Introducing the NTDs and NIoPs

The neglected tropical diseases (NTDs) represent a group of more than a dozen major chronic infectious diseases, most of them parasitic infections, with high endemicity in the developing countries of Africa, Asia, and the Americas. The conceptual framework of the NTDs was formulated in the years following the 2000 launch of the Millennium Declaration (Hotez, 2006, 2008a, 2011; Hotez et al., 2006a, 2007; Molyneux et al., 2005). Both the Millennium Declaration and its eight Millennium Development Goals (MDGs) for sustainable poverty reduction were instrumental in shaping global health policy over the next decade, and they provided a platform and basis for large-scale donor support from both public and private sources. Indeed, MDG 6, “to combat AIDS, malaria, and other diseases,” helped to galvanize a new awareness for the impact of HIV/AIDS, malaria, and to some extent tuberculosis and stimulated the establishment of the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM), the U.S. President's Emergency Plan for AIDS Relief (PEPFAR), and the U.S. President's Malaria Initiative (Hotez, 2011), in addition to increased research and development support from the National Institutes of Health and the Bill & Melinda Gates Foundation, among others. A new generation of global health celebrities also actively helped to advocate for these important new measures (Hotez, 2008a).

Unfortunately, the excitement generated by the activities outlined above left behind the third and almost forgotten component of MDG 6, namely “the other diseases.” In response, a group of concerned scientists and public health experts committed to the study of parasitic helminth and protozoan infections began meeting under the auspices of the World Health Organization (WHO) to discuss how global efforts to control these conditions could be scaled and expanded along the lines of PEPFAR and GFATM (Fenwick et al., 2005; Molyneux et al., 2005). A key basis of these discussions involved several decades of experience with programs of mass drug administration to control or eliminate some of the most widespread parasitic helminth infections, especially lymphatic filariasis (LF), onchocerciasis, and to some extent schistosomiasis, in addition to a global campaign to eradicate dracunculiasis (Molyneux, 2004). Most of these interventions relied on global cooperation between WHO and key public–private partnerships and were backed by World Health Assembly resolutions (Brady et al., 2006; Hotez, 2009a; Hotez et al., 2006a, 2006b, 2007; WHO, 2010). From these discussions an informal consensus was created that there are 13 major conditions, which could be targeted for mass drug administration or other large-scale interventions (Hotez et al., 2006b, 2007) (Table A7-1). Provided annually and over a period of several consecutive years, mass drug administration could ultimately lead to the elimination of LF, onchocerciasis, leprosy, and possibly trachoma as public health problems; whereas for schistosomiasis and the three major soil-transmitted helminth infections—ascariasis, trichuriasis, and hookworm infection—annual mass drug administration would lead to important reductions in childhood morbidity (Fenwick et al., 2005; Molyneux, 2004; Molyneux et al., 2005). Moreover, based on the recognition that there is widespread geographic overlap among seven of the NTDs (ascariasis, trichuriasis, hookworm infection, schistosomiasis, LF, onchocerciasis, and trachoma), especially in sub-Saharan Africa, it was possible to target these conditions simultaneously by combining the drugs in an integrated “rapid-impact package” (Hotez et al., 2006a; Molyneux et al., 2005), so named because the drugs can be easily and quickly deployed by a contingent of community drug distributors and would result in rapid reductions in disabilities, improvement in well-being, and ultimately interruption in disease transmission for LF, onchocerciasis, and trachoma (Hotez et al., 2007).

TABLE A7-1

The Neglected Tropical Diseases.

In 2005 and 2006, the first peer-reviewed papers using the term “neglected tropical diseases” as a medical subject heading appeared in PubMed and other scientific literature databases (Brady et al., 2006; Hotez et al., 2006a, 2006b; Lammie et al., 2006; Molyneux et al., 2005; Utzinger and de Savigny, 2006). These publications also coincided with the establishment of a new Department of Neglected Tropical Diseases at WHO (http://www.who.int/neglected_diseases/en/) and, shortly thereafter, the open-access journal PLoS Neglected Tropical Diseases (http://www.plosntds.org). A key emphasis of the original list of 13 NTDs was that they exhibited a number of common clinical, epidemiological, and historical features suggesting that the NTDs could be treated as a cohesive group of infections. It was determined that according to some estimates the NTDs exhibited a global burden of disease that was roughly equivalent to that of any of the “big three diseases” targeted by the GFATM (Hotez et al., 2006a, 2007), and global efforts could be expanded in order to control or eliminate them through large-scale interventions (Hotez, 2008a, 2011; Hotez et al., 2006a, 2007; Lammie et al., 2006; Molyneux et al., 2005; Utzinger and de Savigny, 2006). Moreover, the concept of the NTDs became critical for purposes of global advocacy and for explaining to health policy makers (and ultimately donors) the opportunity for tackling the NTDs with the same urgency as for HIV/AIDS, tuberculosis, and malaria (Hotez, 2008a).

