Prizes and

Parasites:
Incentive Models
for Addressing
Chagas Disease
Sara E. Crager and Matt Price

Neglected Diseases
Despite the enormous progress made in the advancement of health technologies over the last century, infectious diseases continue to cause significant morbidity and mortality in developing countries. Neglected
diseases are a subset of infectious diseases that lack
treatments that are effective, simple to use, or affordable. Neglected diseases primarily affect populations
in poor countries that do not constitute a lucrative
market sector, thus failing to provide incentives for
the pharmaceutical industry to conduct R&D for these
diseases. Of the treatments that do exist for neglected
diseases, most are completely out-dated, with poor
side-effect profiles, cumbersome logistics of administration, and inadequate efficacy. Historically, the
impetus for a majority of neglected disease research
was driven by early 20th-century colonialism, and in
the post-colonial era, these diseases have been virtually ignored.1 Of the 1556 New Chemical Entities
(NCEs) brought to market during the 30-year period
from 1975 to 2004, only 20 less than 0.02% were
for neglected diseases.2
It is useful to consider neglected diseases in the
context of the three types of disease defined by the
WHO Commission on Macroeconomics and Health
(CMH)3: Type I diseases, such as cardiovascular disease and diabetes, which have a large disease burden
in both rich and poor countries; Type II diseases, such
as malaria and tuberculosis, which affect both rich
and poor countries, but with a significant proportion
of the disease burden in poor countries; and Type III
diseases, such as hookworm infections and Chagas
disease that primarily, or in some cases exclusively,
occur in poor countries. The distinction between
Type II and Type III diseases is clearly reflected in the
global pharmaceutical R&D agenda: of the 20 NCEs
brought to market for neglected diseases mentioned
above, over a third were for malaria or tuberculosis.
Most Type II diseases may be considered neglected
diseases, for which treatment options are inadequate,
but do receive some degree of attention in the global
R&D agenda, while most Type III diseases fall into the
category of most neglected diseases, being almost
completely ignored by the pharmaceutical industry.4
This list of most neglected diseases includes diseases
such as leprosy, dengue fever, trachoma, infectious
Sara E. Crager, B.A., is a MD/PhD candidate (12) at Yale
University working on a Ph.D. in microbiology, and is a member of Universities Allied for Essential Medicines. Matt Price,
B.S., is an Analyst for New Initiatives on the Clinton Foundation HIV/AIDS Initiative Drug Access Team and serves on the
board of directors of Universities Allied for Essential Medicines. The views expressed in this paper do not necessarily
represent those of his employer.

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Crager and Price

diarrheal diseases, and the parasitic diseases African

trypanosomiasis, onchocerciasis, leishmaniasis, schistosomiasis, lymphatic filariasis, onchocerciasis, intestinal parasite infections, and Chagas disease.5 Despite
the importance of these diseases from a global public
health perspective, they are not prioritized by drugmakers.
Drug profitability does not necessarily correlate in
any meaningful way with a prioritized list of unmet
global health needs. Pharmaceutical companies,
being, after all, companies, have as their primary priority profit maximization, not global public health
improvement. In some cases these two goals may be
well aligned in setting R&D agendas, such as with
the discovery of new drugs to treat many Type I diseases. On the other hand, the pharmaceutical industry spends enormous amounts of money researching

tive to compare malaria and Chagas disease, in order

to examine the variables contributing to these R&D
gaps. Two important variables related to the incidence
of parasitic disease are living conditions and climate.9
In countries that have a climate favorable to a particular parasite, the middle and upper classes may still
generally be spared due to their higher quality of living
conditions. For the same reason, there is no travelers
market for these diseases. Even populations who have
access to adequate living conditions may be at risk for
malaria, however, due to the critical importance of climate and regional topography for the proliferation of
the mosquito vector responsible for malaria transmission. To illustrate this point on a global scale, there has
recently been a great deal of concern voiced over the
potential of malaria to increasingly affect the developed world due to global climate change.10 Chagas disease transmission, on the other hand, is
highly dependent on living conditions.
The triatome bug vector responsible
Drug profitability does not necessarily correlate
for disease transmission tends to live in
cracks and roofs of poor quality housin any meaningful way with a prioritized list
ing, and thus almost exclusively affects
of unmet global health needs. Pharmaceutical
people living in poverty. For Chagas
companies, being, after all, companies, have as
disease, a developed country market
emerged only when Chagas-infected
their primary priority profit maximization, not
blood began to appear in blood banks
global public health improvement.
in the southwestern United States, due
to immigration of infected individuals.11 This problem has led to a small
treatments for conditions such as hair loss, erectile
rush of innovation around diagnostic testing but
dysfunction, and skin aging. These lifestyle drugs are
not treatment for Chagas to prevent transmission
highly profitable, but have no relevance to global public
via blood transfusion.
health priorities. When lack of profitability precludes
It can be difficult to generate advocacy around most
the alignment of the pharmaceutical industrys R&D
parasitic diseases. The deaths caused by parasitic disagenda with meeting a particular global public health
eases are less salient than the chronic disabling feaneed, another player needs to intervene if this need is
tures of these diseases,12 and while the indirect costs of
6
to be met. It is no coincidence that all 20 of the NCEs
parasitic disease can be far greater over time than the
for neglected diseases discussed above were developed
direct costs of lives lost, it is more difficult to generate
with public-sector involvement.7 It is critical that the
interventionist support for what is perceived as mere
international community take it upon themselves to
economic and social costs of a disease as opposed to
address the predictable gap in R&D conducted by the
the more dramatic mortality rates. Although malaria
pharmaceutical industry. This is especially important
also carries substantial indirect costs,13 the absolute
because the majority of diseases falling into this gap
mortality numbers are impressive malaria being in
disproportionately impact developing countries, where
the top five most common causes of death in children
the finances or technological capacity to address these
under five globally.14 Malaria has a far higher global
R&D needs may be unavailable.
incidence in comparison to Chagas disease; however,
global disease burden is clearly not the critical variParasitic Disease: The Most Neglected
able in generating support for R&D as illustrated by
Diseases
the fact that hookworm disease is estimated to affect
Parasitic diseases both result from poverty and proclose to one billion people,15 with a disease burden
8
mote poverty. With the exception of malaria, virtually
estimated at up to 22 million disability adjusted life
all human parasitic diseases, including Chagas, fall into
years (DALYs),16 yet has a negligible amount of R&D
the category of most neglected diseases. It is illustradirected towards it.17 Although the overall global incipharmaceutical regulations summer 2009

