Grand Challenges is a family of initiatives fostering innovation to solve key global health and development problems. Each initiative is an experiment in the use of challenges to focus innovation on making an impact. Individual challenges address some of the same problems, but from differing perspectives.
In the developing world, many people with health problems never receive an accurate diagnosis or appropriate treatment because clinicians lack tools to detect and diagnose diseases and conditions quickly, accurately, and inexpensively. Sophisticated medical tests that could help improve care are not only often unaffordable, they require extensive laboratory facilities and deliver results days later - a hardship for people who may live many miles from the nearest health clinic. Dr. Kelso's team is developing rapid, affordable, point-of-care systems for both immunological and molecular tests. The project's objective is to design low-cost delivery platforms that can perform assays in resource-poor settings.
The current vaccine against bacterial pneumonia (pneumococcus) requires a regimen of four injections given at specific intervals. In developing countries, this not only complicates the vaccination process for health workers and children, but it also is a serious obstacle for families who must travel long distances to the nearest health clinic. Dr. Curtiss and his colleagues are working to develop new vaccines against bacterial pneumonia that require only a single dose, can be delivered orally, and are safe for newborns, infants, and people who are malnourished or whose immune systems are compromised.
To develop new vaccines against some of the world's biggest killers, including HIV, malaria, and tuberculosis, scientists must be able to evaluate promising candidates. Some of the most promising potential vaccines, are made from weakened live versions of the infectious agent. As a result, they cannot be studied in human trials unless researchers can be confident that the weakened vaccines will be safe. Dr. Flavell and his colleagues are working to genetically engineer laboratory mice whose immune systems are similar enough to humans to permit testing of vaccines against diseases that disproportionately affect people in the developing world. Flavell (Grand Challenges in Global Health: 2005-2015 retrospective)
In the developing world, lack of convenient and accurate tools that can detect and diagnose diseases and other health problems means that many health risks remain undetected or receive inappropriate treatment. Dr. Yager's team, in collaboration with research groups from private industry as well as the nonprofit sector, is working to develop a low-cost, easy-to-use device that will rapidly test blood for a range of health problems prevalent in developing countries, such as bacterial infections, nutritional status, and HIV-related illnesses.
Attenuated vaccines, composed of weakened organisms incapable of causing disease, provide prolonged exposure to antigens and have proven effective against several viral or bacterial diseases. Dr. Kappe's team is attempting to extend this concept to a malaria vaccine. In the case of malaria, disease develops when the malaria sporozoite – the form of the parasite that is transmitted from mosquitoes to humans – enters the bloodstream and moves to the liver. There, it grows and divides into thousands of parasites that invade and destroy red blood cells, causing disease. Dr. Kappe's team is working toward development of a malaria vaccine using a malaria sporozoite that has been weakened by gene deletion to stimulate immune response. Kappe (Grand Challenges in Global Health: 2005-2015 retrospective)
To maintain stability and viability, most childhood vaccines must be kept cool - both heat and freezing can ruin them. That means they must be refrigerated at the correct temperature throughout transportation, storage, and delivery. This cold chain is difficult and costly to maintain, especially in developing countries. Dr. Sonenshein and his team are working to create childhood vaccines for diphtheria, tetanus, and pertussis (the DTP combination vaccine), and rotavirus-related diarrhea that can withstand a wide range of temperatures without refrigeration by encapsulating them in harmless bacterial spores that are naturally heat-resistant.
Tuberculosis (TB) is a major health problem, especially in developing countries. Dr. Kaufmann is leading an international consortium that is studying differences in immune system responses between people exposed to TB who never become sick and those who develop the disease, focusing particular attention on people infected with both HIV and TB in endemic African countries. The project's participating laboratories in Europe and the United States are attempting to learn which host responses provide protective immunity against TB and to identify correlates of protective immunity and host biomarkers of TB disease that could help guide the design and testing of improved TB vaccines, drugs, and diagnostics.