The major distinguishing features of the 13 NTDs were summarized previously (Hotez, 2008a, 2010a; Hotez et al., 2006a, 2007, 2009b) and include the following elements:

• The 13 NTDs represent the most common infections of people living in extreme poverty in sub-Saharan Africa, Asia, and Latin America and the Caribbean.
• They disproportionately affect the “bottom billion,” which refers to the approximately 1.4 billion people who live below the World Bank poverty figure of US$1.25 per day.
• Among the bottom billion, the NTDs result in chronic infections lasting years or even decades.
• The NTDs produce chronic disability that results in impaired child growth and intellectual and cognitive development, impaired pregnancy outcomes, and decreased worker productivity.
• Through these mechanisms, the NTDs adversely affect not only health but also childhood education and ultimately economic productivity; the NTDs represent an underlying reason why the bottom billion cannot escape poverty.
• Many of the NTDs also cause blindness and disfigurement that are psychologically devastating and result in social stigma.
• This high level of morbidity, economic impairment, and stigma does not necessarily translate into large numbers of deaths; overall, the NTDs cause high-morbidity but low-mortality conditions.
• In contrast to emerging infections such as HIV/AIDS, SARS, and avian influenza, there is a “nonemerging” character about the NTDs. Instead, the NTDs have afflicted humankind for centuries and there are accurate descriptions of some of the NTDs in ancient texts.

In its first report on NTDs published in 2010, WHO listed several additional features (WHO, 2010). In this new document, WHO expands its list of NTDs to also include food-borne trematodiases, cystic echinococcosis, cysticercosis, endemic syphilis and other treponematoses, and selected viral infections, including dengue and other arboviral infections and rabies. In all, WHO considers a total of 17 NTDs by treating the three soil-transmitted helminth infections as a single entity (WHO, 2010). Among the common features that WHO lists for these 17 conditions are the observations that (1) the NTDs are a proxy for poverty and disadvantage; (2) they affect populations with low visibility and little political voice; (3) they do not travel widely; (4) they cause stigma and discrimination, especially of girls and women, and have an important impact on morbidity and mortality; (5) they are relatively neglected by research; and (6) they can be controlled, prevented, and possibly eliminated using effective and feasible solutions (WHO, 2010). Listed in Table A7-2 are diseases that also meet the NTD criteria listed above, but either because they are much less common than the ones in Table A7-1 or because there are insufficient data about their prevalence and intensity, these NTDs have not been included on conventional lists of the major NTDs. Most of these conditions, however, are considered for review by PLoS Neglected Tropical Diseases (http://www.plosntds.org/static/scope.action).

TABLE A7-2

On the Outside Looking In: NTDs of Global Importance Not Typically Found on Lists of Diseases.

Another important feature about the NTDs is their disproportionate impact on selected populations, especially girls and women (including pregnant women) in part because of their effects on female reproductive health and their ability to exacerbate anemia and promote HIV/AIDS susceptibility (see below; Hotez, 2009b, 2011). In addition, the NTDs disproportionately affect African populations and African Americans who are descendents of the Atlantic slave trade (Hotez, 2009c; Hotez and Kamath, 2009; Lammie et al., 2007); indigenous populations (Hotez, 2010f; WHO, 2010); and populations living under conditions of conflict and postconflict (Beyrer et al., 2007; Hotez and Thompson, 2009).

