Sie sind auf Seite 1von 14

Prizes and Parasites:

Incentive Models for Addressing Chagas Disease

Sara E. Crager and Matt Price

292

Neglected Diseases

Despite the enormous progress made in the advance- ment of health technologies over the last century, infec- tious diseases continue to cause significant morbid- ity and mortality in developing countries. Neglected diseases are a subset of infectious diseases that lack treatments that are effective, simple to use, or afford- able. 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 admin- istration, 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 vir- tually 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 dis- ease 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 mem- ber of Universities Allied for Essential Medicines. Matt Price, B.S., is an Analyst for New Initiatives on the Clinton Founda- tion HIV/AIDS Initiative Drug Access Team and serves on the board of directors of Universities Allied for Essential Medi- cines. The views expressed in this paper do not necessarily represent those of his employer.

journal of law, medicine & ethics

Crager and Price

diarrheal diseases, and the parasitic diseases African trypanosomiasis, onchocerciasis, leishmaniasis, schis- tosomiasis, lymphatic filariasis, onchocerciasis, intes- tinal parasite infections, and Chagas disease. 5 Despite the importance of these diseases from a global public health perspective, they are not prioritized by drug- makers. 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 pri- ority 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 dis- eases. On the other hand, the pharmaceutical indus- try spends enormous amounts of money researching

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.

treatments for conditions such as hair loss, erectile dysfunction, and skin aging. These “lifestyle drugs” are highly profitable, but have no relevance to global public health priorities. When lack of profitability precludes the alignment of the pharmaceutical industry’s R&D agenda with meeting a particular global public health need, another player needs to intervene if this need is to be met. 6 It is no coincidence that all 20 of the NCEs for neglected diseases discussed above were developed with public-sector involvement. 7 It is critical that the international community take it upon themselves to address the predictable gap in R&D conducted by the pharmaceutical industry. This is especially important because the majority of diseases falling into this gap disproportionately impact developing countries, where the finances or technological capacity to address these R&D needs may be unavailable.

Parasitic Disease: The Most Neglected Diseases

Parasitic diseases both result from poverty and pro- mote poverty. 8 With the exception of malaria, virtually all human parasitic diseases, including Chagas, fall into the category of most neglected diseases. It is illustra-

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 partic- ular 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 cli- mate and regional topography for the proliferation of the mosquito vector responsible for malaria transmis-

sion. 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 devel- oped world due to global climate change. 10 Chagas dis- ease transmission, on the other hand, is highly dependent on living conditions. The triatome bug vector responsible

for disease transmission tends to live in cracks and roofs of poor quality hous- ing, and thus almost exclusively affects people living in poverty. For Chagas disease, a developed country market emerged only when Chagas-infected

blood began to appear in blood banks in the southwestern United States, due to immigration of infected individu- als. 11 This problem has led to a small rush of innovation around diagnostic testing — but not treatment — for Chagas to prevent transmission via blood transfusion. It can be difficult to generate advocacy around most parasitic diseases. The deaths caused by parasitic dis- eases are less salient than the chronic disabling fea- tures of these diseases, 12 and while the indirect costs of parasitic disease can be far greater over time than the direct costs of lives lost, it is more difficult to generate interventionist support for what is perceived as mere economic and social costs of a disease as opposed to the more dramatic mortality rates. Although malaria also carries substantial indirect costs, 13 the absolute mortality numbers are impressive — malaria being in the top five most common causes of death in children under five globally. 14 Malaria has a far higher global incidence in comparison to Chagas disease; however, global disease burden is clearly not the critical vari- able in generating support for R&D as illustrated by the fact that hookworm disease is estimated to affect close to one billion people, 15 with a disease burden estimated at up to 22 million disability adjusted life years (DALYs), 16 yet has a negligible amount of R&D directed towards it. 17 Although the overall global inci-

pharmaceutical regulations summer 2009

293

SYMPOSIUM

dence of malaria is much higher than Chagas dis- ease, 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 dis- ease 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 imped- iment 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 suc- ceeds when public health needs parallel profitability. 21 These two variables are clearly not aligned for condi- tions 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 coor- dinating an international scientific research agenda in order to produce new treatments for high-priority public health problems, while simultaneously ensur- ing equitable access to these innovations. Nicoletta Dentico and Nathan Ford 23 have described six core concepts of a global R&D treaty: (1) a medical R&D agenda driven by global health needs; (2) pri- oritization of neglected diseases; (3) adequate inter- national 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 deter- mine 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 disease’s 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 pri- marily on health needs rather than market factors. A mechanism for ensuring equitable pricing is neces- sary 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 else- where 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 technolo- gies, especially in developing countries. 24 The implementation of a global R&D treaty is espe- cially important in the post-TRIPS era. The World Trade Organization’s Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS Agree- ment), 25 like a global R&D treaty, is also an inter- national 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 govern- ments could choose whether to give patent protection to pharmaceuticals based on the economic consider- ations of an individual country. The TRIPS Agree- ment 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 innova- tions 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 under- lying objective is to dissociate the incentive for phar- maceutical innovation from the price of the drug. In one model of a prize system, 28 there would be com- petition for a substantial monetary reward between organizations conducting pharmaceutical R&D, with the prize being given for the achievement of a speci- fied 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 develop- ment 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

