Research Roundup: 3D-printed drugs, R&D in emergency settings, a universal flu vaccine, and more

Since its discovery in 2012, cases of Middle East Respiratory Syndrome (MERS)—a disease World Health Organization (WHO) Director-General Dr. Margaret Chan called “a threat to the entire world”— have been reported in 27 countries across four continents. MERS is a type of coronavirus (MERS-CoV)—a common virus that infects the nose, sinuses, and throat—and a close cousin to the Severe Acute Respiratory Syndrome (SARS), infamous for infecting more than 8,000 in the early 2000s. As its name reveals, MERS is a respiratory illness, however, the symptoms are non-specific, and include coughing, sore throat, fever, chills, and muscle pain. The disease can quickly turn into pneumonia, and more than one-third of cases are fatal. History of MERS outbreaks The virus is believed to have passed from bats to camels, and within the last few years, from camels to humans. To date, there have been more than 1,400 lab-confirmed cases resulting in nearly 500 deaths, primarily in the Arabian Peninsula. For the first time since its discovery, a major outbreak has occurred outside of the Middle East, with 186 cases and 36 deaths in South Korea in recent months. Photo: PATH/Teresa Guillien MERS is not particularly contagious. One study from a spring 2014 outbreak in the Middle Eastsuggests that the average MERS patient—outside of a hospital setting—spreads the disease to just one other person. However, the Korean outbreak paints a different picture. Just one man is believed to have spread the disease to more than 20 people. Coronaviruses are particularly adept at mutating, and scientists initially feared that the virus had mutated to become more virulent. While an examination of genetic material from the Korean outbreak debunks this theory, the threat of mutation remains a real possibility. "The fact that MERS has spread around the world is not surprising. The question is, 'Where is it going to spread to next?' It could very easily come to America. Very easily. Any flight could contain someone who was infected in the Middle East." Michael Osterholm, director, Center for Infectious Disease Research and Policy, University of Minnesota Status of MERS R&D According to Ripley Ballou, vice president of Emerging Diseases at GlaxoSmithKline—the sixth largest pharmaceutical company worldwide—“everybody knows what the target for MERS is, it is the core spike protein […] a single protein that can be used to induce an immune response.” Despite this knowledge, there are currently no vaccines or drugs to prevent or treat MERS, and no large pharmaceutical companies have invested in MERS research & development (R&D). In the case of diseases with sporadic outbreaks, investments in R&D can be risky for pharmaceutical companies; if the outbreak is contained, there may no longer be a commercial market for the finished products. However, as Dr. Adrian Hill, director of the Edward Jenner Institute for Vaccine Research at Oxford University, points out “there is no sign of MERS going away. It’s been around since 2012.” The disease is endemic to Saudi Arabia and Hill argues the government of Saudi Arabia could afford to fund MERS R&D. Currently, several small biotech companies and academic institutions are engaged in preclinical research for experimental MERS vaccines and drugs. Below GHTC examines the current R&D pipeline for MERS: Vaccines Greffex, Inc., a biotech company that specializes in the rapid development and production of vaccines, created an experimental vaccine for MERS in 2013, which was tested on mice the following year by the US National Institute of Allergy and Infectious Diseases (NIAID). Within just two months, Greffex produced and tested the vaccine and a complementary booster shot, which resulted in the production of protective antibodies—proteins developed by the immune system to fight a specific virus—in every single mouse. Greffex CEO John R. Price believes the company could produce a stockpile of vaccines for human clinical trials for “pennies on the dollar” in just three weeks, however the company could not afford costly clinical trials. “How long are we going to wait around and just follow these outbreaks before we get serious about making vaccines?" Adrian Hill, professor and director, Edward Jenner Institute for Vaccine Research, Oxford University Dr. Matthew Frieman, a professor of Microbiology and Immunology at the University of Maryland School of Medicine, partnered with Novavax, Inc. to develop and test another experimental vaccine for MERS. This candidate also triggered the production of antibodies in mice and was tested in conjunction with a booster, and similarly, progress has ground to a halt, due to the lack of funding for clinical trials. “There's nothing standing in our way from pushing this forward other than the money and the will to do it,” Dr. Frieman told the International Business Times. Fortunately, human clinical trials are planned for a third candidate, developed by a team of researchers