A subset of women who apparently are resistant to HIV infection may provide scientists with the genetic and immune system information they need to advance vaccine and drug development. Since 1985, investigators have tracked groups of commercial sex workers in Kenya who do not become infected with HIV despite repeatedly having sex without condoms. If investigators can understand what constitutes and results in protective immunity against HIV, they may be able to replicate it through vaccines. Dr. Plummer's team is conducting an exhaustive analysis of the immunologic and genetic factors that mediate HIV resistance in the women, with the goal of gaining a more complete understanding of what constitutes protective immunity against HIV infection.
Dr. Fraser's team is working to develop and test new approaches to suppressing the replication of dengue virus in the cells of its primary vector, Aedes aegypti mosquitoes. The team is using genetic strategies to introduce a molecular mechanism that uses the dengue virus' own genetic make-up to initiate a process that results in the death of infected cells in the mosquitoes, limiting their ability to transmit disease. In addition, investigators are working on tools to enhance the application of this and other genetic strategies in mosquitoes.
In the developing world, infections in the respiratory and intestinal tracts are major causes of sickness and death, especially among children. Vaccine delivery systems that can target respiratory or intestinal mucosal tissue and stimulate immune response there have the potential to be particularly effective against these infections. Dr. Lo's project addresses two needs: the development of vaccine delivery systems that do not require needles and the design of systems that target specific tissues in the body. Using influenza vaccination as a model, Dr. Lo and his team are working to bind vaccine to specially designed molecules that target mucosal tissue.
Bananas are the major staple food in Uganda, where the average person consumes more than 1 kilogram of the fruit each day. Banana-based diets, however, are deficient in vitamin A and iron, as well as in vitamin E. A promising long-term solution to this problem may be to genetically modify crops, including bananas, so that they contain high levels of essential nutrients. Dr. Dale is leading a team of scientists in Australia, Uganda, and the United States who are attempting to genetically modify bananas raised in Uganda so that their content of vitamin A, vitamin E, and iron is equal to or exceeds the required daily allowance. Dale, Tushemereirwe (Grand Challenges in Global Health: 2005-2015 retrospective)
Vaccines are urgently needed to slow the spread of HIV and hepatitis C virus (HCV), which together infect an estimated 240 million people, most of them in developing countries. To prepare a human vaccine, investigators need an animal model that can help them screen and prioritize vaccine candidates. Dr. Deng and his colleagues are working to improve techniques for creating mouse models with immune systems and livers that are similar enough to humans to allow testing of potential HIV and HCV vaccines. The team is working to create chimerical mouse models with hematopoietic cells (HSCs) and hepatocytes differentiated from human embryonic stem (hES) cells.
Mosquitoes that spread malaria parasites use their sense of smell to find human hosts. Dr. Zwiebel is leading an international consortium of investigators that seeks to understand and ultimately interfere with the molecular basis of the insects' sense of smell. Their work seeks to develop safe, effective and low-cost products that would either repel mosquitoes or attract them to traps. Zwiebel (Grand Challenges in Global Health: 2005-2015 retrospective)
An estimated 2 billion individuals - a third of the world's population - have been exposed to Mycobacterium tuberculosis (MTB) and carry the infection in its latent form, retaining a lifelong risk of developing TB disease. Programs to control tuberculosis now focus on childhood vaccination and treatment for people with active disease. Reversing TB's spread, however, requires an intervention that will prevent disease in those who are already infected. The lack of knowledge about the biology of latent TB infection stands in the way of the development of such an intervention. Dr. Young is leading an international team of researchers from the U.K., U.S., Singapore, Korea, and Mexico that is attempting to further elucidate the fundamental biology of latency and use this knowledge to develop drugs against latent TB. Young (Grand Challenges in Global Health: 2005-2015 retrospective)
Dr. Baltimore’s team is exploring a new way of stimulating the immune system to fight infectious diseases, focusing on HIV. The premise of this project is that for some infections, including HIV, the immune system’s natural responses are inherently inadequate, and the traditional approach of using vaccines to stimulate and boost these responses is likely to be ineffective. As an alternative, Dr. Baltimore and his colleagues propose to "engineer immunity," that is, use genetic engineering methods to produce immune cells that will make specific antibodies to fight off infection. Baltimore (Grand Challenges in Global Health: 2005-2015 retrospective)
Although rice is a primary source of food for much of the world's population, it is a poor source of many essential micronutrients, as well as protein. As a result, widespread reliance on rice is the primary cause of micronutrient malnutrition throughout much of the developing world. Dr. Beyer is leading an international, collaborative effort called the ProVitaMinRice Consortium. The consortium's members are developing new varieties of rice with increased levels or bioavailability of pro-vitamin A, vitamin E, iron, and zinc as well improved protein quality and content. As their platform, the consortium's researchers are using Golden Rice, which has been genetically engineered to produce and accumulate pro-vitamin A in the grain, and are working with novel transgene-based technologies to enhance the availability of the target nutrients.
