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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.

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A Population-Based Cohort Study in Matlab, Bangladesh: Establishing a Center of Excellence in Preterm Birth and Stillbirth Investigation

Anisur RahmanInternational Centre for Diarrhoeal Disease Research, BangladeshDhaka, Bangladesh
Grand Challenges in Global Health
Preventing Preterm Birth
1 Feb 2014

Anisur Rahman of the Matlab Health Research Centre at the International Centre for Diarrhoeal Disease Research, Bangladesh (ICCDR,B) will lead a prospective cohort study of pregnant women, building on the ICDDR,B community-based surveillance site, to enroll more than 4,000 pregnant women over three years. His team will visit women monthly at their homes for early identification of pregnancy, followed by accurate gestational age dating by ultrasound and follow up throughout pregnancy and at delivery for collection of clinical data and specimens. The study includes standardized systems for documentation of complications of pregnancy and assessment of birth outcomes. Data and specimens will be used to advance innovative research into the causes of preterm birth and identify novel strategies for prevention.

Identification of Biomarkers for Environmental Enteropathy in Children Using an Evidence-Based Approach

Asad AliAga Khan University - PakistanKarachi, Pakistan
Grand Challenges in Global Health
Gut Function Biomarkers
6 Nov 2012

Asad Ali of Aga Khan University in Pakistan and co-­investigators will test a selected group of candidate biomarkers to identify and monitor environmental enteropathy, which causes malnutrition and stunting. The biomarkers, which include markers of inflammation and enteric pathogens, will be tested in blood, urine and stools, and correlated with structural features of the small bowel using biopsies from malnourished children. They will also attempt to identify new candidate biomarkers in these biopsies using mRNA sequencing. Their results will provide important insight into disease pathophysiology and enable the development of evidence-­based interventions.

Gut Permeability in Environmental Enteropathy

William FaubionMayo ClinicRochester, Maryland, United States
Grand Challenges in Global Health
Gut Function Biomarkers
2 Nov 2012

William Faubion of the Mayo Clinic in the U.S. and colleagues will develop a non-­invasive test of small intestinal permeability to improve the reliability of detection of environmental enteropathy, which causes childhood growth failure. The test involves quantification of sugar absorption in urine samples using mass spectrometry, and will be validated in at risk infants in the developing world. The aim is to provide a simple, safe and inexpensive test to identify all cases of this condition on a global scale, and drive the development of preventative interventions.

Metabonomic Biomarkers of Gut Function and Health: Modeling Enteropathy (EE) and Field Validation

Richard GuerrantUniversity of VirginiaCharlottesville, Virginia, United States
Grand Challenges in Global Health
Gut Function Biomarkers
1 Nov 2012

Richard Guerrant of the University of Virginia in the U.S. and co-­investigators will develop and validate non-­invasive metabolic biomarkers of gut health to identify children at risk of environmental enteropathy and developmental impairment, in order to assess interventions. They will use ongoing MAL­-ED (malnutrition and enteric diseases) and NIH­-supported clinical studies in malnourished and control children, and their own studies in novel murine models, along with a nuclear magnetic resonance approach to perform metabolic profiling of urine, plasma and feces samples. Their goal is to improve the growth, nutrition and development of children at high risk of environmental enteropathy that can lead to morbidity and mortality.

Development of Human mRNA as a Biomarker for Environmental Enteropathy

Mark ManaryWashington University School of MedicineSt. Louis, Missouri, United States
Grand Challenges in Global Health
Gut Function Biomarkers
26 Oct 2012

Mark Manary of Washington University in the U.S. and colleagues will develop a strategy for the non-­invasive diagnosis of environmental enteropathy, which causes malnutrition and growth failure in young children in the developing world. They will devise a robust protocol to isolate human RNA of the small bowel from samples of stool, and will test a broad panel of candidate biomarkers for their ability to identify environmental enteropathy with high sensitivity using samples from at risk Malawian children. These tools will be critical for studying disease etiology and for the development of effective intervention strategies.