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dence of malaria is much higher than Chagas disease, over 99% of the Chagas disease burden occurs
in Latin America, and when a direct comparison is
made between Chagas and malaria in this region,
the DALYs for malaria in Latin America is estimated
at 111,000, while the DALY estimate for Chagas disease is 662,000.18 In addition, the economic impact
of Chagas constitutes a significant percentage of Latin
American external debt,19 and is considered an impediment to achieving the Millineum Development goals
in Latin America.20

Solutions to Address Neglected Diseases

Global R&D Treaty
The current patent-driven system of R&D only succeeds when public health needs parallel profitability.21
These two variables are clearly not aligned for conditions such as parasitic diseases that primarily affect
populations living in poverty. If these needs are to be
met, alternative mechanisms must be created that
are responsive to global public health needs rather
than market forces. One way in which this problem
could be addressed is the formulation of a global R&D
treaty.22 A global R&D treaty conceptualizes medical
innovation as a global public good. The basic goal of a
global R&D treaty is to provide a framework for coordinating an international scientific research agenda
in order to produce new treatments for high-priority
public health problems, while simultaneously ensuring equitable access to these innovations.
Nicoletta Dentico and Nathan Ford23 have described
six core concepts of a global R&D treaty: (1) a medical
R&D agenda driven by global health needs; (2) prioritization of neglected diseases; (3) adequate international financing to support this R&D; (4) equitable
pricing of resultant innovations; (5) open access to
resultant knowledge; and (6) international exchange.
Such an agenda would allow policymakers to determine research priorities based on public health needs
rather than by market considerations. Prioritization of
neglected diseases would seek to close gaps between
the degree of a diseases global impact and the amount
of R&D directed toward the disease. A commitment
to adequate international financing is a prerequisite
to establishing a research agenda that is based primarily on health needs rather than market factors. A
mechanism for ensuring equitable pricing is necessary to ensure that those living in poor nations have
access to the fruits of this publicly funded research.
Open access is critical for maximizing the impact of
this research by stimulating further innovation elsewhere and ensuring that there is not unnecessary
duplication of efforts. Open international exchange
of technologies, information, and ideas will further
294

foster the rapid development of science and technologies, especially in developing countries.24
The implementation of a global R&D treaty is especially important in the post-TRIPS era. The World
Trade Organizations Agreement on Trade-Related
Aspects of Intellectual Property Rights (TRIPS Agreement),25 like a global R&D treaty, is also an international policy instrument that seeks to stimulate
pharmaceutical R&D, but in this case by focusing on
market incentives and a strong system of intellectual
property rights. Previous to TRIPS, individual governments could choose whether to give patent protection
to pharmaceuticals based on the economic considerations of an individual country. The TRIPS Agreement applies to all WTO member states, providing 20
years of patent protection for pharmaceuticals. This
system is highly effective for stimulating R&D only
in the context of existing market based incentives,
and therefore skews the R&D agenda heavily towards
drugs that are likely to be most lucrative, rather than
towards drugs that are likely to have the greatest
public health impact.26 Another international policy
instrument is thus needed to spur R&D for innovations that are unlikely to be lucrative, but important
for addressing global public health priorities.
Prize Funds
An issue often discussed in the context of a global
R&D treaty is the creation of alternate mechanisms to
incentivize research on neglected diseases. One such
alternative that has been proposed is that of a prize
fund (for detailed discussion of various prize fund
models, see the articles cited below).27 While there are
a number of different prize fund models, the underlying objective is to dissociate the incentive for pharmaceutical innovation from the price of the drug. In
one model of a prize system,28 there would be competition for a substantial monetary reward between
organizations conducting pharmaceutical R&D, with
the prize being given for the achievement of a specified outcome. Governments would maintain a fund
for rewarding companies that successfully bring to
market new drugs for specified indications important
to public health.
While patents would still be issued for the development of new medicines, a prize model would make
the patent holder eligible to receive a large annual
payment from a public fund for a specified number of
years in exchange for relinquishing their patent rights
to monopoly production. This system would make it
possible for knowledge to be placed immediately in the
public domain, allowing generic competition to drive
down drug prices, while still maintaining incentives
for innovation.29 The exact amount of the payment
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Crager and Price

