Breakthroughs Blog: DoD

Earlier this year, the World Health Organization (WHO) declared the outbreak of Zika in Latin America a Public Health Emergency of International Concern. The virus, spread by the Aedes aegypti mosquito, was once considered innocuous, causing a mild illness and lasting for only a handful of days. However, the virus has since been linked to devastating birth defects and neurological complications and has spread to more than 60 countries. The virus’s virulence took the research community by storm: although it was discovered in 1947, only 25 scientific papers were published on the topic prior to the current outbreak. As the scientific community learns more about the virus and the disease, the need for tools to prevent, detect, and treat it has become undeniable. On February 22, US President Barack Obama submitted a request to Congress for US$1.9 billion in emergency funding to combat the virus, a critical move, as the US government is unrivaled as the largest funder of global health research and development (R&D). However, 146 days later, Congress has yet to reach a deal, and the US agencies leading the fight against Zika are running out of money. In the meantime, these agencies have made impressive strides in advancing Zika R&D using limited funding and leveraging cross-sector partnerships. An unprecedented number of private-sector partners have also entered the hunt for Zika countermeasures, building out a robust pipeline in record time. Below, we highlight the most promising vaccine, drug, and diagnostic candidates as well as vector control approaches. Vaccines There are currently more than 35 Zika vaccine projects underway, and at least 3 have completed successful animal trials. Inovio Pharmaceuticals and GeneOne Life Sciences partnered to develop a DNA-based vaccine, using a unique delivery approach—electroporation—in which a device is applied to the injection site, sending out electrical pulses that enhance the vaccine’s ability to enter human cells. The vaccine successfully prompted an immune response, including the production of protective antibodies, in both mice and monkeys. In late June, the experimental vaccine became the first to be approved for human clinical trials by the US Food and Drug Administration (FDA). The phase 1 trial, which will enroll 40 healthy adults, is intended to evaluate the safety and tolerability; however, the team will also monitor its ability to induce an immune response. Meanwhile, two more vaccine candidates have proven effective in mice. The candidates include a DNA-based vaccine and one composed of an inactivated version of the Zika virus, the first supported by the US National Institutes of Health (NIH) and the second developed by the US Walter Reed Army Institute of Research. The latter will be tested in phase 1 clinical trials by the US National Institute of Allergy and Infectious Diseases and then transferred to French pharmaceutical company Sanofi for further clinical development. Sanofi is also working on a vaccine of its own; however, it won’t enter clinical trials until 2017. After several months of feasibility studies, British pharmaceutical company GlaxoSmithKline has announced that it will be partnering with the NIH to test its RNA-based vaccine in animals. To date, no DNA or RNA vaccines have been approved for use in humans, although they are often called the future of vaccines. Drugs Due to the dearth of knowledge about the virus and the difficulty of conducting clinical trials and using novel drugs in pregnant women—a key target population for Zika control—the WHO has stated, “It is unlikely at this stage that therapeutics will constitute a priority activity.” However, efforts are underway, both to discover novel treatments and to repurpose existing medicines. Australian biotech company Biotron announced recently that two compounds in their library have proven effective against Zika in test tubes. They will continue to conduct laboratory tests to better assess the safety and efficacy of the compounds in humans. Researchers at the US National Center for Advancing Translational Sciences are screening their compound library—with half a million entities— and have identified a novel drug, which is safe for use in humans and currently in clinical trials for cancer, that prevented the virus from killing progenitor cells, which play a critical role in the neurological system and fetal development. Researchers at the University of California, San Diego are embarking on an ambitious study to virtually screen more than 20 million compounds against the virus. The program—OpenZika—uses a research collaboration platform to harness the power of volunteers’ computers and smartphones. Participants download the software, and when their computer or phone is inactive, it runs calculations to predict how a compound will interact with the virus in the lab. Researchers are also looking at repurposing existing drugs as Zika treatments. Chloroquine—which both prevents and treats malaria—has successfully protected against Zika virus in vitro. A team at Katholieke Universiteit Leuven has identified an experimental treatment for hepatitis C that delayed the manifestation of Zika-related symptoms in mice. And scientists at the University of California, San Francisco reported that the antibiotic azithromycin—which has long been used in pregnant women—blocked the virus from multiplying in petri dishes. Diagnostics As of March, more than 30 diagnostics for the virus were under development, and the FDA has sanctioned the use of five tests—four that detect current infection and one to assess previous exposure—under its Emergency Use Authorization program. However, rapid, point-of-care diagnostics are desperately needed. Eighty percent of cases are asymptomatic, and initial symptoms—fever, rash, joint pain—are nonspecific. Thus, early and accurate diagnosis is critical to ensure appropriate treatment. A team of Harvard University and Massachusetts Institute of Technology researchers have designed a paper-based test that can diagnose cases within a few hours. The device is appropriate for low-resource settings: it’s cheap, it can be stored or shipped at room temperature, and the results are easy to interpret. The tool contains miniscule sensors that change color in the presence of a specific genetic sequence. To ensure accurate detection of the virus, the team developed sensors that can detect 24 different genetic sequences found in the Zika genome. The device has been tested using samples from infected monkeys and has proven to be effective at detecting even low quantities of the virus. Although the results are easy to read—a positive sample turns the strip purple—the team has also created a simple electronic reader that determines the quantity of the virus in the sample. Vector Control As vaccines, drugs, and diagnostics against the virus inch their way through the R&D pipeline, health officials are ramping up vector control efforts against the Aedes aegypti mosquito. New techniques are also underway, and the FDA is currently accepting public comment on a proposal to expand testing of genetically engineered mosquitoes. The mosquitoes mate with the local population, resulting in offspring that die before reaching adulthood and are consequently not able to spread diseases. A trial of the mosquitoes in Brazil led to an 82 percent decrease in the Aedes aegypti population in just nine months. Scientists are using innocuous bacteria and fungi to combat the spread of Zika. Male mosquitoes infected with the Wolbachia bacteria do not produce viable offspring, and tests across the United States have reduced the population of the closely related Aedes albopictus mosquito by an estimated 70 percent. Meanwhile, the Metarhizium brunneum fungus is used as a natural pesticide, killing mosquito larvae. Meanwhile, in North Hempstead, New York, bats have been enlisted in the fight against Zika. The city is building and hanging bat houses in parks to attract the animals, as they can eat more than 1,000 mosquitoes in an hour.

