The goal of this project is to improve newborn survival among low birth weight (LBW) infants through a daily prophylactic dose of bovine lactoferrin (bLF). A two-stage project will be conducted with formative research followed by randomized controlled trial (RCT) to evaluate the appropriate daily dose of bLF and its efficacy in preventing neonatal infections.

PATH's novel infusion pump, the RELI Delivery System, was designed to address many of the barriers surrounding access to infusion pumps in LRS: it does not require electricity or a battery, is inexpensive to manufacture and operate, does not require expensive consumables, and has a simple user interface. We will develop a functional prototype and related job aids to share with stakeholders.

This team proposes to develop and test an innovative microarray patch to deliver a combination of antibiotics for the treatment of neonatal sepsis. An easy-to-use, less-invasive, affordable delivery method for amoxicillin and gentamicin could expand access to lifesaving outpatient antibiotic treatment for infants with severe infection during the neonatal period.

The Safer Deliveries project will improve the ability of nurses and midwives to identify danger signs for a woman and her baby during the critical period of labor and delivery and link these measures to specific decision support rules that guide the health worker in taking corrective action. Using ultra-low-cost disposable ECG leads, D-tree International will build a phone based device that provides continuous tracking of fetal and maternal heart rate and uterine contractions during labor and delivery leading to more timely and effective interventions to save the life of the mother and infant.

PremieBreathe has built a functional infant breathing aid for $450, one tenth the price of commercial models. The device, a humidified high flow nasal cannula (HHFNC), is the gold standard of non-invasive neonatal respiratory care in high-income countries. With the support of Saving Lives at Birth, PremieBreathe will conduct initial trials at Ayder Referral Hospital in the Tigray region of Ethiopia, and identify design, manufacturing, and distribution partners to prepare for scaled production and dissemination.

Lu Lu of Shanghai Medical College, Fudan University in China working with Ling Ye of Emory University in the U.S., will design a potent HIV vaccine using selected sequences of one of the virus's envelope proteins to trigger the production of broadly neutralizing antibodies. This has been problematic due to the diversity of the viral envelope glycoprotein and its glycosylation shield, which prevent the immune system from recognizing it. The membrane-proximal external region (MPER) of the viral envelope protein has been identified as an attractive target for inducing neutralizing antibodies, and they have fused it with another viral protein to form a chimera that can partly neutralize infection. They will build on this result by modifying the structure of the MPER to stabilize it in a more active conformation, and by fusing it with slightly different viral proteins that can then be immunized altogether. They will evaluate whether this vaccine strategy further stimulates broadly neutralizing antibody production and can fully neutralize HIV in several animal models.

The study intends to develop an inter-generational intervention to ameliorate neonatal gut microbiota. It is based on the hypothesis that consuming prebiotic starches such as high amylose maize starch (HAMS) by mothers during the third trimester of pregnancy will modify their fecal microbiota and will subsequently lead to a beneficial variation in the fecal microbiota of the newborn infant. This will consequently guide favorable intestinal activity, thus enhancing growth, and intellectual competence of the infant in the intermediate and long term.

Pamela Schnupf of Paris Descartes University in France will develop an oral vaccine to prevent infectious diarrhea in children by engineering a non-pathogenic bacteria to express pathogen molecules that can be safely delivered in bacterial spores. Diarrheal disease caused largely by Shigella and enterotoxigenic Escherichia coli is a major cause of morbidity and mortality in children under five years of age in low-resource settings. Segmented filamentous bacterium (SFB) is non-pathogenic and normally colonizes the human gut during infancy and stimulates the immune system to protect against infections. They will establish methods to genetically engineer SFB to express selected antigens from enterotoxigenic E.coli and test whether it can stimulate an immune response and protect against infection using established mouse models.

Save the Children proposes an affordable and exclusive point-of-care diagnostic device for accurate measurement and interpretation of key vital signs (oxygen saturation, respiratory rate and temperature) among young infants (0-59 days) and children (2-59 months). It is equipped with a unique universal pulse oximeter sensor. The device will improve the quality of pneumonia case management and possible serious bacterial infections at community and health facility levels in low-resource settings.

Clif Barry of The National Institute of Allergy and Infectious Diseases in the U.S., working with Qian Gao of Shanghai Medical College Fudan University in China, will support a clinical trial to shorten the treatment time for tuberculosis (TB) from six months to four months by helping to identify predictive biomarkers in individuals that only require the shorter treatment. Shortening treatment when possible will substantially reduce costs and the emergence of drug resistance, which is a major barrier to eradicating this deadly disease. The phase 2b clinical trial will recruit 620 TB patients at multiple clinics in South Africa and China who will be monitored for disease burden by PET/CT scans and diagnostic assays during treatment, and will supply blood and sputum samples for testing. He will analyze RNA and inflammatory markers in serum samples from the Chinese trial participants to identify more robust biomarkers for predicting shorter treatments. He will also determine the strains of the causative Mycobacterium tuberculosis, the source of any reinfection (relapse or new infection), and the presence of drug resistant bacteria in these patients, and how these link with treatment duration and disease outcome.