journal of law, medicine & ethics

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 “me- too” 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 Foun- dation has demonstrated that the implementation of well-designed prizes may be effectively used to stimu- late 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 Intergovern- mental Working Group on Public Health, Innova- tion 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 Prop- erty (GSPOA), considered to be “the most important document since Doha on IP and public health.” 33 Sub- element 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 devel- opment including addressing, where appropriate, the de-linkage of the costs of research and develop- ment and the price of health products, for example through the award of prizes, with the objective of addressing diseases which disproportionately affect developing countries 34

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.

pharmaceutical regulations summer 2009

During the final round of negotiations in May of 2008, a working document drafted by the nations of Bolivia and Barbados was put forward 35 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 regard- ing the proposal on Chagas disease as to the feasibil- ity 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 dis- eases — there is no reason that these diseases should be considered insoluble. We are aggressively pursuing treatment for extremely complex conditions such as Alzheimer’s, despite doubt that a cure or even a truly effective treatment will ever be found. Parasitic dis- eases, while certainly not simple to address, should not be thought of in the same category of difficulty as diseases such as Alzheimer’s, 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 con- clude that effective treatments are unattainable. There undoubtedly are a number of hurdles to over- come in the development of medicines and vaccines

for parasitic diseases. Part of the difficulty in address- ing parasitic disease is that parasites have a very com- plex relationship with the human immune system. With the enormous increase in our understanding of immunology that has occurred over the last sev- eral 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 med- icines 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 para- sitic 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-

295

SYMPOSIUM

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 transmis- sion is the contact of infected feces with mucose mem- branes or through broken skin in the area of the bite. Another major important route of T. cruzi transmis- sion 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 dona- tions 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

 

The only two current treatment options for Chagas disease are completely out of date. These drugs are not highly effective in

 

preventing acute to chronic phase progression,

and both have significant toxicities that necessitate cessation of treatment.

can

has been contaminated with infected feces. 40 In 2005, for example, there were 25 confirmed cases of Chagas disease resulting in 6 deaths caused by consumption of contaminated sugar cane juice from a street-vendor in Brazil. 41 Chagas disease has both an acute and chronic phase. The acute phase last from 4-12 weeks and is very frequently asymptomatic, but may also include symptoms such as fever, myalgias, headache, anorexia, lymphadenopathy, splenomegaly, diarrhea, vomit- ing, and fatigue. Acute Chagas is most often seen in children, and if left untreated, approximately 5-10% of patients will die from severe myocarditis or menin- goencephalitis. Approximately 30% of infected indi- viduals go on to develop chronic Chagas disease. Individuals that become chronically infected gener- ally do not present with clinical manifestations until anywhere from 10 to 30 years after initial infection. The main complications of chronic Chagas are cardiac and gastrointestinal. The major cardiac manifesta- tion is a progressive cardiomyopathy that can pres- ent with congestive heart failure, arrythmias, and the potential for sudden cardiac arrest. Patients can also present with sequale of megacolon or megaesophagus.

 

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 pneu- monia. 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 devel- oped 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

in treatment of chronic Chagas disease is still somewhat controversial. 44 Benznidazole is administered in 2 doses a day and requires 60-90 days of treatment in acute infections and, while effective at reducing the sever-

ity and duration of acute infection, only achieves a cure in approximately 60% of patients. 45 The most common side effect of benznidazole is dermati- tis, which may be accompanied by generalized edema, lymphoadenopathy, musculoskeletal pain, and fever. More serious side effects can include serious hemato- logical abnormalities. Nifurtimox is administered in 4 doses a day for 90-120 days. Nifurtimox is effective in the acute and early intermediate states of infection; however, benzidazole is generally preferred because of toxicity issues related to nifurtimox. 46 These side effects of nifurtimox can include anorexia, neuropsy- chiatric disturbances, nausea and vomiting, intestinal colic and diarrhoea, and peripheral neuropathies. In summary, the only two current treatment options for Chagas disease are completely out of date. These drugs are not highly effective in preventing acute to chronic phase progression, and both have significant toxicities that can necessitate cessation of treatment. Furthermore, their efficacy in treating the chronic phase of Chagas disease is still under debate. Finally, they are very cumbersome in terms of the dosing logis- tics, both requiring multiple doses a day for several months. The problems with these types of anti-micro- bial dosing regimens are well documented. In the U.S., patients are unlikely to complete even a 10-day course of antibiotics, 47 and the increasing resistance

296

journal of law, medicine & ethics

Crager and Price

to tuberculosis therapy is partially due to the extended dosing regimes of anti-tuberculosis drug. 48 In addi- tion to being particularly cumbersome for use in low- resource 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 long- term strategy for Chagas control may be a vaccine approach.

