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.

PATH seeks to improve access to improved preeclampsia screening in routine antenatal care (ANC) by addressing the need for a low-cost, accurate proteinuria screening tool to replace the protein-only dipstick as the standard used in routine ANC in LRS. PATH is working in collaboration with LifeAssay Diagnostics, Ltd. (South Africa) to develop and support validation of a simple, low-cost protein-to-creatinine ratiometric urine dipstick test and is seeking to demonstrate the feasibility for implementation and use of the test within routine ANC.

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.

Drawing on 10 years of experience developing and delivering essential newborn care training, this project will develop 3D games using an iterative co-design process in UK and Kenya so it excites users and addresses needs and preferences. This project will explore incentives for learning and develop data capture tools to understand who is playing as well as where and when they are playing. This project will also design a test of the effectiveness of our training in Kenya, explore how to extend the approach to maternal care and plan for dissemination and testing.

Ling Ye of Emory University in the U.S., working with Lu Lu of Shanghai Medical College, Fudan University in China, 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.

José Castillo of Univercells in Belgium will create a compact low-cost and automated vaccine manufacturing platform by integrating three new technologies to produce more affordable vaccines at around 0.15USD per dose. Vaccine doses are generally 1-10USD most of which is due to inefficient production and high manufacturing costs including the need for major infrastructure. This relatively high cost prohibits their widespread use particularly in developing countries with limited funds. Starting with an inactivated poliovirus vaccine they will design and develop a compact high cell density bioreactor that concentrates vaccine production and high affinity capture membranes to streamline purification. They will house the technologies in a compact series of isolators that can be accommodated in a smaller laboratory space and perform pilot testing at a manufacturer's site to evaluate productivity and analyze purity and concentration of the vaccine.

Tarit Mukhopadhyay of University College London in the United Kingdom will develop a manufacturing platform to reduce the production costs of recombinant protein vaccines. Current manufacturing procedures involve serial batch operations in large complex facilities requiring highly trained operators and extensive testing and are inefficient and costly. They will build a platform that integrates and automates key steps to reduce labor costs and capital expenditure and improves product design and control procedures to reduce quality control requirements. Their aim is to maximize the number of doses with the minimal starting material leading to recombinant subunit vaccines at 0.15USD per dose rather than the current costs of several USD per dose. They will develop their approach initially using a rotavirus vaccine candidate.

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.

Qian Gao of Shanghai Medical College Fudan University in China, working with Clif Barry of The National Institute of Allergy and Infectious Diseases in the U.S., 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.

One of the reasons oxygen therapy is not reaching the many thousands of babies and children it could save is due to the fact that electricity is not always available in small health facilities. To address this problem, this team has successfully developed FREO2, an electricity-free oxygen concentrator which runs on the energy from water flowing in a nearby stream, and which requires no fuel. This project will enable a major field trial in a health center in Western Uganda, where the design for this innovation will be refined in close collaboration with the health workers.

Michael Schrader of Vaxess Technologies Inc. in the U.S. will develop a microneedle patch that stabilizes vaccines and can deliver multiple doses through the skin at defined times thereby reducing cost waste and the need for repeat immunizations. Vaccinations delivered intradermally via microneedles are at least as effective as intramuscular delivery via injection but reduce the requirement for needles and trained health workers. The patch uses a silk fibroin protein that protects the vaccine against high temperatures removing the need for cold storage and controls the timing of release through the skin. They will refine the material for delivering two doses of inactivated poliovirus vaccine evaluate its safety and activity in animal models and optimize the manufacturing process to ensure reduced costs.

William Witola of the University of Illinois in the U.S. will help develop new drugs for treating children infected with the protozoa Cryptosporidium by using a gene knockdown approach to evaluate candidate drug targets. Found in contaminated water, Cryptosporidium is the second most common cause of potentially lethal diarrhea in young children in developing countries. There are no safe and effective drugs available due largely to the lack of genetic tools for studying Cryptosporidium in the laboratory. Phosphorodiamidate morpholino oligomers (PPMOs) are small molecules that can be designed to bind and silence specific genes also in protozoa. If these genes encode for proteins critical for vital cellular functions, the PPMOs can cause death. To evaluate his approach, he will design PPMOs and test their ability to silence essential Cryptosporidium genes and thereby block chronic infection in mice.

