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Institute of Medicine (US) Forum on Microbial Threats. The Causes and Impacts of Neglected Tropical and Zoonotic Diseases: Opportunities for Integrated Intervention Strategies. Washington (DC): National Academies Press (US); 2011.

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The Causes and Impacts of Neglected Tropical and Zoonotic Diseases: Opportunities for Integrated Intervention Strategies.

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The Bill & Melinda Gates Foundation13


The Global Health Program at the Bill & Melinda Gates Foundation (BMGF) has over the past decade developed a portfolio of 14 diseases that have been put into a single foundation strategic program around the theme “neglected and other infectious diseases” (NOIDs). As a group, the NOIDs represent one segment of a larger group of global health diseases (as many as 47 different infectious diseases according to some) that share several common characteristics: their impact is overrepresented in tropical areas; they affect the poorest, disenfranchised populations; and they have been underrepresented in terms of attention—including resources for research and development (R&D) of drugs, vaccines, diagnostics, and vector tools, both in the North and in the South.14 These diseases are unified neither by their biology nor by their clinical manifestation in humans (which are extremely diverse), but rather by the populations that they affect and the fact that the world has now chosen to collectively address them.

Over the past decade, parallel to the creation of the BMGF Global Health Program, an increasingly cohesive community has emerged, with strong leadership at the World Health Organization (WHO) and from the scientific community. In his “manifesto” for the control and elimination of neglected tropical diseases (NTDs), Dr. Peter Hotez characterized NTDs as “the most common infections of the world's poorest people and the leading causes of chronic disability and poverty in low and middle-income countries (Hotez and Pecoul, 2010).” The first WHO report on NTDs, published in 2010, identified additional common features of this group of diseases, including their limited geographic focus, unique impact on morbidity as well as mortality, and the public health goal of control, prevention, and elimination using feasible solutions (WHO, 2010). Another criterion has been the relationship to stigma and discrimination, particularly in women. The Global Network for Neglected Tropical Diseases likewise characterizes these diseases as “diseases of poverty, afflicting the world's poorest and trapping them in a cycle of poverty.”15

There are weaknesses to applying any single criterion to the NTD framework. Some diseases that are not included in the NTD category fit the WHO criteria. Malaria and deaths due to pneumonia and diarrhea are also associated with poverty and with excess risk in tropical areas. AIDS also causes stigma and discrimination. Conversely, some diseases proposed as part of the NTD category do not appear to fit the WHO criteria. Effective and feasible solutions are not currently available for dengue and are not optimized to achieve impact goals for human papillomavirus (HPV). With respect to the “poorest of the poor” definition, there are again exceptions (dengue also affects wealthy populations within endemic countries), and there is a lack of robust data (distribution of disease burden by quintile, for example) to substantiate this claim.

Nevertheless, the NTD framework has resonated within the foundation, the donor community, and the disease advocates. As a group, the NTD framework is today viewed by the global health community as a distinct category of diseases. However, prioritization of diseases and approach within that framework varies by organization.

Origin of the BMGF Portfolio

The foundation's investments in these diseases were not originally conceived as a cohesive portfolio. Instead, investment decisions were made on a disease-by-disease basis and classified as “other ID” for record-keeping purposes. Strategy assessments were written for individual diseases. In this manner, investments were made in 13 diseases between 1998 and 2007. In late 2007, the Global Health Program reorganized and strategic program teams were formed, along with the creation of a single NOIDs team. In 2008, the first strategy was developed that provided an aggregate view of the foundation's investments in these diseases.

The foundation's unique terminology for this space—neglected and other infectious diseases, or NOIDs—was coined as part of the 2007–2008 strategy development process. “Neglected” reflected that most of these diseases were part of the group of diseases defined as neglected tropical diseases by the global community. “Other” was retained because there was not a 100 percent overlap between the diseases in the foundation's portfolio and the various definitions from the global NTD community.

