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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.