The Case for a Vaccine Approach In order to create a structure to incentivize the devel- opment of new treatments for Chagas disease, the Bolivia and Barbados Working Document proposes The Chagas Impact Prize Fund:

The WHO should set up a prize fund for Cha- 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 diagnos- tic 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 dis-

ease-specific variables. In the case of Chagas disease, there are three basic control strategies that may be

employed 49 : (1) Primary prevention, which targets dis- ease 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 symp- tomatic stages once there has been irreversible end organ damage, and has the goal of mitigating morbid- ity 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

pharmaceutical regulations summer 2009

from neglected parasitic diseases in developing coun- tries. 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 pos-

sible. 54 Longitudinal studies of chronic Chagas disease patients suggest that despite a prolonged latency to development of clinically significant symptoms, myo- cardial 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 pro- gression, 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; how-

ever, 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 Cha- gas, 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 diag- nostic 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.

297

SYMPOSIUM

Blood supply contamination. Approximately 10% of Chagas disease transmission is due to contamina-

tion 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 contamina- tion of the blood supply by donors unaware of their diagnosis. 59 All of the above concerns would be mitigated by uti- lizing 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 vac- cines licensed for use in humans. One of the reasons

for the slow progress in this area is the extremely com- plex 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

years…every 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 sur- vival, 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 sup- pression. 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 parasites 63 as well as helminthes 64 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 compo- nents: antigen and adjuvant. The antigen is a compo- nent 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 adju- vants, each inducing immune responses with differ- ent 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 approach- ing 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 para- site vaccines. A more effective approach to parasite vaccines may involve a shift of focus toward design- ing vaccines that are “tailor made” to induce specific immune response based on an analysis of the interac- tions of the parasite and the host-immune system. 66 Rather than solely continuing the search for new tar- get 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 elic- ited to parasite target antigens. Our understanding of immunology has grown enormously over the last sev- eral 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 over- taken 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 stud- ies, 68 and both the Chagas genome 69 and proteome 70 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 Cha- gas genome, which provides an enormous array of potential antigenic targets, there has been progress in identifying specific target antigens that are capable of

journal of law, medicine & ethics

Crager and Price

inducing protective immunity. A number of Chagas candidate vaccines have demonstrated robust protec- tion 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 vac- cine 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 dam- age 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 trans- sialidases 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 poly- morphism may ultimately make them suboptimal can- didates 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 com- plete, 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 appro- priate 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 vac- cines are likely to be effective. One promising set of adjuvants targeting this pathway could include the

pharmaceutical regulations summer 2009

CpG-oligodeoxynucleotides (CpG-ODNs), which are powerful enhancers of Th1 immune responses. CpG- ODNs 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 protec- tive immunity to T. cruzi in mice using the receptor activator NFκB (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 het- erologous 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 techno- logically appropriate products for addressing public health needs to combat diseases in developing coun- tries” that leads to the development of innovations that are “user friendly (in terms of use, prescription and management) and accessible (in terms of avail- ability and affordability).” It is far from ideal to cre- ate 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-tempera- ture 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 sub- optimal for several reasons, including the need for a trained health care professional for admin- istration, 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 oral 89 and intra- nasal 90 formulations have already been shown

299

SYMPOSIUM

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 inocula- tion 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 regu- lar follow-up with patients at specified time intervals. 4). Another important issue is whether the vaccine may be administered to HIV positive individu- als. If not, this may exclude large numbers of the population in certain areas. 5). Viral 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 devel- oping 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 geographically- variable 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 Nether- lands. 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 seroposi- tivity. 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, cer- tain viral vectors have potential to administered via non-injectible inoculation routes.