Improved Biomarkers for the Assessment of Environmental Enteropathy

Margaret KosekJohns Hopkins UniversityBaltimore, Maryland, United States
Grand Challenges in Global Health
Gut Function Biomarkers
24 Oct 2012

Margaret Kosek of Johns Hopkins University in the U.S. and co-­investigators will generate a new biomarker panel to assess disease activity in environmental enteropathy, which causes stunted growth and malnutrition. They will analyze markers related to immune system activation and growth factors in samples derived from the children enrolled in the MAL­-ED (malnutrition and enteric diseases) study in Peru, and compare them with growth profiles and diarrheal disease burden as a proxy for disease activity. The identified biomarker panel will ultimately aid in evaluating interventions to prevent and treat enteric diseases.

Environmental Enteropathy in Zambia: Biomarkers Defined by Pathogenesis

Paul KellyQueen Mary & Westfield CollegeLondon, United Kingdom
Grand Challenges in Global Health
Gut Function Biomarkers
23 Oct 2012

Paul Kelly of Queen Mary and Westfield College in the United Kingdom and the University of Zambia will work with colleagues to identify and evaluate candidate biomarkers of environmental enteropathy, which causes growth failure in children in the developing world. Possible markers of enteropathy in serum and gut secretions will be correlated with two severe clinical outcomes, impaired nutrient absorption, and loss of gut barrier function leading to bacteria entering the bloodstream. The aim is to drive the development of new treatments.

Biomarkers of Gut Function and Predictors of Linear Growth and Neurodevelopment Status Among Young Tanzanian Children

Christopher DugganChildren's Hospital BostonBoston, Massachusetts, United States
Grand Challenges in Global Health
Gut Function Biomarkers
23 Oct 2012

Christopher Duggan of Children’s Hospital Boston in the U.S. and his team will test whether known biomarkers of gut dysfunction can accurately predict impaired neurodevelopment and stunting, which reflects chronic malnutrition and is associated with increased morbidity and mortality in young children. The biomarkers will be validated in a well­-characterized group of young Tanzanian children. The goal is to facilitate the identification of at risk children early in life, so that appropriate intervention strategies can be applied.

Cell Wall Glycan Biomarkers for Tuberculosis

Todd LowaryUniversity of AlbertaEdmonton, Alberta, Canada
Grand Challenges in Global Health
Tuberculosis Biomarkers
24 Jan 2012

Todd L. Lowary of the University of Alberta in Canada will develop a library of chemically synthesized glycans, which are antigens found on the cell wall of M. tuberculosis, and prepare a microarray of them to screen for antibodies that signal the presence of active TB.

SOMAmer-based Detection of Tuberculosis Biomarkers

Urs OchsnerSomaLogic, Inc.Boulder, Colorado, United States
Grand Challenges in Global Health
Tuberculosis Biomarkers
12 Jan 2012

Urs Ochsner of SomaLogic, Inc. in the U.S. will lead a team to expand and test a library of SOMAmers (slow off­-rate modified aptamers) to identify protein biomarkers that indicate active tuberculosis from a small sample of blood. SOMAmers, which are modified nucleic acid-­based protein-­binding agents, offer several advantages over the antibodies traditionally used in diagnostic tests including greater stability, lower cost, and no need for refrigeration.

Parathyroid-Vitamin D Axis Dysregulation in Early-Onset Infant Stunting in Resource-Poor Settings

Daniel RothThe Hospital for Sick ChildrenToronto, Ontario, Canada
Grand Challenges in Global Health
Achieving Healthy Growth
1 Jan 2012

Daniel Roth of the Hospital for Sick Kids in Canada and colleagues will test whether endocrine factors cause stunting in early infancy. They will analyze parathyroid hyperactivity in a cohort of infants from Bangladesh, where stunting is estimated to affect almost half of all children under the age of 5. To uncover the mechanisms responsible for this hyperactivity, they will conduct a vitamin D supplementation trial and analyze maternal, cord, and infant plasma specimens for evidence of dysregulation of the parathyroid-­vitamin D axis. Their goal is to understand the cause of widespread vitamin D deficiency in the region, which is under­-appreciated, and its linkage to early growth retardation.