at the Ludwig Maximilian University of Munich, thanks to funding from the German Center for Infection Research. Rather than using antibodies against MERS-CoV, this vaccine triggers the recipient’s immune system to produce its own antibodies against the virus by introducing a weakened poxvirus that has been genetically altered to express the characteristic MERS-CoV spike protein. The body recognizes the poxvirus as foreign, and develops antibodies against that spike protein, without ever seeing the MERS virus itself. While three different vaccine candidates may seem like a foolproof defense against an outbreak, the work has only just begun. Clinical trials are not only expensive, but can take years to complete. For example, the US National Institutes of Health (NIH) announced the success of an Ebola vaccine in monkeys as early as 2000 and initiated a human clinical trial in 2003. However it wasn’t until 2006 that the results were published. While the vaccine seemed safe and effective, research ground to a halt until the recent Ebola outbreak in West Africa, and clinical trials continue to this day. Photo: PATH/Teresa Guillien Drugs Outbreaks are unpredictable, and given the costs and difficulty of vaccinating the entire world against MERS, treatment options are absolutely critical for this disease that kills more than one-third of those infected. In South Korea, two hospitals are testing an experimental treatment for MERS known as convalescent plasma therapy, which uses blood plasma from survivors of the disease to boost the immune response of a current patient. The technique was also tested in the ongoing Ebola outbreak in West Africa and the 2000-2003 SARS outbreak in southern China. During the SARS outbreak, it decreased mortality by 23 percent. Plasma therapy is fast and inexpensive, and while it isn’t “medically proven” it’s “often carried out in the absence of other treatments,” a representative of the Hallym University Medical Center told The Korea Times. In addition to his vaccine research, Dr. Frieman has partnered with Regeneron Pharmaceuticals Inc. to search for a treatment for MERS. The researchers genetically modified mice so that their cells would display the human version of a receptor protein—known as DPP4—to which the MERS virus attaches during an infection. This allowed them to mirror the human immune response to the virus. The team then examined more than 1,000 antibodies from the immune systems of the mice and tested the ability of those antibodies to prevent the MERS virus from latching on to human cells (via the DPP4 receptor). Left with 30 promising antibodies, the team needed to find two different antibodies that would not compete against each other and could be paired together, thereby producing a treatment that would be more effective against the mutability of the virus because it contained two different antibodies. The team identified two such antibodies that could work together, known as REGN3051 and REGN3048. Dr. Frieman is also exploring the possibility of using drugs which are approved for other conditions to treat MERS. With NIAID funding, Frieman tested 290 different compounds, 27 of which were active against MERS-CoV in test tubes. The team will next examine the efficacy of these compounds in combatting MERS-CoV in mice. Several of these compounds are the basis of treatments for cancer or psychiatric conditions; similarly, Zoloft and Vascor—drugs for depression and angina, respectively—have been shown to be effective in combatting Ebola in mice. Scientists at Purdue University have discovered a certain enzyme that plays a key role in the replication of the MERS virus, calling it the “Achilles’ heel of the virus.” They have since identified molecules that can stop the enzyme, making it much harder for the virus to replicate. However, that same molecule actually helped the virus spread at low doses, so determining the perfect amount of the molecule to administer will be a major barrier to translating their findings into a safe and effective treatment. Other treatments are in development as well. Shanghai Kaibo Pharmaceutical plans to unveil an injectable treatment for MERS, however no information on the product has been released. Researchers at Fudan University in Shanghai, China have partnered with the NIH to develop an antibody against MERS known as m336 that they believe is even more promising than other antibodies against the virus. As with vaccine candidates, the search for drugs and treatments against MERS is far from over. Not only do vaccines, medicines, and other tools need to be tested in clinical trials, but they need to be manufactured and distributed in adequate quantities to ensure a rapid response to an outbreak. Since its discovery in 2012, MERS has been widely considered a contender for the next major outbreak, or even pandemic. Researchers and public health advocates alike are wondering: will we learn from the Ebola outbreak and invest in R&D to create the tools needed to respond to a MERS pandemic, or will we wait until it’s too late?