The priority diseases over the past decade include onchocerciasis, lymphatic filariasis (LF), schistosomiasis, trachoma, human African trypanosomiasis (HAT), visceral leishmaniasis (VL), soil-transmitted helminths (STHs; hookworm, Ascaris, and Trichuris), rabies, HPV, Japanese encephalitis (JE), and dengue. Our investments across the NOIDs portfolio are summarized by disease in Figure A10-1. The distribution of these investments by tool and approach is seen in Figure A10-2, which shows the balance of what our investments have been irrespective of disease.

A bar graph showing BMGF NOIDs investment by disease through 2010 with payments through 2014


BMGF NOIDs investment by disease through 2010 with payments through 2014. SOURCE: BMGF grants database.

A chart showing BMGF NOIDs commitments by tool and strategic approach through 2010


BMGF NOIDs commitments by tool and strategic approach through 2010. SOURCE: BMGF grant database.

Bill & Melinda Gates Strategy Process

Grant investments from the foundation are guided through a process that has evolved and been refined over the first 10 years of the foundation's history. Strategies are in a constant state of development and refinement going through three distinct stages. First, is the primary Strategy Development, which is basically creating a de novo strategy. This happens only once in a disease area and is the result of a period of learning, consultation, and exploration that can range from months to years. The second stage is annual and is referred to as the Strategy Review. This is a yearly update for foundation leadership, which critically evaluates the progress against a strategy and may result in minor course corrections in response to shifts in knowledge and external factors. The third stage is known as the Strategy Refresh, which is a fundamental reexamination of a strategy with the expectation and openness to significant changes in strategic direction in light of developments in the environment either as progress, learning, or setbacks. This process happens every three to five years and is associated with an extensive evaluation process to guide the new strategic choices.

Currently, in 2011, we are conducting a Strategy Refresh for the NOIDs. During the Strategy Refresh, there is a multistep process taken on by a responsible cross-foundation team. The process is designed to question assumptions and bring in new evidence to refine our approach and define both priorities as well as potential areas of deemphasis. By the end of the process, each strategy redefines goals and how progress against reaching those global health goals will be measured. Our attribution to achieving these goals can be indirect, as most programs and initiatives in which we are engaged are implemented through a number of grant and strategic partnerships where accountability and credit are shared. Critical steps to the refresh include the following:

  • A historical “look back” to see what has been learned and what has changed;
  • Scope of the problem and potential solutions, and examination of public health goals;
  • Defining the theory of change (what the world needs to do to reach those goals);
  • Developing a Theory of Action (strategic choices for foundation action);
  • Estimating resource requirements;
  • Creating an execution plan to implement the strategy; and
  • Creating a monitoring, learning, and evaluation (MLE) plan to ensure that the right information is collected to evaluate progress and guide future choices.

This process and the questions we ask ourselves are further described in Table A10-1

TABLE A10-1. Summary of the Bill & Melinda Gates Foundation Strategy Refresh Process.


Summary of the Bill & Melinda Gates Foundation Strategy Refresh Process.

State of the Field

The epidemiology and pathology of the neglected diseases varies widely. Pathogens include viruses, bacteria, protozoa, and worms. Transmission is human-to-human for some diseases and via vectors or environmental contamination for others. In the cases of vectored transmission, vectors include multiple species of mosquitoes, flies, and snails. Some diseases are 100 percent fatal (e.g., untreated HAT, rabies); others are chronic, nonfatal conditions (e.g., soil-transmitted helminths). Some diseases have widespread prevalence (LF infects up to 120 million people globally); others are more geographically limited. (HAT, for example, only occurs in sub-Saharan Africa in a zone of 36 countries known as the tsetse-fly belt.) In addition, disease foci may be confined to only certain areas within countries (for instance, soil-transmitted helminth infections in Mozambique—though very high in the southern half of the country—are rare around the northern border with Malawi).

