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In the fight against tuberculosis (TB), October 2016 will be remembered best as a month that delivered two sobering wakeup calls. First, the World Health Organization (WHO)—citing new surveillance data released by the Indian government—announced that the TB epidemic is larger than previously estimated: TB killed 1.8 million people and caused 10.4 million to fall ill in 2015. Second, Treatment Action Group (TAG) released its 11th annual Report on Tuberculosis Research Funding Trends, showing that funding for TB research and development (R&D) in 2015 fell to its lowest level in seven years, declining by US$53.4 million from the prior year. This juxtaposition between rising estimates of TB mortality and morbidity and diminishing investment in the research required to overcome TB suggests that countries have yet to mobilize in pursuit of the ambitious targets of WHO’s End TB Strategy, which sets a vision to achieve a world free of TB by 2035. The action needed is clear: governments must make deliberate, concerted efforts to overcome the deep funding deficit inherited from the five years preceding the End TB Strategy’s launch. The Stop TB Partnership’s Global Plan to Stop TB, 2011–2015 estimated that the world needed to spend $9.84 billion on TB R&D between 2011 and 2015 to enable the scientific advances in TB prevention, diagnosis, and treatment required to end TB as a public health threat. TAG’s most recent report presents new data on TB research funding in 2015, the fifth and final year of the Stop TB Partnership’s 2011–2015 Global Plan, and, in closing out this five-year reporting period, provides a report card on the plan’s financial and scientific milestones. By both measures, reality fell far short of aspiration. Worldwide, funders invested $3.29 billion in TB R&D from 2011 to 2015, amounting to just one-third of the $9.84 billion target. Instead of narrowing the funding gap, over the five-year period, global investments stalled or fell. Funding declined in three of the past five years, dropping by $36.5 million in 2012, $12.3 million in 2014, and $53.4 million in 2015 (in relation to prior year). The period ended with a lower level of funding than it started ($620.6 million spent in 2015 compared to $675.3 million in 2011; see figures 1 and 2). Compounding this instability, the TB research field remains in the precarious position of relying on just a handful of donors; 57 percent of funding from 2011 to 2015 came from just two organizations—the US National Institutes of Health and the Bill & Melinda Gates Foundation. Over the same period, pharmaceutical industry investments in TB R&D decreased by 40 percent, dropping from $145 million in 2011 to $87 million in 2015.   In addition to tracking funding for TB research, TAG analyzed progress in TB diagnostic, drug, and vaccine development. In each field, advances over the past five years came up short against the 2011–2015 Global Plan’s scientific goals (see figures 3 through 5). For example, TB drug developers set a goal of ending 2015 with 21 compounds in phase 1 clinical trials; in fact, the year ended with only 2. Disappointing results published in 2013 from a phase 2b trial of TB vaccine candidate MVA85A meant that instead of advancing four vaccine candidates into phase 3 trials by the end of 2015 as envisioned, the TB vaccine field redirected efforts to earlier stages of discovery and clinical development. TB diagnostic developers made greater progress, but still ended the period without satisfying the goal of delivering a new test capable of diagnosing drug-resistant TB (DR-TB) in peripheral labs and a test able to predict an individual’s risk of progressing from TB infection to active TB disease. Despite these scientific disappointments and financial shortfalls, the TB research field managed to make several significant advances over the five years including: Conditional approval of two new drugs from novel classes to treat DR-TB (Janssen’s bedaquiline and Otsuka’s delamanid), the first such novel drugs in over four decades. The development of a shorter regimen (3HP) for treating latent TB infection that is safe and efficacious in children and people with HIV and AIDS. The development of several new diagnostic tests, including the rollout of a rapid alternative to smear microscopy (GeneXpert), a simple test (Determine LAM TB) that can identify TB in people with HIV who have very low CD4+ T-cell counts, and several options for diagnosing first- and second-line drug resistance faster than conventional culture (line probe assays). Intensified efforts to study the safety and pharmacokinetics of first- and second-line TB drugs in children. •Significant advances in fundamental understanding of TB biology. Building on these successes in the post-2015 period and putting research on track to meet the long-term goals of the End TB Strategy will require a massive step-up in funding. Most of this additional money will need to come from governments, and this responsibility must be shared by all countries—developed and developing, those with high TB burdens, and those already approaching TB elimination. To this end, TAG has embarked on two advocacy drives to increase public funding for TB research. First, in June 2016, TAG published a policy brief setting the first-ever US government targets for TB R&D funding. The brief calls for US government agencies to spend $300 million on TB R&D by 2017 (enough to pull even with inflation and match 2009 purchasing power) and $400 million by 2020 (enough to outpace the rising costs of biomedical research and increase funding for TB R&D by $72 million in real terms over 2009). Second, TAG is petitioning leaders of the BRICS countries—Brazil, Russia, India, China, and South Africa—to triple their funding for TB R&D, echoing demands first voiced by the hundreds of people who marched with Treatment Action Campaign in support of TB research in Cape Town, South Africa, in December 2015. As those marchers pointed out, the BRICS countries are home to nearly half of the world’s new TB cases and deaths, yet only provide 4 percent of reported funding for TB R&D. We’ll deliver the petition to BRICS country ministers of health when they meet in New Delhi, India, at the 6th Meeting of the BRICS Health Ministers in December 2016. 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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.

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.