Breakthroughs Blog: Zika

Last Wednesday, researchers from the Washington University School of Medicine, the University of São Paulo, and the Chinese Academy of Sciences offered new insights into the impact of the Zika virus on fetal brain development in mice, publishing their findings in Cell, Nature, and Cell Stem Cell, respectively. The first two studies sought to successfully infect pregnant mice with Zika—a feat in itself as mice don’t often fall ill after infection with the virus. Consequently, the team at Washington University used a genetically modified mouse with a weakened immune system as well as a mouse whose immune system was weakened by an antibody, while researchers at the University of São Paulo used a particularly high dose. The team at Washington University detected placental insufficiency in the infected mice—which limits blood flow to the fetus—and the team at University of São Paulo reported intrauterine growth restriction, a condition restricting the growth of the fetus. When the virus reached the fetal brains, both teams witnessed a thinning of brain tissue and cell death. The concentration of the virus in the brain was limited, which inhibited further research on how Zika behaves once in the brain. The team at the Chinese Academy of Sciences, however, injected the virus directly into the brains of fetal mice, and they determined that the virus targets neural progenitor cells and causes the fetal brain to shrink. Silk has been used in developing heat-stable vaccines and drugs, and now, researchers at Tufts University have demonstrated that silk can be used to maintain blood samples in low-resource settings. Blood-based diagnostics are only effective if certain proteins, which indicate either the presence of a pathogen or the immune system’s response to it, are preserved, however, heat and humidity can directly damage the proteins or cause enzymes in the blood to attack the proteins. Labs prefer that blood samples are refrigerated, although they can also be dried on special filter paper that can withstand heat but which often doesn’t hold enough blood for analysis. The team at Tufts created a silk-based powder and solution, combined it with blood samples, and allowed it to dry. The samples were then stored at high temperatures (72 to 113ºF) and remained viable for 84 days. GHTC member the International Vaccine Institute (IVI) announced last week that a single dose of the oral cholera vaccine Shanchol, currently administered in two-dose regimens, provides protection against the disease. The two-dose regimen provides 65 percent protection against cholera for at least five years, while the single dose demonstrated 40 percent protection against the disease for at least six months. While the two-dose regimen is preferred, the single dose could be appropriate for epidemics or in settings where the two-dose vaccine schedule is impractical. The study enrolled 204,700 individuals residing in the urban slums of Mirpur in Dhaka, Bangladesh, where cholera is endemic. In addition to reducing cases by 40 percent, the vaccine resulted in a 63 percent decrease in cases of severely dehydrating cholera.

There is a safe, affordable, single-dose vaccine that protects against yellow fever for 99 percent of those vaccinated, yet a recent outbreak of the disease has resulted in nearly 2,000 cases and killed 258 in Angola. Yellow fever is endemic in 44 countries, including Angola, and the global demand for the vaccine surpasses availability by 42 percent. Additionally, the cost of the vaccine has increased 30 percent annually. The vaccine is currently produced by four manufacturers, and its production is complicated, requiring embryos in chicken eggs. A vaccine with an inactivated version of the virus, which would be much easier to manufacture, has successfully completed phase 1 clinical trials, however, it has not yet been commercialized. As the World Health Organization is leading negotiations to divert yellow fever vaccines from routine immunization programs to Angola, the existing vaccine could also be delivered in smaller quantities to more people: just one-fifth of the standard dose has proven to be effective against the virus. A team of American and German scientists have demonstrated that an injection with potent anti-HIV antibodies can protect against the virus in monkeys for nearly six months. The researchers used four different antibodies that have proven to be effective against various HIV strains and administered one type each to four different groups of monkeys. The monkeys were then exposed to the virus on a weekly basis. On average, the monkeys were protected for 12 to 14 weeks, although some were protected for up to 23 weeks. Previous studies have shown that antibodies can provide short-term protection against HIV in monkeys, however, in most studies, the monkeys were exposed to the virus in one high-dose shot. In reality, most infections in humans develop gradually as a result of repeated, low-dose exposures, and thus, this study sought to emulate standard human transmission. Currently, the first-ever clinical trial of a single antibody is being tested in individuals at high-risk for HIV infection, however, it’s expected that a cocktail of these potent antibodies would be even more effective at preventing infection.  New research out of Florida Gulf Coast University indicates that previous infection with dengue virus could exacerbate symptoms from the Zika virus. This phenomenon—antibody-dependent enhancement, in which the presence of protective antibodies against one disease increases vulnerability to another—has been reported among different strains of dengue virus. The team at Florida Gulf Coast University confirmed that in cell cultures, the presence of antibodies against dengue intensified Zika infection, however the research also suggests that a single vaccine candidate could be effective against both diseases. These findings, coupled with the shared Aedes aegypti mosquito vector, indicate that the spread of Zika in dengue-endemic regions could be more virulent than expected. 