Dr. Hill and his colleagues are exploring a novel approach to enhancing the ability of plasmid DNA, pox, or adenoviral vectored vaccines to stimulate strong immune responses. Building on recent advances in understanding of pattern recognition molecules as well as intracellular signaling pathways, investigators are working to add intracellular adjuvants (molecular signals that have the potential to enhance immunogenicity) to the vaccine vectors. Also being explored is the effect of adding molecules designed to inhibit regulatory pathways that may be limiting protective immune response. The team is focusing on improving vectors for vaccines against malaria, HIV, and tuberculosis. Hill (Grand Challenges in Global Health: 2005-2015)
Approaches to controlling disease-carrying insects might include inhibiting the development of virus in the mosquito or altering the insects' lifespan so that they die before they can transmit disease. A major challenge to this approach, however, is ensuring that such strategies are effective, safe, and socially and environmentally acceptable. Dr. James is leading an international team of scientists that is seeking to develop methods of controlling the transmission of dengue viruses using genetic techniques, including those that may block virus transmission by mosquitoes and reduce or eliminate populations of mosquitoes that transmit the virus.
The inability to ensure that newly introduced genes will become established within regional mosquito populations has been a major roadblock to the advancement of genetic strategies for vector control. Dr. Burt and his colleagues are investigating homing endonuclease genes (HEGs), so-called "parasitic" genes that can spread rapidly through mosquito populations even if they harm the host insect. This gives HEGs the potential to move newly introduced traits, such as sterility or inability to transmit disease, through a population quickly. The project's ultimate goal is to develop HEGs as a flexible, robust, powerful, and safe system to drive useful traits through populations of mosquitoes that transmit malaria. Burt (Grand Challenges in Global Health: 2005-2015 retrospective)
Acute respiratory infections, often due to Streptococcus pneumoniae (pneumococcus), are a primary cause of death in young children in developing countries. A new vaccine effectively prevents the most serious form of pneumococcal disease and also reduces nasopharyngeal colonization with pneumococci. Because only some people who are infected become ill, researchers must study tens of thousands of vaccinated individuals over a long period of time to determine whether the vaccine guards against disease. Dr. Käyhty is leading an international consortium of investigators whose goal is to establish a quick and inexpensive method of determining the efficacy and expected effectiveness of the pneumonia vaccine.
People infected with many serious illnesses, including tuberculosis and hepatitis C, may show no symptoms of disease for long periods of time. These inactive, or "latent," infections, however, can develop into active disease without warning, and also can be passed on to others. New approaches that focus on controlling or stimulating the immune system to cure latent infections or prevent them from causing disease have the potential to significantly reduce illness, death, and disease transmission. Dr. Ahmed and his team are working to create safe and effective immunological therapies for chronic hepatitis C infection and other viral infections such as HIV by developing methods to reactivate "exhausted" immune cells that are thought be unable to clear the infection.
Dr. Steinman's team is developing vaccines that stimulate the immune system's dendritic cells, which are known to play an important role in stimulating protection against infectious diseases. One approach is to engineer vaccine antigens into monoclonal antibodies against receptors on the surface of dendritic cells. A secondary approach involves engineering genes for the antigens of interest into the yellow fever virus. The project will focus on creating experimental vaccines for a range of diseases, including HIV and malaria. If successful, this technology could identify a better way to create vaccines that stimulate multiple components of the body's immune response, including those that have been difficult to target with existing vaccine approaches.
