Breakthroughs Blog: Child health

This weekend, Kenya became the first country to roll out the world’s first and only pediatric tuberculosis (TB) medicines. TB infects one million children each year, resulting in 140,000 deaths, and yet, children have historically been treated with crushed up pills in estimated doses. The new formulations, which were developed by TB Alliance, are not only appropriately dosed for kids, but they are fruit-flavored and dissolvable—making them much more kid-friendly than a handful of bitter pills that must be swallowed. Kids must remain on treatment for six months, and the improved dose, flavor, and delivery are expected to have a significant impact on adherence to the regimen, preventing the development of drug-resistant strains. An additional 17 countries have placed orders and plan to introduce the medicines in the coming months. Vaccines and drugs could soon be manufactured on-the-go with the use of a portable, handheld kit developed by researchers at Harvard University. The kit contains all the ingredients needed to produce biologics (medical products derived from biological, rather than chemical sources): both the DNA that triggers the production of proteins to fight disease and the proteins that synthesize the final product. The DNA and proteins are freeze-dried into pellets, making them easy to store and transport, and with just the addition of water, the vaccine or therapy is ready to use. The team put the kit to work, successfully producing four different biologics, however, the vaccine candidate had to be purified before use. More research and testing is needed, and it could be more than a decade before such a system would be safe and appropriate for use in low-resource settings. Diarrheal diseases are a leading cause of death among children under five, and a new study suggests that 89 percent of cases are caused by pathogens. Further, 78 percent of cases are caused by just six pathogens, including rotavirus, Shigella, enterotoxigenic Escherichia coli (ETEC), Cryptosporidium, Campylobacter, and adenovirus. The researchers analyzed stool samples from more than 10,000 children under five, half of whom had diarrhea, to determine the leading causes of childhood diarrhea. Of the six, there is currently only a vaccine against rotavirus, however, GHTC member PATH is currently developing vaccines against Shigella and ETEC. Scientists are exploring whether the powerful antimicrobials created by certain species of ants could be used to fight infection in humans. Over the past 15 million years, more than 200 ant species have evolved to farm fungi—a symbiotic relationship in which the ants collect plants, feed them to fungi, and in turn, the ants feed off of the fungi. However, some ant species are vulnerable to hostile fungi that attack the ants’ nests and farmed fungi and have consequently adapted to fight off pathogens. These species cultivate bacteria—which appear as white patches along the ants’ bodies—that produce antibacterial and antifungal compounds. So far, the results have been encouraging: 1 in every 15 of these antimicrobial agents have proved promising in the lab, compared to just one in a million of those discovered through soil sampling.

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. In this edition, we cover new insights into the impact of the Zika virus on the brain. Researchers have released medical images of 46 fetuses and infants born to women who were infected with the Zika virus during pregnancy, revealing serious brain damage beyond microcephaly. The images, which include 23 MRI scans, 41 CT scans, and 93 ultrasounds, were taken at Instituto de Pesquisa in Campina Grande State Paraiba in northeastern Brazil and analyzed by neurologists at the Instituto in partnership with a team at the Beth Israel Deaconess Medical Center in Boston. The brain damage manifests in distinct ways: many of the scans showed skulls filled with cerebrospinal fluid, and in one case there was so little brain tissue that the skull collapsed in on itself, resulting in a flattened skull with extra skin. The images indicated damage to the brain stem, which regulates breathing and heart rate; the cerebellum, which is responsible for motor control; and the cortex, which is involved for learning, memory, emotion, and language. New research suggests that Hofbauer cells, found in the placenta and tasked with protecting the fetus from pathogens, may be the key to the Zika virus' ability to cross the maternal-fetal barrier. Hofbauer cells are macrophages, immune cells that combat pathogens by consuming them. However, dengue virus—a flavivirus related to Zika—is able to hijack macrophages, using them to replicate and disseminate throughout the body. While the researchers have confirmed that the Zika virus is able to survive within Hofbauer cells, they suspect that the immune cells may also be enabling the virus to travel to the fetal brain. The study also confirms that the virus can replicate within fibroblasts, a critical component of the placenta’s structure, a finding described as, “a bit of a surprise,” by one of the study’s authors. Scientists at Rockefeller University have also described their recent findings as "kind of a surprise," in this case, that certain adult brain cells are also susceptible to the virus. Fetal brains are primarily comprised of neural progenitor cells; while these stems cells are not as ubiquitous in adults, they play a critical role in learning and memory. Earlier this year, researchers determined that fetal neural progenitor cells are particularly vulnerable to Zika. Now, the team at Rockefeller has confirmed that adult neural progenitor cells are no exception. The study revealed an increase in cell death but a decrease in the production of new brain cells in infected adult mice. More research is needed to determine how this translates to humans, however, such damage could increase risk for cognitive challenges, depression, and Alzheimer’s disease.