Many infants have difficulty breastfeeding and must rely on cup feeding. Photo: PATH/Amy MacIver Breast milk is the perfect first food for newborns; it provides nutrients and energy that infants need and contains substances that strengthen their immune systems. Ideally, newborns are breastfed within their first hour of life with breastfeeding continuing for their first several months of life. However, some babies are not able to breastfeed—preterm babies often do not have the fine motor skills and babies born with facial anomalies like cleft palates cannot breastfeed. And in some cases, babies who are orphaned or have mothers too sick to breastfeed who must be fed with donor milk. In high-resource settings, these infants could have breast milk fed to them through feeding tubes or specially-designed bottles, but in low-resource settings these solutions are impractical and often unsafe in areas where reliable clean water is not available. Tubes must be inserted by a trained medical professional and are often not available in low-resource settings; while bottles are expensive—particularly those that adapted for use by infants with cleft palates— and difficult for mothers to keep free of bacteria due to their crevices. For infants in low-resource settings who cannot breastfeed, the World Health Organization recommends hand expression of breast milk and use of a small cup to feed newborns. Cups are easier to clean so reduce the risk of infection, and cup feeding has been shown in some studies to improve the transition of preterm infants to exclusive breastfeeding. The problem? There is no cup designed specifically for the job, and the household cups many mothers use have some serious drawbacks that can put their baby’s health at risk. A solution? A group of innovators from the University of Washington, Seattle Children’s Hospital Craniofacial Center, and PATH have invented the NIFTY™ cup—a simple-to-use, easy-to-clean, inexpensive cup designed specifically for delivering breast milk to infants. Your average cup won’t do for breastfeeding Because there is no standard cup designed for the purpose, mothers who need to cup feed typically use whatever small cups or devices they have on hand. For example, in India mothers typically use a miniature gravy-boat like device called a paladai—originally used to burn oil during religious ceremonies—that have sharp-edged metal spouts and can cause oral cuts or injuries to an infant. A young infant being cup fed with a mug in Kenya. Photo: PATH/Evelyn Hockstein In other areas of the world, mothers use coffee mugs, shot glasses, medicines cups, or whatever small cups they can find. Unfortunately, the relatively wide rims of these cups can make it difficult for a mother to maintain a consistent flow of milk to her newborn which can be problematic and even dangerous. Too much milk too fast can cause a newborn to aspirate, while too little milk can mean the baby does not get sufficient nutrition. “These infants are getting an erratic, inconsistent, sometimes too rapid flow [of milk] or not enough access to milk while they are feeding,” explained Christy McKinney, PhD, MPH, a clinical assistant professor at the University of Washington who helped design the NIFTY™ cup, “So the infants don’t get enough nutrients within the short amount of time to grow and fight infection.” During lengthy cup feedings, an infant can actually expend more energy trying to feed than it takes in, which can lead to a rapid decline in health. Another problem with standard cups is spillage. “About a third of milk is spilled at each feeding, said McKinney, “If you are trying to feed and hand expressing your breast milk, it’s a pretty painful experience to have a third of that spilled and wasted every time you are feeding, which can be 12 times a day for a newborn.” The NIFTY™ cup: a game changer for cup feeding A demonstration of feeding using the NIFTY cup. Photo: Marissa Chmiola/GHTC McKinney and her collaborators kept these drawbacks in mind as they set out to create the perfect cup for cup feeding. The NIFTY™ cup was designed with a unique reservoir that can hold a bolus of milk at its end. McKinney called this reservoir a “game changer.” It reduces spillage and allows the milk to be constantly available to the infant. McKinney explained that unlike a spout which only allows milk to be poured into an infant’s mouth, the unique reservoir of the NIFTY™ cup enables cup feeding to become a two-way street just like traditional breastfeeding or bottle