Kat Kelley

Virginia Commonwealth University (VCU) received a grant from the Global Alliance to Prevent Prematurity and Stillbirth, a member of the GHTC, to study the human microbiome in search of biomarkers to predict preterm birth. The human microbiome is comprised of all the microorganisms (i.e., bacteria) normally found in the human body and the genetic material of those microorganisms. The team at VCU will study the microbiome of women throughout pregnancy, assessing the impact of changes in the microbiome on pregnancy outcomes. Existing research has demonstrated a correlation between an imbalance in the vaginal microbiome of pregnant women and preterm birth, specifically for African Americans. A recent study out of The Rockefeller University in New York could pave the way for a new treatment against human African trypanosomiasis (sleeping sickness), a disease caused by the Trypanosoma brucei parasite and transmitted by the tsetse fly. Once in the human bloodstream, the parasite evolves, and constantly changes the proteins on its surface so that the immune system can’t recognize it. The team at The Rockefeller University determined that by blocking bromodomains—a particular type of protein—through either genetic modification of the parasite or the use of a molecule known as I-BET151, they could trick the parasite into thinking it was still in the tsetse fly. Thus, the parasite would revert to the form it takes within the fly, making it much easier for the immune system to detect and attack it. The method was tested in sleeping sickness–infected mice, and those treated with I-BET151 survived much longer than their counterparts. Child receiving a vaccine. Photo: PATH/Robin Biellik The world’s first vaccine against dengue fever—a mosquito-borne disease that causes fever, headache, and, muscle and joint pain—has been approved for use in people aged 9 to 45 by the national regulatory authority of Mexico. Nearly half the world’s population lives in dengue-endemic countries, and an estimated 390 million infections occur each year. The vaccine, which cost US$1.65 billion to develop over 20 years, is projected to generate $1.4 billion in sales by 2020. Sanofi, the pharmaceutical company that developed “Dengvaxia,” is currently pursuing regulatory approval in 19 other countries and has stated that the vaccine will be sold at a “fair, affordable, equitable, and sustainable price.”

Photo credit: TB Alliance GHTC member TB Alliance announced last week the creation of the first-ever child-friendly tuberculosis (TB) medicines, which are currently undergoing regulatory review by the World Health Organization and should be available in early 2016. While TB is curable, a patient must take multiple drugs a day for six months, and existing medicines are not available in appropriate doses for children. Consequently, parents must crush or cut the pills. This arduous process—combined with the bitter taste—makes the six-month regimen difficult to follow. The new treatment is comprised of strawberry- and raspberry-flavored, child-friendly doses of the three most commonly used TB medicines. The new regimen is expected to significantly enhance adherence to treatment for the 1 million children diagnosed with TB each year. Researchers at Texas A&M University have developed a device that, when attached to a smartphone, can diagnose malaria in minutes. Using a polarized light and the phone’s camera, the device serves as a microscope. The photos taken by the device are then analyzed by a software app that diagnoses infection by counting both red blood cells and Hemozoin crystals, which are produced by the malaria parasite. The device, which is expected to cost less than US$50 and be used with cartridges costing $1 each, will be tested in Rwanda next summer. A preclinical study conducted by GHTC member Population Council in partnership with CONRAD suggests that candidate microbicide gel MZC could be even more effective against HIV than tenofovir gel, a leading microbicide candidate. Containing a potent antiretroviral, a zinc-based salt, and the compound carrageenan, the gel is intended to protect against HIV, human papillomavirus (HPV), and herpes simplex virus 2 (HSV-2). The study demonstrated that MZC was more potent than tenofovir against both HIV and HSV-2. While the study did not test the gel’s efficacy against HPV, existing research suggests that carrageenan is one of the most potent compounds against HPV. Next, MZC will be tested in delivery systems, including vaginal rings and rectal gels, as well as in combination with a hormonal contraceptive. In other microbicide news, GHTC Member the International Partnership for Microbicides (IPM) has entered an agreement with pharmaceutical company Janssen Sciences that provides IPM the rights to develop a microbicide using the antiretroviral darunavir, which is currently available in pill form and marketed as PREZISTA®. IPM is also conducting a phase III clinical trial of a vaginal ring using antiretroviral dapirivine, licensed to the organization through a partnership with Janssen initiated in 2004.