Finally, there exists a group of infections that are closely related to the NTDs but, because they occur among impoverished people living in the midst of great wealth in the United States, Canada, and Europe, they are referred to as the neglected infections of poverty (NIoPs; see Table A7-3) (Hotez, 2008b, 2009c, 2010f). In the United States, the NIoPs tend to cluster in areas of extreme poverty, such as the Mississippi Delta and post-Katrina Louisiana, the border with Mexico, appendixes.app1.7lachia, inner cities, and selected tribal lands. In such areas, the NIoPs disproportionately affect under-represented minorities living in poverty, including African Americans, Hispanics, and Native Americans (Hotez, 2008b), with the major NIoPs sometimes referred to as “the 3Cs and the 3Ts”—Chagas disease, cysticercosis, congenital cytomegalovirus infection, toxocariasis, toxoplasmosis, and trichomoniasis. In addition, dengue fever has emerged as an important NIoP in the United States (Hotez, 2008b). Thus, three of the NIoPs are also NTDs listed in Table A7-1 Recently, Congressman Hank Johnson. Jr., of Georgia introduced legislation known as the Neglected Infections of Impoverished Americans Act of 2010 (H.R. 5986), which calls on the U.S. Department of Health and Human Services to collect additional information about these important yet neglected conditions.

TABLE A7-3

Neglected Infections Amid Wealth: Major Neglected Infections of Poverty in the United States and Europe.

Global Disease Burden

The NTDs are considered high-morbidity but low-mortality infections. Estimates for the number of deaths that result from the 13 NTDs range from 146,000 (Hotez et al., 2006b) to 534,000 (Hotez et al., 2006a) annually. On the basis of deaths alone and in terms of their attention by global health policy makers, the NTDs cannot compete with HIV/AIDS, tuberculosis, or malaria, each of which results in 1 million deaths or more annually. Instead, the adverse health impact of the NTDs is better understood in terms of disability-adjusted life-years (DALYs), that is, the number of healthy life-years lost from premature death or disability. It is the chronic disabling features of the NTDs that provide a more complete picture of their global health impact. Estimates of the DALYs lost that result from the NTDs range from approximately 20 million DALYs (Hotez et al., 2006b), which would place the NTDs among the top 20 global health conditions, all the way to almost 57 million DALYs (Hotez et al., 2006a, 2007), which would place the NTDs on par with any of the big three conditions. The basis for this wide range in DALY estimates reflects a number of factors, but primarily there is an ongoing scientific debate on whether to incorporate the chronic morbidities associated with long-standing anemia, malnutrition, inflammation, and pain that result from the very high prevalence of soil-transmitted helminth infections and schistosomiasis (King and Dangerfield-Cha, 2008; King et al., 2005).

Still another important feature of the NTD global disease burden is the observation, especially in sub-Saharan Africa, that these conditions geographically overlap with HIV/AIDS and malaria and may affect the susceptibility or clinical progression of these two killer diseases (Hotez et al., 2006a). For example, in the case of malaria there is a high degree of geographic overlap with hookworm infection (Brooker et al., 2006), with evidence to show that co-infections of malaria and hookworm result in severe anemia (Brooker et al., 2007; Hotez and Molyneux, 2008). Similarly, urinary tract schistosomiasis, which occurs in more than 100 million people in sub-Saharan Africa (Van der werf et al., 2003), commonly results in female genital schistosomiasis that is associated with a threefold increased susceptibility to HIV/AIDS (Hotez et al., 2009a; Kjetland et al., 2006). Thus, the NTDs have important collateral effects on the AIDS and malaria epidemics in Africa (Hotez and Molyneux, 2008; Hotez et al., 2006a).