Clarity on agreed-upon public health goals for each disease has been extensively worked out by the relevant communities for some (onchocerciasis in the Americas, for example) but is still evolving for others (STHs). One key step in this process has been the assessment by the International Task Force on Disease Eradication of the biologic plausibility and feasibility of eradication versus control for a host of infectious diseases. For some diseases, the existence of animal reservoirs makes elimination or eradication biologically infeasible. For other diseases, the goal of elimination or eradication has nearly been achieved (e.g., the remarkable progress on Guinea worm, and progressive elimination of onchocerciasis in the Americas). A critical evaluation of the investment case that evaluates the basis for the public health goals, looking at feasibility, careful assessment of technical tools, and resources, can be a powerful planning and advocacy tool and help achieve program impact.

Partner Landscape

Industry plays a uniquely critical role in the partner landscape for neglected diseases. Many pharmaceutical and biotechnology companies donate philanthropically to low-income countries, especially in times of emergency. In the neglected disease sphere, however, such firms also make long-term direct, or “single-drug,” donations. These occur in partnership with the specific disease community, have a targeted goal and a defined strategy, and have allocated volumes of drugs associated with them as well as at least a plan for obtaining additional program support.

The largest and oldest of the programs, the Mectizan donation program, was established by Merck in 1987 to treat onchocerciasis with ivermectin. In 1998, it was expanded in partnership with GlaxoSmithKline (GSK) to treat LF as well, using a combination of ivermectin and albendazole. Merck has pledged an unlimited supply of Mectizan for LF and onchocerciasis, and GSK an unlimited supply of albendazole for LF. GSK has even constructed a plant in Nashik, India, built specifically to produce albendazole for donation. At this point, more than 70 million treatments are approved for onchocerciasis in Africa and Latin America and 80 million for LF in Africa and Yemen each year, and more than 2 billion treatments have been dispensed. Each donation program has its own specifications and processes, but all are impressive commitments. Pfizer pledged its donation of azithromycin sufficient to reach elimination of blindness due to trachoma by 2020. Others, which historically were more limited in scope, such as Johnson & Johnson's donation of mebendazole, have recently expanded fourfold to 200 million tablets annually for the treatment of STHs. This was matched by an expansion of the GSK albendazole donation to cover STH needs in Africa, increasing its total donation to 1 billion tablets. One, praziquantel for schistosomiasis, still presents a particularly important gap between current programs and global need. An important but limited donation is available through Merck KGaA (German Merck), but the quantity does not meet the need, especially in light of the expanding programs. As summary is provided in Figure A10-3

A chart giving an overview of drug donation for the NTDs


Overview of drug donation for the NTDs.

Rapid changes in the pharmaceutical industry have aided the growth of these donation programs. Companies' growing focus on improving their public perception, expanding their presence in emerging markets, and attracting and retaining talent are all fueling their interest in donation programs. There are also new opportunities for greater engagement of industry on R&D priorities. Recent examples include the GSK announcement committing intellectual property to a neglected diseases patent pool; the Novartis Vaccine Institute for Global Health creating affordable vaccine for neglected diseases; and the MDS Wellcome Trust Hilleman Laboratories in India, which are dedicated to vaccines for developing countries.

The key challenge for neglected diseases remains to ensure that they receive sufficient attention despite competing priorities. Endemic-country governments, nongovernmental organization (NGOs) under the global framework of the WHO, create a rich framework of key stakeholders in the delivery space (WHO, 2010). The past decade has witnessed a significant shift in the relationship between funding groups and the public health arms of endemic countries. The latter, rather than being viewed as beneficiaries, have become empowered delivery partners. Training and direction of government health workers, along with the development of investment cases meant to engender increased attention to neglected diseases, have become key priorities of funding groups. Civil society, including NGOs, has played and continues to play an essential role in support of countries both technically and programmatically according to their need.