Pyramax® Granules (Photo: MMV) After four successful Phase 3 clinical trials enrolling more than 3,500 patients in 18 countries, the European Medicines Agency (EMA) has granted Pyramax® Granules, a pediatric malaria medicine, a positive opinion under Article 58—a mechanism through which the EMA reviews and issues a scientific opinion on products that are not intended for use in Europe. Pyramax® Granules is a combination of two antimalarials and was developed by Medicines for Malaria Venture (MMV), a member of the GHTC, in partnership with Shin Poong Pharmaceutical Co. Ltd. The treatment is designed to be easy for children to consume: its bitter taste is masked and it is taken in liquid form, as children often struggle to swallow pills. Next, MMV and Shin Poong will work to introduce Pyramax® Granules as well as Pyramax®, the tablet version which is suitable for adults, in malaria-endemic countries. A recent article in NPR: Goats & Soda examines Zika virus, a disease transmitted by the same mosquito vector of dengue fever and chikungunya, that has been rapidly spreading throughout South America and the Pacific Islands in recent years. One in five individuals infected with the virus experience Zika fever, which in addition to fever involves rashes, joint pain, conjunctivitis, headaches, vomiting, and muscle pain. Cases of Zika fever are likely underdiagnosed, as awareness of the disease is limited and its symptoms are similar to infections associated with other members of the Flaviviridae virus family, including dengue fever, yellow fever, West Nile, and Japanese encephalitis. There are no reported deaths to date, but there is growing evidence that the virus can be transmitted sexually or from mother to infant during pregnancy. As there are no vaccines or drugs for Zika fever, treatment involves addressing the symptoms, using fever reducers and painkillers. A group of global health advocacy organizations—including GHTC members the Drugs for Neglected Diseases initiative, TB Alliance, Infectious Diseases Society of America Center for Global Health Policy, Sabin Vaccine Institute, and Treatment Action Group—sent an open letter to the US Senate Health, Education, Labor and Pensions (HELP) committee, calling for amendments to the priority review voucher (PRV) program at the US Food and Drug Administration (FDA) to ensure it adequately incentivizes research and development (R&D) for neglected diseases, as intended. Under the program, companies that receive FDA approval for a drug for a neglected disease (see list of eligible diseases) are awarded a voucher for expedited FDA review (six months rather than ten) of a future product. The vouchers are transferable and have been sold at increasing rates, the most recent going for US$350 million. The letter calls for PRVs to only be awarded for products that are "truly new" as two of the six vouchers that have been awarded were for products that had long been in use outside of the United States.[1] The organizations are also calling for recipients of the voucher to be required to develop a strategy to ensure the product is made affordable and accessible to patients in the countries in which the eligible disease is endemic. The United Kingdom (UK) announced last week the creation of the Ross Fund which will provide £1 billion ($1.5 billion) over five years to fight malaria and other infectious diseases. The funding, which will come from the UK overseas aid budget, includes £90 million for malaria eradication; £100 million for infectious disease R&D; £115 million for the development of drugs, diagnostic, and insecticides for malaria, tuberculosis, and other infectious disease resistance; and £188 million for biodefense and rapid response systems for epidemic preparedness. Global Good has developed a cooler that can store and transport vaccines at freezing temperatures for over a month using just ice and no electricity. The Arktek cooler uses vacuum thermal insulation, an approach used to preserve spacecraft entering extreme temperatures. The cooler has been tested in Senegal (with support from GHTC member PATH) and Ethiopia, and last year, the Arktek was modified for use in Ebola vaccine clinical trials, during which the cooler kept the vaccines between -76 and -112 degrees Fahrenheit for three days. [1] There are two separate PRV programs at the FDA, one for neglected tropical diseases and one for rare pediatric diseases. Of the six PRVs that have been awarded, three each have been for neglected tropical diseases and rare pediatric diseases. Since the beginning of the PRV program, six PRVs have been awarded—three for neglected tropical diseases and three for rare pediatric diseases.  

