Breakthroughs Blog: Ebola

New research suggests that viral hepatitis is a leading infectious disease killer, resulting in 1.45 million deaths in 2013, more than HIV and AIDS and just short of tuberculosis, which killed 1.2 and 1.5 million in 2014, respectively. Five viruses—hepatitis A, B, C, D, and E—cause the disease, and a new World Health Organization (WHO) strategy seeks to reduce new cases of hepatitis B and C—responsible for the most deaths worldwide—by 30 percent over the next four years. Vaccines are available against hepatitis A and B, and new treatments, including cures, against hepatitis C are on the market and under development, although treatment costs remain prohibitive. The WHO is calling for expanded vaccination efforts and treatment coverage, as well as prevention of mother-to-child transmission of hepatitis B. The US National Institute of Allergy and Infectious Diseases is partnering with the Ministry of Health of Liberia and pharmaceutical company Gilead Sciences to test drug candidate GS-5734 in adult male survivors of Ebola, with the goal of eliminating the virus from the body. Since 2014, more than 28,000 cases of Ebola have been reported in West Africa, and survivors continue to experience a range of symptoms. The virus persists in the blood and semen, and at least one resurgence of the outbreak was due to transmission from a healthy survivor. The drug has proven safe for use in humans and effective against the virus in animals. During the six-month trial, 120 adult male survivors will receive either the drug candidate or a placebo, and will provide blood and semen samples, which will be examined for presence of the Ebola virus. Researchers at the University at Buffalo are developing a vaccine delivery system using innocuous strains of the Escherichia coli (E. coli) bacteria—many of which actually aid in human digestion. The team created a synthetic capsule with an E. coli core to deliver an investigational vaccine against pneumococcal disease. The vaccine effectively caused an immune response and protected against sepsis and pneumonia in mice. Both the vaccine and delivery system are being commercialized by biotech startup Abcombi Biosciences Inc., founded by Dr. Charles Jones, a co-author on the study and a former student of the study’s lead author, Dr. Blaine Pfeifer, a professor of Chemical and Biological Engineering at the University of Buffalo.

Just one case of yellow fever in an unvaccinated population is considered an outbreak, according to the World Health Organization (WHO). And now, an outbreak in Angola has spread to Kinshasa, a city of 12 million in the Democratic Republic of Congo. Health experts are calling it the worst yellow fever outbreak in Africa in decades. The outbreak in Angola has resulted in nearly 350 deaths, and unrelated outbreaks are ongoing in Uganda and Peru. Meanwhile, the WHO’s emergency stockpile of the yellow fever vaccine—the only available countermeasure against the virus—has been depleted twice this year, and is currently running low at only 6 million doses, raising concerns about global ability to respond to growing outbreaks.Background: The illness and impact of a historic virus Yellow fever is a mosquito-borne disease—spread by both the Aedes and Haemogogus species—found in both urban and rural settings. The disease is endemic in forty-seven countries across Africa and Latin America, and each year results in anywhere from 84,000 to 170,000 severe cases and 29,000 to 60,000 deaths. Many cases of yellow fever are asymptomatic, and when they manifest, initial symptoms are nonspecific: fever, fatigue, aches and pains, nausea, and vomiting. Fifteen percent of cases progress to a more severe illness  characterized by high fevers, liver and kidney damage, jaundice—thus the name yellow fever—and even hemorrhaging. Half of those who enter this toxic stage of infection die. While the yellow fever virus has plagued the world since the 17th Century, it was first isolated in 1900 by American pathologist Walter Reed, earning it the distinction of being the first human virus ever to be discovered. A safe and effective vaccine was first introduced in 1936; however, in the eight decades since, few new tools against the virus have been developed. Below, we break down the status of research and development (R&D) for vaccines, drugs, and diagnostics for yellow fever.Status of R&D and access to yellow fever countermeasures Vaccines Yellow Fever vaccine manufacturing facility Val de Reuil Sanofi Pasteur site, France (Photo: Sanofi Pasteur / Patrick Boulen)The yellow fever vaccine is effective, safe, and affordable. Just one dose provides lifetime protection from the virus for 99 percent of those vaccinated. However, the vaccine contains live virus, and in extremely rare cases, can result in illness. Since 2000, the price of the vaccine has risen 30 percent annually. However, this increase has not incentivized manufacturers to scale up production. There are only four manufacturers of the vaccine, and it’s notoriously difficult to produce. Consequently, the global demand for the vaccine surpasses availability by 42 percent. Yellow fever vaccine production relies on eggs from pathogen-free chickens flocks, which are hard to come by. The embryos are infected with the yellow fever virus, and after three to four days, the embryos are harvested under sterile conditions. Each egg can provide anywhere from 100 to 300 doses of the vaccine. The entire production process takes about one year. A vaccine candidate with an inactivated version of the virus completed successful phase 1 clinical trials in 2011. However, since GE Healthcare acquired the intellectual property for the vaccine in 2012, no additional clinical trials have been undertaken. Fortunately, last month PnuVax Incorporated entered into an agreement with GE Healthcare, under which PnuVax will advance the vaccine through clinical trials and will partner with GE Healthcare for manufacturing. In the meantime, the WHO is recommending that the vaccine be administered in fractional doses, using just one-fifth of the standard amount. Studies suggest that this approach still confers at least 12 months of protection from the virus, however, booster shots would be required to sustain immunity when a global shortage is no longer imminent. Additionally, fractional dosing has not been tested in children, raising concerns that this approach might not be sufficient for kids, whose immune responses, including to vaccines, are typically weaker. Drugs There are no specific therapies for yellow fever. Current treatment involves supportive care (i.e., addressing the symptoms). Animal studies suggest that the widely-used antiviral ribavirin and an active carboxamide drug reduce mortality in hamsters, and the molecule interferon-α, used in some cancer therapies, effectively treats the disease in monkeys. However, these treatments were only effective when administered within a few days of infection. Thus, even if they were to prove effective in humans, their application would be limited. The yellow fever virus incubates for three to four days in the body before symptoms appear, and as aforementioned, initial symptoms are nonspecific and easily confused with anything from malaria to dengue fever or leptospirosis to poisoning. Diagnostics As yellow fever is hard to distinguish from other illnesses based on initial symptoms alone, the development of rapid, point-of-care diagnostics is critically needed. Currently, cases can only be confirmed in laboratory settings. Diagnosis requires examining blood or serum for either the virus itself or antibodies against the virus. However, researchers at the Massachusetts Institutes of Technology are currently developing a paper-based diagnostic that simultaneously tests for Ebola, dengue fever, and yellow fever. The test is designed for use in low-resource settings, requiring no electricity or specialized lab equipment and the results are easy to interpret. Testing requires a small amount of blood, and colored nanoparticles appear—red for Ebola, orange for yellow fever, and green for dengue—based on the proteins in the blood. While this new tool is showing promise, it could be some years before testing is completed and regulatory approval is secured. With a limited pipeline of countermeasures against yellow fever, the global community is scrambling to ramp up vaccine production, expand vaccination coverage, and scale up vector control efforts. However, R&D for rapid, point-of care diagnostics; lifesaving treatments; and a safe, affordable, easy-to-produce vaccine is critical to combat this virus after a centuries-long battle.

