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A new briefing paper from the Infectious Diseases Society of America Center for Global Health Policy explores the state of tuberculosis (TB) research and development (R&D) including challenges for products currently in the pipeline and gaps in TB research. The paper notes that existing TB diagnostic tools are not practical for low-resource settings, as the leading device is expensive and requires electricity and skilled health workers. Alternative diagnostic approaches are unreliable, missing nearly half of cases, and there’s a paucity of tools to detect drug-resistant strains. In terms of treatment, there is very limited access to novel drugs, due in part to delayed regulatory review and delivery. While the report notes that the “world still waits for a significant tuberculosis vaccine breakthrough,” more than a dozen experimental vaccines are currently being tested in clinical trials. New research suggests that malaria in pregnancy could impact fetal brain development, which is particularly concerning as pregnant women are at increased risk for malaria. The study, which was conducted in mice, suggests that a mother’s immune response to malaria disrupts the production of certain proteins involved in brain development, resulting in depression or cognitive disorders. Upon further investigation, the team was able to prevent the immune system disruption and successfully prevent any brain damage. While this approach would be impractical and too expensive for scale-up in humans in low-resource settings, the team plans to confirm the phenomenon in humans and search for a safe, affordable alternative. A patient with lymphatic filariasis (Photo: CDC) Last week, three researchers were awarded the Nobel Prize for Physiology and Medicine for discovery of artemisinin and avermectin, the leading treatments for malaria and two filarial diseases caused by roundworm parasites: lymphatic filariasis and onchocerciasis. Both treatments were identified in the 1970s and are currently facing challenges: resistance to artemisinin has been growing and avermectin treats the symptoms of these filarial diseases by killing the larvae, but is unable to kill the adult worms, ultimately requiring years of treatment. A team led by Professor Mark Taylor of the Liverpool School of Tropical Medicine is searching for new ways to treat filarial diseases by targeting Wolbachia, a bacterium that is critical to roundworms’ ability to both mature and elicit the symptoms associated with lymphatic filariasis and onchocerciasis. In the 1990s, Taylor’s team determined that the antibiotic doxycycline could combat Wolbachia, killing the adult worms in three-fourths of patients within 18 months. However, as ensuring access to doxycycline and retaining patients over 18 months can be challenging, Taylor’s team has been searching for alternatives through the Anti-Wolbachia Consortium (A-WOL), established in 2007 and funded by the Bill & Melinda Gates Foundation. A-WOL has facilitated the screening of nearly sixty thousand chemical compounds and is currently testing the antibiotic minocycline for treatment of lymphatic filariasis and onchocerciasis in Ghana and Cameroon. Early results suggest that minocycline, a more expensive drug, is 50 percent more effective than doxycycline. Neither are safe for use in children or pregnant women, however, Professor Taylor believes the team has enough drug candidates to overcome this challenge, as they’ve developed dozens of promising compounds to test further.

In this guest post, Dr. Monica Parise—deputy director for program and science—and Dr. Larry Slutsker—director of the Division of Parasitic Disease and Malaria—at the US Centers for Disease Control and Prevention (CDC) Center for Global Health—discuss the role of research in advancing efforts to detect, prevent, and eliminate parasitic diseases. Research is critical to preventing, detecting, and eliminating parasitic diseases. Photo: PATH/Gabe Bienczycki It’s an inspiring time for those of us working on parasitic diseases. Combined, the two of us have spent several decades working to address these infectious diseases that are major causes of death, disability, and suffering for millions of people. Since 2000, we’ve witnessed tremendous successes in reducing the devastating toll from malaria and several of the neglected tropical diseases (NTDs). None of this happened by accident. Sustained commitment from global partners, combined with unrelenting work and attention, has produced results. Massive scale-up of malaria interventions has saved more than 4.2 million lives since 2000, and globally, child deaths have fallen by 47 percent and in sub-Saharan Africa, by 54 percent. There has been similarly impressive progress in eliminating lymphatic filariasis, also known as elephantiasis, with an estimated 97 million cases prevented. We have also seen massive reductions in cases of Guinea worm disease, with only 126 cases from the four remaining endemic countries reported globally in 2014 compared to 3.5 million in 1986. Based on these gains, several NTDs, including lymphatic filariasis, onchocerciasis, and