received by the patent holder would be determined by

the magnitude of the public health benefits provided
by the drug. The current patent system has resulted in
a situation where three-fourths of new drugs approved
by the Food and Drug Administration (FDA) are metoo drugs that represent no real therapeutic advance
over existing drugs.30 Payments based on the degree of
global health benefit will incentivize the production of
truly innovative treatments with the greatest potential
for public health impact. The concept of a prize fund
has received support from many quarters, including
the Nobel Prize winning economist Joseph Stiglitz,
who believes this paradigm to be more efficient and
more equitable, and that it would provide strong
incentives for research but without the inefficiencies
associated with monopolization.31 The X-Prize Foundation has demonstrated that the implementation of
well-designed prizes may be effectively used to stimulate R&D in a large variety of areas.32
Intergovernmental Working Group on Public
Health, Innovation, and Intellectual Property
and a Chagas Prize
The prize fund concept recently attracted a great deal
of debate on the international stage during the May
2008 meeting of the WHO-convened Intergovernmental Working Group on Public Health, Innovation and Intellectual Property (IGWG). The IGWG
was created by the WHO in 2006 with a mandate to
develop a strategy and plan of action addressing the
failure of the current system of pharmaceutical R&D
to generate innovations that meet the health needs of
developing countries.
The IGWG negotiations ultimately resulted in the
adoption by the World Health Assembly (WHA) of
Resolution 61.21: Global Strategy and Plan of Action
on Public Health, Innovation and Intellectual Property (GSPOA), considered to be the most important
document since Doha on IP and public health.33 Subelement 5.3a of this Resolution contained a mention
of prizes:
( 5.3a) explore and, where appropriate, promote a
range of incentive schemes for research and development including addressing, where appropriate,
the de-linkage of the costs of research and development and the price of health products, for example
through the award of prizes, with the objective of
addressing diseases which disproportionately affect
developing countries34
While this was recognized as a step forward, there is a
notable absence of any mention of a prize fund, or any
other financing mechanisms for this award of prizes.

During the final round of negotiations in May of

2008, a working document drafted by the nations of
Bolivia and Barbados was put forward35 consisting of
six proposals, one of which was the creation of a prize
fund to incentivize R&D for treatments for Chagas
disease.36 One of the issues raised regarding these
proposals was the relative difficulty of the research
programs described. Questions were raised regarding the proposal on Chagas disease as to the feasibility of addressing such a difficult problem, citing the
lack of success to date. While it is indeed true that
we currently lack effective treatments and vaccines
for Chagas and in fact the majority of parasitic diseases there is no reason that these diseases should
be considered insoluble. We are aggressively pursuing
treatment for extremely complex conditions such as
Alzheimers, despite doubt that a cure or even a truly
effective treatment will ever be found. Parasitic diseases, while certainly not simple to address, should
not be thought of in the same category of difficulty as
diseases such as Alzheimers, a disease to which we
devote many times the amount of resources. Given the
relatively tiny amount of funding allocated to parasitic
diseases thus far, it would be highly premature to conclude that effective treatments are unattainable.
There undoubtedly are a number of hurdles to overcome in the development of medicines and vaccines
for parasitic diseases. Part of the difficulty in addressing parasitic disease is that parasites have a very complex relationship with the human immune system.
With the enormous increase in our understanding
of immunology that has occurred over the last several decades, we now have a much better foundation
of knowledge to understand many of the intricacies
involved in manipulating the host response to fight
parasitic infections. As will be discussed below, what
is currently known about parasitic diseases indicates
that the obstacles to the development of effective medicines and vaccines are by no means insurmountable.
A juncture has been reached when is it political and
social apathy rather than lack of scientific capability
that is the rate-limiting factor in addressing parasitic
diseases.37 Chagas is an excellent example of a parasitic disease that illustrates the problems inherent in
addressing the most neglected parasitic diseases, as
well as potential avenues for solutions.

