & Prevention (CDC) ~ http://www.cdc.gov/ncidod/dbmd/diseaseinfo/
shigellosis_g.htm
Key Organizations
n International Center for Diarrheal Disease Research, Bangladesh (ICDDR,B): ~ www.icddrb.org/pub
Important Papers
n Walker, RI. Considerations for development of whole cell bacterial vaccines to prevent diarrheal diseases in
children in developing countries. Vaccine 23:3369-3385 (2005)
Global Burden
One-third of the global population – two billion people – is infected with TB; between five and ten percent of those
infected will develop active TB disease. WHO estimates that each year close to nine million people become sick with
TB and two million die. TB is the leading killer of HIV-positive patients.
Geographic Distribution
TB is a worldwide problem. Eighty percent of the global burden is borne by only 22 countries, and one-third of those
infected live in India and China.
TB case numbers in 2005, by WHO region, were as follows: Africa (3,773,000), the Americas (448,000), Eastern
Mediterranean (881,000), Europe (525,000), Southeast Asia (4,809,000), and the Western Pacific (3,616,000).
Causative Agent/Transmission
TB is caused by Mycobacterium tuberculosis (MTB) and is spread via an aerosol route; when persons with active
pulmonary TB exhale, cough, sneeze, or talk, they release tiny droplets containing bacteria that can be inhaled
by others. Once inside the lung, MTB invades and replicate within macrophages. The host’s immune response
may result in the formation of granulomas that contains 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 (~20–24 hour doubling time in log phase), a fact that has important
implications on course of treatment.
Presentation
Symptoms 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.
Trends
TB 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 (~425,000 cases in 2004) 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.
E x i s t i n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
Current TB therapies are delivered as n BCG (Bacille Calmette-Guerin) There are no rapid, point-of-care
combinations of multiple antibiotics over − Most commonly administered diagnostics to distinguish latent from
six to nine months. Serious problems of vaccine in the world active disease; tuberculin tests do not
efficacy and toxicity reduce compliance − Safe and inexpensive work in HIV-positive patients.
and increase the generation of resistant − Targeted at newborn n Stained Sputum Smear
bacteria. infants only, per WHO − Microscopic first indicator of the
n Rifampicin − Not used in the United States, presence of mycobacteria
− Introduced in 1963 Canada, or parts of Europe, but − Provides physician with a preliminary
n Isoniazid, Pyrazinamide, common in the developing world confirmation of the diagnosis
Streptomycin & Ethambutol − Variable and limited efficacy n Purified Protein Derivative (PPD)
− Introduced in 1940s-60s − Appears to reduce risk of severe Skin Test, a.k.a. Mantoux Test
− Most frequently used in three- childhood TB disease, but, when given − Used to diagnose LTBI
and four-drug combinations to infants, it may provide limited or − Nonspecific
− Treatment often causes no protection against pulmonary TB n Culture
toxic side effects in adults or adolescents; this subject − Gold standard for diagnosis, needed
n Ethionamide, Para-Amino Salicylate is controversial with numerous for drug susceptibility testing to
(PAS), Cycloserine, Amikacin, studies providing conflicting results diagnose MDR- and XDR-TB
Kanamycin, Fluoroquinolones n Molecular Amplification
− Second-line drugs − Rapid, sensitive
− Generally less potent and more − Too expensive for use in
toxic (except fluoroquinolones) developing countries
− Used to treat drug-resistant TB n QuantiFERON-TB Gold & T-
SPOT.TB Antigen Tests
− Antigens are not present in non-
tuberculosis mycobacteria or in BCG
T a r g e t P r o d u c t P r o f i l e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Rapid acting (courses of two months n Safe to administer to HIV-positive n Rapid and easily performed
or less) infants and to adolescents n Specific and sensitive (to
n Can be co-administered with n At least 70 percent efficacy replace existing skin test)
antiretrovirals against TB disease n Safe and effective in HIV-
n Safer than existing treatments n At least as safe as BCG positive patients
n Effective against MDR-TB n Able to distinguish latent
n Highly potent TB from active disease
n Easily used in the field n Unaffected by prior BCG inoculation
P ipe l i n e nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Research & Pre- Clinical- Clinical- Clinical-
Drugs Discovery Clinical Phase I Phase II Phase III
OFLOTUB consortium/EC/WHO TDR/Lupin (Gatifloxacin) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Albert Einstein College of Medicine (6020 & 6030 attenuated Mtb) nnnnnnnnnnnnnnnnnnnnn
M a r k e t Opp o r t u n i t ie s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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 nine million new cases each year, and many fold 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.