The Geography of the NTDs

The NTDs and NIoPs occur in the setting of extreme poverty, especially in sub-Saharan Africa, South Asia, Southeast Asia, and in tropical regions of the Americas (Hotez, 2011; Hotez et al., 2009b). Sub-Saharan Africa is estimated to account for approximately one-third of the world's soil-transmitted helminth infections, most of the world's cases of schistosomiasis and onchocerciasis, and all of the world's cases of dracunculiasis and human African trypanosomiasis (Hotez and Kamath, 2009). In many areas of sub-Saharan Africa it is not unusual to find seven or more NTDs in one area—the three major soil-transmitted helminth infections, schistosomiasis, LF, onchocerciasis, and trachoma (Molyneux et al., 2005). Latin America and the Caribbean region also exhibit high rates of NTDs, especially in Brazil, where these conditions (with the exception of Chagas disease and possibly trachoma) were imported during the 500 years of the Middle Passage of the African slave trade (Hotez, 2011; Hotez et al., 2008; Lammie et al., 2007). Southeast Asia is also responsible for one-third of the cases of soil-transmitted helminth infections and almost all of the food-borne trematodiases, in addition to high rates of dengue and other arbovirus infections (Hotez, 2011; Hotez and Ehrenberg, 2010). There are no published studies about the overall prevalence of NTDs in central Asia, but in India, Bangladesh, and Nepal it is believed the rates of these infections (especially LF and the soil-transmitted helminth infections) are extremely high (Hotez, 2011). There are approximately 10 million cases of NIoPs in the United States and an unknown number in Europe and Australia (Hotez, 2008b, 2009c).

There are also a number of interesting geopolitical features about the NTDs (Hotez, 2010b). Among them is the finding that high rates of infection occur in conflict zones (Hotez and Thompson, 2009) as well as in certain Islamic countries, such as Indonesia, Bangaldesh, Sudan, and the west African countries of Mali, Chad, Niger, and Nigeria (Hotez, 2009d). Overall, up to 40 to 50 percent of the world's NTDs occur in the nations that comprise the Organisation of the Islamic Conference (Hotez, 2009d). Similarly, another one-third of the world's NTDs occur in large middle-income countries such as India, China, Pakistan, and Iran, which are also considered nuclear weapons countries (Hotez, 2010c). As shown below, these geopolitical features connect the control of the NTDs with elements of U.S. foreign policy (Hotez, 2010b, 2010c, 2010d, 2010e).

Approaches to Control and Elimination Through Mass Drug Administration

WHO points out that the NTDs can be controlled, prevented, and possibly eliminated using effective and feasible solutions (WHO, 2010). Possibly the most obvious example is the near eradication of dracunculiasis (Guinea worm) through the filtering and treatment of water contaminated with larval-infected copepods, together with case detection and management (Hopkins et al., 2008; Molyneux, 2004; WHO, 2010). Over the next few years it is expected that dracunculiasis would become only the second human infection to ever be eradicated and the first disease eradicated without the requirement of a vaccine. However, in addition to dracunculiasis, there are at least five other NTDs that, through the World Health Assembly or the Pan American Health Organization resolutions, have also been targeted by WHO for elimination as public health problems: LF, onchocerciasis, trachoma, Chagas disease, and leprosy (WHO, 2010). With the exception of Chagas disease (which relies largely on insecticidal spraying and improved housing), these other NTDs would be eliminated primarily through mass drug administration, in which large populations are simultaneously treated with one or two drugs on a once-yearly or twice-yearly basis (LF, onchocerciasis, and blinding trachoma) or through multidrug therapy (leprosy) (Brady et al., 2006; Hotez, 2009a; Lammie et al., 2006; Molyneux, 2004). Over time, this approach would lead to reductions in disease prevalence to the point where transmission of these infections is interrupted (WHO, 2010).

For the most part, mass interventions comprised of population-based drug administration (often together with other allied measures) have been extremely successful in terms of reaching large numbers of affected populations, even in the most remote areas of Africa, Asia, and the Americas, and in achieving control and elimination targets. In part, these successes have occurred because the medicines used in mass drug administration have an excellent safety profile and can be administered to large populations based on community-wide prevalence assessments (Hotez, 2009b; WHO, 2006). Once a threshold prevalence of a particular NTD has been ascertained, WHO has established algorithms for treating large populations regardless of whether it has been determined if any given individual is currently infected (WHO, 2006). This practice obviates the requirement of bringing in trained microscopists or other skilled workers, as well as expensive equipment, into the field. Also of critical importance, the drugs used in mass administration are either being donated by some of the major multinational pharmaceutical companies or they can be purchased as extremely low-cost generics (WHO, 2010). To date, the number of people who have received mass drug administration is one of the more impressive achievements in global public health over the past century (Hotez et al., 2007; Molyneux, 2004). For instance, more than 500 million people, that is, almost one-half of the more than one billion people at risk for LF, have received either diethylcarbamazine citrate or ivermectin (usually coadministered with albendazole; Ottesen et al., 2008), while more than one-half of the world's people at risk for onchocerciasis have received or are receiving ivermectin (Hotez, 2009a; WHO, 2010). To date, elimination of LF has been achieved in China, Cape Verde, Costa, the Republic of Korea, the Solomon Islands, Suriname, and Trinidad and Tobago (WHO, 2008); onchocerciasis has been eliminated from Mali and Senegal (Diawara et al., 2009); and blinding trachoma has been eliminated from Gambia, Morocco, Iran, Oman, and Mexico (Burton et al., 2010). In addition, leprosy has been eliminated as a public health problem (defined as a prevalence below 1 case per 10,000 populations) in all but 3 of the 122 previously endemic countries (WHO, 2010). The control and elimination programs for these diseases rely on established public–private partnerships that work closely with the disease-endemic countries and WHO (Hotez et al., 2009b).