Chagas Disease
Epidemiology and Clinical Manifestations
Chagas is a parasitic disease endemic to Latin America.
The Centers for Disease Control and Prevention (CDC)
estimates that up to 11 million people are infected with
Chagas,38 although these numbers may underestimate
the true disease burden due to the difficulty of obtain-

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ing accurate data in many of the populations that bear

the greatest burden of disease.
Chagas is a zoonotic, vector-borne disease caused by
the parasite Trypanosoma cruzi. T. cruzi is excreted in
the feces of triatome bugs (or kissing bugs), which feed
on mammalian blood. The major route of transmission is the contact of infected feces with mucose membranes or through broken skin in the area of the bite.
Another major important route of T. cruzi transmission is through blood products, which is an important
route of transmission in urban areas, and is becoming
an increasing problem in the U.S. In January of 2007,
T. cruzi blood screening went into widespread usage
in the U.S., and by mid-June 2008, over 500 donations infected with T. cruzi were detected.39 T. cruzi
can also be transmitted from a pregnant woman to the
fetus, or through consumption of uncooked food that

Colonic dilation presents with abdominal distension

or intractable constipation, and in severe cases can
result obstruction, perforation, and sepsis. Esophageal
dilation result in dysphagia and regurgitation, which
can often lead to the development of aspiration pneumonia. More rarely, meningoencephalitis or hepatitis
may also occur.42

Current Available Treatments

There are two drugs currently approved for treatment
of Chagas disease: benznidazole, launched in 1972, and
nifurtimox, launched in 1967. Both drugs were developed in the 1960s for treatment of T. cruzi infection.43
There has not been a single new drug approved for the
indication of Chagas disease in over 35 years. Despite
the fact that the vast majority of acute infections occur
in children, there are no currently existent pediatric
formulations of drugs that may be used
to treat Chagas. To what extent either
benznidazole or nifurtimox is effective
The only two current treatment options for
in treatment of chronic Chagas disease
Chagas disease are completely out of date.
is still somewhat controversial.44
Benznidazole is administered in 2
These drugs are not highly effective in
doses a day and requires 60-90 days
preventing acute to chronic phase progression,
of treatment in acute infections and,
and both have significant toxicities that can
while effective at reducing the severity and duration of acute infection,
necessitate cessation of treatment.
only achieves a cure in approximately
60% of patients.45 The most common
side effect of benznidazole is dermatihas been contaminated with infected feces.40 In 2005,
tis, which may be accompanied by generalized edema,
for example, there were 25 confirmed cases of Chagas
lymphoadenopathy, musculoskeletal pain, and fever.
disease resulting in 6 deaths caused by consumption
More serious side effects can include serious hematoof contaminated sugar cane juice from a street-vendor
logical abnormalities. Nifurtimox is administered in
in Brazil.41
4 doses a day for 90-120 days. Nifurtimox is effective
Chagas disease has both an acute and chronic
in the acute and early intermediate states of infection;
phase. The acute phase last from 4-12 weeks and is
however, benzidazole is generally preferred because
very frequently asymptomatic, but may also include
of toxicity issues related to nifurtimox.46 These side
symptoms such as fever, myalgias, headache, anorexia,
effects of nifurtimox can include anorexia, neuropsylymphadenopathy, splenomegaly, diarrhea, vomitchiatric disturbances, nausea and vomiting, intestinal
ing, and fatigue. Acute Chagas is most often seen in
colic and diarrhoea, and peripheral neuropathies.
children, and if left untreated, approximately 5-10%
In summary, the only two current treatment options
of patients will die from severe myocarditis or meninfor Chagas disease are completely out of date. These
goencephalitis. Approximately 30% of infected indidrugs are not highly effective in preventing acute to
viduals go on to develop chronic Chagas disease.
chronic phase progression, and both have significant
Individuals that become chronically infected genertoxicities that can necessitate cessation of treatment.
ally do not present with clinical manifestations until
Furthermore, their efficacy in treating the chronic
anywhere from 10 to 30 years after initial infection.
phase of Chagas disease is still under debate. Finally,
The main complications of chronic Chagas are cardiac
they are very cumbersome in terms of the dosing logisand gastrointestinal. The major cardiac manifestatics, both requiring multiple doses a day for several
tion is a progressive cardiomyopathy that can presmonths. The problems with these types of anti-microent with congestive heart failure, arrythmias, and the
bial dosing regimens are well documented. In the
potential for sudden cardiac arrest. Patients can also
U.S., patients are unlikely to complete even a 10-day
present with sequale of megacolon or megaesophagus.
course of antibiotics,47 and the increasing resistance
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Crager and Price