In the R&D sector, product development partnerships (PDPs) have come to play a major role in the creation of new tools. The PDP model has been applied to address many NTD product needs through the Institute for OneWorld Health, the Drugs for Neglected Disease Initiative, the Program for Appropriate Technology in Health (PATH), the Foundation for Innovative New Diagnostics, the Sabin Vaccine Institute, and the International Vaccine Institute (IVI)/Pediatric Dengue Vaccine Initiative. For the diseases the foundation has prioritized, progress in R&D depends on national research funders, PDPs, and public/philanthropic funding, particularly because of the potential large-volume but limited-profit commercial market, particularly because donations are a keystone of the community-distributed mass drug administration (MDA) platform. Notable exceptions include dengue, HPV, and rabies, which have significant middle- or high-income markets, as well as products with agricultural or veterinary applications. Nevertheless, most neglected diseases represent an orphan market. As such, these partnerships working in NTDs are heavily reliant on philanthropic funding. Many donors have a long history of investment in this space and remain committed, playing an active role as seen in Figure A10-4 In this work done by G-FINDER for 2009, BMGF represents the second largest contribution to R&D in this space after the National Institutes of Health (NIH).

A chart showing research and development investments for NOIDs globally, 2009


Research and development investments for NOIDs globally, 2009.

Emerging manufacturers are also playing an important role as partners to R&D efforts. These companies have shown they can deliver particularly low-cost global health goods and solid global access commitments. One example is JE vaccine and the Chengdu Institute of Biological Products (CDIBP). The JE SA-14-14-2 live attenuated vaccine was wholly researched and developed in China but had the potential for broad use in Asia to address the uncontrolled outbreaks of JE plaguing endemic countries. In partnership with PATH, CDIBP engaged in, expanded, and improved GMP manufacturing with a commitment to low-cost access for public-sector use. The vaccine has now been internationally licensed and is the first new vaccine introduced and supported by the Indian government. Well over 100 million doses have been exported and the vaccine is now in use in India, Nepal, South Korea, North Korea, Cambodia, and Sri Lanka and the file for future WHO prequalification will soon be submitted to allow procurement by the United Nations Children's Fund. This type of success demonstrates the role that emerging manufacturers can play in solving these public health problems by committing their resources and know-how.

BMGF Investments Through 2010

In the late 1990s, the concept of the NTDs as a single field did not exist. There was a set of individual diseases that affected the most impoverished, with disease champions trying to push forward control efforts on behalf of affected communities. Even where drug donation programs existed, progress was limited because of limited delivery momentum and political will to implement. The initial BMGF investments focused on the empowerment of the groups, often driven by civil society, to scale up and roll out these programs and test whether public health goals could be accomplished. One key strategy that evolved out of necessity was the need for integration of the MDA platform. The confluence of overlapping epidemiology of diseases controlled by once- or twice-a-year community administration of donated drugs, and the need for efficiencies to extend access, resulted in a delivery platform that has successfully reached high-risk communities with a coherent, evaluated set of drugs and interventions. This approach has also strengthened country programs.

Integration sounds simple and logical but is actually quite a challenge in the field. With results from BMGF projects exploring integration, the first investment through the U.S. Agency for International Development (USAID) was made into the rollout of the integrated NTD package addressing seven of the most common NTDs including onchocerciasis, LF, schistosomiasis, the three most common STHs (Trichuris, Ascaris, and hookworm), and trachoma. USAID applied the integrated MDA platform, expanding the scale significantly and increasing the lessons learned. The USAID program exceeded all of its targets in the first few years of the program. This impressed Congress and resulted, even with a change in administration, in a significant increase in U.S. government investment as well as an investment from the United Kingdom through its Department for International Development (DFID).

In addition to the integration platform, this initial progress and the challenges faced by the programs in scaleup informed the second phase of our investments. The next phase of investment for the MDA NTDs had two aspects: first, the sustainability of the programs and scale up to meet the need of endemic populations; and second, how to overcome the operational barriers in the specific disease areas that were discovered as the programs moved from smaller-scale programs, expanding and moving into new epidemiological settings. At the time, there was an ongoing debate about these vertical projects because they were reaching people at the end of the line and giving them one intervention when they and their communities were actually most frequently polyparasitized. This presented a huge missed opportunity and inefficiency within the parallel vertical programs. We participated in this global debate, and the next series of grants worked on integrating the approaches and aligning programs to work out the issues from each of the different disease perspectives to create a single platform addressing all of these diseases at the same time in endemic villages with the unifying platform of MDA.