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 pos- sible 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, identi- fying appropriate antigenic targets, and demonstrat- ing the ability to induce durable protective immu- nity 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 prog- ress. 96 These promising innovations are unlikely to be translated into products that may be used clini- cally in the current patent-based system driven pri- marily by market-considerations. The problem is well described in the report by the Commission on Intellectual Property Rights, Innovation and Public Health (CIPIH):

the 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

300

journal of law, medicine & ethics

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

ultimately be an inoculation regimen that combines vaccines that are being developed by two or more dif- ferent labs. As such, the structure of the prize should encourage the exploration of the effects of combining vaccines being developed by different labs. The Cha- gas 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 knowl- edge, 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 adju- vant. As discussed above, adjuvant selection is likely to be critically important to a successful anti-parasite vaccination strategy. A number of potential immuno- logic pathways have been highlighted in Chagas vac- cine 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.

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 candi-

dates forward into preclinical and clinical trials. Can- didate target antigens for further pre-clinical devel- opment must have demonstrated robust protection in animal models over multiple studies. In clinical stud- ies, 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 admin- istrations. If all the above criteria are met, an addi- tional 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) non- injectable route of administration; (3) requires fewer than three vaccine administrations; or (4) if incorpo- rating 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

Conclusions

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,

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 stimu- late 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 dis- ease, 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.

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 admin- istered in combination with a viral vectored malaria vaccine. 103 The most effective Chagas vaccine could

pharmaceutical regulations summer 2009

301

SYMPOSIUM

References

1.

P. Trouiller, P. Olliaro, E. Torreele, J. Orbinski, R. Laing, and

N.

Ford, “Drug Development For Neglected Diseases,” The

Lancet 360, no. 9339 (2002): 1102.

2.

Id.

3.

Report of the WHO Commission on Macroeconomics and Health, Presented to the 55th World Healh Assembly, April 23, 2002, avaliable at <www.who.int/macrohealth/en/> (last visited March 9, 2009).

4.

J. D. Sachs et al., Macroeconomics and Health: Investing in Health for Economic Development, Report of the Commission on Macroeconomics and Health, Geneva, World Health Organi- zation, 2001.

5.

Id.

6.

See Trouiller et al., supra note 1.

7.

Id.

8.

P. J. Hotez, E. Ottesen, A. Fenwick, and D. Molyneux, “The Neglected Tropical Diseases: The Ancient Afflictions of Stigma and Poverty and the Prospects for their Control and Elimina- tion,” Advances in Experimental Medicine and Biology 582 (2006): 23–33.

9.

J. A. Patz and S. H. Olson, “Malaria Risk and Temperature:

Influences from Global Climate Change and Local Land Use Practices,” Proceedings of the National Academy of Sciences USA 103, no. 15 (2006): 5635–5636. )

10.

T. Kington, “Climate Change Brings Malaria Back to Italy,” The Guardian (London), January 6, 2007: 20.

11.

Centers for Disease Control and Prevention, “Blood Donor Screening for Chagas Disease—United States, 2006-2007,” MMWR 56, no. 7 (2007): 141-3

12.

P. J. Hotez and M. T. Ferris, “The Anitpoverty Vaccines,” Vac - cine 24 (2006): 5787–5799.

13.

Roll Back Malaria Partnership, Economic Costs of Malaria, available at <http://rbm.who.int/cmc_upload/0/000/015/ 363/RBMInfosheet_10.htm> (last visited February 20, 2009).

14.

J. Bryce, C. Boschi-Pinto, K. Shibuya, and R. E Black, “WHO Estimates of the Causes of Death in Children,” The Lancet 365, no 9465 (2005): 1147–1152.

15.

P. J. Hotez et al., “Incorporating a Rapid-impact Package for Neglected Tropical Diseases with Programs for HIV/AIDS, Tuberculosis, and Malaria,” Public Library of Science (PLoS)

Medicine 3 (2006): e102; P. J. Hotez et al., Control of Neglected Tropical Diseases, New England Journal of Medicine 357, no. 10 (2007): 1018-1027.

16.

Disability-adjusted life years are a measure of overall disease burden that combines morbidity and mortality into a single metric, with one DALY being equal to one year of healthy life lost. DALYs are used commonly in the field of health impact assessment.

17.

J. Bethony, S. Brooker, M. Albonico, S. M. Geiger, and A. Lou- kas et al., “Soil-transmitted Helminth Infections: Ascariasis, Trichuriasis, and Hookworm,” The Lancet 367, no. 9521 (2006):

1521-1532; Hotez et al., “Incorporating a Rapid-impact Pack- age for Neglected Tropical Diseases with Programs for HIV/ AIDS, Tuberculosis, and Malaria,” supra note 15.

18.

World Health Organization, World Health Report 2004:

Changing History, Burden of Disease in DALYs by Cause, Sex and Mortality Stratum in WHO Regions, Estimates for 2002, Annex Table 3 (Geneva: World Health Organization, 2004), available at http://www.who.int/whr/2004/en/> (last visited February 23, 2009).

19.

Id.

20.

C.