Snakebites, which Médecins Sans Frontières describes as “one of the world's most neglected public health emergencies,” kill 200,000 people each year. This makes snakes the second deadliest animal after mosquitoes. However, not only has research and development for snakebite antivenoms received little investment, but production of existing treatments is also declining due to their low profitability for pharmaceutical companies. Antivenoms are traditionally developed using antibodies produced by animals that have been bitten by snakes, but a number of small biotech companies and even individuals are testing innovative ways to create new, multipurpose antivenoms. Dr. Claire Komives, a professor of Chemical Engineering at San Jose State University, is working to enlist the E. coli bacteria to produce a promising antivenom, as the use of bacteria could make production significantly cheaper and easier to scale up. Meanwhile, a team of researchers across Europe and Central America are developing a treatment for a myriad of common venoms, starting with an antivenom that is effective against three different venoms. Their plan is to identify deadly venoms against which their product is not effective and then develop and incorporate a treatment for that venom into their product. Finally, a team at the California Academy of Sciences is screening chemical compounds in existing, approved drugs to develop a product that could stabilize a bitten patient, giving them more time to seek treatment. The World Health Organization estimates that one-third of the world’s population has latent tuberculosis (TB), only 10 percent of whom will actually contract the disease. However, co-infection with a helminth, a parasitic worm, increases one’s chance of developing TB and exacerbates the symptoms, particularly lung damage. Scientists have long suspected that the parasitic infection impeded the immune system’s ability to fight TB, inhibiting immune cells that provide protection against TB. However, new research out of Washington University in St. Louis suggests that a specific molecule produced by helminths’ eggs prompts an inflammatory immune response that increases one’s susceptibility to TB and its symptoms. The team was able to engineer immune cells that do not produce the molecule, and mice co-infected with TB and the parasite who were given the engineered immune cells did not have the damaging, inflammatory immune response. Analyses of blood samples from TB patients also demonstrated a correlation between the presence of the molecule and the severity of TB symptoms. Photo: PATH/Wendy Stone Researchers at The Scripps Research Institute (TSRI) are developing an HIV and AIDS vaccine candidate that targets a region found on 90 percent of known strains of the HIV virus. The team at TSRI has been conducting experiments to prompt the immune system to generate broadly neutralizing antibodies—proteins which fight multiple strains of the HIV virus—and discovered that four of these antibodies all targeted the same part of the virus, the V2 apex. Further, two of the antibodies have an unusual advantage. While most antibodies mutate from their original form to become more effective at fighting a virus, two of the antibodies were able to bind to the V2 apex in their initial form, consequently speeding up the immune response. However, the body doesn’t naturally make a large number of these antibodies, instead focusing on the further developed antibodies. To address this, the team at TSRI engineered a version of an HIV protein to which those basic antibodies bind with the anticipation that it will lead to their increased production. The engineered protein is being used in a vaccine candidate that will next be tested in animal studies.

Photo: PATH/Gabe Bienczycki Preterm birth complications are the leading cause of death for children under five years of age. Survival rates, particularly for babies born extremely premature (three months early), can vary drastically from 10 percent in low-resource settings to 90 percent in high-resource settings. While many babies are born in low-resource settings, outside of hospitals, and without access to high-tech interventions, it is still possible to provide the basic care many preemies need to survive. For example, a number of low-cost innovations and interventions, such as breathing support and clean cord care, have the potential to slash newborn mortality. GHTC member, The Global Alliance to Prevent Prematurity and Stillbirth (GAPPS), in partnership with Project Concern International and the American College of Nurse Midwives, has received a five-year, US$9 million grant from the US Agency for International Development for the Every Preemie—SCALE initiative to identify lifesaving interventions for the prevention and treatment of preterm birth and low birthweight and to support the scale-up of these interventions in 23 countries across Asia and Africa. To learn more about GAPPS’ work on the Every Preemie—SCALE initiative, we’re joined by Dr. Jim Litch, director of the Perinatal Interventions Program at GAPPS. Q: Central to the Every Preemie—SCALE initiative is research to identify evidence-based solutions for the treatment and management of preterm birth and low birthweight. What’s been done so far and what key findings are emerging? A: Ideally, pregnant women should have access to prenatal care, which is particularly important for women at risk of preterm birth who need particular prevention services and care interventions. Far too often, however, prenatal care is out of reach for families, of poor quality, or does not include the special needs for preterm births and preterm newborn care. Preterm birth has only recently received attention from the global health community, and there are many emerging opportunities to learn from current efforts to expand maternal and newborn health programs to include preterm birth prevention and care content. Preterm babies have different needs than full-term babies, and recognizing this helps us develop tools and interventions across the continuum of care. Just this month, accurate growth curves for weight, length, and head circumference for healthy preterm babies born as a single birth were published to complement existing growth standards for full-term infants and provide new, accurate standards for fetal growth. Through Every Preemie, GAPPS is supporting implementation research with local partners in Bangladesh, Ethiopia, India, and Malawi. In Bangladesh, we are testing a simple method of estimating gestational age during pregnancy using a tape measure and weight scale. In Ethiopia, we are evaluating implementation of preterm