Martin Matzuk, along with Nicholas Simmons of Baylor College of Medicine in the U.S. and Masahito Ikawa of Osaka University in Japan, will build a male contraceptive drug discovery platform comprising a library of two billion small compounds generated by DNA-Encoded Chemistry Technology (DEC-Tec) at relatively low cost, and a panel of male-specific fertility proteins. Contraception options for men are currently limited to condoms or vasectomy. A safe, low-cost small molecule contraceptive similar to the female "pill", could also help men to better control family planning. They are using the CRISPR/Cas9 mutagenesis strategy to identify new genes essential for male fertility in mice. For ten of these new genes, they will synthesize the corresponding fertility proteins and test them for binding to the compounds in their new, expanded DNA-tagged drug library.

Paul Crits-Christoph and Chelsea Morroni of the University of Pennsylvania in the U.S. will develop a mobile phone application that enables women to identify the method of contraception best suited to their needs to help reduce the number of unwanted pregnancies in Botswana, which is currently estimated at 44%. Although around 61% of women are reported to not want any more children, the most commonly used contraceptives are single use, such as condoms, despite the availability of longer-term measures like intrauterine devices. They will work together with individuals in Botswana to compile a list of 10-20 attributes valued by women in a contraceptive, such as duration of protection and ease of use, and program existing software to identify a woman's preferred choice using a simple series of questions. The application will then be used to test their hypothesis that the method of contraception most suited to an individual is different to that being prescribed by health workers in Botswana.

Xun Suo of China Agricultural University in China will develop a rabbit model of cryptosporidiosis that mimics the human disease, which presents as severe diarrhea particularly in young children, to help identify new treatments. Current animal models of infection by the parasite Cryptosporidium are suboptimal: mice are not naturally infected, while pigs and calves can be infected but are expensive and more difficult to manage, and none show the same symptoms as humans. Rabbits are naturally infected by Cryptosporidium and display human-related symptoms. They are also practical to handle and breed, and are relatively inexpensive. They will isolate infective oocysts from diseased rabbits in the wild, and establish the infection in the laboratory. They will also devise protocols to evaluate the disease such as scoring the severity of symptoms, and sequencing the parasite strains. The value of their model as a screening platform for identifying new drugs will also be tested.

Marion Sumari-de Boer and Kennedy Ngowi from Kilimanjaro Clinical Research Institute in the United Republic of Tanzania and Rosalijn Both from Segel Research and Training Consulting in Ethiopia will use mobile phones to learn about the contraceptive needs and behaviors of young unmarried men in Ethiopia and Tanzania in order to promote the use of contraception. This group is mostly overlooked in studies aiming to improve contraceptive and family planning practices, even though their behavior is directly relevant. They will recruit a diverse group of men aged between 18 and 29 years old and collect data by sending them weekly SMS messages containing specific questions. They will also conduct regular interviews and group discussions to identify contraceptive practices and needs.

Edward Thomsen of the Liverpool School of Tropical Medicine in the United Kingdom will build an open-source software platform tailored to support efforts to eliminate malaria by amalgamating desirable features from two existing disease data management platforms. The Disease Data Management System (DDMS) is an existing platform that integrates multiple datasets and supports operational decision-making through unique functionality such as automated outbreak alerts. In contrast, the District Health Information Software 2 (DHIS2) is a well-established platform that is the preferred solution for managing aggregated and individual case data. It has a large user-base and powerful analytics interface. They will develop software to modify DHIS2 with the desired features of DDMS and evaluate the performance of their integrated platform over one year in a malaria control program in Zambia.

Samuel Arnold of the University of Washington in the U.S. will develop methods to evaluate drug candidates for treating Cryptosporidium infections, which cause severe diarrhea particularly in young children from developing countries. There are no effective drugs against the Cryptosporidium parasite. This is partly because when it infects humans it becomes isolated in specific cells lining the gastrointestinal tract, which is where a drug would also need to be located at sufficient concentrations to be effective. However, the standard in vitro models are unable to easily and rapidly predict the efficacy of multiple drug candidates at this specific location. To address this, they will build a cell model of the intestinal wall that can also be infected with Cryptosporidium, and measure the permeability of a panel of protein kinase inhibitors that they have developed to kill the parasites. They will also use the software platform Gastroplus that can simulate the behavior of a drug once it has been administered and predict concentrations at multiple sites in the gastrointestinal tract. They will evaluate their method for predicting drug activity in vivo by testing the drugs in a neonatal mouse model of Cryptosporidium infection.

