Breakthroughs Blog: Ebola

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. During the recent Ebola epidemic in West Africa, an experimental drug, ZMapp, showed promise in treating the disease, but with only enough doses to treat seven people, the drug’s true impact remained unknown. Now, results of a randomized control trial conducted during the outbreak indicate that ZMapp likely increases a patient’s chance of survival, but fall just short of statistical significance. The researchers hoped to enroll 200 patients across Liberia, Sierra Leone, and Guinea, however, as the number of new cases waned, so too did eligible participants for the trial. Ultimately, the team recruited only 72 participants, all of whom received the standard care for Ebola and half of whom also received ZMapp. Further complicating the results, many of the patients were enrolled after the virus had already caused irreparable tissue damage and did not survive long enough to receive all three doses of ZMapp. The results suggest high probability—91.2 percent—that ZMapp is effective against the virus and confirm the drug’s safety. ZMapp is composed of three antibodies against Ebola, and research is underway to develop improved antibodies which could enhance the drug’s efficacy. Viruses are constantly mutating, and often incorporate genes from the organisms they infect—viruses that infect bacteria often have bacterial DNA and viruses that infect animals often have animal DNA. The WO virus targets the bacteria Wolbachia, which in turn targets spiders and insects. Consequently, when researchers at Vanderbilt University sequenced the genome of WO, they expected to find snippets of Wolbachia DNA. Instead, they found that one third of WO’s genes came from the arthropods that Wolbachia infects. Further, WO contains genes for latrotoxin, the chemical cornerstone of the venom found in black widow spiders, a particularly surprising discovery as latrotoxin has never been reported outside of spiders. The scientists suspect WO’s unique evolution relied on the way Wolbachia intertwines itself with animal cells, requiring WO to drill through the animal cell membranes to reach the bacteria. Zika virus, first discovered in 1947, was long considered innocuous, rarely reported in humans and associated with a mild infection. The virus raised concern, however, when scientists discovered its connection to microcephaly—a birth defect in which an infant’s brain does not develop properly, resulting in an abnormally small head. Now, one year after a spike in microcephaly cases in Brazil led to this important discovery, infants with what’s been deemed congenital Zika syndrome are coping with a range of devastating symptoms not usually reported in infants with microcephaly, including seizures, impaired vision and hearing, difficulty swallowing, and arm and leg deformities. Additionally, some infants have presented with neurological and physical defects despite having normal-sized heads and others still have developed microcephaly after birth, as the growth of the head has not kept up with that of the body.

Scientists have devised a Trojan horse strategy to prevent the Ebola virus from infecting human cells. To infect humans, the virus binds to the surface of a human cell, enters the cell, and then binds to the protein Niemann-Pick C1 (NPC1). Once it binds to NPC1, the virus can start replicating and spreading throughout the body. Consequently, the researchers first engineered two antibodies: one that targets the human protein NPC1 and another that targets the viral protein that binds to NPC1. However, they needed a Trojan horse: a molecule that could deliver the antibodies to the scene of the crime, deep inside human cells, where the virus binds to NPC1. The solution? The team synthesized each antibody with a third antibody that binds to the surface of the Ebola virus. In short, the team created two molecules by combining the antibody that could latch onto the virus with two antibodies that could prevent the virus from infecting human cells. Both combinations proved effective in the lab against all five strains of the Ebola virus and in mouse trials, one of the molecules effectively treated infected mice. Next, the molecules will be tested in nonhuman primates. A recent piece in STAT takes an in-depth look at the critical advances in hepatitis C research that paved the way for the development of Sovaldi, the first drug proven to cure hepatitis C. Hepatitis C was first discovered in 1989, however, the virus is notoriously difficult to reproduce in the lab. Consequently, the time and cost of producing the virus hindered research. Ralf Bartenschlager and Charles Rice, researchers at the University of Heidelberg and Rockefeller University, respectively, determined that certain mutations of the virus enabled select strains of the virus to survive in the lab, and engineered versions of the virus—deemed “replicons”—with those mutations. Using these replicons, drug companies were able to rapidly screen the efficacy of different compounds in combatting hepatitis C. Among these companies, the small biotech firm Pharmasset developed a particularly promising drug, which was eventually—after the company was acquired by Gilead Sciences—approved and marketed as Sovaldi. The drug became the first cure for Hepatitis C, however, its price tag of up to US$94,000 for the full regimen has impeded access to it. While existing evidence suggests that Zika infection has the greatest impact on fetal brain development during the first trimester of pregnancy, new research indicates that infection later in pregnancy can still have a devastating impact. Scientists at the University of Washington infected a pregnant monkey with the virus at the beginning of her third trimester, and in less than a month, significant damage to the fetus was reported: both the white matter in the brain and the head itself stopped growing. However, the team administered the virus in higher doses than would be found in individual mosquitoes, and researchers at the University of Wisconsin-Madison, who used lower doses, found no fetal brain damage after infecting four pregnant monkeys.