Poor nutrition is a major global health problem, contributing to half of the nearly 10 million deaths that occur each year in children younger than 5 and much of the death disease and suffering impacting sub-Saharan Africa. A starchy root crop called cassava is the major source of calories for more than 250 million Africans in this region, but cassava has the lowest protein-to-energy ratio of any staple crop. Dr. Sayre is leading a multidisciplinary team of scientists, brought together as BioCassava Plus, that is working to create nutritious cassava for sub-Saharan Africa. Team members are screening additional transgenic plants and expect that complimentary genetic strategies currently underway will soon yield plants that achieve their targeted levels of iron, zinc, and protein.
To maintain stability and viability, most childhood vaccines must be kept cool – both heat and freezing can ruin them. That means many must be refrigerated at the correct temperature throughout transportation, storage, and delivery. This cold chain is difficult and costly to maintain, especially in developing countries. Dr. Gardner and his colleagues are adapting high-throughput formulation technology developed by TransForm Pharmaceuticals, Inc. that can quickly screen different formulations of vaccines to identify those that are most likely to be stable, safe, and effective. The team's initial work focuses on reducing refrigeration requirements for the existing live attenuated vaccine for measles, a freeze-dried vaccine that must be stored at between 2° and 8° Celsius and is very sensitive to heat and light once it is reconstituted.
Due to differences in their immune systems, individuals respond to malaria in different ways. While some die, others survive, and still others are infected without becoming ill. Understanding how and why some people naturally resist malaria may help lead to the development of an effective vaccine against the disease. Dr. Kwiatkowski is leading the Malaria Genomic Epidemiology Network, or MalariaGEN, an international partnership of malaria research groups. MalariaGEN partners in 20 countries, including in 14 countries where malaria is endemic, are combining genomic technology with large-scale epidemiological analyses to identify mechanisms of protective immunity against malaria in humans. Their ultimate goal is to guide the development of tools and markers to facilitate the design and testing of vaccines against malaria. Kwiatkowski (Grand Challenges in Global Health: 2005-2015 retrospective)
Vaccinating infants against infectious disease is complicated by newborns' immature immune systems, the tendency of their immune systems to mount Th2-biased responses, and interference from maternal antibodies. Dr. Babiuk's team is working to develop new formulations of vaccines that can induce a long-lasting, balanced immune response in infants after a single-administration vaccination.
Scientists have long known that only relatively old mosquitoes can transmit the agents that cause certain diseases, including dengue fever and malaria. Dr. O'Neill and his multinational team are working on a plan to shorten the lifespan of mosquitoes that transmit the dengue virus, which infects up to 100 million people each year. They are introducing into populations of Aedes mosquitoes, strains of a naturally occurring bacterial symbiont, Wolbachia, that kill infected insects before they are old enough to transmit disease. Wolbachia are inherited though the eggs of the mosquitoes and so are passed on from generation to generation. O'Neill (Grand Challenges in Global Health: 2005-2015 retrospective)
Dr. Shaw is leading a consortium of investigators from clinical and laboratory research sites in Africa, the Caribbean, and the United States. They are conducting a comprehensive, integrated analysis of humoral and cellular responses to HIV-1 in people in early and acute stages of infection. Investigators are basing their work on the hypothesis that HIV-1 leads to chronic, persistent infection rather than a rapidly lethal disease because elements of the human immune system partially constrain viral replication over long periods. Ultimately, the project's goal is to contribute to the development of vaccines for HIV and AIDS through better understanding of natural immune response to the virus. Shaw (Grand Challenges in Global Health: 2005-2015 retrospective)
Efforts to control the spread of malaria face serious challenges, including the parasite’s increased resistance to both medications and insecticides and environmental concerns about the use of traditional insecticides. Mosquitoes that spread malaria parasites use their sense of smell to find human hosts, most often by cueing in on the scent of human sweat and the carbon dioxide present in breath. Drs. Axel and Vosshall and their colleagues are seeking to develop a new generation of insect repellents that work by disrupting the olfactory system of the Anopheles mosquito, the primary vector in Africa. Axel, Vosshall (Grand Challenges in Global Health: 2005-2015 retrospective)
The malaria parasites' increased resistance to both medications and insecticides and environmental concerns about the use of traditional insecticides pose major challenges to decreasing the rate and breadth of infection. Dr. Bloomquist and his colleagues are using advanced molecular modeling and a novel chemical synthesis method called "click chemistry" in an effort to produce insecticides specifically targeted to the primary malaria vector mosquitoes, Anopheles gambiae. The insecticides would work by inhibiting the essential enzyme acetylcholinesterase (AChE) in mosquitoes. They could be used as a potentially safer and more effective alternative to existing insecticides used in treating bed nets.