De v e l o p m e n t I s s u e s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs Vaccines Diagnostics
n Latent TB is difficult to reach n Lack of immune correlates of n New diagnostics will require
with standard antibiotics protection or surrogate markers that the discovery of TB-specific
n Persistent bacteria often predict clinical efficacy of a vaccine serum biomarkers
minimally affected by therapy n Development and maintenance
of clinical trial site capacity
A d d i t i o n a l I n f o r m a t i o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n World Health Organization (WHO) ~ www.who.int/tb/en
n Centers for Disease Control & Prevention (CDC) ~ www.cdc.gov/nchstp/tb/default.htm
Key Organizations
n Global Alliance for TB Drug Development ~ www.tballiance.org
n Aeras Global TB Vaccine Foundation ~ www.aeras.org
n Stop TB Partnership ~ www.stoptb.org
n Global Fund to Fight AIDS, Tuberculosis & Malaria ~ www.theglobalfund.org/en
Important Papers
n Andries, K, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis.
Science 307:223-227 (2005)
n Ghandi, 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 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.pdf
n Tuberculosis Vaccines: The Case for Investment ~ www.bvgh.org/documents/
BVGHTBVaccineReport10-6FINAL.pdf
BVGH Accomplishments
BVGH works at the interface of industry, donors,
BIO Ventures for Global Health, a nonprofit organization, disease-focused foundations, and academia. We identify
is accelerating the development of innovative vaccines, compelling targets for biopharmaceutical impact, define
drugs and diagnostics to treat the most devastating diseases viable markets for new global health products, and catalyze
of the developing world. Our mission is to harness private sector R&D through new strategies, partnerships,
the biopharmaceutical skills and resources that have and funding. Recently we–
transformed medicine in the industrialized world to help n Published a comprehensive business case for
save the lives of millions in the developing world. investment in TB vaccines, revealing a viable global
market sufficient to attract industry investment, and
Bringing Innovation to Neglected Diseases presented our findings to leading biopharmaceutical
Despite many recent initiatives to improve health care vaccine firms. Spurred by our conclusion that the TB
for patients in the developing world, we are still far from vaccine market could generate as much as $1 billion
launching groundbreaking new medicines that could per year, several companies boosted their TB vaccine
conquer infectious diseases such as malaria, tuberculosis, R&D efforts and have sought to license technologies
and African sleeping sickness. Tools and technologies exist key to creating a new vaccine.
today that can make major inroads on developing world n Launched our Innovation Map project designed to
diseases – and offer hope for cures in our lifetimes. link proven technology platforms in biotech’s top
drug discovery companies with scientific needs for key
To access these tools, we must address the barriers that neglected diseases. Our published report, to be released
have hindered the most innovative players in modern in November 2007, will outline our findings and lay
medicine from engaging in global health research and the groundwork for new models of collaboration and
development. The perceptions of insufficient markets, partnership for the fight against neglected diseases.
inadequate funding, and unfamiliarity with these diseases n Announced plans with the Biotechnology Industry
have so far deterred industry involvement. Organization (BIO) and the Bill & Melinda Gates
Foundation to co-host an international conference
By focusing more of today’s global health investment on in March 2008—Partnering for Global Health
innovation and bringing to bear the full capabilities of Forum. The Forum will promote new collaborations
advanced biopharmaceutical R&D, we can succeed in our and ideas to tackle global health challenges by bringing
quest for better health for patients throughout the world. together leaders from the biopharmaceutical industry,
academia, international NGOs, governments, investors
BVGH Goals and donors. www.pghforum.org
At BVGH we are devoting our efforts to building market-
based solutions to encourage greater industry investment Learn more about BIO Ventures for Global
and ensure a sustainable pipeline of new products to save Health at our website www.bvgh.org
lives and relieve suffering from developing-world diseases.
Specifically, we aim to–