There is international consensus that syringe pumps are an essential medical device to support care of mothers and newborns at district hospitals. Yet, they are often unavailable in low-resource settings because of high cost, technical complexity, and lack of brand name consumables. The project's idea is to scale AutoSyp, a low cost, low power, syringe pump in maternity and neonatal wards of hospitals in Malawi.

Patricia Donahoe and David Pepin of Massachusetts General Hospital in the U.S. are using a cell-based screening platform to develop a new class of hormonal contraceptive that works at the early stage of primordial follicle activation to prolong the contraceptive effect and reduce side effects, thereby promoting wider use particularly in the developing world. This early stage of follicle development in the ovary is suppressed by a hormone (Mullerian inhibiting substance or MIS) to regulate egg production. They considered that a drug that could mimic MIS could completely suppress ovulation and act as a powerful contraceptive. In contrast, most available hormonal contraceptives work once ovulation has begun, thereby requiring daily dosage, and share unwanted side effects including migraine and increased risk of some diseases. In Phase I, they designed a luciferase-based screening platform using engineered mammalian cells and screened 5,500 compounds from which they validated three candidate contraceptive compounds with high specificity and activity and limited toxicity. In Phase II, they will adapt their assay for higher throughput screening and screen 100,000 compounds to identify diverse classes of molecules for evaluation as ovarian suppressants. The contraceptive efficacy of validated candidates with favorable properties will then be tested in mice.

Jianjun Sun of the University of Connecticut in the U.S. is developing non-hormonal contraceptives using a fly-based ovulation assay to identify compounds that specifically block the rupture of follicles, which is required to release eggs for fertilization also in mammals. The popular female contraceptive "pill" alters the hormonal cycle and is widely used throughout the Western world. However, it can have undesirable side effects. In Phase I, they developed a medium-throughput follicle rupture assay using Drosophila follicles and showed that three out of four drugs inhibiting Drosophila follicle rupture had the same effect in mice. They discovered that these drugs also inhibited the production of superoxide, which promotes follicle rupture. Building on this new knowledge, in Phase II, they will develop a high-throughput luminescence-based superoxide-detection assay in Drosophila and screen 13,000 compounds. Top hits will again be validated for activity also in mice, and they will further identify their cellular mechanisms of action using available genetic tools in Drosophila.

Anastasios Tsaousis of the University of Kent in the United Kingdom will build a screening platform to identify drugs that can be used to treat diarrhea caused by the parasite Cryptosporidium, which is the second major cause of death in children under five years old in developing countries. There are currently no effective drugs for treating Cryptosporidium, largely because it cannot easily be grown in the laboratory making it difficult to study and test for new drugs. They have developed a two-dimensional cell culture system using a specific cell type that can be stably infected with Cryptosporidium and cultivated long term. They will use the CRISPR/Cas9 gene modification technique to alter selected Cryptosporidium genes for monitoring parasite growth, and use it in their cell culture system to screen a library of FDA-approved drugs to identify candidate drugs that block Cryptosporidium growth.

Jane Harries of the University of Cape Town in South Africa will take a multisensory approach to increase the use of contraception, particularly over the long term, across South Africa. By exploring how different contraceptives are perceived via multiple senses, not only visual perceptions but also how they feel, and how their use impacts the daily life of the woman, and her wider network, they hope to identify new barriers that influence uptake. They will present a range of contraceptives to 150 women and 50 men, and encourage them to take photographs and make drawings as a way to explore their different perspectives on the contraceptives and on family planning in general. Group discussions and individual interviews will also be held to further evaluate how people react to the contraceptives, and how they affect their lives.

Howard Ochman of the University of Texas in the U.S. will develop an approach to identify bacteria that can spread antibiotic resistance genes to other bacteria and harm human health. Most methods for monitoring antibiotic resistance are used once resistance has occurred. Here they will measure the capacity for developing resistance, which should help better evaluate how antibiotic resistance persists, spreads and circulates on a global scale. They will develop a simple method based on a single-cell technology to link a marker rRNA gene, for classifying the bacterial species, with a gene known to confer antibiotic resistance. They will use this method to identify antibiotic resistance gene-carrying bacteria within microbial communities comprising trillions of cells, and analyze how it spreads through a mixed bacterial population.

Paul Fleming of the University of Michigan School of Public Health along with Jay Silverman and Holly Shakya at the University of California, San Diego Center for Gender Equity and Health in the U.S. will learn about the social networks of husbands of adolescent girls in Niger, and how these networks influence decisions to use of family planning. The study will be conducted in collaboration with Pathfinder International, building on their Reaching Married Adolescents program. Niger has the highest fertility rate in the world, and men usually control all decisions on use and type of contraception. However, it is unclear how and why they make these decisions, and particularly how other men in their lives influence these decisions. They will conduct in-depth interviews with a group of 20 husbands of adolescent girls in Niger, and characterize the social networks of a further 300 such men. They will also interview key members of these social networks to determine their views on these husbands’ of adolescent girls use of contraception. Together, they hope to identify social barriers and, ultimately, effective models for increasing use of family planning to improve the health of married adolescent girls.