to tuberculosis therapy is partially due to the extended

dosing regimes of anti-tuberculosis drug.48 In addition to being particularly cumbersome for use in lowresource settings, anti-microbial therapy that must be
taken multiple times a day over an extended period of
time almost inevitably leads to decreased compliance
and increased resistance. It is clear that new drugs to
treat acute and especially chronic phases of Chagas
are urgently needed, however, a more effective longterm strategy for Chagas control may be a vaccine
approach.
The Case for a Vaccine Approach
In order to create a structure to incentivize the development of new treatments for Chagas disease, the
Bolivia and Barbados Working Document proposes
The Chagas Impact Prize Fund:
 he WHO should set up a prize fund for ChaT
gas disease. The prize fund should be resourced
at $250 million. The money would be used to
resource several initiatives involving prizes. The
$250 million principal of the prize should be given
to new treatments that improve health outcomes
for the populations at risk for Chagas disease. No
money should be disbursed from the fund until at
least one new medicine, vaccine, medical diagnostic device or other technology is introduced that
actually improved health outcomes for persons at
risk for Chagas disease.
The Working Document does not specify a preferred
focus on any of the potential approaches mentioned.
The best approach to improving health outcomes for
a particular disease is dependent on a multiple disease-specific variables. In the case of Chagas disease,
there are three basic control strategies that may be
employed49: (1) Primary prevention, which targets disease transmission, and could involve strategies such as
vector control and vaccines; (2) Secondary prevention,
which targets early asymptomatic stages in an attempt
to prevent end-organ damage, and would require both
a screening paradigm using an accurate diagnostic
test, as well as an effective anti-Trypanosomal drug;
(3) Tertiary prevention, which targets the late symptomatic stages once there has been irreversible end
organ damage, and has the goal of mitigating morbidity and mortality. Primary prevention is thought by
many to be the most feasible way to address Chagas
disease.50 Other primary prevention strategies have
been discussed in detail elsewhere,51 and so we will
focus here on vaccines.
Vaccine approaches have been previously proposed
to decrease the economic and social costs resultant

from neglected parasitic diseases in developing countries.52 While the obvious disadvantage to a vaccine
approach is that it would be unlikely to be able to help
those patients already harboring chronic parasitic
infection, there are nevertheless a number of reasons
why a vaccine approach could be particularly useful in
the case of Chagas.
Asymptomatic acute phase. While it is hoped that
a new generation of drugs could be highly effective
in preventing the progression from acute to chronic
Chagas disease, the vast majority of acute infections
are asymptomatic.53 In order for drug treatment to
be most effective, an accurate diagnosis of Chagas
must be made and treatment initiated as early as possible.54 Longitudinal studies of chronic Chagas disease
patients suggest that despite a prolonged latency to
development of clinically significant symptoms, myocardial damage begins early in the course of chronic
Chagas.55 Even if a new generation of Chagas drugs
could completely prevent acute to chronic phase progression, these drugs would not be able to prevent the
development of chronic disease in those individuals
who are unaware that they are infected, and thus fail
to seek medical treatment in the acute or intermediate
phases of the disease. In many of the places that Chagas
is endemic, the population does not have ready access
to medical treatment, and as a result, even infections
that are symptomatic in the acute phase have great
potential to go untreated.
Chronic phase diagnosis. Cardiac involvement is
the main cause of mortality in chronic Chagas; however, the differential diagnosis for the development of
many of the cardiac symptoms associated with chronic
Chagas disease is broad. A clinician would require a
high degree of suspicion to test specifically for Chagas, which is especially problematic because it may be
difficult to identify an inciting even that could have
occurred decades earlier. As such, the effectiveness of
a drug in chronic Chagas is highly dependent on the
additional development of sensitive and specific diagnostic tests that are easily administered in the field.
In addition, it would be necessary to develop robust
screening protocols to attempt to identify patients in
the asymptomatic intermediate phase of Chagas.
Treatment duration. Untreated, approximately
30% of patients infected with T. cruzi will go on to
develop chronic disease that could require long-term
therapy.56 Even if a new generation of Chagas drugs
were low-cost, treatment of this duration is very
expensive, not to mention logistically cumbersome for
already overtaxed healthcare systems. Additionally,
drug administration over this time-scale is generally
associated with overall lower compliance, leading to
the development of drug-resistance.

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Blood supply contamination. Approximately 10%

of Chagas disease transmission is due to contamination of blood products.57 This is particularly prominent
in urban areas of Latin America, but, with increasing
rates of migration, is becoming a problem, in many
areas in the industrialized world.58 Individuals that are
asymptomatic in the acute and intermediate stages of
Chagas disease still maintain a low-grade parasitemia.
This parasitemia can have life-long persistence even
in individuals that never develop clinical symptoms.
As such, an additional danger of being asymptomatic
in the acute and intermediate phases is contamination of the blood supply by donors unaware of their
diagnosis.59
All of the above concerns would be mitigated by utilizing a vaccine approach to Chagas.