Vaccines that can be delivered without needles have the potential to be simpler to administer and less prone to spreading infection. Dr. Baker's team is developing a new way of preparing vaccines so that they can be given as nasal drops. These nanoemulsion-based vaccines use non-toxic lipid droplets less than 200 nanometers in diameter that are absorbed through the mucosal surfaces of the nostrils. They can be easily produced using an extrusion process available worldwide and are antimicrobial, eliminating the need for preservatives or refrigeration. The team is performing proof-of-concept, feasibility, and toxicology studies for a nanoemulsion-based vaccine for hepatitis B surface antigen. Baker (Grand Challenges in Global Health: 2005-2015 retrospective)
Dr. Jiang's team is identifying components of human cells that microbes use to establish an infection and replicate but that are not essential to the human host. Better understanding of microbial replication and survival from the view of host cells, the project team anticipates, will provide a foundation for novel therapeutic approaches to combat infectious diseases while simultaneously providing a low likelihood of inducing drug resistance. These compounds could potentially work by interrupting microbes from creating the environment they need to replicate in human cells.
Many serious infections, such as the measles virus, can enter the body through inhalation. Vaccine delivery systems that can target respiratory mucosal tissue and stimulate immune response there have the potential to be particularly effective against these types of infections. Collaborating with an international group that includes the Serum Institute of India (SII), the U.S. Centers for Disease Control and Prevention (CDC), the University of Colorado, and private companies, Dr. Sievers and his colleagues at Aktiv-Dry, LLC (AD) are developing a dry-powder version of the measles vaccine that can be inhaled through a disposable plastic device. Sievers (Grand Challenges in Global Health: 2005-2015 retrospective)
Vaccine delivery systems that target specific areas of the body have the potential to be especially effective against some types of infection. For example, inhaled vaccines may better guard against respiratory diseases, such as tuberculosis, and those that commonly infect the tissues of the nose and throat, such as diphtheria. Dr. Edwards is leading a multidisciplinary team using materials science technologies combined with infectious disease, device, and toxicology expertise to reformulate tuberculosis and diphtheria vaccines into aerosol sprays that can be inhaled. The team's ultimate objective is to develop a cell-based BCG vaccine for tuberculosis and a protein antigen CRM 197 vaccine for diphtheria in the form of novel porous nanoparticle aggregate (PNAP) aerosols.
Dr. Shattock and collaborators in the U.K. and South Africa will attempt to develop an HIV vaccine that stimulates immunity to the virus in the lining of the vagina. The investigators hypothesize that an HIV vaccine will be most effective at the site where the virus enters the body. Innovative combinations of vaccine antigen formulas and delivery technologies will be used to develop a potentially potent and effective vaccine. The vaccine will be designed to be delivered via low-cost vaginal gels or via silicone rings that fit inside the vagina and can be self-administered.
