Kat Kelley

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.

While overuse of antibiotics is often cited as a leading contributor to the development and spread of drug-resistant bacteria, recent studies reveal that pollution from antibiotic manufacturing plants in India and China is also playing a role. The wastewater released from these manufacturing facilities contains active antimicrobial ingredients, and in some cases, higher concentrations of these compounds are found downstream from these facilities than is found in patients currently taking antibiotics. One type of bacteria can acquire from another type of bacteria genes that confer resistance to a certain drug. Consequently, resistance is spreading rapidly in wastewater treatment plants in China—for every bacterium that goes into the plants, four to five drug-resistant bacteria come out. To combat this dangerous trend, advocates are calling on the US government, drugmakers, pharmaceutical retailers, and consumers to put pressure on these plants to stop polluting using diplomatic tactics and purchasing power. Meanwhile, new data from the European Medicines Agency indicate that while sales of antibiotics for use in livestock has declined modestly in the European Union, sales have increased for many of the world’s strongest antibiotics, including last-resort treatments and those deemed by the World Health Organization (WHO) to be “critically important in human medicine.” Between 2000 and 2015, insecticides prevented nearly 500 million deaths from malaria, however, this remarkable progress could be upended as mosquitoes develop resistance to pyrethroids, the most commonly used class of insecticides. Pyrethroids have been around for nearly 40 years, and while resistance to this class first appeared in 1993, it has been growing rapidly over the past decade, which has resulted in increased transmission of the parasite in some countries. The pipeline for new insecticides is limited, particularly those that are safe for use in bednets. IVCC, a public-private partnership and member of GHTC, is catalyzing research to both develop novel insecticides and products that combine pyrethroids with other agents to combat growing resistance. The organization has partnered with several pharmaceutical companies and is screening their libraries of more than 4 million chemical compounds to identify the three most promising, which they will then test to determine not only safety and efficacy, but also whether they are long lasting (i.e., effective for at least three years and able to withstand 20 rounds of washing). Other entities have created bednets that combine pyrethroids with pyriproxyfen—which sterilizes the mosquitoes—and piperonyl butoxide—which could make resistance mosquitoes vulnerable to pyrethroids again. For the former, results from an evaluation will be released shortly, and for the latter, results of small trials have been encouraging, but larger, more rigorous trials are needed. The WHO recently convened pharmaceutical companies and humanitarian organizations with the goal of establishing a mechanism to facilitate the sale of low-cost vaccines during emergencies. Under the program, pharmaceutical companies would pledge to provide predetermined vaccines at the lowest price possible during crises such as natural disasters or wars. Currently, many of the targeted drugmakers have agreements with Gavi, the Vaccine Alliance, through which vaccines are purchased in high volumes at these rock-bottom prices. However, the proposed mechanism would limit sales to nonprofits, rather than governmental bodies, to ensure that the vaccines procured would only be deployed as part of a crisis response. GlaxoSmithKline has already agreed to participate, providing its vaccine against pneumonia—the leading cause of death for children under five—at a reduced price during emergencies. The WHO is working to engage additional drugmakers as it seeks to expand the mechanism to cover vaccines against 23 different diseases, including cholera, measles, yellow fever, and hepatitis.

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.