Franco-Paredes, A. Von, A. Hidron, A. J. Rodriguez-

Morales, and I. Tellez et al., “Chagas Disease: An Impediment in Achieving the Millennium Development Goals in Latin America,” BMC Internal Health and Human Rights 7, no. 7 (2007): 7-12.

21.

C.

M. Correa, “New ICTSD (International Center for Trade

and Sustainable Development) Series on New Opportunities Through Innovation: Fostering R&D and Promoting Access to Medicines,” Paper delivered October 22-26, 2007, Bellagio, Italy.

302

22. T. Hubbard and J. P. Love, “A New Trade Framework for Global Healthcare R&D,” PLoS Biology 2, no. 2 (2004): 147-150.

23. N. Dentico and N. Ford, “The Courage to Change the Rules: A Proposal for an Essential Health R&D Treaty,” PLoS Medicine

2, no. 2 (2005): 14.

24. K. Maskus and J. Reichman, “The Globalization of Pri - vate Knowledge Goods and the Privatization of Global Pub- lic Goods,” Journal of International Economic Law 7, no. 2 (2004): 279-320.

25. World Trade Organization, Declaration on the TRIPS agree- ment and Public Health, adopted on November 14, 2001, ava- iable at <www.who.org/english/theWTO_e/minist_e/min01_e/ mindecl_trips_e.htm> (last visited March 9, 2009).

26. See Correa, supra note 21.

27. J. Love, “Measures to Enhance Access to Medical Technologies, and New Methods of Stimulating Medical R&D,” University of

California Davis Law Review 40, no. 3 (2007): 679-715; J. Love, “Drug Development Incentives to Improve Access to Essential Medicines,” Bulletin of the World Health Organization 84, no. 5 (2006): 408-411; T. Pogge, “Human Rights and Global Health:

A Research Program,” Metaphilosophy 36, no. 1-2 (2005) 182-

209.

28. J. Love and T. Hubbard, “The Big Idea: Prizes to Stimulate R&D for New Medicines,” KEI Research Paper 1 (2007): 1519- 1544, adapted from the Ruby Hutchison Memorial Address, Nov. 12, 2006.

29. J. Love, “Drug Development Incentives to Improve Access to Essential Medicines,” supra note 27.

30. National Institute for Health Care Management (NIHCM), Changing Patterns of Pharmaceutical Innovation (2002), available at <http://www.nihcm.org/innovations.pdf> (last visited February 25, 2009).

31. J. Stiglitz, “Give Prizes not Patents,” New Scientist (2006): 21.

32. See <http://www.xprize.org/> (last visited February 23,

2009).

33. W. New, “WHO Adopts ‘Most Important Document Since Doha’ On IP And Public Health,” Intellectual Property Watch (2008), avaiable at <www.ip-watch.org/weblog/> (last visited March 9,

2009).

34. “Global Strategy and Plan of Action on Public Health, Inno- vation and Intellectual Property,” Sixty-first World Health Assembly, WHA61.21 Agenda item 11.6. May 24, 2008.

35. Working Document Proposed by Barbados and Bolivia, Inter- governmental Working Group on Public Health, Innovation and Intellectual Property (2008). On file with author.

36. Working Document Proposed by Barbados and Bolivia, Pro- posal 2: Prize for the Development of New Treatments for Chagas Disease, Intergovernmental Working Group on Public Health, Innovation and Intellectual Property (2008). On file with author.

37. See Hotez and Ferris, supra note 12.

38. Centers for Disease Control and Prevention, Division of Para - sitic Diseases, Chagas Disease Epidemiology and Risk Factors, available at <http://www.cdc.gov/chagas/epi.html> (last vis- ited February 23).

39. C. Bern, S. P. Montgomery, L. Katz, S. Caglioti, and S. L. Stramer, “Chagas Disease and the US Blood Supply,” Current Opinion in Infectious Disease 21, no. 5 (2008): 476-82.

40. S. H. Gillespie and R. D. Pearson, ed., Principles and Practice of Clinical Parasitology (New York: John Wiley & Sons, Ltd, 2001). Chapter 14b: American Trypanosomiasis: 335-353.

41. J. Woodall, “Soda, With a Side of Chagas,” The Scientist 21, no. 11 (2007): 73-73.

42. See Gillespie and Pearson, supra note 40.

43. For a comprehensive review of Chagas drug development, see J. Rodrigues Coura and S. L. de Castro, “Critical Review on Chagas Disease,” Chemotherapy Memorias Do Instituto Oswaldo Cruz 97, no. 1 (2002): 3-24.

44. Id; A. Magil and S. Reed, Hunter’s Tropical Medicine, 8th ed. (Philadelphia: W. B. Saunders Company, 2000): 653-663.

45. See Coura and de Castro, supra note 43.

46. See Magil and Reed, supra note 44.

journal of law, medicine & ethics

Crager and Price

47.

