Kat Kelley

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.

Ebola is hard to diagnose in low-resource settings. It requires specialized laboratories and trained personnel, blood samples must remain in cooled containers when transported from health clinics to labs, and the test itself takes several hours. However, researchers at the American Chemical Society have developed a handheld device that can diagnose Ebola and determine a patient’s viral load in less than 40 minutes. The tool tests four samples at once—two from the patient and two controls—and requires a small amount of blood which can be obtained via finger prick. The team hopes that the device could also be used to monitor the virus in survivors' semen and breast milk, which is particularly critical as increasing evidence suggests the disease remains transmissible through bodily fluids long after a patient has recovered. During their time at the International Institute of Water and Environment in Burkina Faso, two students developed a shea butter–based soap to fight malaria, using lemongrass and other oils that are natural mosquito repellants and larvicides. The students received a US$25,000 grant from University of California Berkeley as part of the Global Social Ventures Competition and are now hosting a crowdfunding campaign to finance the testing and production of the soap. The inventors, Gerard Niyondiko of Burundi and Moctar Dembele of Burkina Faso, hope that with adequate funding the soap could save 100,000 lives by 2018. In addition to the benefits of using the soap—which repels mosquitos for several hours after use—the discarded soapy water is expected to kill mosquito larvae, as it is often thrown into the street or dumped in stagnant water. The bacteria Bacillus thuringiensis israelensis has been approved for use as a pesticide by the US Environmental Protection Agency, as it kills mosquito and blackfly larvae but does not harm humans. However, its use in mosquito control was expensive until Dr. Palmira Ventosilla, a microbiologist at the Universidad Peruana Cayetano Heredia in Lima, Peru, devised an innovative system of delivery. Ventosilla has created kits for individuals, without any scientific training, to inoculate coconuts with the bacteria at home. The coconuts are then opened and left in small bodies of water (i.e., ponds), eliminating 90 percent of mosquito larvae within four days and keeping the water larvae-free for twelve days. The mosquitoes don’t develop resistance to the bacteria, as they do with chemical pesticides, and the bacteria is completely safe—even in human drinking water.

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. 

On Tuesday, GHTC launched our seventh annual policy report through a congressional briefing and panel discussion. The critical role played by the US government in catalyzing global health research and development (R&D) was a recurring theme, as panelists discussed the interconnectedness of global and American health and emphasized the need for new health tools to protect against outbreaks and continue progress. As moderator, GHTC Director Erin Will Morton opened the briefing, reminding attendees that despite the landmark progress achieved in global health over the past fifteen years, the US government must continue to invest in health R&D to achieve the next milestones in global health. “Goal setting works. And R&D for new technologies is key to achieving global health goals,” said Morton. Morton emphasized how past investments have had a remarkable impact, highlighting that the neglected disease pipeline has grown from 365 products under development in 2012 to 485 in 2015. However, as the GHTC policy report points out, US funding for global health R&D has stagnated or declined since 2009, and with the exception of the emergency funding for Ebola, 2014 funding levels were down 13 percent. “Our dollars are best spent when [US] agencies are working closely together,” said Morton, highlighting three goals the US government should embrace to advance innovation, as detailed in the report, including the importance of sustainable, long-term funding and innovative financing mechanisms; improved coordination of global health R&D efforts across US agencies; and streamlined and strengthened regulatory pathways. Panelist Dr. Peter Hotez—president of the Sabin Vaccine Institute and US science envoy—reiterated the need for long-term, sustainable funding for global health R&D, noting that the science to develop an Ebola vaccine was first published in 2013, but the technology sat there and was not advanced to product development because Ebola is a neglected disease and the technology offered little financial incentive to the private sector. He emphasized the role of US government investment in catalyzing health research, noting that when the US government “stepped in” and put up more than US$100 million to develop an Ebola vaccine, three leading pharmaceutical companies joined in. Dr. Hotez called for new actors, partnerships, and innovative models to advance R&D, lamenting that “our technical ability to make these innovations has outpaced our social, political, and financial instruments.” Further, Dr. Hotez challenged the notion that neglected tropical diseases (NTDs) are restricted to low- and middle-income countries, noting that 70 percent of NTD cases occur in G20 countries and that “there are 12 million Americans living in poverty with a neglected disease,” adding that neglected diseases are common but are “mostly striking the poor, mostly people of color, more in the American South.” Ambassador Jimmy Kolker discusses how HHS work contributes to both helping individuals overseas and protecting the health of Americans. (Photo: GHTC/Marissa Chmiola)The other panelists concurred, echoing that global health is American health. Panelist Dr. Patrick Kachur—principal deputy director of the Center for Global Health at the US Centers for Disease Control and Prevention (CDC)—made clear that CDC’s global health work is grounded in the agency’s responsibility to protect Americans. Ambassador Jimmy Kolker, assistant secretary for Global Affairs at the US Department of Health and Human Services (HHS), added that “over the next 50 years, the cost of lives and money to the global system of the threat of terrorism, climate change, and epidemics is in the same ballpark,” however, noting that what the US government is investing in fighting terrorism and climate change “so far outstrips what we’re doing in terms of outbreaks and epidemics.” Dr. Kachur called for enhanced coordination, stating “R&D is a whole-of-government and cross-sector affair.” Panelist Dr. David Shoultz—global program leader for Drug Development and Devices and Tools at PATH—furthered this point, noting that “innovation takes place within an enabling ecosystem, and in our context, that enabling ecosystem involves the NIH [National Institutes of Health], the FDA [Food and Drug Administration], HHS, the CDC, our close colleagues and friends at other product development partnerships, and private-sector participants.”In closing, Ambassador Kolker argued that the US government must continue to invest in R&D and consider “how the public sector can be the enabler of the private sector,” both to develop new health tools and to ensure the United States keeps its “competitive edge” as a leader in science and innovation. Dr. Shoultz agreed, stating that “US leadership [in global health] has mattered, it continues to matter, it will matter” in an increasingly globalized world and that investing in health research and innovation is “enlightened self-interest.”To watch the entire discussion, see below:

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.

Until very recently, no new class of antibiotics had been discovered in nearly 30 years. However, as antimicrobial resistance spreads, there is an urgent need for new antibiotics, particularly those that can treat infections resistant to existing drugs. In article in Health Affairs, Allan Coukell, senior director for health programs at the Pew Charitable Trusts, is calling on Congress to pass the Promise for Antibiotics and Therapeutics for Health (PATH) Act, which would permit the US Food and Drug Administration (FDA) to approve new antibiotics for use in limited patient populations with modified clinical trial requirements that would be determined by the agency itself. There is little financial incentive for antibiotic R&D as they are prescribed for short periods of time and as there is much competition among antibiotics. Conducting clinical trials, particularly for drug-resistant infections, is challenging: not only are these infections rare, but many patients are disqualified from participation due to compromised immune systems or pre-existing conditions. Additionally, the dearth of rapid tests results in many patients starting antibiotic regimens before being diagnosed with a drug-resistant infection. The PATH Act has passed the Senate Health, Education, Labor and Pensions Committee and was included in the 21st Century Cures Act, which passed the House of Representatives last year. Pharmaceutical company GlaxoSmithKline (GSK) announced that it will not file patents for its products in least developed and low-income countries, enabling manufacturers to produce and distribute generic versions of their medicines in 50 countries with a combined population of nearly 1 billion people. In lower middle income countries, GSK will continue to file patents but will offer ten-year licenses to generic manufacturers for a small royalty. GSK is also exploring innovative ways to increase access to its new and future cancer drugs through voluntary licensing via the Medicines Patent Pool, a United Nations–backed initiative that partners with patent holders and generic manufacturers to facilitate access to medicines. The Pool was founded in 2010, exclusively for HIV and AIDS drug patents, but has since been expanded to include tuberculosis and hepatitis C. The HIV virus mutates rapidly, and thus, standard approaches to vaccine development have not been successful. Rather, researchers have been testing and adapting antibodies—proteins targeting a specific pathogen—from patients, searching for the rare broadly neutralizing antibodies which are effective against manifold strains of the virus. Scientists at The Scripps Research Institute (TSRI) have now characterized the first “teenage” broadly neutralizing antibody, an immature version of the molecule, not yet effective against the HIV virus. The molecule was discovered by the Chinese Center for Disease Control and Prevention (China CDC). The team at China CDC collected blood samples from hundreds of HIV-positive patients, identifying those with the most effective anti-HIV antibodies. The patients were then monitored for five years, enabling the researchers to observe antibody development. Previously, scientists believed that broadly neutralizing antibodies matured over 10–15 years, however, from its teenage stage, this potent antibody developed rapidly in just 2 years. The researchers hope this discovery could inform HIV vaccine research and development by providing insight into how to prompt the human immune system to rapidly produce effective broadly neutralizing antibodies.