Thomas Churcher of Imperial College London in the United Kingdom will develop an analytical method to more accurately determine the origin of new cases of malaria in regions with low levels of the disease, which is critical for elimination efforts. Current methods are unreliable as there are no standardized criteria and they often rely solely on interviews. They will use routinely collected travel history data and disease maps to develop rigorous methods for estimating whether a case of malaria is either acquired locally or imported from another region. The accuracy of their method will be tested by comparing it with available data from Swaziland.

Olga Tosas Auguet of the University of Oxford and collaborators at the Modernising Medical Microbiology Consortium, Guy's and St Thomas' NHS Foundation Trust, Oxford Genomics Centre and London School of Hygiene and Tropical Medicine in the United Kingdom, and Oxford Tropical Network Overseas Programs in southeast Asia and Africa, will develop a new approach for the large-scale surveillance of bacterial antibiotic resistance in low-income settings. Current methods mainly involve the collection and analysis of individual clinical samples, which requires diagnostic equipment often unavailable in developing countries. They will pool together ~300 samples of rectal swabs and stools taken from biobanks, and analyze each pool by shotgun sequencing to identify the abundance of bacterial species and antibiotic resistance genes. They will use these data to calculate resistance potential and to determine how accurately this metric approximates the numbers of infections in a population that are resistant to a specific antibiotic.

Jan Mead of Emory University in the U.S. will develop a mouse model of cryptosporidiosis using human fecal transplants to mimic changes in the bacterial populations (microbiome) in the gut that occur in the human disease, which causes substantial morbidity and mortality in young children from developing countries. Drugs used to eradicate the intestinal parasite Cryptosporidium are thought to be affected by the levels and types of bacteria that populate the human gut, which is of particular importance in malnourished children who most often become infected. They will colonize germ-free mice with human fecal material and infect them with Cryptosporidium. The effect of the infection and of selected drugs on the microbiome will then be evaluated by DNA sequencing.

Brian Reich of North Carolina State University in the U.S. will develop a software model to measure the risk of local malaria outbreaks in real-time in the Democratic Republic of Congo and identify treatment strategies for control efforts to more effectively allocate their limited resources. They will build this "recommendation engine" using demographic health survey data from household surveys on disease incidence and types of treatment used, and devise a simple mathematical formula that calculates priority scores, defined by user-specified risk factors, for different regions, which can be easily interpreted by stakeholders.

Elmar Stroomer of Design without Borders Uganda Ltd. in Uganda will develop an interactive game combining methods from game-based learning to collect data on decisions made around family planning in Uganda. These data can then be used to develop strategies that encourage effective family planning for individuals and communities. They will recruit participants to co-create the game to simulate real-life situations using a human-centered design process. This includes interviews and role-playing sessions to identify the contexts in which family planning decisions are made to ultimately gain a deeper understanding of what influences them. The methods help motivate people to change their behaviour by involving them in the design process and enabling them to experience the consequences of certain choices. They will pilot their game-based learning concept on 5 to 8 groups and develop a manual to guide participants and assessors.

Alejandro Castellanos-Gonzalez of the University of Texas Medical Branch in the U.S. will use their gene silencing approach involving premade complexes of protein and small RNA to identify drug targets in the Cryptosporidium parasite, which causes severe diarrhea in young children in developing countries. Their gene silencing method involves synthesizing the so-called argonaute protein that is able to cut a single gene and attaching it to a single-strand antisense RNA that is designed to target a specific gene. This method can be easily scaled up for high-throughput drug target screens. They identified 100 candidate genes that are likely to be essential for the parasite to function and are not similar to genes found in humans, making them potentially suitable as targets for drugs. They will determine whether these genes can be fully silenced using their approach, and for 20 candidate targets evaluate the effect of silencing on parasite infection in cultured cells.