Hepatitis C virus (HCV) is a major cause of liver diseases, including cirrhosis and liver cancer. Treatment for chronic hepatitis C is often out of financial reach for people in developing countries, and there is no vaccine against the virus. To prepare a human vaccine, investigators need an animal model that can help them screen and prioritize vaccine candidates. Dr. Balling's team, partnering with Dr. Di Santo's group at the Institut Pasteur in France, is working toward the development of mice with livers and immune systems that are similar to those of humans. These animals might be used to test vaccines for HCV, and potentially, other human pathogens.
Each year, about a half-million women, 80 percent of them living in low-income countries, develop cancer of the cervix. The disease kills 250,000 women annually, and is the second leading cause of cancer deaths among women living in less developed countries. Nearly all cases of cervical cancer are caused by infection with human papillomavirus (HPV), the most common viral infection of the reproductive tract. Dr. Garcea's team is working to develop an inexpensive therapeutic vaccine against HPV that will not only protect people from developing new infections, but could potentially trigger an immune system response to cure those who are already infected.
Dr. Finlay's team is investigating a new approach to treating bacterial and parasitic infections by enhancing the body's innate defense mechanisms. By acting on the cells of the immune system rather than on the disease-causing microbe directly, investigators expect to lessen the risk of developing drug-resistant organisms and the potential for broad-spectrum activity. The project team is focusing on a number of bacterial and parasitic pathogens, including enteric bacteria, Mycobacterium tuberculosis, and Plasmodium falciparum.
More than 300 million people in arid and semi-arid regions of Africa rely on sorghum as their primary source of food. The grain is one of the few crops that grow well in arid climates, but it is deficient in most essential nutrients and is difficult to digest. The African Bio-fortified Sorghum (ABS) Project, a consortium of nine institutions led by Africa Harvest Biotech Foundation International, is working to develop new varieties of sorghum that are easier to digest and contain higher levels of vitamins A and E, iron, zinc, and the essential amino acids lysine, threonine, and tryptophan.
In the developing world, major gaps in methods and technologies to measure health status make it difficult to address inequities in health through changes in policy. Dr. Murray is leading an international team of investigators that is working to develop new technologies and methods for assessing health status in the developing world. Combining epidemiology, biomedical research, and population health assessment, the team hopes to produce new measurement tools that are science-based, standardized, and applicable to different resource-poor settings.
To stop the spread of tuberculosis, scientists are working to develop methods that prevent new infections and also eliminate infection in the huge reservoir of people who already are infected with MTB. New approaches that focus on controlling or stimulating the immune system to cure latent infections or prevent MTB from causing disease have the potential to significantly reduce illness, death, and disease transmission. Dr. Andersen's is leading a collaborative team of international researchers who are studying Mycobacterium tuberculosis to identify the mechanisms that, in some people, allow it to escape natural immune system responses. The project's ultimate goal is to develop vaccines that target latent TB, either before or after an individual is infected.
More than a million people die of malaria each year -- most of them infants, young children, and pregnant women, and most of them in Africa. Although severe malaria has a high mortality rate, some children in areas where the disease is endemic might experience only one or two episodes of severe illness before they become resistant to further bouts of the disease. Dr. Duffy's team is attempting to identify the antibodies and other immunological responses that protect children from severe illness and death due to the malaria parasite Plasmodium falciparum, the most deadly of the four parasite species of human malaria.
Most vaccines are delivered by injection, which increases the risk that HIV, hepatitis, and other serious diseases may be transmitted by syringes and needles that are not sterile. Dr. Alonso's team is working to develop a new generation of delivery systems that can easily and effectively carry hepatitis B vaccine through the mucosal lining of the nose. In addition, the team is evaluating whether these delivery systems and the vaccine they carry can be freeze-dried into an inhaled powder that could be stored without refrigeration.
To maintain stability and viability, most childhood vaccines must be kept cool – both heat and freezing can ruin them. Drs. Sarkari and Coeshott and their colleagues are working to identify Pluronic polymer-based formulations that stabilize vaccines from -10°C to 45°C. Their aim is to develop vaccines that are resistant to freezing and form protective matrices at elevated temperatures. Investigators are evaluating formulations based on Pluronic F127 using vaccines for measles and hepatitis B.