For other extremely high-prevalence diseases, such as the three major soil-transmitted helminth infections and schistosomiasis, each affecting hundreds of millions of people in low- and middle-income countries, the coverage through mass drug administration has not been nearly as successful (Hotez, 2009a; WHO, 2010). Even though mass drug administration for these conditions has been shown to improve child growth, development, and cognition, currently only about 10 percent of school-aged children in areas affected by soil-transmitted helminth infections receive regular treatments with either albendazole or mebendazole, while fewer than 10 percent of children receive praziquantel for schistosomiasis (Hotez et al., 2010b; WHO, 2010). These helminth infections, but especially hookworm infections, cause important adverse effects in pregnancy and up to one-third of pregnant women in sub-Saharan Africa are affected (Brooker et al., 2008). In order to increase coverage for the seven most common NTDs, including the three major soil-transmitted helminth infections, schistosomiasis, LF, onchocerciasis, and blinding trachoma (Table A7-4), it was proposed in 2005 to bundle the drugs in mass drug administration for these conditions in a “rapid impact package,” costing as little as US$0.50 per individual (Brady et al., 2006; Hotez, 2009a, 2010a; Hotez et al., 2006a; Lammie et al., 2006; Molyneux et al., 2005; Utzinger and de Savigny, 2006; WHO, 2006). Safety data are now in place to support the coadministration of albendazole, ivermectin, and praziquantel, with studies under way to also examine the addition of azithromycin (Hotez, 2009a).

TABLE A7-4

The Seven Major NTDs Targeted for Integrated Control and Elimination with “Rapid Impact Packages”.

Today, through support from the U.S. Agency for International Development, national programs of integrated NTD control for the seven most common NTDs in Table A7-4 are under way in the African countries of Burkina Faso, the Democratic Republic of Congo, Ghana, Mali, Niger, Sierra Leone, Southern Sudan, Tanzania, and Uganda, as well as Bangladesh and Nepal in Asia, and Haiti (http://www.neglecteddiseases.gov). In 2010 the U.S. President's Global Health Initiative established targets to reduce the prevalence of the seven NTDs by 50 percent among 70 percent of affected populations and to contribute to the elimination of onchocerciasis in the Americas by 2016, the elimination of LF globally by 2020, and the elimination of leprosy (http://www.neglecteddiseases.gov). In addition, the British Department for International Development (DFID) is supporting national control programs, as is a Global Network for NTDs, which is currently supporting NTD control in Burundi and Rwanda with additional countries planned through funds raised privately (Hotez, 2010a). In all, there are approximately 56 countries with multiple NTDs that should be targeted for rapid impact packages (Hotez et al., 2007, 2008a). However, providing global coverage at this scale will require the participation of wealthy nations beyond the United States and the United Kingdom, including other European nations, countries of the Gulf Cooperation Council, and some of the larger emerging economies such as Brazil, China, and India, which have the capacity to control or eliminate some of their indigenous NTDs (Hotez, 2010e).