D.

Guillemot, C. Carbon, and B. Balkau, et al. “Low Dosage

 

V.

Machado, R. T. Gazzinelli O. Bruna-Romero, J. M. Alvarez,

and Long Treatment Duration of Beta-Lactam: Risk Factors for Carriage of Penicillin-Resistant Streptococcus Pneumo- niae,” JAMA 279, no. 5 (1998): 365-370.

B. Boscardin, and M. M. Rodrigues, “Protective Immunity

Against Trypanosoma Cruzy Infection in a Highly Susceptivle Mouse Strain After Vaccination with Genes Encoding the Amastigote Sruface Protein-2 and Trans-Sialidase,” Human Gene Therapy 15, no. 9 (2004): 878-886.

S.

48.

Y. Zhang, “Advances in the Treatment of Tuberculosis,” Clinical Pharmacology and Therapeutics 82, no. 5 (2007): 595-600.

49.

A.

Rassi, Jr., J. C. Pinto Dias, J. Antonio Marin-Neto, and A.

72.

F. M. Frank, P. B. Petray, S. I. Cazorla, M. C. Munoz, R. S. Cor - ral and E. L. Malchiodi, “Use of a Purified Trypanosoma Cruzi Antigen and CpG Oligodeoxynucleotides for Immunoprotec- tion against a Lethal Challenge with Trypomastigotes,” Vaccine 22, no. 1 (2003): 77–86.

Rassi, “Challenges and Opportunities for Primary, Secondary, and Tertiary Prevention of Chagas Disease,” Heart (published online January 8, 2009).

50.

Id.

51.

Id.

73.

See Cazorla and Frank et al., supra note 71; Frank et. al., supra note 72; S. I. Cazorla and P. D. Becker et al., “Oral Vaccina- tion with Salmonella Enterica as a Cruzipain-DNA Delivery System Confers Protective Immunity against Trypanosoma Cruzi,” Infection and Immunity 76, no. 1 (2008): 324-333; A.

52.

P.

J. Hotez and M. T. Ferris, “The Anitpoverty Vaccines,” Vac -

cine 24, no. 31-32 (2006): 5787–5799.

53.

See Rassi, Jr., et al., supra note 49; A. Prata, “Natural History of Chagasic Cardiomyopathy in America: Trypanosomiasis Research,” Pan American Health Organization Science Publi- cations 318, no. 4 (1975): 191-193.

R.

Schnapp, C. S. Eickhoff, D. Sizemore, R. Curtiss III, and

D.

F. Hoft, “Cruzipain Induces both Mucosal and Systemic

54.

J. Jannin and L. Villa, “An Overview of Chagas Disease Treat- ment,” Memorias Do Instituto Oswaldo Cruz, Rio de Janeiro 102, supplement I (2007): 95-98.

Protection against Trypanosoma Cruzi in Mice,” Infection and Immunity 70, no. 9 (2002): 5065–5074.

74.

See Cazorla and Frank et al., supra note 71.

55.

J. H. Maguire, R. Hoff, I. Sherlock, A. C. Guimaraes, A. C. Sleigh,

75.

B. Wizel, M. Nunes, and R. L. Tarleton, “Identification of Try- panosoma cruzi Trans-sialidase Family Members as Targets of Protective CD8+ TC1 Responses,” Journal of Immunology 159,

N.

B. Ramos, K. E. Mott, and T. H. Weller, “Cardiac Morbidity

and Mortality due to Chagas’ Disease: Prospective Electrocar-

diographic Study of a Brazilian Community,” Circulation 75 (1987): 1140-1145.

no.

6 (1997): 6120–6130.

76.

B.

Chou et al., “Critical Contribution of Immunoproteasomes

56.

See Gillespie and Pearson, supra note 40.

in the Induction of Protective Immunity against Trypanosoma Cruzi in Mice Vaccinated with A Plasmid Encoding A CTL Epitope Fused to Green Fluorescence Protein,” Microbes and Infection 10, no. 3 (2008): 241-250.

57.

A.

Prata, “Clinical and Epidemiological Aspects of Chagas Dis-

ease,” The Lancet Infectious Diseases 1, no. 2 (2001): 92-100.

58.

Centers for Disease Control and Prevention, “Blood Donor Screening for Chagas Disease – United States, 2006-2007,” MMWR Morbidity and Mortality Weekly Report 56, no. 7 (2007): 141-3.

77.

R.

L. Tarleton, “New Approaches in Vaccine Develop-

ment for Parasitic Infections,” Cell Microbiology 7, no. 10

(2005):1379–86.