Postpartum Deworming: Improving Breastfeeding and Optimizing Infant Growth

Theresa GyorkosMcGill University Health CentreMontreal, Quebec, Canada
Grand Challenges in Global Health
Achieving Healthy Growth
1 Jan 2012

Theresa Gyorkos of McGill University in Canada and colleagues will investigate whether treating worm infections in lactating women has a beneficial effect on breast milk production and on infant and maternal health. They will conduct a double blind, randomized, controlled trial in Peruvian mothers following in-hospital delivery, and analyze the effect of de-worming on quantity and quality of breast milk, maternal anemia, and infant growth and morbidity, over a 24-month period. Their ultimate aim is to improve the health of both mother and child by informing global policy on maternal postpartum care.

Biomarkers and Interventions to Prevent Preterm Birth and Stillbirth Associated with Placental Malaria

Kevin KainUniversity Health NetworkToronto, Ontario, Canada
Grand Challenges in Global Health
Preventing Preterm Birth
1 Jan 2012

Kevin Kain of the University Health Network and the University of Toronto in Canada will investigate malaria infections of the placenta to reveal specific roles of the immune response that lead to preterm birth, low birth weight, and stillbirth. This project will focus on discovering biomarkers to identify at-risk pregnancies as well as new interventions to prevent adverse pregnancy outcomes. Funding partners: Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) and Bill & Melinda Gates Foundation.

Inflammatory Pathways to Preterm Birth

David OlsonUniversity of AlbertaEdmonton, Alberta, Canada
Grand Challenges in Global Health
Preventing Preterm Birth
1 Jan 2012

David Olson from the University of Alberta in Canada will work to better understand how infections can cause preterm birth. Using animal models and later in studies of women in low-income countries, he and his team will investigate multiple mediators of inflammation in the uterus early in pregnancy, as well as test new diagnostics and therapeutics that can identify women at risk, modulate the inflammatory response, and prolong pregnancy. Funding partners: Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) and Bill & Melinda Gates Foundation.

Epigenetic Mechanisms, Stunting and Poor Growth; Targets for Interventions

Peter GluckmanUniversity of AucklandGrafton, New Zealand
Grand Challenges in Global Health
Achieving Healthy Growth
1 Jan 2012

Peter Gluckman of the University of Auckland in New Zealand and colleagues will test whether intrauterine growth retardation and childhood stunting, which are commonly seen in developing countries, are caused by epigenetic changes that can be corrected in pregnancy and infancy by modifying nutrition. Stunting is associated with many negative outcomes including decreased cognitive ability and immune function. Using epigenetic analyses, and clinical and epidemiological approaches in stunted and control children from Jamaica, Ghana and Singapore they will identify underlying pathophysiological mechanisms of stunting that can act as targets for intervention. The long-­term goal is to prevent infant stunting and its associated adverse consequences.

Azithromycin Administration to Prevent Growth Faltering in Gambian Infants: Understanding Mechanisms for Public Health Intervention

David MabeyLondon School of Hygiene and Tropical MedicineLondon, United Kingdom
Grand Challenges in Global Health
Achieving Healthy Growth
1 Jan 2012

David Mabey of the London School of Hygiene and Tropical Medicine in the United Kingdom and his team will test whether treatment with the broad­-spectrum antibiotic azithromycin can prevent growth faltering linked to environmental enteropathy, which is prevalent in young children of developing countries. They will utilize a double blind, randomized, controlled trial of Malawian children aged 1­-60 months, and analyze growth over a two year period after a single administration of either the antibiotic or a placebo control. They will also analyze immune responses and composition of the intestinal microbiota to identify the molecular pathways underlying environmental enteropathy. Their aim is to improve growth and development in affected infants in low­-income countries.

