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Priti Patel visits dispensary in Togo. Photo: Rob Oxley/DFIDLast week, the United Kingdom’s (UK) Department for International Development (DFID) released it’s first-ever research review, laying out a vision for how it will invest £390 million in research and technology per year over the next four years to tackle the world’s toughest challenges—including committing £357 million to support research and development (R&D) for infectious diseases through the Ross Fund. DFID’s new head Priti Patel released the review during a speech at the annual Grand Challenges Meeting in London. The occasion marked the first time Patel has provided public detail on her plans to prioritize research during her tenure. What does the review do?The review sets out a to-do list for DFID and provides details on how the department will target ongoing investments in research and technology to tackle development challenges. Notable highlights from the review include commitments to: Continue to invest 3 percent of the annual DFID budget in research. Spend an average of ₤390 million per year over the next four years on research, including a ₤357 million investment on research on infectious diseases through the new Ross Fund. Coordinate across the government and with other stakeholders to ensure UK development to maximize the impact of research investments.  A key theme throughout the review is the importance of high quality research to drive better development outcomes and value for money. Highlighted among the review findings is the high return on investment of DFID’s R&D activities, which are expected to deliver an annual internal rate of return of 10 percent across the portfolio. One priority development outcome outlined by DFID is using research to understand how to build foundations for economic development in low and middle income countries—including through trade, innovation and private-sector growth—shedding light on Patel’s vision for using her budget to spur future trade. During the announcement of the review, Patel also noted that, “As countries develop and leave aid dependency behind they will increasingly turn to the UK, not for financial resources, but for its intellectual leadership and scientific expertise.” Role of the Ross FundPriti Patel visits dispensary in Togo. Photo: Rob Oxley/DFIDA major priority outlined in the review will be scaling up the UK’s commitment to accelerate the development of new technologies to eliminate infectious diseases through the Ross Fund. Announced last year and laid out in the UK’s new AID Strategy, the Ross Fund is a cross-government portfolio of programs made up of both new and existing global health R&D projects. As currently laid out, the Ross Fund will focus on the development of new health technologies to combat serious diseases in developing countries, including antimicrobial resistance, emerging diseases with epidemic potential, and neglected tropical diseases that threaten more than one billion people. As the fund is co-managed by both DFID and the Department of Health, questions remain around the role it will play in prioritization of new investments and coordination of projects across the government.R&D in the context of BREXITWhile DFID has proven itself as a world leader in global health R&D, the new era of Brexit has raised questions among advocates and politicians alike about how DFID’s development activities might be impacted and how the UK will maintain its reputation as a global leader in science and technology innovation. Over the summer, the UK Parliament’s Science and Technology Committee conducted an inquiry exploring the implications of Brexit on the UK’s science and technology activities and ongoing relationships with international research institutes. Valid concerns, like how the UK will continue to attract top scientific talent and how the research community will remain strong without investment from the European Union (EU), are still unanswered.While many questions still remain—and the UK has yet to declare Article 50, which officially initiates the process to separate from the EU—all signals point to the fact that the UK plans to honor its longstanding commitment to aid and continue to make critical contributions to advancing science and technology. In her first round of parliamentary questions since taking over as head of DFID, Patel reaffirmed the UK’s commitment to spend 0.7 percent of GDP on aid. Additionally, the research review signals that DFID is intent on playing its part to ensure that the UK remains a leader in innovative research to advance global health. What’s next?The research review marks the first of a series of reviews that DFID will be releasing. In the coming weeks, DFID is expected to release a multilateral aid review, a bilateral aid review, and a civil society partnership review, shedding further light on how its aid budget is being spent and what ongoing priorities will be for the department.

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.