A typical pitch for venture capital investment highlights three topics: the problem a technology solves, the size of the market, and the profit potential of the product. But at the pitches I witnessed from innovators last Thursday at the Saving Lives at Birth DevelopmentXChange, this formula was turned on its head. While the discussion focused on problem solving, the questions being asked were not how large the market, but how great the need, and not how much money can be made, but how many lives could be saved.The DevelopmentXChange marked the final stage of competition in the 6th annual Saving Lives at Birth Grand Challenge, a prize program sponsored by the US Agency of International Development, the government of Norway, the Bill & Melinda Gates Foundation, Grand Challenges Canada, the UK Department of International Development, and the Korea International Cooperation Agency to identify and advance transformative, cost-effective solutions to improve maternal and newborn health. The program operates much like a venture capital firm. Innovators apply and pitch their ideas, and the program determines whether to issue them grants to develop, test, and bring their ideas to scale.This year the program received more than 650 applications from 78 countries, with 49 teams chosen as finalists to compete at this year’s DevelopmentXChange and showcase their innovations. At the conclusion of the event, Saving Lives at Birth announced the selection of 12 winning teams in the validation and seed grant categories, who will receive more than $3.4 million in funding to move their projects forward. Award winners in the transition-to-scale category will be announced later this year.  GHTC members featured among finalistsAmong the 48 finalists were five promising innovations from GHTC member organizations, profiled below: Finalization and validation of a postpartum screening tool focused on identifying risk factors for maternal infection as part of routine, predischarge service delivery Jhpiego Despite widespread availability of treatment, postpartum infections account for 11 percent of maternal deaths worldwide. A number of risk factors are strongly associated with postpartum infection, and symptoms usually manifest within 48 hours after birth. In Uganda, women are increasingly giving birth in hospitals; however, they are often discharged early due to overcrowding.To address this challenge, Jhpiego has developed a simple screening tool to assess a woman’s risk of postpartum infection. The tool is a checklist of the key risk factors, composed of eight yes or no questions. The assessment is easy to use, and the results are even easier to interpret. If the tool proves to be predictive of postpartum infection, it could be used by health workers, including nurses and midwives, to make evidence-based decisions on whether a new mother can be safely discharged or whether she should remain in the hospital for an additional 48 hours. At Saving Lives at Birth, Jhpiego was seeking funding to finalize and validate the tool—to determine its predictive value—by rolling it out in two regional referral hospitals in Uganda. If successful, Jhpiego plans to partner with the ministry of health to expand its use across public- and private-sector hospitals.Field validation of a new protein-to-creatinine (PrCr) strip test: An impactful new tool to improve diagnosis of preeclampsia at the front lines of antenatal care in low-resource settingsPATH At least 16 percent of maternal mortality worldwide is attributable to preeclampsia, a dangerous condition that can cause organ failure, seizures, and maternal and newborn death. Screening for preeclampsia—which is characterized by high blood pressure and protein in urine (proteinuria)—ideally occurs as part of the care a woman receives during pregnancy. Throughout the day, the concentration of urine often fluctuates, and so, too, does the concentration of protein in the urine. Consequently, the gold standard for diagnosing proteinuria involves collecting and analyzing urine samples over 24 hours. However, this approach is unrealistic in many low-resource settings, and current diagnosis involves a protein-only dipstick test that catches just 51 to 68 percent of cases.PATH has developed a simple, low-cost protein-to-creatinine strip test to improve the accuracy of preeclampsia screening in low-resource settings and was seeking funding through the Saving Lives at Birth program to evaluate