Progress toward a Chagas Vaccine

Parasites-Host Interactions and Vaccine Design
A Chagas vaccine may be desirable, but is it possible?
Although a vaccine approach has great potential for
control of Chagas disease, it is nonetheless true that
currently there does not exist any anti-parasite vaccines licensed for use in humans. One of the reasons
for the slow progress in this area is the extremely complex relationship that parasites have with the human
immune system. The interaction between parasites
and the host immune system has been compared to
a game of chess that has been going on for millions of
yearsevery move is accompanied by a counter move
until eventually an intricate network of interactions
ensues.60
Because a parasite is dependent on its host for survival, it is against the interest of a parasite to kill its
host. Parasites have thus evolved to strike a careful
balance between virulence and ensuring their survival
within their host, and often elicit inappropriate and
ineffective immune responses.61 As such, parasitic
infections unlike infection with many bacterial or
viral pathogens tend to be chronic. Parasites also
have the ability to actively induce host immune suppression.62 Patients with parasitic infections often
show reduced immune responses not only to the
infecting parasite, but to other unrelated infectious
organisms. For example, infection with both malaria
parasites63 as well as helminthes64 has been shown
to suppress immune responses to totally unrelated
vaccines. This suggests a mechanism of generalized
immunosuppression, rather than simply resistance of
the parasite to attack by the immune system.
Vaccines are generally composed of two components: antigen and adjuvant. The antigen is a component of the microbe, often a protein, that is targeted
by the immune system. Adjuvant are substances that
298

may be administered with vaccines to stimulate the

immune system so that it responds more strongly to
the antigen. There are many different types of adjuvants, each inducing immune responses with different attributes. In most vaccine efforts, the selection
of an appropriate antigen is the major critical step
in designing an effective vaccine. Experience during
clinical trials of several malaria vaccines, however, has
highlighted the vital importance of adjuvant selection
to the ability of a malaria vaccine to induce a durable
immune response, or even any immune response at
all.65 The central importance of adjuvant selection to
the success of malaria vaccine efforts suggests that the
particular immunomodulatory effects of the specific
adjuvant selected may have an importance approaching that of the actual choice of target antigen(s).
The conventional approach to vaccine development
concentrating on a small number of antigens that
elicit one or more well-defined immune responses
has not been highly successful when applied to parasite vaccines. A more effective approach to parasite
vaccines may involve a shift of focus toward designing vaccines that are tailor made to induce specific
immune response based on an analysis of the interactions of the parasite and the host-immune system.66
Rather than solely continuing the search for new target antigens, future parasite vaccine efforts need to
acknowledge the importance of understanding how
the parasite interacts with the host immune system in
order to rationally shape the immune response elicited to parasite target antigens. Our understanding of
immunology has grown enormously over the last several decades, and there has been a great deal of work
done on elucidating mechanisms of host-parasite
interactions. The current lack of parasitic vaccines
available for human use can no longer be justified
by citing scientific hurdles. Our technical ability to
address many neglected parasitic diseases has overtaken the social and political will needed to transform
scientific discoveries into usable vaccines.67
Chagas Vaccine Research
While Chagas vaccine research has received a relatively
tiny amount of funding, there has been clear progress.
Proof of concept has been established in animal studies,68 and both the Chagas genome69 and proteome70
have been completed. A number of recent studies in
animal models suggest an encouraging picture about
the possibility of developing an effective vaccine for
Chagas disease.
Antigen selection: Despite the large size of the Chagas genome, which provides an enormous array of
potential antigenic targets, there has been progress in
identifying specific target antigens that are capable of
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Crager and Price

inducing protective immunity. A number of Chagas

candidate vaccines have demonstrated robust protection of vaccinated mice against challenge with a lethal
dose of T.cruzi.71 One of the major candidate antigens
identified is cruzipan, an important T. cruzi enzyme.
Cruzipan is expressed in all strains and developmental
forms of the T. cruzi parasite,72 and has been shown in
multiple studies, using several different types of vaccine delivery systems, to induce robust protection in
animal models.73 Importantly, it has also been shown
in animal models that vaccination with this antigen
was capable of completely eliminating tissue damage during the chronic stage of infection.74 Antigens
encoded by the T. cruzi sialidase/trans-silidase gene
superfamily have also been identified as important
targets of immune responses,75 and have been shown
to have potential as vaccine candidates.76 The transsialidases are attractive vaccine targets because they
are immunodominant epitopes targeted by killer
T-cells, however the large number of trans-sialidase
genes and the potential for high a high degree of polymorphism may ultimately make them suboptimal candidates for further development.77 Another promising
vaccine effort using a recombinant adenovirus vector
expressing two different antigens, trans-sialidase and
amastigote surface protein-2, was able to induce complete, long-term protection in all animals tested.78 In
addition, there is accumulating evidence suggesting
that the secreted and GPI-anchored protein, which
are expressed in both the extra- and intra-cellular
stages of infection, are likely also important targets for
immune activation.79 Other candidate target antigens
include paraflagellar rod proteins and kinetoplastid
membrane proteins.80
Adjuvant development: T. cruzi has both intra- and
extracellular forms in the mammalian host, and it
is therefore likely that a vaccine will need to induce
a wide spectrum of immune responses.81 Multiple
studies have been performed using animal models
exploring the importance of a number of endogenous
immunostimulatory molecules in inducing an appropriate immune response to control T. cruzi infection.
These studies have elucidated a basic picture of the
important interactions between T. cruzi and the host
immune system. These studies strongly suggest that
induction of an immune response with a particular
set of attributes, known as a Th1-type response, is
important for control of T. cruzi.82 Certain types of
vaccine adjuvants are better at inducing this type of
response than others, and knowing which immune
responses are important can guide choice of adjuvant,
as well as providing a means of evaluating which vaccines are likely to be effective. One promising set of
adjuvants targeting this pathway could include the