Understanding Mechanisms and Identifying Biomarkers for the Relationship Between Aflatoxin Exposure and Child Stunting

Yun-Yun GongQueen's University BelfastBelfast, United Kingdom
Grand Challenges in Global Health
Achieving Healthy Growth
1 Jan 2012

Yun Yun Gong of Queen’s University Belfast in the United Kingdom and colleagues will identify mechanistic biomarkers of child stunting caused by the dietary contaminant aflatoxin, which is common in many parts of sub-Saharan Africa. They will determine the mechanism by which aflatoxin inhibits growth in early life using blood samples and growth charts from 300 children in Gambia and analyzing the relationship between aflatoxin exposure and changes in insulin-like growth factor signaling, epigenetic marks, and gene expression. Candidate biomarkers will be validated in an in vitro cell model of human liver, which is the primary target of aflatoxin, and used to drive future intervention strategies, such as hand-sorting food to reduce contamination, for ultimately improving child health.

Enhancing Infant Immunity: Effect of Early Maternal Treatment for Parasitic Infections

Charles KingCase Western Reserve UniversityCleveland, Ohio, United States
Grand Challenges in Global Health
Achieving Healthy Growth
1 Jan 2012

Charles King of Case Western Reserve University in the U.S. and his team will study how chronic parasitic infections in pregnant mothers affect infant immunity and childhood development. Using existing and prospective maternal­-child cohorts in Kenya they will analyze the effect of parasitic infections, such as schistosomiasis and intestinal helminths, encountered in utero on subsequent infant vaccine responses, and on general growth and development later in childhood. They will also test whether specific anti­-parasitic treatment during pregnancy can improve childhood immunity and development.

Identification of Nutritionally Modifiable Hormonal and Epigenetic Drivers of Positive and Negative Growth Deviance in Rural African Fetuses and Infants

Robin BernsteinGeorge Washington UniversityWashington, District of Columbia, United States
Grand Challenges in Global Health
Achieving Healthy Growth
1 Jan 2012

Robin Bernstein of the George Washington University in the U.S. and colleagues will undertake one of the most detailed longitudinal studies to date to examine the effects of epigenetic and hormonal factors on growth during the first 1000 days of life. Assessment of a variety of parameters, including infectious exposures and hormone levels, as well as epigenome and transcriptome analyses will be collected from the 13th week of gestation through infant and early childhood from a cohort of 200 Gambian children. These extensive data sets will reveal the mechanisms of growth faltering, and will aid in the development of targeted interventions to promote healthy infant growth and development.

Perinatal Treatment of Adrenergic Dysregulation to Correct Skeletal Muscle Metabolism in IUGR Infants

Sean LimesandUniversity of ArizonaTucson, Arizona, United States
Grand Challenges in Global Health
Achieving Healthy Growth
1 Jan 2012

Sean Limesand of the University of Arizona in the U.S., along with co-­investigators, will test whether infants with intrauterine growth restriction, caused during gestation by oxygen and nutrient deprivation, could benefit from pharmacological intervention using well­-characterized adrenergic drugs to improve skeletal muscle metabolism. Intrauterine growth restriction affects around 24% of babies born in developing countries and leads to perinatal morbidity and mortality. The team will perform intervention studies using the adrenergic drugs in a well­-defined sheep model of intrauterine growth restriction, and identify related biomarkers using placental tissue from affected human infants. These studies will increase understanding of the pathophysiological mechanisms underlying intrauterine growth restriction and could lead to new treatment options.

Balance of Th17 Cells and Regulatory T Cells in Candidal Vaginal Colonization in Pregnant Macaques and Humans

Margaret HostetterCincinnati Children's Hospital Medical CenterCincinnati, Ohio, United States
Grand Challenges in Global Health
Preventing Preterm Birth
1 Jan 2012

Margaret Hostetter from Cincinnati Children's Hospital Medical Center in the U.S. and her co-investigators will examine how disruption of the normal bacteria and other micro-organisms (the microbiome) of the lower female genital tract may increase risk of preterm birth. These investigations will focus on vaginal Candida infections in pregnancy, inflammation, and regulation of the immune response. Research will be conducted using animal models and laboratory investigations connected to studies of women in low-resource countries. Their goal is to investigate protective and pathogenic mechanisms of preterm birth and identify novel treatment strategies for vaginal fungal infections to prevent preterm birth. Funding partners: Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) and Bill & Melinda Gates Foundation.