Each year, a new flu vaccine is developed, containing proteins from three to four strains of influenza. These proteins train the immune system to recognize different versions of the virus, enabling a rapid response in the case of infection. For the past eight years, the same strain of H1N1 (swine flu) has been included in flu vaccines globally, however, the World Health Organization has recommended this strain be replaced with a more recent version of the ever-changing virus. Normally, flu vaccines prompt the greatest immune response in healthy adults, however, since 2013, their efficacy has been decreasing in adults aged 30 to 60. The theory? Many of these adults were first exposed to H1N1 between 1977 and 1985, and the strains circulating at that time shared one critical component with those circulating between 2009 and 2013. Consequently, those who had been exposed to H1N1 between 1977 and 1985 responded to the flu vaccine as if it were a booster shot. Rather than producing entirely new antibodies tailored to the new version of the virus, their immune systems ramped up production of the existing antibodies tailored to the old version. In 2013, the virus mutated further, losing the component it shared with older strains, and thus, adults who experienced the booster shot phenomenon were no longer protected by the vaccine. Fortunately, experts have identified a new version of the virus, retrieved from a patient in Michigan, which should provide broader protection against H1N1 for future flu vaccines. A recent study out of South Africa suggests that one in ten children who are infected with HIV have no immune response to the virus and consequently experience none of the symptoms associated with HIV and AIDS. The researchers analyzed blood samples from 170 children who are HIV positive and have not received treatment, but nonetheless have not developed AIDS. The samples confirmed high volumes of the virus in the blood, and the lack of either an immune response or symptoms demonstrates, “HIV disease is not so much to do with HIV, but with the immune response to it,” according to Dr. Philip Goulder, an author of the study. This response—or lack thereof—has also been reported in more than 40 nonhuman primate species, but has not been seen in adults, who often have more aggressive immune reactions to pathogens. While limited, existing research indicates that some children with this protective attribute develop AIDS as they age, while others continue to display no symptoms. However, treatment may still be needed to prevent further transmission of the virus. SciDev.Net took an in-depth look at the European & Developing Countries Clinical Trials Partnership (EDCTP) and how its second iteration (EDCTP2) could be a catalyst for increased investments in health research and development (R&D) by African governments. EDCTP was launched in 2003 and ran through 2014, during which time it invested US$425 million into 254 collaborations between African and European scientists. The Partnership funded phase 2 and 3 clinical trials for HIV and AIDS, malaria, and tuberculosis. In 2014, EDCTP2 was established, expanding the scope to cover phase 1 and phase 4 (postmarketing surveillance) and to include other neglected infectious diseases. In just two years, EDCTP2 has mobilized nearly US$115 million. The role of the African member countries has been elevated in the second iteration—they have voting rights in the EDCTP General Assembly and have each pledged EUR€200,000 (US$224,000) to the Partnership.

This weekend, Kenya became the first country to roll out the world’s first and only pediatric tuberculosis (TB) medicines. TB infects one million children each year, resulting in 140,000 deaths, and yet, children have historically been treated with crushed up pills in estimated doses. The new formulations, which were developed by TB Alliance, are not only appropriately dosed for kids, but they are fruit-flavored and dissolvable—making them much more kid-friendly than a handful of bitter pills that must be swallowed. Kids must remain on treatment for six months, and the improved dose, flavor, and delivery are expected to have a significant impact on adherence to the regimen, preventing the development of drug-resistant strains. An additional 17 countries have placed orders and plan to introduce the medicines in the coming months. Vaccines and drugs could soon be manufactured on-the-go with the use of a portable, handheld kit developed by researchers at Harvard University. The kit contains all the ingredients needed to produce biologics (medical products derived from biological, rather than chemical sources): both the DNA that triggers the production of proteins to fight disease and the proteins that synthesize the final product. The DNA and proteins are freeze-dried into pellets, making them easy to store and transport, and with just the addition of water, the vaccine or therapy is ready to use. The team put the kit to work, successfully producing four different biologics, however, the vaccine candidate had to be purified before use. More research and testing is needed, and it could be more than a decade before such a system would be safe and appropriate for use in low-resource settings. Diarrheal diseases are a leading cause of death among children under five, and a new study suggests that 89 percent of cases are caused by pathogens. Further, 78 percent of cases are caused by just six pathogens, including rotavirus, Shigella, enterotoxigenic Escherichia coli (ETEC), Cryptosporidium, Campylobacter, and adenovirus. The researchers analyzed stool samples from more than 10,000 children under five, half of whom had diarrhea, to determine the leading causes of childhood diarrhea. Of the six, there is currently only a vaccine against rotavirus, however, GHTC member PATH is currently developing vaccines against Shigella and ETEC. Scientists are exploring whether the powerful antimicrobials created by certain species of ants could be used to fight infection in humans. Over the past 15 million years, more than 200 ant species have evolved to farm fungi—a symbiotic relationship in which the ants collect plants, feed them to fungi, and in turn, the ants feed off of the fungi. However, some ant species are vulnerable to hostile fungi that attack the ants’ nests and farmed fungi and have consequently adapted to fight off pathogens. These species cultivate bacteria—which appear as white patches along the ants’ bodies—that produce antibacterial and antifungal compounds. So far, the results have been encouraging: 1 in every 15 of these antimicrobial agents have proved promising in the lab, compared to just one in a million of those discovered through soil sampling.