CpG-oligodeoxynucleotides (CpG-ODNs), which are

powerful enhancers of Th1 immune responses. CpGODNs are being studied for their potential as vaccine
adjuvants for a variety of viral, bacterial, and parasitic
diseases,83 and have been shown in multiple studies
to significantly enhance immune responses to T. cruzi
antigens.84 Other studies have shown excellent protective immunity to T. cruzi in mice using the receptor
activator NFB (RANK) ligand as an adjuvant.85 A
number of additional studies have successfully used
the cytokine IL-12 to boost immune response to T.
cruzi antigens.86 Finally, similar to what has been seen
in malaria vaccine research,87 a vaccine using a heterologous prime-boost viral vector model was highly
successful in inducing robust protective immunity in
mice to T. cruzi infection.88
Vaccines Designed for Use in Developing Countries
Given that a Chagas vaccine is likely to only be used
in developing countries, it is important to take into
consideration variables that would make it most
appropriate for use in resource-poor settings. This is
discussed in element 1.2 in the IGWG Global strategy
and plan of action that addresses the formulation of
a prioritized global R&D strategy. Sub-elements 1.2
a and e describe conducting research appropriate
for resource-poor settings and research on technologically appropriate products for addressing public
health needs to combat diseases in developing countries that leads to the development of innovations
that are user friendly (in terms of use, prescription
and management) and accessible (in terms of availability and affordability). It is far from ideal to create a highly effective anti-parasitic vaccine that is too
logistically cumbersome to administer effectively in
developing countries.
There are a number of important variables to take
into consideration when developing vaccines for use
in resource poor settings:
1). Many vaccines are unstable at room-temperature and need to be refrigerated. These vaccines
require a cold-chain for distribution, which may
not be consistently available in all areas.
2). The majority of vaccines currently on the
market are given by an injection. This is suboptimal for several reasons, including the need
for a trained health care professional for administration, as well as the expense of needles
and syringes and the potential for spreading
blood-borne infections via needle-reuse if in
short supply. A non-injectable Chagas vaccine
is a very real possibility since oral89 and intranasal90 formulations have already been shown

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SYMPO SIUM

A Chagas prize fund could provide the catalyst needed to advance the progress
made thus far from animal models to an effective public health tool. The
Chagas Impact Prize Fund recently proposed in the Bolivia and Barbados
Working Document suggests a $250 million principle, which would be
dispersed in $10 million and $25 million allotments per year for single
and multiple products brought to market, respectively.
to be effective in animal models. These inoculation routes may have the added advantage of
facilitating the induction of mucosal immunity,
which could promote control of the parasite
very early in the process of infection.91
3). Vaccines that need a large number of boosters
are also sub-optimal in developing countries
where it may be more difficult to ensure regular follow-up with patients at specified time
intervals.
4). A
 nother important issue is whether the vaccine
may be administered to HIV positive individuals. If not, this may exclude large numbers of
the population in certain areas.
5). V
 iral vectors have the potential to be excellent
parasite vaccine platforms;92 however, when
selecting a particular viral vector for vaccine
development, it must be considered whether
that vector has high seroprevalence in developing countries. Viral vector vaccines may be
much less effective in populations that have
high rates of previous exposure to the vector
used, and most viruses have geographicallyvariable rates of seroprevalence. For example,
certain viruses that are used as vaccine vectors
have very high seroprevalence in developing
countries, such as adenovirus 5, which has a
seroprevalence of over 90% in sub-Saharan
Africa, in comparison to 20% in The Netherlands.93 The relevance of this point has been
clearly demonstrated with the recent failure of
the adenovirus 5 vectored HIV vaccine. It has
been hypothesized that part of what caused
higher rates of HIV to be observed in vaccinees
was the highly prevelant adenovirus 5 seropositivity.94 Other vaccine vectors, such as vesicular
stomatitis virus, rarely infect humans, and so
generally have very low rates of seroprevalence,
even in developing countries. In addition, certain viral vectors have potential to administered
via non-injectible inoculation routes.

300

While it is likely impossible to design a vaccine that

performs optimally in terms of every single one of the
criteria discussed above, it is nevertheless important
to attempt to take them into account to the extent possible during the vaccine development process.