trachoma, have been slated for elimination within the next five years. Equally significant, the newly released Global Technical Strategy for Malaria calls for eliminating malaria in at least 35 new countries by 2030. But this progress is fragile. This is no time to be complacent. While the documented and real successes should be applauded, they’ve also produced a changing epidemiological landscape that has altered such things as the infection levels, where transmission still occurs, and other factors. Increasing resistance of parasites to drugs and mosquitoes to insecticides threatens to unravel progress in malaria elimination. NTD elimination programs are reaching a point where they now require better and different tools for making decisions about when to stop mass drug administration and how best to monitor for disease reoccurrence. To succeed we must adapt so that we keep pace with rapid changes in our foes—the parasites and their vectors. We must identify new tools and approaches to continue to achieve gains. That requires introspection and the willingness to occasionally stop and ask hard but essential questions. As scientists, as well as public health professionals, we constantly ask ourselves: Do we as a community have what it takes to get to the end? Do we have the information, tools, and interventions needed to successfully support a path to elimination? If not, what do we need to do about it? Over the past several months, the two of us, along with colleagues in CDC’s Division of Parasitic Diseases and Malaria, reflected on these challenges and considered possible solutions. The result is a set of strategic priorities to guide our work over the next five years. An important area of focus is research to develop new tools and approaches—to further drive down transmission, overcome technical challenges, and measure progress. We identified specific gaps that need to be addressed: Strengthening the evidence base to support elimination of malaria and NTDs: Additional guidance is needed to help define when a program should stop mass drug administration and transition from control to elimination strategies. Guidelines are also needed to identify which interventions are most appropriate in low transmission settings. Developing and evaluating tools and interventions targeting both the malaria parasite and its mosquito vector: Drug and insecticide resistance are forcing us to think about novel ways to battle those long-time foes, including evaluation of promising vaccines and novel vector control strategies such as spatial repellents—airborne chemicals that prevent human-vector contact with given space—and insecticide-treated durable wall linings. Malaria screening undertaken by community health workers. Photo: PATH/Lynn Heinisch Developing interventions to improve management of malaria cases: Achieving further reductions in malaria burden will require moving diagnosis, treatment, and risk mapping beyond the health facilities and community health workers providing clinical care, to developing strategies for population-based approaches such as focused screening and treatment, mass screening and treatment, and mass drug administration. Optimizing the effectiveness and mix of interventions: Whether it is a promising vaccine or a new method of vector control, no single intervention is likely to be a “magic bullet” for malaria control and elimination. Adding new tools and interventions into the mix of ones currently in use will require an understanding of which tools—used when and how—are needed. Evaluating the impact of parasitic disease control programs on other endemic diseases: Because individuals are commonly infected with more than one parasite or other disease-causing organism, opportunities and efficiencies exist for integrating interventions. Evaluating how parasitic disease control programs impact other endemic diseases can provide additional information on how to maximize resources and further integrate programs. Improving global research capacity for parasitic disease prevention and control through technical assistance and training: Ultimately, the goal is for governments and their academic partners in endemic countries to develop the capacity to lead research efforts to advance disease control and elimination within their own setting. The advancement of parasitic disease research is dependent upon strong research collaborations both with ministries of health and their partners in endemic countries and here in the United States. While adequate research infrastructure exists in some areas, there is a need to strengthen capacity through technical assistance and training that will facilitate collaborative research. We should celebrate the successes of the work so far that has saved millions of lives and eased suffering worldwide. But there is more—much more—to do. We must continue to scale-up existing technologies to sustain progress while at the same time advancing scientific research that will inform the way forward. With a strong base in science to support effective programs and policies, we are in a far stronger position to meet the challenges we face on the path towards elimination.

