Breakthroughs Blog: Zika

At last week’s World Health Assembly, the World Health Organization (WHO) and the Drugs for Neglected Diseases initiative launched the Global Antibiotic Research and Development (GARD) Partnership, an initiative to develop new antibiotics to combat the growing threat of antimicrobial resistance. More than EU€2 million has been pledged to the GARD Partnership, from nonprofit Médecins Sans Frontières and the governments of Germany, the Netherlands, South Africa, and the United Kingdom. This innovative financing approach will enable the partnership to delink the costs of research and development (R&D) from sales and product price; new treatments can be sold affordably and promoted responsibly, without the pressure to recoup the costs of R&D. During the incubation period, the partnership will finance three to four projects while developing a long-term business plan, with the goal of becoming an independent entity by the end of 2017. At a recent meeting of G7 finance ministers and central bank governors, World Bank President Jim Yong Kim announced the creation of an insurance fund to fight pandemics, which will provide up to US$500 million for pandemic response in the world’s poorest countries. The Pandemic Emergency Financing Facility will be funded by reinsurance markets and World Bank–issued catastrophe bonds, which have been used to respond to natural disasters. Premiums will be covered by the World Bank and development partners. Funding eligibility will be determined by the size, growth, and spread of an outbreak and will be limited to pandemics in 78 low-income countries, caused by certain virulent, infectious diseases, including influenza, SARS, MERS, Ebola, and other zoonotic diseases. The facility was established in collaboration with the WHO and insurance providers Swiss Re and Munich Re. The Japanese government has committed US$50 million to the facility. Researchers at the Icahn School of Medicine in New York have identified a protein on the Zika virus that inhibits the human immune system from effectively combatting the virus. The protein—NS5—blocks signals between Zika-infected cells and the immune system; consequently, the immune system fails to produce the potent antiviral interferon. NS5 plays a similar role in other flaviviruses, including dengue and West Nile, but the mechanism by which NS5 prevents interferon production varies. The study suggests that altering or removing NS5 would enable the immune system to swiftly attack the virus. The team believes that a vaccine against the virus could be developed using a live strain of Zika, weakened by modifying or removing NS5. Meanwhile, Australian biotechnology company Biotron announced last week the identification of two compounds in its library that are effective against Zika virus in test tubes. The company specializes in HIV and AIDS and hepatitis C treatments and uses a broad antiviral platform to target specific proteins known as vioporins that are also found in the Ebola, MERS, and Zika viruses.

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.