The US National Institutes of Health (NIH) announced the Antimicrobial Resistance Diagnostic Challenge last week, a competition which will award US$20 million for the development of rapid, point-of-care diagnostics to combat antimicrobial resistance. The competition will be funded by NIH's National Institute of Allergy and Infectious Diseases and the US Department of Health and Human Services’ Biomedical Advanced Research and Development Authority, while the US Centers for Disease Control and Prevention and the US Food and Drug Administration will provide scientific and regulatory expertise. Eligible diagnostics are those that either test for drug-resistant bacteria or differentiate between viral and bacterial infections, critical tools to reduce ineffective and unnecessary antibiotic prescriptions. The recently launched Coalition for Epidemic Preparedness Innovations (CEPI) will fund early stage human clinical trials and stockpile vaccine candidates for the viruses most likely to cause the next major epidemic. CEPI will collaborate with product developers and the World Health Organization (WHO) to facilitate regulatory review of vaccine candidates and to ensure that large scale clinical trials can be rapidly rolled out in the case of an outbreak. Eligible vaccine candidates will target viruses identified by the WHO as the greatest threats, including Crimean Congo hemorrhagic fever, Ebola and Marburg, Lassa fever, Rift Valley fever, Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS), and Nipah virus. The coalition was formed by the governments of India and Norway, philanthropic organizations the Wellcome Trust and the Bill & Melinda Gates Foundation, and the World Economic Forum and will be housed at the Norwegian Institute for Public Health in Oslo. The International Vaccine Institute (IVI) is partnering with Xiamen Innovax Biotech Co., Ltd. (Innovax) to expand access to the world’s first and only vaccine against Hepatitis E—a viral disease that causes 20 million infections and results in 70,000 deaths and 3,000 stillbirths each year. The vaccine, Hecolin®, was developed by Innovax and is only licensed for use in China. The Gates Foundation will support an assessment of the vaccine to determine its eligibility for WHO prequalification—a process that evaluates the safety, efficacy, and quality of a specific health tool produced by a specific manufacturer and that enables the product to be purchased by United Nations agencies. Hecolin® offered complete protection against hepatitis E in a phase 3 clinical trial with more than 100,000 participants. Pharmaceutical company Takeda has initiated a phase 3 clinical trial of its vaccine candidate against dengue fever, a mosquito-borne infection caused by four closely related viruses. Last year, pharmaceutical company Sanofi launched the world’s first dengue vaccine, however, new research suggests that the vaccine could actually increase the severity of infections in children who have never been exposed to dengue. This is due to antibody-dependent enhancement, in which protective antibodies against a virus (in this case, one strain of dengue virus) can actually help related viruses (the other three strains of dengue virus) attack human cells. Consequently, the antibodies produced by children receiving the vaccine could actually exacerbate the symptoms of future infections. In phase 1 and 2 trials, Takeda’s vaccine candidate appeared to be safe and resulted in the production of antibodies against all four strains of the virus. For its phase 3 trial, Takeda plans to enroll 20,000 children in dengue-endemic nations in Latin America and Asia. The trial will evaluate safety and efficacy against all four strains of dengue and in children with and without prior exposure to the virus.

Penicillin, the world’s first antibiotic, works by targeting certain proteins—appropriately named penicillin-binding proteins (PBPs)—that play a critical role in building and maintaining the bacterial cell wall. Now, scientists at Harvard Medical School have identified another class of proteins which play a similar role and could be a target for the next generation of antibiotics. The road to discovery started in 2003, when it was determined that certain bacteria could grow without PBPs. In their absence, the proteins responsible for maintaining cell wall shape, elongation, division, and spore formation (SEDS proteins) continued to function normally, enabling the bacteria to thrive. SEDS proteins are found in more types of bacteria than PBPs, and consequently a treatment targeting SEDS proteins could have even broader application than penicillin. On February 22, the Obama Administration requested US$1.9 billion in emergency funding for the Zika response, and 181 days later, Congress has yet to approve it. Consequently, the Department of Health and Human Services (HHS) has shifted $81 million from other programs to support Zika vaccine research and development—$34 million of which will go to the National Institutes of Health (NIH) and $47 million of which will be allocated to the Biomedical Advanced Research and Development Authority (BARDA). Earlier this year, HHS repurposed $589 million in funding from the Ebola response to combat Zika, however, that funding will run out by the end of this month. The NIH will use its funding for human clinical trials of its leading Zika vaccine candidate, however, the agency will need an additional $196 million for additional trials and to advance a second and third candidate. BARDA’s funding will enable the agency to secure contracts and establish partnerships for Zika vaccine development, however, an additional $342 million will be required to continue its work. New research suggests that infection with the Plasmodium parasite, which causes malaria, could reduce the severity of Ebola infection. A team of scientists at the US National Institute of Allergy and Infectious Diseases has examined 1,868 blood samples from an Ebola treatment unit in Liberia—1,182 of which tested positive for Ebola—concluding that patients co-infected with malaria were 20 percent more likely to survive. These results held true even when controlling for the patient’s age and viral load. Viral load actually correlated with survival rates: those with the highest levels of Plasmodium had an 83 percent survival rate, compared to 46 percent of those only infected with Ebola. At the treatment center, all patients were provided with antimalarials, and consequently, treatment for malaria was not responsible for survival rates. While the reason for this trend remains a mystery, Drs. Emmie de Wit and Kyle Rosenke—the study’s lead scientists—suspect that an existing malaria infection expedites the immune response to Ebola, consequently increasing survival rates.