Photo: CDC/ Melissa Dankel A new study conducted by the Malaria Genomic Epidemiology Network (MalariaGEN)—a community of researchers across malaria-endemic regions—reveals a formerly unknown genetic variations that make people less susceptible to malaria. The team collected over 20,000 samples from across sub-Saharan Africa, and have identified a genetic variation that provides 33 percent protection against malaria (although the rate varies across populations) as well as dozens of additional genes that appear to have some connection to natural resistance to the disease. The location of these genetic mutations in the human genome is near a region unusually similar to the chimpanzee genome, which suggests that these mutations could have developed millions of years ago. According to the study’s lead author Dominic Kwiatkowski, a process known as balancing selection might have occurred: “[the mutations] would be maintained at a sort of intermediate frequency”—common but not ubiquitous—“implying that it had both beneficial and deleterious effects.” Furthermore, this phenomenon has been observed with sickle cell trait, a gene mutation well known for providing partial protection against malaria, but that can cause a serious blood disorder when two copies of the mutation are present.   A new report from the Access to Medicine Foundation evaluates the vaccine pipelines of 20 major pharmaceutical companies, calling on these leaders in vaccine development to address the gaps in vaccine research and development (R&D) and take steps to ensure that their products will ultimately be accessible and affordable in low- and middle-income countries. The report identifies 70 vaccine candidates against 13 high-burden diseases, noting that nearly half are being developed by just three companies: GlaxoSmithKline, Novartis, and Sanofi. Of the 70 candidates, 16 target diseases for which there are currently no approved vaccines, including dengue fever, HIV and AIDS, malaria, tuberculosis, leishmaniasis, and Chagas disease. Nearly half of the candidates are for lower-respiratory infections (19 candidates), including pneumonia and influenza, or diarrheal diseases (14 candidates). There are currently access provisions—plans to ensure access to the final product—for only 12 of the candidates. Starting October 15, the US Food and Drug Administration (FDA) will have the ability to destroy   drugs sent to the US by mail if they are denied admission into the country. The FDA blocks the importation of drugs that are incorrectly labeled, not approved for use in the United States, or that appear to be counterfeit, including those that do not have the active ingredient, that have inadequate or excessive amounts of the active ingredient, or that contain the wrong, or even harmful, ingredients. Currently, the FDA returns these refused packages to the sender, and not only does this allow the sender to make another attempt, but it’s not uncommon for the same exact parcel to be sent right back to the United States “with the sticker indicating prior refusal by FDA still attached and visible.”

The US Department of Health and Human Services (HHS) is partnering with New York–based Regeneron Pharmaceuticals, Inc. for the development of an Ebola treatment. The treatment, developed by Regeneron, is comprised of three monoclonal antibodies that help the human immune system identify and bind to the Ebola virus, and thus prevent the virus from entering human cells and reproducing. Through the Biomedical Advanced Research and Development Authority, HHS will contribute up to US$38 million over two years, which will support both the advanced development of the treatment, as well as manufacturing enough doses of the treatment to be used in clinical trials. Swiss pharmaceutical company Novartis announced a new program last week to expand access to 15 of its medicines by offering them to health care providers in low- and middle-income countries for just $1 per drug per month. The program will initially be launched in Kenya, Ethiopia, and Vietnam, but could be expanded to as many as 30 countries. The 15 medicines included in the Novartis Access portfolio treat chronic diseases including cardiovascular and respiratory illnesses, diabetes, and breast cancer. Novartis will partner with governments and nongovernmental organizations to implement the program. Photo credit: CDC/ Melissa Dankel Researchers at Stanford University may have discovered a way to combat Clostridium difficile (C. diff)—a deadly bacteria that affects the intestines—without using antibiotics. C. diff’s virulence relies on a specific toxin—Toxin B—it releases that is responsible for the diarrhea, abdominal pain, and damage to the intestinal wall associated with the bacteria. While broad-spectrum antibiotics combat C. diff and other bacteria by attacking all bacteria—including safe, healthy bacteria—this new approach uses a molecule called ebselen that targets and deactivates Toxin B. The team at Stanford gave mice multiple rounds of antibiotics followed by a multidrug-resistant strand of C. diff; in other words, they made the mice particularly susceptible to infection and then introduced a particularly virulent bacteria. However, the use of ebselen to treat the infection almost completely protected the mice from symptoms. Ebselen is currently being tested for use in humans to treat other conditions, and initial results suggest that it is safe and well-tolerated. The US Food and Drug Administration (FDA) gives breakthrough designation to drugs that treat serious conditions and that have the potential to be significantly better than anything on the market. The FDA expedites the development and review of drugs deemed to be breakthroughs, but the designation is not a guarantee of safety, efficacy, or ultimate approval of the drug. However, a new study suggests that use of the word “breakthrough” could give patients “unwarranted confidence […] which could prevent them from making a fully informed decision about whether to take the drug or not,” according to the study’s coauthor Tamar Krishnamurti. The team recruited 600 online participants, each of whom were given one of five descriptions of a drug that has received breakthrough designation. The first description included just the facts, while the second and third described the drug as “promising” and “breakthrough,” respectively. The fourth and fifth clarified that continued approval of the drug depended on the results of additional clinical trials. In the subsequent survey, participants who read that the drug was “promising” or “breakthrough” were more than twice as likely to describe the drug as very or completely effective. While nearly a third of those who read the “breakthrough” description falsely considered the drug’s efficacy to be proven, compared to only 10 to 16 percent of participants who read the clarification regarding continued approval. All participants were then asked to read two descriptions of the same drug and identify which they would take. Ninety percent of respondents chose the description that used the word “breakthrough.”