birth services within multi-partner maternal and newborn health programs across the continuum from the community to district hospital level in different living contexts (settled, semi-settled and urban). In India we are preparing to assess the safe use of antenatal corticosteroids (ACS)—which have been shown to reduce preterm birth complications—among women in imminent preterm labor, including pre-referral first dose of ACS administered by auxiliary nurse midwives. And in Malawi we are investigating the effectiveness of a comprehensive community mobilization approach designed to better link communities to preterm-related health services from the household to the facility level. A recurring finding from the implementation and research communities is that context is critical. What works well in one setting may not work well in another. This is a lesson that returns to us time and again. Standardized outcomes and robust descriptions of the settings from which evidence is obtained create a greater burden on research, evaluation, and program resources. Q: Can you talk a bit about some of the technologies identified as potential solutions under Every Preemie? And what characteristics make a product or intervention realistically scalable in low-resource settings? A: Infant death and morbidity following preterm birth can be reduced through interventions provided to the mother before and during pregnancy, including the period around delivery, and to the preterm infant after birth. The most beneficial set of maternal interventions are those that could improve survival chances and health outcomes of preterm infants when preterm birth is inevitable. In August 2015, the first World Health Organization recommendations on the Interventions to Improve Preterm Birth Outcomes were issued. These recommendations provide important guidance on interventions and related technologies that could be provided during pregnancy, labor, and the newborn period with the aim of improving outcomes for preterm infants. Understanding the demand for services is of critical importance when working to realistically reach scale in low-resource settings. This includes a need to better understand the knowledge, attitudes, and perceptions of families around preterm birth and preterm newborns in individual communities and settings, as well as the demand created by care providers within existing maternal, newborn, and reproductive health service delivery systems. Now more than ever, improvement in preterm outcomes requires a truly integrated approach. Q: What role will advocacy—whether at the global, national, and local level—play in advancing the innovations and interventions identified through Every Preemie? A: Advocacy is fundamental at all levels for real, lasting change. Moving a community to success can be accelerated by advocacy. When professional organizations, parent groups, economists, and others all demonstrate the effects of quality prenatal and newborn care, governments will institute policies to provide not just for the wealthy but also for the most vulnerable. The best interventions, products, and services can have impact on preterm survival only when the required attention and ongoing needs are continuously met for these highly vulnerable developing fetuses and preterm newborns. Ultimately a chain of basic newborn care, combined with special basic care for preterm newborns (thermal care, adequate feeding, hygiene, and counseling) is essential for more sophisticated clinical interventions and products to be successful in saving lives and limiting morbidity. Doing basic care well, for all pregnant women and newborns, will go a long way in supporting preterm survival and the effectiveness of clinical interventions directed at preterm complications. The numbers support this approach. Infants born before 34 weeks gestation, for which more advanced clinical interventions target, comprise roughly 3 percent of all births and about 30 percent of all preterm births. Also, the majority of newborns who die as a result of intrapartum complications, birth asphyxia, and severe newborn infection (also among the leading causes on newborn mortality) are preterm. Success depends on the right care, in the right place, at the right time—every time.

Photo: PATH/Eric Becker A new study suggests that the use of anti-parasitic drugs and insecticides in cattle can reduce human cases of Trypanosomiasis (sleeping sickness) by as much as 90 percent. Sleeping sickness is caused by parasites and transmitted by tsetse flies, and while cattle are not susceptible to human sleeping sickness, they do carry the parasite. The study, conducted in rural Uganda, involved injecting 500,000 cattle with two anti-parasitic drugs and spraying their legs, which the tsetse flies bite, with an insecticide. The team estimates that the program saved US$15 to $60 million in health care costs and increased Uganda’s gross national product by $400 million. Researchers at the Washington University School of Medicine in St. Louis have identified antibodies—immune system proteins—that could protect against or treat multiple alphaviruses, including Chikungunya. The antibodies are known as “broadly neutralizing antibodies,” a term which normally refers to antibodies that target different strains of the same virus (i.e., HIV, Hepatitis C) rather than different viruses altogether. The team, led by Dr. Michael Diamond, director of the Division of Infectious Diseases and Vaccine Development at Washington University School of Medicine, evaluated 60 human and mouse antibodies for Chikungunya and identified 10 that are active against three or more alphaviruses. The two most potent antibodies were then used as a treatment for mice infected with Chikungunya as well as two other alphaviruses—O’nyong’nyong and Mayaro virus—and the team confirmed that the antibodies reduced the symptoms of the infections. The team is using their findings to develop more antibodies which will then be tested on animals. New research conducted by professors Drs. Bruce Freedman and Ron Harty of the University of Pennsylvania School of Veterinary Medicine could pave the way for treatments against Ebola, among other viruses. Viruses utilize their hosts’ cells to mature, reproduce, and spread and Freedman and Harty have developed a mutated gene that blocks the pathways that many viruses use to communicate. By blocking those pathways, the virus remains trapped, unable to leave the cell and infect other cells. The team will next test their approach in mice with the ultimate goal of developing an anti-viral medicine effective against any virus that uses those same pathways to communicate.