the feasibility and efficacy of the diagnostic test in Ghana. The test is nearly identical to the commonly used protein-only test. However, where the existing tool only tests for protein concentration, the new device also tests for creatinine concentration. By comparing the concentration of both protein and creatinine, a health worker can control for how diluted or concentrated the urine is at the time. PATH has confirmed that the diagnostic strip remains effective when stored for at least four months at 37 to 45°C, and the tool costs just pennies on the dollar. Due to its similarity to the existing protein-only test, rollout of the test should be straightforward, requiring very little additional training.Developing a Rapid Integrated Sepsis Risk Calculator (RISC) to detect and manage severe sepsis in newbornsPATH PATH's Rapid Integrated Sepsis Risk Calculator. Photo: Matthew Robinson/GHTCSepsis kills an estimated 421,000 infants in the first 28 days of life in low- and middle-income countries every year. To address this glaring need, the World Health Organization (WHO) recently published guidelines for diagnosis and treatment of possible serious bacterial infection (PSBI), which will require primary-level health care providers to be versed in sepsis detection and management. Many providers do not currently have the necessary training or tools.The RISC is a smartphone or tablet-based app and off-the-shelf device measuring oxygen saturation levels in the blood that enables even primary-level providers to identify sick infants and either provide the correct treatment or refer them to higher-level care. The app incorporates algorithms that walk the provider step by step through the diagnostic process, increasing provider confidence and greatly improving the accuracy of diagnoses. Because the app will be built using Open Data Kit (ODK) free open-source software and off-the-shelf hardware, it will be highly cost-effective and adaptable. The app also works offline, which is critical in remote primary care facilities. The team was seeking a Saving Lives at Birth seed award to complete the development of the ODK app and conduct a pilot evaluation of RISC’s usability, feasibility, and acceptability in Ghana.Development and evaluation of the RELI Delivery System—an innovative, simplified, low-cost infusion pump for obstetric and newborn emergenciesPATH With a few pumps of a handle, a health worker can power an intravenous fluid infusion pump for an entire work shift, all without the use of electricity or batteries. That’s the idea behind PATH’s RELI Delivery System—an innovative, low-cost infusion pump for obstetric and newborn care. Controlled intravenous delivery of medicines like antibiotics or anesthesia is the gold standard of care for many diseases and conditions, but it’s often not feasible in low-resource settings. Existing infusion pumps cost thousands of dollars to purchase and maintain, require substantial training to operate, and require electricity or batteries. PATH designed the RELI System to overcome many of these barriers to access in low-resource settings. The device, which requires no electricity or batteries, is powered pneumatically, through air pressure. It requires about two minutes of pumping to generate the power needed to operate the device for an entire 12-hour shift. The system also has a simple-to-use interface and can be manufactured inexpensively, with an expected retail price at less than $100 a machine. With the seed grant it won through the program, PATH plans to take the device to the field to solicit user feedback and then refine the design for further field testing.  Outpatient treatment of neonatal sepsis by rectal administration of gentamicinPATH Neonatal sepsis is a leading cause of infant death worldwide. WHO recommends treatment of the condition with intramuscular injection of the commonly used antibiotic gentamicin. But in many low-resource settings, this is easier said than done. Neonatal dosing is extremely sensitive—just a fraction of a difference in dose size can affect effectiveness and safety—so administration requires a highly trained health worker. Additionally, many health providers may not have access to safe injection devices or may be inclined to reuse needles, promoting the spread of the disease.Unfortunately, gentamicin is not effective when delivered orally, so PATH is exploring the feasibility of an alternative method of gentamicin delivery—rectal