Another learning from our investment was the need to identify and overcome disease-specific program barriers to achieve impact. In the initial rollout stage, each of the programs had identified weaknesses in its strategy and key gaps of knowledge that were holding back the program from reaching its full potential. Operational research projects were launched that went beyond the MDA platform to include vector control and environmental issues and addressed disease-specific challenges. These investments started with LF as a priority to help the program attempt to reach its elimination goal in 2020. This was followed by similar grants that were made for trachoma and schistosomiasis.

Another group of diseases in the BMGF strategy are VL (Kala-Azar) and HAT (or sleeping sickness). Both of these diseases were plagued with poor tools both for treatment and diagnosis that have hindered the success of programs. Our approach to these 100 percent fatal diseases has been focused on improving the tools with significant investments in new tool development (drugs, diagnostics, and vector control) and understanding the drivers of transmission, including vectors, to be able to eliminate the disease.

The NOIDs have both benefited from and been a target of many of our vector control investments. Grants in this space cover a broad range of approaches, including very innovative and high-risk investments such as genetically modified mosquitoes through to evaluating very basic approaches with existing tools to create a home free of mosquitoes. In addition to tools that directly target the vector, we also have several investments looking at vectors for xenomonitoring disease transmission for dengue, HAT, and VL. New creative approaches to attack the vectors through their animal blood meal are also being evaluated for VL to decrease transmission and improve the chances of elimination of anthroponotic disease. These approaches have the chance to significantly affect the NTDs and increase the success of control and elimination of the vector-borne NTDs.

Our final area of investment in the NOIDs strategy focused on vaccines. JE, dengue, HPV, rabies, and hookworm all have had investments in either vaccine development or introduction and use. JE is the most advanced, with a low-cost vaccine now available, which has been introduced in several settings. HPV has two new successful vaccines (created without foundation investment), and our focus has been on evaluating and developing tools for appropriate diagnosis and treatment to support introduction of vaccine and elimination of cervical cancer. Our investment in rabies came after a significant time of looking at the options of what would generate impact. Our single investment evaluates a strategic approach for canid-transmitted rabies focusing on appropriate approaches to immunizing domestic dogs in low-resource settings. The most upstream investments are exploring the possibilities of a human hookworm vaccine and an animal leishmaniasis vaccine. Both diseases are immunologically challenging and are adding significant data to understanding the disease as well as potentially developing a vaccine.

The NTDs have been a significant investment for BMGF, which has resulted in significant progress in the field as a whole as well as significant health benefits for the world's most impoverished. Table A10-2 summarizes the disease areas and elements of our assessment of key areas of progress and challenges in the neglected diseases that have been part of our investment in the NTDs.

TABLE A10-2. Summary of Bill & Melinda Gates Foundation Investments in NOIDs Through 2010.


Summary of Bill & Melinda Gates Foundation Investments in NOIDs Through 2010.

Reflections and Learning from NOIDs

Much has been learned looking back over our 10+ years investing in NOIDs. The foundation approach has transitioned through the decade to be more proactive and evidence-based. We now better appreciate the need to clearly articulate goals and be increasingly realistic about how to achieve them as the backbone to our broader strategy. It is clear that more time, resources (both financial and human), and greater flexibility are required to achieve NTD goals than originally anticipated, particularly in the case of elimination and eradication programs. Each program needs to build an evidence base through operational research and a funding base through advocacy. Delivery partners need to be identified early. Success must be defined to ensure investments are focused and to create transparency that can allow us to better work with and within a multipartner landscape. Ultimately, we need to clearly communicate our strategy and priorities to the field, to stakeholders, and to partners to help other donors plan their funding and to enable clear handoff points for sustainability and impact.

