News

Researchers at the US National Institutes of Health (NIH) have developed a test that can rapidly screen chemical compounds for their ability to treat drug-resistant infections. The team at NIH has already put the test to use, evaluating approved medicines, promising compounds, and drug combinations against common drug-resistant bacteria. After screening an estimated 4,000 drugs and compounds, the researchers identified 25 that effectively killed drug-resistant Klebsiella pneumoniae in the lab, including not only antibiotics, but also antifungals, antivirals, antiseptics, and even anticancer medicines. The test has also revealed three drug cocktails—each comprised of three different medicines—that can effectively treat ten common multidrug-resistant bacteria. These findings will enable clinicians to prescribe drug combinations with near certainty that they will treat a drug-resistant infection without waiting on lab results. While the tool is not yet commercialized, it can be mobilized to rapidly respond to emerging drug-resistant infections. A new study has revealed that during the 2014–2015 Ebola outbreak in West Africa, the virus evolved, enhancing its ability to infect humans. Previously, Ebola was thought by many scientists to be relatively static; however, researchers at the University of Massachusetts Medical School and University of Nottingham have independently identified a mutation in the Ebola genome—A82V—that appeared during the outbreak and could have made the virus two to four times more virulent. The mutation affects the cells on the surface of the virus that are responsible for infiltrating a host’s cells. For viral cells, shape matters, as it enables them to latch onto host cells like a key in a lock. The researchers suspect that A82V adjusts the shape of these surface proteins, allowing them to better fit into human cells. The mutation also enhances the virus’ ability to infect the cells of chimps and monkeys, while hampering its ability to infect bats, dogs, cats, rats, and mice. The team also discovered that patients with the new, mutated strain of Ebola were 27 percent more likely to die. Further research is needed to confirm this finding. Last week, the NIH and the Walter Reed Army Institute of Research (WRAIR) initiated clinical trials of an experimental Zika vaccine—the first of five phase 1 trials evaluating the vaccine. The vaccine platform was first used by WRAIR in developing a vaccine against Japanese encephalitis, a fellow flavivirus. The Zika Purified Inactivated Virus (ZPIV) contains complete, inactivated virus particles that will not cause disease but train the immune system to recognize and mount a robust response to the Zika virus. In preclinical trials, the vaccine candidate successfully induced an immune response and protected animals against the virus. The five phase 1 clinical trials will test the vaccine compared to placebos in different doses and schedules, as well as in different populations, including individuals previously exposed to flaviviruses (including Zika, yellow fever, dengue, Japanese encephalitis, and West Nile) and dengue, individuals who have received yellow fever or Japanese encephalitis vaccines, and those who have received the NIH’s experimental DNA-based Zika vaccine.

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. You can join the call by signing on here.

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.