Development of Gene-Specific Progesterone Receptor Modulators to Prevent Preterm Birth

Sam MesianoCase Western Reserve UniversityCleveland, Ohio, United States
Grand Challenges in Global Health
Preventing Preterm Birth
1 Jan 2012

Sam Mesiano of Case Western Reserve University School of Medicine in the U.S. and his team will investigate the body's receptors for progestin-based therapies in pregnancy to identify ways to enhance anti-inflammatory processes in all pregnant women and prevent preterm birth. The long-term goal of this project is to develop an inexpensive oral therapy that will reduce the prevalence of preterm birth worldwide. Funding partners: Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) and Bill & Melinda Gates Foundation.

Mechanisms of Intrauterine Group B Streptococcal Infections During Pregnancy

David AronoffUniversity of MichiganAnn Arbor, Michigan, United States
Grand Challenges in Global Health
Preventing Preterm Birth
1 Jan 2012

David Aronoff of the University of Michigan in the U.S., with an interdisciplinary team of experts in microbiology, immunology, reproductive biology, and vaccine development, will examine how infections of the female reproductive tract interact with and evade the immune system, resulting in infections of the uterus that cause preterm birth and stillbirth. This work will research potential targets for prevention of invasive infections of the female genital tract, including plans to investigate strains of group B Streptococcus (GBS) from low-income countries for vaccine and drug development. Funding partners: Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) and Bill & Melinda Gates Foundation.

Modifying Mosquito Population Age Structure to Eliminate Dengue Transmission

Scott Leslie O'NeillUniversity of QueenslandBrisbane, Queensland, Australia
Grand Challenges in Global Health
Biological Vector Control
1 Jul 2005

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)

Development of Bananas with Optimised Bioavailable Micronutrients

James DaleQueensland University of TechnologyBrisbane, Queensland, Australia
Grand Challenges in Global Health
Crop Biofortification
1 Jul 2005

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)

Linking Innate and Specific Immunity to Develop Single Dose Vaccines for Neonates

Lorne BabiukUniversity of SaskatchewanSaskatoon, Saskatchewan, Canada
Grand Challenges in Global Health
Single-Dose Vaccines
1 Jul 2005

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.

Comprehensive Studies of Mechanisms of HIV Resistance in Highly Exposed Uninfected Women

Francis PlummerUniversity of ManitobaWinnipeg, Manitoba, Canada
Grand Challenges in Global Health
Protective Immunity
1 Jul 2005

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.

Novel Therapeutics That Boost Innate Immunity to Treat Infectious Diseases

Barton Brett FinlayUniversity of British ColumbiaVancouver, British Columbia, Canada
Grand Challenges in Global Health
Drug Resistance
1 Jul 2005

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.

Development of Novel Mouse Models for HIV and HCV Infection

Hongkui DengPeking UniversityBeijing, China
Grand Challenges in Global Health
Vaccine Model Systems
1 Jul 2005

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.

Natural Products Inhibit Intracellular Microorganisms via Cellular Mechanisms

Jian-Dong JiangInstitute of Medicinal Biotechnology, Chinese Academy of Medical SciencesBeijing, China
Grand Challenges in Global Health
Drug Resistance
1 Jul 2005

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.

Preclinical and Clinical Evaluation of Post-Exposure TB Vaccine

Peter AndersenStatens Serum InstitutCopenhagen, Denmark
Grand Challenges in Global Health
Curing Chronic Infection
1 Jul 2005

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.

Immunity to Prevent Pneumococcal Transmission: Correlates of Protection and Herd Immunity

Helena KäyhtyNational Institute for Health and WelfareHelsinki, Finland
Grand Challenges in Global Health
Protective Immunity
1 Jul 2005

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.

Novel Mouse Models for Testing HIV and HCV Vaccines

Rudi BallingThe Helmholtz Centre for Infection ResearchBraunschweig, Germany
Grand Challenges in Global Health
Vaccine Model Systems
1 Jul 2005

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.

