Breakthroughs Blog: Zika

The North Dakota–based SAB Biotherapeutics, Inc. has devised a way to elicit the production of human, disease-fighting antibodies in cows. Antibodies, which are produced by the immune system in response to an infection, recognize and eliminate specific pathogens. Antibodies have long been used in medicine: in the recent Ebola outbreak, antibodies from survivors were used to treat new patients. While humans can only produce 4 liters of antibodies per month—enough to treat three patients—cows produce 30 to 60 liters per month. Researchers have tried to use several mammals to produce antibodies for use in humans, but the immune system sees animal antibodies as foreign, resulting in an allergic reaction. Now, the team at SAB Biotherapeutics has designed a strategy in which cows’ antibody-producing genes are replaced with human genes. Consequently, when a cow is infected with a pathogen, it produces human antibodies in response. The company is currently testing the technology, evaluating its ability to produce antibodies against Middle East Respiratory Syndrome (MERS). While it may not be available for three to five years, the World Health Organization has already recognized the platform as one of the six most promising approaches for pandemic preparedness. The Zika virus has made headlines for its devastating impact on fetal development, and the global response has consequently focused on women who are or may become pregnant. However, new research suggests that the virus may not be so mild in men. In humans, the virus can remain in semen for up to six months, and a recent study in mice reveals that the continued presence of the virus can damage cells that are critical to reproduction. The research team at Washington University in St. Louis, Missouri, infected male mice with Zika, and within three weeks, their testes shrunk to one-tenth their original size; the seminiferous tubules—critical to producing new sperm—were damaged; and the Sertoli cells—involved in sperm growth—were dwindling in number. Ultimately, infected mice had lower sperm counts and sex hormones and were only able to impregnate a fraction of the female mice compared to their healthy counterparts. Further research is needed to determine whether Zika has the same impact on the reproductive system and fertility of human males. New drugs have made hepatitis C curable, but researchers continue to hunt for a preventative vaccine since treatment is prohibitively expensive for many patients and the virus often causes irreparable liver damage by the time of diagnosis. One protein on the surface of the virus—E2—has been a target for many vaccine candidates, however, despite its ability to induce an immune response, the protein has not successfully protected against the virus in either animal or human trials. By precisely mapping and analyzing the structure of E2, scientists at The Scripps Research Institute have discovered that E2 is an unusually flexible protein. As E2 morphs, the immune system produces an assortment of antibodies to match its dynamic shape, many of which are ineffective against the virus. Now, the team is engineering a synthetic, stable version of E2 that will generate a batch of similar, highly-effective antibodies to protect against infection.

A key target of the HIV virus is immune cells known as T cells. The virus infects T cells and hijacks the cell’s genetic machinery, enabling it to multiply and spread throughout the body. However, some T cells have genetic mutations that protect against HIV infection, and scientists at University of California, San Francisco (UCSF), are using CRISPR—a novel approach to gene editing—to insert these protective genetic mutations into ordinary T cells. First, the team used CRISPR to rapidly identify all T cell genes involved in HIV infection. Next, they inserted 149 different genetic mutations into T cells, 6 of which successfully blocked the virus. Eventually, the researchers hope that one or more of these mutations could be developed into a drug to prevent or treat HIV and AIDS. Biotech company Sangamo Biosciences is currently testing one such gene mutation that in early results appears to lower the viral load of participants. However, other studies suggest that the virus may be able to outsmart this approach, mutating until it is able to infect T cells. Consequently, an effective treatment may need to elicit multiple gene mutations in T cells, either concurrently or sequentially. Over the past five years, the Eliminate Dengue Program has released mosquitoes infected with the innocuous Wolbachia bacteria into small communities in Colombia, Brazil, Vietnam, Indonesia, and Australia. The bacteria colonizes a multitude of insect species, and while it doesn’t harm the Aedes aegypti mosquito—which spreads Zika, dengue, and yellow fever—it does prevent these viruses from replicating and blocks further transmission. Wolbachia is passed down from generation to generation of A. aegypti with each generation only living for a few weeks. Consequently, within weeks of releasing Wolbachia-infected mosquitoes into the wild, disease transmission drops drastically. Now, Eliminate Dengue will be conducting two large-scale trials in Bello, Colombia, and Rio de Janeiro, Brazil, to determine if this approach can successfully combat mosquito-borne illnesses in urban areas home to millions. The trials are funded by the United States and United Kingdom governments and philanthropic organizations the Wellcome Trust and the Bill & Melinda Gates Foundation. The highly drug-resistant Methicillin-resistant Staphylococcus aureus (MRSA) bacteria is only susceptible to a few, last-resort antibiotics, including daptomycin, which is effective against two-thirds of MRSA infections. Now, scientists at Imperial College London have discovered how the remaining one-third of MRSA infections evade antibiotics. The bacterial cells use chemical signals to communicate with one another, however, some cells can shut down this communication system. Once that system is deactivated, the bacterial cells are able to produce decoys—molecules that have a similar outer layer to the bacteria, and consequently are targeted by the antibiotics. Thus, the antibiotics are wasted on the decoy cells and the bacterial cells are able to thrive. These findings could pave the way for new ways to treat MRSA, by combining daptomycin with a drug that interferes with the decoy system. Currently, clinical trials are underway to test such an approach, combining daptomycin with approved and experimental antibiotics that impede either the production or release of decoy molecules.

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.