Kathryn Colborn of University of Colorado Denver in the U.S. will develop a statistical model to predict future outbreaks of malaria and help identify the most effective intervention strategy. Current models can help work out where and why malaria outbreaks occur rather than predicting future outbreaks. They will use supervised machine learning to develop a set of predictive algorithms using available data including weather, demographics, and malaria incidence in children under five years old from Mozambique. From this set, the best algorithm for predicting malaria will be selected by cross validation on an independent dataset, and subsequently tested in the field using monthly malaria case reports.

Honorine Ward of Tufts Medical Center in the U.S. will develop a three-dimensional model of the human intestine for rapid screening of drugs targeting the parasite Cryptosporidium, which causes potentially lethal diarrhea in young children in developing countries. Developing drugs against Cryptosporidium has been particularly difficult, partly because of the limited understanding of the parasites behavior in the human intestine, and particularly of the effect of malnutrition, which commonly co-occurs with infection and likely contributes to disease severity. They will build a three-dimensional model of the human intestine using a scaffold of silk proteins and a hollow lumen structure lined with cells derived from human intestinal stem cells supported by underlying human myelofibroblasts. They will infect their cell model with fluorescently labelled Cryptosporidium to evaluate how the parasite affects the intestine, and to determine its capacity for high-throughput drug screens.

Kevin Osteen of Vanderbilt University Medical Center in the U.S. is developing a three-dimensional cell model that mimics the lining of the human uterus (endometrium), including different cell types and a vascular system, that can be used for affordable medium-to-high-throughput compound screening to discover new contraceptives with minimal adverse side effects. The endometrium is a multi-layered tissue that supports embryo implantation and maintains pregnancy and responds to hormonal cues to undergo renewal during each menstrual cycle. Recapitulating this environment in vitro could provide a valuable, contraceptive screening platform to identify new contraceptives. In Phase I, they built a compartmentalized two-chamber device to model the cross-talk between two endometrial cell layers. They showed that this EndoChip was able to mimic the process of decidualization that is critical for establishing pregnancy. In Phase II, they will refine a second-generation EndoChip to include an epithelial component in the form of organoids by incorporating a three-dimensional synthetic hydrogel and complete endometrial microenvironment for in vitro contraceptive screens. This will be validated with existing drugs known to affect endometrial function. They will also incorporate microfluidic platforms and existing in vitro organ models to establish a multi-organ system that mimics the effect of the liver or gut for analyzing candidate drug efficacy and safety.

Jennifer Brown of the University of Cincinnati in the U.S. will apply cultural consensus modeling (CCM) to identify cultural factors that affect contraceptive practices among South African adolescent girls aged between 14 and 17. This demographic currently has one of the highest rates of unwanted pregnancies and sexually transmitted infections (STIs). However, there is limited empirical data on the underlying reasons, particularly related to the use of so-called dual contraceptives, which protect against both pregnancy and STIs. The CCM approach involves a series of questions and interviews designed to identify factors that individuals believe influences the use of contraceptives within their group as a whole, rather than themselves individually. This will help identify cultural barriers that limit the use of contraceptives. They will test their approach using around 300 girls in South Africa and evaluate how these perceived factors are associated with actual contraceptive practices.

Andrew Hopkins of the University of Dundee in the United Kingdom is developing a screening platform using live human sperm to identify new male contraceptive drugs that inhibit two separate activities required for fertilization, namely motility and formation of the acrosome on the head of sperm cells. Currently, the only effective, widely available, and reversible form of male contraception is the condom, which has limited appeal. Alternative male contraceptives are needed to help reduce the estimated 89 million unintended pregnancies each year. In Phase I, they successfully developed a high-throughput screening platform incorporating confocal microscopy and phenotypic analysis tools optimized for 384-well culture plates for automated screening of large numbers of candidate male contraceptive compounds. In Phase II, Christopher Barratt also of the University of Dundee, will further the development of new contraceptives by studying the properties and mechanism of action of the hits identified in Phase I and perform additional screens with both focused and diverse compound libraries.

Kenneth Stedman of Portland State University in the U.S. will test a low-cost and simple method for simultaneously collecting and stabilizing stool samples that can be used for diagnosing helminth infections in remote locations. The samples allow quantification of eggs from the helminth parasite, which causes intestinal infections that are endemic in many developing regions, and will help monitor large-scale treatment efforts. The method is based on his vaccine-stabilization technology, which was developed along with James Laidler at Portland State University.

Boris Striepen of the University of Georgia in the U.S. will develop a new, more natural mouse model for cryptosporidiosis, which is a leading cause of severe diarrhea in children, to help identify effective treatments. Unlike previous mouse models of this disease, these mice do not need to be immune deficient as they can be infected by a natural strain of the Cryptosporidium parasite, which they previous isolated from house mice. They will genetically modify this strain so it will fluoresce and can thus be easily located in the mice and within individual cells. These mice also experience symptoms more similar to the human disease, and they will use it to assess the effects of malnutrition, which often co-occurs with infection and appears to worsen symptoms. They will also study the effect of different bacterial communities in the gut on disease progression and the effects of existing and emerging treatments.