Breakthroughs Blog: Research Roundup

Photo: National Institute of Allergy and Infectious Diseases (NIAID) Researchers at Tulane University successfully tested an experimental aerosol tuberculosis (TB) vaccine in monkeys, demonstrating that the candidate was more effective in protecting against infection than BCG—the only TB vaccine on the market. To create the vaccine, the researchers genetically modified the TB bacterium, removing a gene that plays a key role in infection. The vaccine was then administered to seven monkeys, while another seven each received either an aerosol version of BCG or no vaccine. After eight weeks, the monkeys were exposed to TB at a lethal level. The experimental vaccine not only was more protective than BCG, but it also induced a stronger immune response in the lungs, which is thought to be key to preventing infection. A new formulation and coating for existing HIV and AIDS medicines could significantly decrease the frequency with which the drugs must be taken. Researchers at the University of Nebraska Medical Center used a process called nanoformulation, which involves modifying drugs at the most basic level (i.e., atomic or molecular level) in order to convert them into nanoparticle crystals. In this experiment, the antiretroviral medicine crystals were coated with fat and protein, allowing them to last much longer in the body. In the lab, the drug proved to be effective in combatting HIV and AIDS. The team hopes its findings could eventually lead to the development of an HIV and AIDS treatment that could be administered once or twice per year, rather than daily. Resistance to the leading antimalarial—artemisinin—was first reported in Cambodia in 2008, and a new study in Nature Communications suggests that the drug-resistant parasite has the ability to infect African mosquito species. A team of researchers at the US National Institute of Allergy and Infectious Disease infected two Asian and one African mosquito species with the drug-resistant malaria parasite, and all three species proved to be susceptible. Furthermore, the African species were no less vulnerable to infection, which came as quite a surprise as the species have evolved independently for more than 30 million years. Health officials from the United States and Saudi Arabia are considering a collaboration for the development of a vaccine against Middle East Respiratory Syndrome (MERS), which has infected more than 1,500 people across 27 countries. There are currently a number of MERS vaccines in development and several have yielded promising results in animal studies. The Saudi Ministry of Health has US$70 million available for the project; however, the proposed role of the US government remains unknown.

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.

A new briefing paper from the Infectious Diseases Society of America Center for Global Health Policy explores the state of tuberculosis (TB) research and development (R&D) including challenges for products currently in the pipeline and gaps in TB research. The paper notes that existing TB diagnostic tools are not practical for low-resource settings, as the leading device is expensive and requires electricity and skilled health workers. Alternative diagnostic approaches are unreliable, missing nearly half of cases, and there’s a paucity of tools to detect drug-resistant strains. In terms of treatment, there is very limited access to novel drugs, due in part to delayed regulatory review and delivery. While the report notes that the “world still waits for a significant tuberculosis vaccine breakthrough,” more than a dozen experimental vaccines are currently being tested in clinical trials. New research suggests that malaria in pregnancy could impact fetal brain development, which is particularly concerning as pregnant women are at increased risk for malaria. The study, which was conducted in mice, suggests that a mother’s immune response to malaria disrupts the production of certain proteins involved in brain development, resulting in depression or cognitive disorders. Upon further investigation, the team was able to prevent the immune system disruption and successfully prevent any brain damage. While this approach would be impractical and too expensive for scale-up in humans in low-resource settings, the team plans to confirm the phenomenon in humans and search for a safe, affordable alternative. A patient with lymphatic filariasis (Photo: CDC) Last week, three researchers were awarded the Nobel Prize for Physiology and Medicine for discovery of artemisinin and avermectin, the leading treatments for malaria and two filarial diseases caused by roundworm parasites: lymphatic filariasis and onchocerciasis. Both treatments were identified in the 1970s and are currently facing challenges: resistance to artemisinin has been growing and avermectin treats the symptoms of these filarial diseases by killing the larvae, but is unable to kill the adult worms, ultimately requiring years of treatment. A team led by Professor Mark Taylor of the Liverpool School of Tropical Medicine is searching for new ways to treat filarial diseases by targeting Wolbachia, a bacterium that is critical to roundworms’ ability to both mature and elicit the symptoms associated with lymphatic filariasis and onchocerciasis. In the 1990s, Taylor’s team determined that the antibiotic doxycycline could combat Wolbachia, killing the adult worms in three-fourths of patients within 18 months. However, as ensuring access to doxycycline and retaining patients over 18 months can be challenging, Taylor’s team has been searching for alternatives through the Anti-Wolbachia Consortium (A-WOL), established in 2007 and funded by the Bill & Melinda Gates Foundation. A-WOL has facilitated the screening of nearly sixty thousand chemical compounds and is currently testing the antibiotic minocycline for treatment of lymphatic filariasis and onchocerciasis in Ghana and Cameroon. Early results suggest that minocycline, a more expensive drug, is 50 percent more effective than doxycycline. Neither are safe for use in children or pregnant women, however, Professor Taylor believes the team has enough drug candidates to overcome this challenge, as they’ve developed dozens of promising compounds to test further.