GHTC member the Drugs for Neglected Diseases initiative will test an affordable hepatitis C regimen in Malaysia and Thailand, with a guarantee from generic drug manufacturer Pharco Pharmaceuticals that, if successful, the product will be priced at no more than US$294 for the entire regimen. The regimen combines the registered drug sofosbuvir with the candidate ravidasvir, a promising treatment that cured up to 100 percent of patients with Hepatitis C genotype 4—the most common strain of the virus in the Middle East and Africa—in a phase 3 clinical trial in Egypt. The phase 2 and 3 trials in Malaysia and Thailand will test the regimen among 1,000 patients with different genotypes and the trial will be open to patients with varying levels of liver damage and those co-infected with HIV and AIDS. PATH announced last week that two new rapid diagnostics for onchocerciasis (river blindness) and lymphatic filariasis (LF) are now commercially available. Onchocerciasis and LF are neglected tropical diseases, caused by parasitic worms, and spread by blackflies and mosquitoes, respectively. Onchocerciasis primarily affects the skin and eyes, resulting in itching, skin nodules, and blindness, while LF damages the lymphatic system resulting in physical disfigurement and disability. The tests were developed by PATH in partnership with the US National Institutes of Health and Centers for Disease Control and Prevention and will be commercialized by Standard Diagnostics/Alere moving forward. The new tools include a diagnostic for LF and another that tests for both diseases simultaneously. Both provide results in just 30 minutes and can be stored at temperatures ranging from 1 to 40°C (34 to 104°F). These tools offer significant improvements over existing diagnostics for LF and onchocerciasis. Previously, diagnosing LF required health workers to draw blood at night, when the parasites are active and consequently detectable, while onchocerciasis tests relied on a skin snip—the removal of inflamed skin. The tests will be invaluable for surveillance, control, and elimination programs. Researchers from Canada and Mexico are using old tires and milk to reduce the population of Aedes aegypti mosquitoes, which carry the dengue, chikungunya, yellow fever, and Zika viruses. The device, known as an Ovillanta, is comprised of two 50-cm (20-in) sections of old tires—in which A. aegypti mosquitoes often breed—that are stacked to form a mouth-like shape. The Ovillanta is then filled with milk and a piece of wood or paper that floats like a raft. A. aegypti mosquitoes secrete a hormone when they lay eggs, which other mosquitoes use to identify ideal breeding spots. This hormone is initially added to the milk in the Ovantilla, and the mosquitoes are drawn to it, laying their eggs on the floating wood/paper, which are then collected and destroyed. The Ovillanta is an adaptation of the ovitrap, which uses a bucket and water rather than old tires and milk. The team, funded by Grand Challenges Canada, has been testing the Ovillanta in Sayaxché, Guatemala, and over ten months, the Ovillanta has proven seven times more effective than standard ovitraps. The team will next test the device throughout the region and have shared the design online so that anyone can create one for personal use.

Aedes aegypti mosquitoes which carry Zika. Photo: Dean Calma/IAEAApril showers bring standing pools of water, the onset of mosquito season, and a new wariness of getting bitten. In 1999, we were caught off guard when the West Nile virus first appeared in North America. In 2010, an outbreak of dengue fever spread locally in Florida after an absence of 60 years. In 2014, chikungunya first arrived in the United States after travelling breathtakingly fast through the Western hemisphere. Now, in 2016, Zika virus is the latest mosquito-borne disease to threaten Americans. Yet our collective national response continues to be one of short-term planning rather than long-term preparedness.Since Zika virus arrived in the Americas in May 2015, there has been an alarming spike in reports of birth defects such as microcephaly, particularly in Brazil. Zika infection has also been linked to adverse pregnancy outcomes and Guillain-Barré syndrome—a temporary paralysis that can prove deadly. The World Health Organization has declared Zika a Public Health Emergency.The virus has now spread to 26 countries, including 312 travel-associated cases in the United States. So far, mosquitoes in the United States haven’t infected anyone, but the Centers for Disease Control and Prevention (CDC) just issued a revised map that shows the mosquitoes that carry this virus and others can be found across the Southern tier of the United States all the way up to southern New England on the East Coast.Faced with this chilling situation, we don’t have ready the tools we need to fight Zika. Just like with Ebola, crucial tools did not exist or were still under development when the outbreak began. R&D is urgently needed to understand the Zika virus and its associated health conditions, and develop new diagnostics, vaccines, or other treatments to combat it. A pregnant woman in El Salvador receives an ultrasound as part of the country's response to the Zika outbreak. Photo: Office of the President of El Salvador Today, the Band-aid approach of emergency funding is the only option available to mitigate the crisis. We applaud President Obama’s call for accelerated research efforts, and the need to inform Americans about how to protect themselves, which the CDC has been quick to do. The National Institute of Allergy and Infectious Diseases, led by Dr. Anthony Fauci, has also called for a “full court press” on research.This requires increased funding for those searching for ways to stop this virus. Diverting resources from the Ebola response, however, is short-sighted. Those efforts are just beginning to show the promise of new diagnostics, advanced therapeutics, and more resilient health systems in Ebola-affected countries. Redirecting funding before the job is finished is dangerous, and will most certainly leave the United States and the world unprepared for the next Ebola outbreak.The fact remains that this long-standing patchwork approach to global health R&D funding only degrades our ability to respond to the guaranteed next global health crisis. With more than 500 mosquito-borne diseases across this globally interconnected world, the question is not if but when we see another virus or disease.Just as we need primed and ready firehouses and firefighters, we need a primed and ready research infrastructure. That requires a prioritized agenda and sufficient funding. America’s “firehouses and firefighters” are the National Institutes of Health, CDC, President’s Malaria Initiative and the Army and Navy’s tropical infectious disease programs.Global health means everyone’s health. It’s time US policymakers stop funding by crisis and commit to sustainable, long-term investment in global health R&D so the most effective health solutions are available when they are needed.Stephen Higgs, PhD, FRES, FASTMH is the president of the American Society of Tropical Medicine and Hygiene and a professor at Kansas State University. Erin Will Morton, MA is director of the Global Health Technologies Coalition, a group more than 25 nonprofits that work to save and improve lives by encouraging the research and development of essential health technologies.