A multipronged investment approach is required to successfully carry through investments to impact. A key learning from the past decade is that the creation of transformative tools is necessary, but not sufficient. Within R&D, the foundation has learned the risks of basing success on the results of a single, large bet. Adequately resourcing fewer priority areas will allow us to take a portfolio approach to R&D investments and, therefore, increase our probability of success. Support for disease champions must be combined with robust target-product profiles and corroborated by stakeholder engagement, particularly the end user. Programs should be challenged and critiqued, even as they are supported. Although focusing on program priorities is critical, maintaining flexibility and having a broader perspective in case there are changes in each field is critical.

Our NOIDs strategy analysis has pointed to the potential for a foundation's involvement in research and development to be transformative. Even relatively small amounts of money can serve to attract others to the field and leverage, often sizable, investments by others. For example, our investments in integrated MDA were an entryway for investments from USAID and DFID, as well as significant investments from private-sector donors. Using challenge grants for Guinea worm doubled the size of BMGF contributions to these eradication efforts and increased awareness of their impressive progress for many additional donors that were engaged. In addition, the foundation leveraged areas where the original work was funded through other donors such as the NIH in a drug for trypanosomiasis, by the WHO Tropical Disease Research program, which we leveraged to develop a VL drug, and investments by the Chinese government in the SA 14-14-2 JE vaccine to successfully get a safe, efficacious, and affordable vaccine for the region.

At the time of the IOM meeting, the foundation NOIDS team is undergoing its Strategy Refresh. The aim is to provide clarity to our internal priority areas for additional investment, and equal clarity as to where the foundation will not engage. The strategy would ultimately define for each disease the areas for foundation action and leverage, including a detailed plan for MLE to define how success will be measured, and what data are required to answer those questions. The final goal, of course, is impact: the eradication of Guinea worm, and the progressive impact on individual diseases to decrease the suffering and disability caused. We are confident that the great progress that has marked the past decade will continue into the future in a richer and more complex landscape that can transform the neglected diseases to diseases of the past.


  1. Hotez P, Pecoul B. “Manifesto” for advancing the control and elimination of NTDs. PLoS Neglected Tropical Diseases. 2010;4(5):e718. [PMC free article: PMC2876053] [PubMed: 20520793]
  2. WHO (World Health Organization) Working to overcome the global impact of neglected tropical diseases, First WHO Report on Neglected Tropical Diseases. Geneva: WHO; 2010. [January 7, 2011]. http://www​​/2010report/en/index​.html.

Acknowledgements to the Neglected and Other Infectious Diseases Team who have contributed to this strategy over the past 12 years including David Brandling Bennett, Jan Agosti, Thomas Kanyok, Kathryn Aultman, Anastasia Pantelias, Erin Shutes, Ken Duncan, and Guy Stallworthy.

The Global Health Program encompasses the following strategy programs: Diarrhea and Enteric Diseases, Malaria, Pneumonia, Tuberculosis, HIV, Reproductive Health, Nutrition, and Maternal, Neonatal, and Child Health.

Global Network for Neglected Tropical Diseases website, globalnetwork​.org.



The Global Health Program encompasses the following strategy programs: Diarrhea and Enteric Diseases, Malaria, Pneumonia, Tuberculosis, HIV, Reproductive Health, Nutrition, and Maternal, Neonatal, and Child Health.


Global Network for Neglected Tropical Diseases website, globalnetwork​.org.


Acknowledgements to the Neglected and Other Infectious Diseases Team who have contributed to this strategy over the past 12 years including David Brandling Bennett, Jan Agosti, Thomas Kanyok, Kathryn Aultman, Anastasia Pantelias, Erin Shutes, Ken Duncan, and Guy Stallworthy.

Copyright © 2011, National Academy of Sciences.
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