There are additional NTDs of great public health importance for which mass drug administration approaches are not immediately relevant but which in some cases could still be controlled or eliminated. The example of dracunculiasis was mentioned earlier; in addition, human African trypanosomiasis rates in West Africa caused by Trypanosoma brucei gambiense have been greatly curtailed by aggressive case identification and treatment and tsetse control, particularly in postconflict countries such as Angola and the Democratic Republic of Congo, and currently Sudan, which suffered some of the worst epidemics in the 1970s, 1980s, and 1990s (Hotez, 2008a; Jannin et al., 2001). Between 1999 and 2008 the number of new reported cases of this infection fell by 62 percent, to approximately 10,000 cases; similarly, the number of new cases of east African trypanosomiasis caused by T. brucei rhodesiense fell by 58 percent to only a few hundred reported reported cases (WHO, 2010). Through insecticide spraying, improved housing, and case detection and treatment, Chagas disease has been eliminated as a public health problem in the Southern Cone countries of Argentina, Brazil, Chile, Paraguay, the Plurinational State of Bolivia, and Uruguay (WHO, 2010), although an estimated 8 to 9 million cases remain in Latin America, with the greatest number of cases in Bolivia. A program to reduce the incidence of visceral leishmaniasis in Bangladesh, India, and Nepal—the three countries with highest disease burden— is under way through a program of early case finding, delivering oral treatment, and vector control (WHO, 2010). Treatments for several of the NIoPs including Chagas disease, cysticercosis, toxocariasis, toxoplasmosis, and trichomoniasis, are available even if the treatments are underused because of their overall neglect by the public health community in the United States (Hotez, 2008b).

Collateral Benefits: Malaria, HIV/AIDS, and Other Co-Infections

Beyond the seven NTDs and leprosy, mass drug administration is expected to have a number of other important collateral effects. For instance, the drugs that comprise the rapid impact package would also target additional high-prevalence NTDs (listed in Tables A7-1 and A7-2) such as strongyloidiasis; taeniasis; the food-borne trematodiases clonorchiasis, opisthorchiasis, and paragonimiasis; and scabies (Hotez et al., 2006a). A recent study conducted in Ethiopia also showed that once-yearly azithromycin used for mass drug administration to combat blinding trachoma resulted in dramatic overall reductions in child mortality (Porco et al., 2009), possibly as a result of reducing bacterial colonization that would otherwise lead to other respiratory or gastrointestinal bacterial infections. It is also possible that by reducing anemia from hookworm and schistosomiasis the rapid impact package could indirectly reduce severe anemia in sub-Saharan Africa that results from malaria co-infections (Brooker et al., 2007).

Two additional studies suggest that NTD control is of potentially great importance on the HIV/AIDS pandemic, but especially in sub-Saharan Africa. To date, three randomized controlled trials evaluating the effects of deworming on HIV/AIDS progression showed a benefit in reducing plasma viral loads and/or increasing CD4 counts (Walson et al., 2009), while female genital schistosomiasis was shown to result in a threefold increase in horizontal transmission of HIV/AIDS (Kjetland et al., 2006). These studies suggest that widespread administration of praziquantel or the rapid impact package could represent an inexpensive and highly cost-effective intervention to complement widespread AIDS control measures currently being implemented by the GFATM or PEPFAR (Hotez et al., 2006a). In the coming years, an extensive program of operational research and implementation science will be required to maximize use of the rapid impact package and how it can interface with global malaria and HIV/AIDS control efforts.

Access to Innovation

For almost all of the NTDs, there is a desperate need for research and development leading new innovations for control, including improved diagnostics, medicines, or vaccines (Hotez and Pecoul, 2010). The older concept of “tool-ready” versus “tool-deficient” NTDs has been discredited as most of the tool-ready diseases currently targeted by the rapid impact package still require a new generation of improved anthelminthic drugs and vaccines, while tool-deficient diseases such as human African trypanosomiasis, Chagas disease, and leishmaniasis can still be controlled or even eliminated in some areas using currently available insecticides and medicines (Hotez and Pecoul, 2010). Among the diseases now targeted by the rapid impact package, high rates of mebendazole drug failure have been reported for hookworm infection, with a recent meta-analysis reporting only a 15 percent cure rate for single-dose mebendazole (Hotez et al., 2010a; Keiser and Utzinger, 2008). Similarly, single-dose albendazole exhibits a low cure rate for trichuriasis (Keiser and Utzinger, 2008), while high rates of post-treatment re-infection have been described for all of the soil-transmitted helminth infections and schistosomiasis (Hotez et al., 2010a; Keiser and Utzinger, 2008). Several potential backup anthelminthic drugs previously developed for veterinary purposes could potentially be transitioned into human medicines, and there is a need to establish a product development public–private partnership (PD-PPP) for this purpose (Hotez and Pecoul, 2010). Alternatively, the Sabin Vaccine Institute is a PD-PPP developing new vaccines to prevent hookworm infection and schistosomiasis (Hotez et al., 2010a). Such vaccines are sometimes referred to as the “antipoverty vaccines” because of their potential economic impact as well as their effects on health (Hotez and Ferris, 2006). There is also a need for a new macrofilaricide for onchocerciasis to reduce the number of years for which ivermectin treatments must be provided annually (Hoerauf, 2008). The drug moxidectin is a potential macrofilaricide under development jointly between WHO-TDR (the Special Programme for Research and Training on Tropical Diseases) and Pfizer, as are antimicrobial drugs that target bacterial endosymbionts and also exhibit a macrofilaricidal effect (Hoerauf, 2008; Hotez and Pecoul, 2010). For all seven NTDs targeted for rapid impact packages, there is a pervasive need for new diagnostics (Hotez and Pecoul, 2010).