59.

L.

V. Kirchhoff, “American Trypanosomiasis (Chagas’ Disease)

78.

See Alexandre et al., supra note 71.

– A Tropical Disease Now in the United States,” New England Journal of Medicine 329, no. 9 (1993): 639-644.

79.

Garg and V. Bhatia, “Current Status and Future Prospects for

a Vaccine Against American Trypanosomiasis,” Expert Review of Vaccines 4, no. 6 (2007): 867-880. (

N.

60.

F.

E. Cox, “Designer Vaccines for Parasitic Diseases,” Interna-

tional Journal of Parasitology 27, no. 10 (1997): 1147–1157.

80.

N.

Chamond, N. Coatnoan, and P. Minoprio, “Immunotherapy

61.

Id.

of Trypanosoma cruzi Infections,” Current Drug Targets –

62.

H.

Hisaeda and K. Yasutomo et al., “Malaria: Immune Evasion

Immune, Endocrine, and Metabolic Disorders 2, no. 3 (2002):

by Parasites,” International Journal Biochemistry and Cell Biol- ogy 37, No. 4 (2005): 700-6.

247–254.

81.

See Garg and Bhatia, supra note 79.

63.

W.

A. Williamson and B. M. Greenwood, “Impairment of the

82.

Z. Brener and R. T. Gazzinelli, “Immunological Control of Try - panosoma Cruzi Infection and Pathogenesis of Chagas’ Dis- ease,” International Archives of Allergy and Immunology 114,

Immune Response to Vaccination after Acute Malaria,” Lancet 1, no. 8078 (1978): 1328-9.

64.

A.

A. Da’Dara and N. Lautsch et al., “Helminth Infection Sup-

no.

2 (1997): 103-110.

presses T-cell Immune Response to HIV-DNA-based Vaccine in Mice,” Vaccine 24, no. 24 (2006): 5211–5219.

83.

Jurk and J. Vollmer, “Therapeutic Applications of Synthetic

CpG Oligodeoxynucleotides as TLR9 Agonists for Immune Modulation,” BioDrugs 21, no. 6 (2007): 387-401.

M.

65.

C.

Guinovart and P.L. Alonso, “Methods for Determining Vac-

cine Efficacy and Effectiveness and the Main Barriers to Devel- oping Fully Deployable Malaria Vaccine,” American Journal of Tropical Medicine and Hygiene 77, No. 6, suppl (2007): 276-

81.

84.

D.

F. Hoft, C. S. Eickhoff, O. K. Giddings, J. R. Vasconcelos, and

M.

M. Rodrigues, “Trans-sialidase Recombinant Protein Mixed

with CpG Motif-containing Oligodeoxynucleotide Induces Protective Mucosal and Systemic Trypanosoma Cruzi Immu- nity Involving CD8+ CTL and B Cell-mediated Cross-Priming,” Journal of Immunology 179, no. 10 (2007): 6889-6900; B. C.

66.

See Cox, supra note 64.

67.

See Hotez and Ferris, supra note 52.

68.

Id .

de Alencar, A. F. Araújo, M. L. Penido, R. T. Gazzinelli, M. M. Rodrigues, “Cross-priming of Long Lived Protective CD8+ T Cells against Trypanosoma Cruzi Infection: Importance of a TLR9 Agonist and CD4+ T cells,” Vaccine 25, no. 32 (2007):

6018-27.

69.

N.

M. El-Sayed, P. J. Myler, D. Bartholomeu, D. Nilsson, G.

Aggarwal, and A. N. Tran, et al., “The Genome Sequence of

Trypanosoma Cruzi, Etiologic Agent of Chagas Disease,” Sci- ence 309, no. 5733 (2005): 409–15.

70.

R.

L. Tarleton, “The Trypanosoma cruzi proteome,” Science 309

85.

Y.

Miyahira and Y. Takashima et al., “Immune Responses

(2005): 473–6.

Against a Single CD8+-T-Cell Epitope Induced by Virus Vec- tor Vaccination Can Successfully Control Trypanosoma cruzi

71.

G.

H. Fontanella and K. De Vusser et al., “Immunization with

an Engineered Mutant Trans-sialidase Highly Protects Mice from Experimental Trypanosoma Cruzi Infection: A Vaccine Candidate,” Vaccine 26, no. 19 (2008): 2322-2334; S. I. Cazorla and F. M. Frank et al., “Prime-boost Immunization with Cru- zipain Co-administered with MALP-2 Triggers a Protective Immune Response able to Decrease Parasite Burden and Tis- sue Injury in an Experimental Trypanosoma Cruzi Infection Model,” Vaccine 7, no. 26 (2008): 1999-2009; J. R. Vascon- celos, M. I. Hiyane, C. R. F. Marinho, C. Claser, V. Alexandre,

Infection,” Infection and Immunity 73, no. 11 (2005): 7356-

 

7365.