The US Department of Health and Human Services (HHS) is partnering with New York–based Regeneron Pharmaceuticals, Inc. for the development of an Ebola treatment. The treatment, developed by Regeneron, is comprised of three monoclonal antibodies that help the human immune system identify and bind to the Ebola virus, and thus prevent the virus from entering human cells and reproducing. Through the Biomedical Advanced Research and Development Authority, HHS will contribute up to US$38 million over two years, which will support both the advanced development of the treatment, as well as manufacturing enough doses of the treatment to be used in clinical trials. Swiss pharmaceutical company Novartis announced a new program last week to expand access to 15 of its medicines by offering them to health care providers in low- and middle-income countries for just $1 per drug per month. The program will initially be launched in Kenya, Ethiopia, and Vietnam, but could be expanded to as many as 30 countries. The 15 medicines included in the Novartis Access portfolio treat chronic diseases including cardiovascular and respiratory illnesses, diabetes, and breast cancer. Novartis will partner with governments and nongovernmental organizations to implement the program. Photo credit: CDC/ Melissa Dankel Researchers at Stanford University may have discovered a way to combat Clostridium difficile (C. diff)—a deadly bacteria that affects the intestines—without using antibiotics. C. diff’s virulence relies on a specific toxin—Toxin B—it releases that is responsible for the diarrhea, abdominal pain, and damage to the intestinal wall associated with the bacteria. While broad-spectrum antibiotics combat C. diff and other bacteria by attacking all bacteria—including safe, healthy bacteria—this new approach uses a molecule called ebselen that targets and deactivates Toxin B. The team at Stanford gave mice multiple rounds of antibiotics followed by a multidrug-resistant strand of C. diff; in other words, they made the mice particularly susceptible to infection and then introduced a particularly virulent bacteria. However, the use of ebselen to treat the infection almost completely protected the mice from symptoms. Ebselen is currently being tested for use in humans to treat other conditions, and initial results suggest that it is safe and well-tolerated. The US Food and Drug Administration (FDA) gives breakthrough designation to drugs that treat serious conditions and that have the potential to be significantly better than anything on the market. The FDA expedites the development and review of drugs deemed to be breakthroughs, but the designation is not a guarantee of safety, efficacy, or ultimate approval of the drug. However, a new study suggests that use of the word “breakthrough” could give patients “unwarranted confidence […] which could prevent them from making a fully informed decision about whether to take the drug or not,” according to the study’s coauthor Tamar Krishnamurti. The team recruited 600 online participants, each of whom were given one of five descriptions of a drug that has received breakthrough designation. The first description included just the facts, while the second and third described the drug as “promising” and “breakthrough,” respectively. The fourth and fifth clarified that continued approval of the drug depended on the results of additional clinical trials. In the subsequent survey, participants who read that the drug was “promising” or “breakthrough” were more than twice as likely to describe the drug as very or completely effective. While nearly a third of those who read the “breakthrough” description falsely considered the drug’s efficacy to be proven, compared to only 10 to 16 percent of participants who read the clarification regarding continued approval. All participants were then asked to read two descriptions of the same drug and identify which they would take. Ninety percent of respondents chose the description that used the word “breakthrough.”