For human African trypanosomiasis, Chagas disease, and leishmaniasis, there is an urgent need for new and safer drugs to replace the ones now in use, many of which were developed in the early part of the 20th century (Hotez and Pecoul, 2010; McKerrow et al., 2009; Priotto et al., 2009; Yun et al., 2009). Also needed are improved diagnostics, and there is a need for new vaccines, including possibly new therapeutic vaccines for these kinetoplastid diseases (Hotez and Ferris, 2006). Several PD-PPPs are in place for new drugs for kinetoplastid infections, including the Drugs for Neglected Diseases Initiative (DNDi) and the Institute for One World Health (iOWH), while the Infectious Diseases Research Institute (IDRI) is developing a leishmaniasis vaccine, and the Foundation for Innovative Diagnostics (FIND) is investigating new kinetoplastid diagnostics.

For some of the other diseases not yet mentioned, there are also needs to develop new biomarkers to predict the onset of bile duct cancer from the food-borne trematodiases clonorchiasis and opisthorchiasis, in addition to new anticancer vaccines for these helminthiases (Sripa et al., 2010); veterinary transmission blocking vaccines for cysticercosis and echinococcosis (Lightowlers, 2010); and new Buruli ulcer drugs, vaccines, and diagnostics (Hotez and Pecoul, 2010; Portaels et al., 2009). Currently at least five candidate dengue vaccines are under development both by major multinational pharmaceutical companies as well as the International Vaccine Institute (Durbin and Whitehead, 2010). Of interest, today many of the PD-PPPs are partnering with both private- and public-sector manufacturers located in middle-income countries—sometimes referred to as innovative developing countries—such as Brazil, China, Cuba, India, and Indonesia (Morel et al., 2005). For the NIoPs there is an urgent need to develop improved diagnostics, especially for each of the 3C and 3T diseases, and for efforts to accelerate the development of new vaccines combat congenital CMV infection, Chagas disease, and toxoplasmosis (Hotez, 2008b).

Implications for U.S. Foreign Policy

The observation that most of the world's NTDs occur in countries of geopolitical interest to the Untied States has potential foreign policy implications for the U.S. government (Hotez, 2009d, 2010b, 2010c, 2010d). The human right to live in a world free of NTDs has been pointed out previously (Beyrer et al., 2007; Hotez, 2008a; Hunt, 2006), thereby providing a framework for NTD control as a low-cost yet high-profile U.S. humanitarian intervention (Hotez, 2006). However, the potential for NTDs to actually cause poverty and promote conflicts in the world's Islamic nations and nuclear weapons states (Hotez and Thompson, 2009) provides added urgency for the United States to intervene today through wide-scale interventions with rapid impact packages in all these nations and, ultimately, all of the 56 affected developing countries (Hotez, 2008, 2010b). Finally, there are important opportunities to look to joint research and development cooperation between the United States and some of the world's more advanced Islamic countries and NTD-affected nuclear weapons states in order to develop a new generation of antipoverty vaccines, just as the United States and former Soviet Union cooperated on joint polio and smallpox vaccine development during the middle of the 20th century (Hotez, 2010c, 2010d).

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