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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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)

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.

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.

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.

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.

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 retrospective)

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)

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)

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.

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.

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)

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.