Photo: CDC/ Prof. Woodbridge Foster; Prof. Frank H. Collins Findings of a study presented at the American Society of Tropical Medicine and Hygiene Annual Meeting last week suggest that ivermectin—a drug long used to treat river blindness and elephantiasis—can combat malaria when used in mass drug administration programs. The study, which was conducted by researchers from Colorado State University and the Institut de Recherche en Sciences de la Santé, found that mass distribution of ivermectin (six times, in three week intervals) resulted in a 16 percent decrease in incidence of childhood malaria. Ivermectin isn’t toxic to the malaria parasite; rather, it weakens the mosquito vector, serving as a form of vector control. After a mosquito becomes infected with malaria, it can take up to two weeks before it is able to transmit the parasite to humans. With ivermectin present in the human population, multiple humans might transmit ivermectin to the mosquito before it is able to spread the malaria parasite to even one human. The study was conducted in the West African nation of Burkina Faso, and the leading malaria parasite and mosquito vectors vary between sub-Saharan Africa and Southeast Asia. However, researchers at the US Walter Reed Army Institute of Research have recently determined that ivermectin can inhibit the development of the malaria parasite and kill the mosquito vector endemic to Southeast Asia. Researchers at the University of Malaya in Kuala Lumpur, Malaysia, have developed LED street lights that are environmentally friendly and a public health tool. The street lights are powered by wind and solar energy, and serve a dual purpose of trapping mosquitos to combat dengue fever and other infectious, mosquito-borne diseases. The lamps release carbon dioxide, to which mosquitos are attracted, and use a fan to trap the mosquitos. The lamps are currently being piloted in Malaysia at two different sites. Professors at Duke University have designed a colposcope, a cervical cancer diagnostic tool, to be used in low-resource settings, and will soon begin testing the device in a pilot study in Peru. Existing colposcopes are large and include equipment to magnify and illuminate the cervix (see Image 1), whereas this device, the Point of Care Tampon (POCKeT), includes a camera that provides images of comparable quality. The POCKeT is small (see Image 2), connects to a smartphone or tablet, requires less training, and is expected to be more culturally appropriate than a traditional colposcope. The testing of the POCKeT will be supported by a US$3.7 million grant from the US National Institutes of Health. A recent report from the Review on Antimicrobial Resistance, commissioned by United Kingdom Prime Minister David Cameron to address the growing threat of drug-resistant infections, calls for the research and development of rapid, point-of-care diagnostics to reduce the overuse of antibiotics. Such diagnostics would allow health care workers to pinpoint the cause of an illness and treat it accordingly, rather than prescribe a broad-spectrum antibiotic without confirmation that the cause is bacterial and/or that the pathogen will be susceptible to the drug. The Review notes that drug companies, which benefit from antibiotic sales, have little incentive to invest in diagnostics that could limit those sales. The report includes a diagnostic 'wish list,' which identifies 12 potentially "game-changing" tools, including an at-home test to determine if an illness is an infection at all or to distinguish between bacterial and viral infections.