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.

The dapivirine ring (Photo: International Partnership for Microbicides) GHTC member the International Partnership for Microbicides (IPM) announced last week the results of two phase 3 clinical trials demonstrating that a monthly vaginal ring filled with the antiretroviral drug dapivirine can reduce the risk of HIV infection in women. The dapivirine ring is the first long-acting HIV prevention method designed for women, and IPM plans to seek regulatory approval for the product. The trials, conducted by IPM and the Microbicide Trials Network (MTN), enrolled 1,959 and 2,629 HIV-negative women and reduced infection rates by 31 and 27 percent, respectively. Efficacy rates were affected by participant age and adherence: for women over 21—who reportedly used the ring more consistently—the dapivirine ring reduced HIV infections by 37 and 56 percent in the trials led by IPM and MTN, respectively. As IPM Founding Chief Executive Officer Dr. Zeda Rosenberg stated, “These findings give new hope to many women at high risk who need more and different options to effectively protect themselves from HIV.” Researchers at the Scripps Research Institute (TSRI) and the US Army Medical Research Institute of Infectious Diseases have discovered potent antibodies against Ebola that could play a critical role in the research and development (R&D) of Ebola vaccines and treatment. The team identified 300 different antibodies against Ebola in the blood of a survivor, using molecules developed by TSRI to hunt for antibodies. Seventy-seven percent of the antibodies were able to combat the virus in mice, providing protection rates ranging from 60 to 100 percent. The three strongest antibodies all targeted distinct vulnerable spots on a certain protein found on the virus’ surface. Anti-Ebola antibodies have been used before, including in ZMapp™, an experimental treatment deployed during the 2014 Ebola outbreak. However, the number of known, effective antibodies was previously limited. This research also revealed a weak spot on the base of the aforementioned Ebola surface protein. As the virus mutates, so do the surface proteins. However, the base of these proteins remains largely the same, and thus, a weak spot on the base of the protein could be a potential target for manifold strains of the virus. US President Barack Obama is calling on Congress to allocate an additional US$200 million for the President’s Malaria Initiative (PMI), a 30 percent increase that would bring the Initiative’s budget to US$874 million. The funding would enable PMI to expand into three new countries—Sierra Leone, Cote D’Ivoire, and Cameroon; eliminate malaria in Zambia and Cambodia; scale up the use of bed nets; and advance R&D for vaccines, drugs, diagnostics, and vector control methods. As resistance grows to both malaria treatments and insecticides, the need for R&D remains critical. Further, resistance to the leading antimalarial was first reported in Cambodia and the most virulent strains are found on the border between Cambodia and Thailand. Thus, eliminating malaria in Cambodia would impede the global spread of drug resistance. With this new funding, PMI would be able to reach an additional 70 million people, ultimately reaching 92 percent of those in malaria endemic regions.