Biomarkers of Protective Immunity and Surrogate Markers of TB Disease in Africa

Stefan KaufmannMax Planck Society for the Advancement of Science EVBerlin, Germany
Grand Challenges in Global Health
Protective Immunity
1 Jul 2005

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.

Engineering Rice for High Beta-Carotene, Vitamin E and Enhanced Fe and Zn Bioavailability

Peter BeyerAlbert Ludwigs Universitat FreiburgFreiburg, Germany
Grand Challenges in Global Health
Crop Biofortification
1 Jul 2005

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.

Surface Modified Nanostructures as Delivery Vehicles for Transmucosal Vaccination

Maria AlonsoUniversity of Santiago de CompostelaSantiago de Compostela, Spain
Grand Challenges in Global Health
Needle-Free Vaccines
1 Jul 2005

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.

Enhancing the Immunogenicity and Efficacy of Vectored Vaccines

Adrian HillUniversity of OxfordOxford, United Kingdom
Grand Challenges in Global Health
Antigen Design
1 Jul 2005

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 retrospective)

Novel Antigen Design and Delivery for Mucosal Protection Against HIV-1 Infection

Robin ShattockSt. George's Hospital Medical SchoolLondon, United Kingdom
Grand Challenges in Global Health
Antigen Design
1 Jul 2005

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.

Learning from the Human Genome How Protective Immunity Against Malaria Works

Dominic KwiatkowskiUniversity of OxfordOxford, United Kingdom
Grand Challenges in Global Health
Protective Immunity
1 Jul 2005

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)

Homing Endonuclease Genes: New Tools for Mosquito Population Engineering and Control

Austin BurtImperial College LondonLondon, United Kingdom
Grand Challenges in Global Health
Biological Vector Control
1 Jul 2005

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)

Drugs for Treatment of Latent Tuberculosis Infection

Douglas YoungImperial College LondonLondon, United Kingdom
Grand Challenges in Global Health
Curing Latent Infection
1 Jul 2005

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)

A Live Recombinant Attenuated Salmonella Anti-Pneumococcal Vaccine for Newborns

Roy CurtissArizona State UniversityTempe, Arizona, United States
Grand Challenges in Global Health
Single-Dose Vaccines
1 Jul 2005

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.

Bacterial Spores as Vaccine Delivery Systems

Abraham SonensheinTufts University School of MedicineMedford, Massachusetts, United States
Grand Challenges in Global Health
Vaccines Without Refrigeration
1 Jul 2005

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.

Increasing Vaccine Stability Through Novel Technology

Juan AlvarezTransForm Pharmaceuticals, Inc.Lexington, Massachusetts, United States
Grand Challenges in Global Health
Vaccines Without Refrigeration
1 Jul 2005

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.

Thermostable Vaccines With Improved Stability at Non-Refrigerated Temperatures

Claire CoeshottEndo Pharmaceuticals, IncBoulder, Colorado, United States
Grand Challenges in Global Health
Vaccines Without Refrigeration
1 Jul 2005

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.

Development of a Targeted Mucosal Vaccine Delivery Technology

David LoUniversity of California, RiversideRiverside, California, United States
Grand Challenges in Global Health
Needle-Free Vaccines
1 Jul 2005

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.

Nanoemulsions as Adjuvants for Nasal-Spray Vaccines

James BakerUniversity of MichiganAnn Arbor, Michigan, United States
Grand Challenges in Global Health
Needle-Free Vaccines
1 Jul 2005

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)

Needle-Free Delivery of Stable, Respirable Powder Vaccine

Robert SieversAKTIV-DRY LLCBoulder, Colorado, United States
Grand Challenges in Global Health
Needle-Free Vaccines
1 Jul 2005

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)

Needle-free Vaccination via Nanoparticle Aerosols

David EdwardsPresident and Fellows of Harvard CollegeCambridge, Massachusetts, United States
Grand Challenges in Global Health
Needle-Free Vaccines
1 Jul 2005

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.

A Mouse Model to Evaluate Live Attenuated Vaccine Candidates

Richard FlavellYale UniversityNew Haven, Connecticut, United States
Grand Challenges in Global Health
Vaccine Model Systems
1 Jul 2005

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)

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