delivery. As a needle-free method of administration, rectal delivery could improve access to gentamicin by making it safer for the product to be administered by lower-level health workers, increasing dose accuracy, and removing the risks associated with injections. Existing scientific literature suggests rectal delivery could be a biologically viable option for gentamicin. PATH was seeking a grant to conduct further lab studies to assess how different additives or formulations can improve uptake of gentamicin in colon cells and conduct stakeholder interviews to assess feasibility of the concept.The innovation effectGHTC congratulates both our members and the other teams who were selected as finalists and award winners.This year’s prize winners will join the growing community of over 93 innovators supported by the Saving Lives at Birth program. Many of these innovations are beginning to have an impact as they are brought to scale. To date, the program has supported 1.5 million women and newborns and saved nearly 10,000 lives.The Saving Lives at Birth program has made it clear that by putting innovation at the center of global health, we can accelerate the pace of change and transform lives, faster.Kat Kelley, senior program assistant, and Matthew Robinson, MA, policy officer, contributed to this article.

Researchers at the University of Pennsylvania have designed a placenta-on-a-chip: a small device that mimics the placental barrier, enabling scientists to study the transport of molecules from mother to fetus. The silicone device contains a permeable membrane surrounded by endothelial and trophoblast cells, which are found in fetal blood vessels and where the placenta meets the maternal blood supply, respectively. The model imitates the development of the placenta throughout pregnancy, as trophoblast cells merge and as the barrier becomes thinner. Previously, donated placental tissue has been used in research, however samples are scarce and only viable for a few hours after delivery. The team completed an initial, successful test of the device by comparing the transfer of glucose across the placental barrier in both donated tissue and the placenta-on-a-chip. As testing continues, plans are underway to use the device in studies on preterm birth. The secret to fighting methicillin-resistant Staphylococcus aureus (MRSA) could be an antibiotic produced by the microbes inhabiting the human nose. MRSA is a dangerous bacterium, resistant to several leading antibiotics, that causes staph infections, sepsis, and pneumonia, resulting in 20,000 deaths annually. Researchers at the University of Tübingen in Germany cultured the bacteria in snot samples from 37 healthy individuals, hoping to understand why vulnerability to staph infections varies from person to person. Next, they placed S. aureus alongside the different bacteria, and identified another species of staph— Staphylococcus lugdunensis—that successfully combatted S. aureus. The team then collected snot samples from 187 hospital patients, and with just one exception, found either S. aureus or S. lugdunensis in every sample, suggesting that the two cannot flourish in unison. The key compound—lugdunin—successfully treated staph infections in mice and, after leaving the two bacteria in petri dishes for a month, S. aureus was unable to develop resistance to S. lugdunensis. An ongoing outbreak of yellow fever in Angola and the Democratic Republic of the Congo has resulted in more than 5,000 cases and nearly 450 deaths. The existing vaccine against the virus is extremely effective, but is not recommended for pregnant women and those over 60 years of age. The vaccine takes a year to produce and the limited global stockpile has already been depleted twice this year. Last week, the US National Institutes of Health initiated a phase 1 clinical trial to test the safety and tolerability of an experimental yellow fever vaccine. The vaccine candidate, developed by Danish company Bavarian Nordic, uses a weakened version of the Modified Vaccinia Ankara virus as a vector to transport genes from the yellow fever virus. This delivery platform has been used in vaccinating more than 7,600 individuals, 1,000 of them immunocompromised. The trial will enroll 90 healthy volunteers, 15 of whom will receive the existing, approved yellow fever vaccine, and 75 of whom will receive one or two doses of the experimental vaccine or a placebo, with or without a booster.