Designing a Chagas Vaccine Prize

There are undoubtedly a number of scientific hurdles
to be overcome in the development of vaccines for
parasitic diseases, however these have ceased to be
the rate-limiting factor.95 Chagas vaccine research has
made a good deal of progress in elucidating some of
the basic mechanisms of protective immunity, identifying appropriate antigenic targets, and demonstrating the ability to induce durable protective immunity in animal models. While we are still a long way
from having a useable Chagas vaccine, this progress
is significant, especially given the funding situation of
Chagas to date. Other major parasite vaccine efforts
currently ongoing, most notably malaria, continue to
broaden our understanding of the critical components
of effective parasitic vaccines.
While there still remains a great deal of research to
be done, we have reached a point where there are a
number of promising Chagas vaccine strategies that
have demonstrated protection in animal models.
There are, however, no programs to develop human
vaccines against Chagas disease currently in progress.96 These promising innovations are unlikely to
be translated into products that may be used clinically in the current patent-based system driven primarily by market-considerations. The problem is
well described in the report by the Commission on
Intellectual Property Rights, Innovation and Public
Health (CIPIH):
t he genomes of the trypanosomes which cause
Chagas disease have been published. While
these advances are critical, the Science editorial
accompanying publication captured the dilemma
well: The Tritryp genomes are thus intrinsically
interesting but what will they contribute to the
amelioration of disease?...we need resources and

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Crager and Price

commitment on a far larger scale to transform

drug targets into clinical successes. It is clear that
the traditional pharmaceutical industry will not
become effectively involved in this area, and the
current promotion-and-reward system in academia
does not attract or sustain the necessary human
and financial resources.97
A Chagas prize fund could provide the catalyst
needed to advance the progress made thus far from
animal models to an effective public health tool. The
Chagas Impact Prize Fund recently proposed in the
Bolivia and Barbados Working Document suggests
a $250 million principle, which would be dispersed
in $10 million and $25 million allotments per year
for single and multiple products brought to market,
respectively.
A Chagas prize fund could provide the impetus for
moving the most promising Chagas vaccine candidates forward into preclinical and clinical trials. Candidate target antigens for further pre-clinical development must have demonstrated robust protection in
animal models over multiple studies. In clinical studies, it must be demonstrated that the vaccine is: (1)
safe; (2) robustly immunogenic; (3) induces durable
immunologic memory; (4) provides a high degree of
protection; (5) can be administered to children; and
(6) requires no more than three total vaccine administrations. If all the above criteria are met, an additional amount could be added to the yearly dispersal
allotment for meeting any of the following criteria: (1)
stable at room temperature, or heat stable; (2) noninjectable route of administration; (3) requires fewer
than three vaccine administrations; or (4) if incorporating a viral vector, uses one with low seroprevalence
in Chagas endemic regions.
It is critical that the prize be designed to foster
cooperation between different labs. Many of the most
effective parasite vaccine efforts to date have involved
combinations of different types of vaccines or the use
multiple antigens.98 The combination of two different
vaccines (e.g., a recombinant protein or DNA priming
inoculation with a viral vector boosting inoculation,
or priming with one viral vector and boosting with
a different viral vector) has been shown to be more
effective than individual vaccines for many parasitic
infections such as leshmaniasis,99 toxoplasmosis,100
tapeworm infection,101 and in numerous studies of
malaria.102 Most recently, the Glaxo Smith Klein RTS,
S recombinant protein vaccine, which completed
Phase II clinical trials last year, has been shown to have
significantly enhanced immunogenicity when administered in combination with a viral vectored malaria
vaccine.103 The most effective Chagas vaccine could

ultimately be an inoculation regimen that combines

vaccines that are being developed by two or more different labs. As such, the structure of the prize should
encourage the exploration of the effects of combining
vaccines being developed by different labs. The Chagas Impact Prize Fund proposes to create incentives
for open exchange of information among scientists
by allocating the prize fund such that the winning
entrant is awarded 90% of the prize money, while the
remaining 10% is allotted to researchers scientists that
openly shared useful information or materials. While
this could effectively facilitate open access to knowledge, other approaches may also be useful to facilitate
exploring the effects of combining individual vaccines
that are being developed in parallel. One strategy that
might be used to truly incentivize cooperation on this
level could involve increasing the amount allotted to
each scientist for the generation of a product brought
to market if the product contained components from
two or more labs.
Finally, part of the prize fund could be reserved for
the development of an effective parasite vaccine adjuvant. As discussed above, adjuvant selection is likely
to be critically important to a successful anti-parasite
vaccination strategy. A number of potential immunologic pathways have been highlighted in Chagas vaccine development as potential targets of new vaccine
adjuvants. There are currently a number of candidate
adjuvants being explored for use in Chagas disease,
most, if not all of which have the potential for wider
applications in furthering other parasite vaccine
efforts. Again, cooperation between different labs is
critical, because the most effective approach could
ultimately involve a vaccine developed by one lab
combined with an adjuvant developed by a different
lab.

Conclusions
Chagas disease exemplifies many of the issues faced in
developing treatments for parasitic diseases. Despite
their importance in the context of public health, there
are virtually no market-based incentives to stimulate R&D for Chagas disease, making alternative
approaches necessary to the future development of
these treatments. While a number of approaches are
likely necessary to adequately address Chagas disease, a vaccine strategy could be highly effective. The
recent proposal made at the IGWG regarding a prize
fund approach to Chagas was timely. With many of the
scientific barriers to developing vaccines for parasitic
diseases being overcome, there is now a great need to
create a system that ensures that these discoveries are
translated into public health tools.

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