feeding. “The mother is making sure that the reservoir is filled and then the infant gets to help pace the feed,” said McKinney, “That pacing results in a much calmer infant. They don’t run the risk of aspirating from too much milk poured into their mouth; instead, they can get the milk they need at the rate they want it, which allows for a calmer, integrated feeding experience between mother and infant.” The NIFTY™ cup inventors also made the cup out of silicone, which offers several advantages: The cup is soft and easy to squeeze, it prevents mouth injuries, it’s durable, and it can be boiled, which makes it easy to sterilize. Because the NIFTY™ has a reservoir that controls the flow of milk, the cup can be sized much larger than other cups used for cup feeding. This allow mothers to directly hand express the milk into the NIFTY™ cup rather than using multiple cups which in turn reduces spillage and opportunities for contamination. In addition, the NIFTY™ cup contains tracking markers on the side to monitor milk intake, it’s ergonomically designed for comfort, and it can be affordably produced at less than $1.00 per cup. In short, the NIFTY™ cup offers more advantages for mothers and infants than any other available cup. The long road to innovation For McKinney it has been over a five-year odyssey to turn the NIFTY™ cup from idea to reality. Inspired by her time as a Peace Corp volunteer in Ethiopia and having just completed her PhD studying craniofacial anomalies and beginning her new post-doctoral position, McKinney was looking for ways she could help children in low-resource settings with oral clefts. She saw feeding as the most problematic area and an area most in need of innovation. “So I just thought it would be nice to come up with an idea to feed these infants with,” said McKinney. With this concept in mind, McKinney began searching for a partner who could help make such an idea possible. She discussed the idea with Dr. Michael Cunningham, the director of the Seattle Children’s Hospital Craniofacial Center, where she completed her PhD, and they approached GHTC member PATH, based in Seattle. “We reached out to PATH…and there was sufficient interest to say let’s try and make this work,” said McKinney. Together they developed a design team which included McKinney (an epidemiologist); Dr. Cunningham (a craniofacial pediatrician); a social scientist, engineer, and commercialization officer from PATH; and an occupational therapist/lactation consultant from Seattle Children’s Hospital. Together, with funding from PATH and the Seattle Children’s Hospital Craniofacial Center, the team designed their first prototype cup. A product can only have impact if it meets end-user needs and people are actually interested in obtaining it. To make sure both applied to the NIFTY™ cup prototype, the team set out to test drive the cup in low-resource settings. With support from a nonprofit Transforming Faces—which supports care for children with oral clefts in South India—and additional funding from the University of Washington CoMotion, McKinney and the team took the NIFTY™ cup to Sri Ramachandra University in South India to do formative design work in both the cleft center and the Neonatal Intensive Care Unit. They introduced the cup to mothers and health providers including lactation consultants, watched the product in use, and conducted surveys to gauge interest in the product and to inform design. The NIFTY™ cup was a big hit. “I was really excited that they liked it more than what they were using,” said McKinney, “I didn’t quite know what to expect on that, but they are really excited to get it commercialized.” Armed with valuable feedback from South India, McKinney and the team regrouped and are doing a minor redesign of the product which will be complete this summer. Last month, the team won a grant from the Saving Lives at Birth Challenge. With this funding, the NIFTY™ cup developers plan to conduct a clinical study in Ethiopia to evaluate the product’s effectiveness compared to standard cups being used, and also develop a market shaping strategy for introducing the product. While it could still be some time before the product is widely available to those who need it, McKinney and the rest of the team are energized by the NIFTY™ cup’s lifesaving potential and the support they are receiving to continue development and introduction. “I’m so excited. This little idea has percolated so long, and people have finally seen the value it can bring,” said McKinney.