86.

B. Bhatia and N. Garg, “Previously Unrecognized Vaccine Can - didates Control Trypanosoma Cruzi Infection and Immunopa- thology in Mice,” Clinical and Vaccine Immunology 15, no. 8 (2008): 1158-1164; M. Katae and Y. Miyahira et al., “Coadmin- istration of an Interleukin-12 Gene and a Trypanosoma Cruzi Gene Improves Vaccine Efficacy,” Infection and Immunity 70,

no.

9 (2002): 4833-4840.

pharmaceutical regulations summer 2009

303

SYMPOSIUM

87. P. Bejon, O. K. Kai, J. Mwacharo, S. Keating, T. Lang, S. C. Gil - bert, N. Peshu, K. Marsh, and A. V. S. Hill, “Alternating Vector Immunizations Encoding Pre-erythrocytic Malaria Antigens Enhance Memory Responses in a Malaria Endemic Area,” European Journal of Immunology 36, no. 8 (2006): 2264-

2272.

100.

B. C. Caetano, O. Bruna-Romero, B. Fux, E. A. Mendes, M. L.

Penido, and R. T. Gazzinelli, “Vaccination with Replication- deficient Recombinant Adenoviruses Encoding the Main Surface Antigens of Toxoplasma Gondii Induces Immune Response and Protection Against Infection in Mice,” Human Gene Therapy 17, no. 4 (2006): 415–426.

88. See Cazorla and Becker et al., supra note 81.

101.

J.

S. Rothel, D. B. Boyle , G. W. Both, A. D. Pye, J. G. Water-

89. Id .

keyn, P. R. Wood, and M. W. Lightowlers, “Sequential Nucleic Acid and Recombinant Adeno Virus Vaccination Induces Host- protective Immune Responses against Taenia Ovis Infection in Sheep,” Parasite Immunology 19, no. 5 (1997): 221–227.

O. J. Ophorst, K. Radosevic, M. J. Havenga, M. G. Pau, L. Holterman, B. Berkhout, J. Goudsmit, and M. Tsuji, “Immu- nogenicity and Protection of a Recombinant Human Adeno- virus Serotype 35-based Malaria Vaccine against Plasmodium Yoelii in Mice,” Infections and Immunity 74, no. 1 ( 2006):

313–320; see Bejon et al., supra note 87; C. L. Hutchings, A.

90. See Hoft et al., supra note 93.

91. See Cazorla and Frank et al., supra note 71.

92. A. Crampton and T. Vanniasinkam, “Parasite Vaccines: The New Generation,” Infection, Genetics and Evolution 7, no. 5 (2007) 664–673.

93. S. Kostense, W. Koudstaal, M. Sprangers, G. J. Weverling, G. Penders, N. Helmus, R. Vogels, M. Bakker, B. Berkhout, M. Havenga, and J. Goudsmit, “Adenovirus Types 5 and 35 Sero- prevalence in AIDS Risk Groups Supports Type 35 as a Vac- cine Vector,” AIDS 18, no. 8 (2004): 1213-1216.

102.

J.

Birkett, A. C. Moore, and A. V. S. Hill, “Combination of Pro-

94. H. Ledford, “HIV Vaccine May Raise Risk,” Nature News 450 (2007): 325-325.

tein and Viral Vaccines Induces Potent Cellular and Humoral Immune Responses and Enhanced Protection from Murine

95. See Hotez and Ferris, supra note 52.

Malaria Challenge,” Infection and Immunity 75, no. 12 (2007):

96. Id.

5819–5826;

97. Commission on Intellectual Property Rights, Innovation and Public Health (CIPIH), Public Health, Innovation and Intel- lectual Property Rights, 2006.

98. See Crampton and Vanniasinkam, supra note 92.

103.

V.

A. Stewart, S. M. McGrath, P. M. Dubois, M. G. Pau, P.

Mettens, and J. Shott et al., “Priming with an Adenovirus

35-circumsporozoite Protein (CS) Vaccine Followed by RTS, S/AS01B Boosting Significantly Improves Immunogenicity to Plasmodium Falciparum CS Compared to that with Either Malaria Vaccine Alone,” Infections and Immunity 75, no. 5 (2007): 2283–2290.

99. E. Perez-Jimenez, G. Kochan, M. M. Gherardi, M. Esteban, “MVA-LACK as a Safe and Efficient Vector for Vaccination against Leishmaniasis,” Microbes and Infection 8, no. 3 (2006):

810–822.

 

304

journal of law, medicine & ethics