Dr. Robert Gallo co-discovered the HIV virus and subsequently led the development of the first HIV and AIDS blood test. Now, his team at the University of Maryland School of Medicine is initiating human clinical trials of an experimental HIV and AIDS vaccine that aims to prevent the virus from attaching to immune cells. The HIV virus uses a protein on its surface—gp120—to bind onto one part of human immune cells—the CD4 receptor—and then subsequently bind onto a second part of the cell—CCR5. This vaccine candidate interrupts this process by preventing the HIV virus from attaching to CCR5, therefore disrupting the process of infection. While many vaccines target specific viral strains, this candidate is intended to neutralize all strains of the HIV-1 virus. The first phase of the trial will enroll 60 healthy, adult volunteers to determine the vaccine’s safety and to ascertain if it successfully triggers an immune response. A 23-year-old engineer has developed an inflatable incubator that is designed to be easy to transport, use, and maintain, which could dramatically reduce deaths of premature babies in refugee camps. Developer Briton James Roberts has created electronic and functional prototypes which indicate that the incubator, known as MOM, will provide the required warm, stable, and sterile environment. Roberts designed the product with Syrian refugee camps in mind, as an estimated three-fourths of premature infant deaths in camps could be prevented with proper incubation. The incubator can be collapsed (see Figure 1) to fit in care packages commonly distributed in refugee camps and while it does require electricity, it can run off of a car battery or solar power. Roberts recently won two cash prizes to support product development and manufacturing but is continuing to fundraise to support the costly process of regulatory approval for medical devices. Roberts believes the product could be ready for market by 2018. Photo: CDC/ Dr. Scott Smith The US Department of Defense (DoD) and National Institutes of Health (NIH) have both supported the research and development (R&D) of drugs and vaccines for Ebola since the early 2000s. In both agencies, budget constraints halted progress despite promising clinical trials. In 2004, a researcher at army installation Fort Detrick was exposed to Ebola, prompting the DoD to partner with pharmaceutical company Sarepta Therapeutics to rapidly develop an experimental treatment for Ebola. The treatment was given emergency approval by the US Food and Drug Administration (FDA), but the researcher did not become infected and the treatment remained unused. In 2010, the DoD awarded Sarepta a US$291 million contract to continue its work. Sarepta’s drug demonstrated 60 to 80 percent efficacy in clinical trials with primates and proved safe for use in phase 1 human clinical trials. In September 2012, the FDA granted Sarepta’s drug fast-track status—to expedite its regulatory review—but just one month later, the DoD discontinued the project, in light of looming budget cuts that seemed inevitable due to congressional gridlock. In mid-2014, after the onset of the Ebola epidemic in West Africa, Sarepta CEO Chris Garabedian approached the DoD about the possibility of continuing their work, however, the agency chose to fund products that were not as far along as Sarepta’s. While the DoD has since reconsidered—inviting Sarepta to apply for funding for phase II trials—Sarepta declined, and under new leadership, has terminated their Ebola R&D. The US Department of Agriculture (USDA) has contracted two veterinary pharmaceutical companies—Harrisvaccines and Ceva Santé Animale—to manufacture, store, and ship vaccines to prevent the strain of avian influenza which caused an outbreak and consequent shortage of eggs and turkey in the United States earlier this year. The contract requires the companies to store the vaccines for up to five years, regularly testing them for quality assurance, and will ship them within ten days to anywhere in the United States if requested by the USDA National Veterinary Stockpile. To improve clarity and expediency of communication—for which the agency was criticized by veterinary, poultry, and egg groups during this year’s outbreak—the USDA has also worked with Iowa State University to translate avian influenza–related biosecurity materials for Spanish-speaking farm workers.

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. In a bit of good news, the fiscal year (FY) 2015 defense appropriations bill—which was approved by the Appropriations Committee last Thursday—includes a $7 million increase for peer-reviewed medical research—from $200 million in FY 2014 to $207 million this year—despite a reduction in overall Department of Defense (DoD) funding from FY 2014 levels. In addition, in the accompanying report, the Appropriations Committee included very strong language recognizing DoD’s substantial contributions to global health research and development (R&D) and the need to support sustained US investments in this area. FHI 360 sat down with International Partnership for Microbicides CEO Zeda Rosenberg to discuss last week’s 20th International AIDS Conference. In this short video, Rosenberg highlights the need to focus on key populations—such as young women in sub-Saharan Africa—and the importance of women-initiated products like microbicides as a HIV prevention tool. Nearly 40 years after the discovery of the Ebola virus, no licensed treatments or prevention options are currently available. With the largest outbreak ever of the virus currently underway in West Africa, some are arguing that scientists should begin to develop new drugs and vaccines to combat this deadly disease. According to CNN, it’s likely too late for a vaccine to have enough of a preventative impact now, but using this time to test experimental vaccines—such as one developed by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health—could help when Ebola emerges again in the future. Last week, the United Nation (UN) General Assembly’s Open Working Group on Sustainable Development Goals released its proposal for a set of goals to succeed the UN Millennium Development Goals which come to an end in 2015. These proposed goals—referred to as the Sustainable Development Goals—will define the post-2015 development agenda. Of the 17 proposed goals put forward by the group, two contain targets related to R&D of new health technologies. Chagas disease—a neglected tropical disease (NTD) transmitted from the kissing bug and affecting millions of people in Latin America—is now on the rise in northern Virginia. Some doctors in the United States are not familiar with the disease and therefore do not test their patients regularly, which poses a risk to the general population in the United States. Many of the 8 million people with Chagas disease around the world never show signs of the disease, but about a third develop heart disease or megacolon and—when untreated—appear to die from sudden heart attacks. Chagas disease is just one example of NTDs affecting more and more people in the United States.