Breakthroughs Blog: Malaria

Photo credit: TB Alliance GHTC member TB Alliance announced last week the creation of the first-ever child-friendly tuberculosis (TB) medicines, which are currently undergoing regulatory review by the World Health Organization and should be available in early 2016. While TB is curable, a patient must take multiple drugs a day for six months, and existing medicines are not available in appropriate doses for children. Consequently, parents must crush or cut the pills. This arduous process—combined with the bitter taste—makes the six-month regimen difficult to follow. The new treatment is comprised of strawberry- and raspberry-flavored, child-friendly doses of the three most commonly used TB medicines. The new regimen is expected to significantly enhance adherence to treatment for the 1 million children diagnosed with TB each year. Researchers at Texas A&M University have developed a device that, when attached to a smartphone, can diagnose malaria in minutes. Using a polarized light and the phone’s camera, the device serves as a microscope. The photos taken by the device are then analyzed by a software app that diagnoses infection by counting both red blood cells and Hemozoin crystals, which are produced by the malaria parasite. The device, which is expected to cost less than US$50 and be used with cartridges costing $1 each, will be tested in Rwanda next summer. A preclinical study conducted by GHTC member Population Council in partnership with CONRAD suggests that candidate microbicide gel MZC could be even more effective against HIV than tenofovir gel, a leading microbicide candidate. Containing a potent antiretroviral, a zinc-based salt, and the compound carrageenan, the gel is intended to protect against HIV, human papillomavirus (HPV), and herpes simplex virus 2 (HSV-2). The study demonstrated that MZC was more potent than tenofovir against both HIV and HSV-2. While the study did not test the gel’s efficacy against HPV, existing research suggests that carrageenan is one of the most potent compounds against HPV. Next, MZC will be tested in delivery systems, including vaginal rings and rectal gels, as well as in combination with a hormonal contraceptive. In other microbicide news, GHTC Member the International Partnership for Microbicides (IPM) has entered an agreement with pharmaceutical company Janssen Sciences that provides IPM the rights to develop a microbicide using the antiretroviral darunavir, which is currently available in pill form and marketed as PREZISTA®. IPM is also conducting a phase III clinical trial of a vaginal ring using antiretroviral dapirivine, licensed to the organization through a partnership with Janssen initiated in 2004.

Pyramax® Granules (Photo: MMV) After four successful Phase 3 clinical trials enrolling more than 3,500 patients in 18 countries, the European Medicines Agency (EMA) has granted Pyramax® Granules, a pediatric malaria medicine, a positive opinion under Article 58—a mechanism through which the EMA reviews and issues a scientific opinion on products that are not intended for use in Europe. Pyramax® Granules is a combination of two antimalarials and was developed by Medicines for Malaria Venture (MMV), a member of the GHTC, in partnership with Shin Poong Pharmaceutical Co. Ltd. The treatment is designed to be easy for children to consume: its bitter taste is masked and it is taken in liquid form, as children often struggle to swallow pills. Next, MMV and Shin Poong will work to introduce Pyramax® Granules as well as Pyramax®, the tablet version which is suitable for adults, in malaria-endemic countries. A recent article in NPR: Goats & Soda examines Zika virus, a disease transmitted by the same mosquito vector of dengue fever and chikungunya, that has been rapidly spreading throughout South America and the Pacific Islands in recent years. One in five individuals infected with the virus experience Zika fever, which in addition to fever involves rashes, joint pain, conjunctivitis, headaches, vomiting, and muscle pain. Cases of Zika fever are likely underdiagnosed, as awareness of the disease is limited and its symptoms are similar to infections associated with other members of the Flaviviridae virus family, including dengue fever, yellow fever, West Nile, and Japanese encephalitis. There are no reported deaths to date, but there is growing evidence that the virus can be transmitted sexually or from mother to infant during pregnancy. As there are no vaccines or drugs for Zika fever, treatment involves addressing the symptoms, using fever reducers and painkillers. A group of global health advocacy organizations—including GHTC members the Drugs for Neglected Diseases initiative, TB Alliance, Infectious Diseases Society of America Center for Global Health Policy, Sabin Vaccine Institute, and Treatment Action Group—sent an open letter to the US Senate Health, Education, Labor and Pensions (HELP) committee, calling for amendments to the priority review voucher (PRV) program at the US Food and Drug Administration (FDA) to ensure it adequately incentivizes research and development (R&D) for neglected diseases, as intended. Under the program, companies that receive FDA approval for a drug for a neglected disease (see list of eligible diseases) are awarded a voucher for expedited FDA review (six months rather than ten) of a future product. The vouchers are transferable and have been sold at increasing rates, the most recent going for US$350 million. The letter calls for PRVs to only be awarded for products that are "truly new" as two of the six vouchers that have been awarded were for products that had long been in use outside of the United States.[1] The organizations are also calling for recipients of the voucher to be required to develop a strategy to ensure the product is made affordable and accessible to patients in the countries in which the eligible disease is endemic. The United Kingdom (UK) announced last week the creation of the Ross Fund which will provide £1 billion ($1.5 billion) over five years to fight malaria and other infectious diseases. The funding, which will come from the UK overseas aid budget, includes £90 million for malaria eradication; £100 million for infectious disease R&D; £115 million for the development of drugs, diagnostic, and insecticides for malaria, tuberculosis, and other infectious disease resistance; and £188 million for biodefense and rapid response systems for epidemic preparedness. Global Good has developed a cooler that can store and transport vaccines at freezing temperatures for over a month using just ice and no electricity. The Arktek cooler uses vacuum thermal insulation, an approach used to preserve spacecraft entering extreme temperatures. The cooler has been tested in Senegal (with support from GHTC member PATH) and Ethiopia, and last year, the Arktek was modified for use in Ebola vaccine clinical trials, during which the cooler kept the vaccines between -76 and -112 degrees Fahrenheit for three days. [1] There are two separate PRV programs at the FDA, one for neglected tropical diseases and one for rare pediatric diseases. Of the six PRVs that have been awarded, three each have been for neglected tropical diseases and rare pediatric diseases. Since the beginning of the PRV program, six PRVs have been awarded—three for neglected tropical diseases and three for rare pediatric diseases.  

Photo: National Institute of Allergy and Infectious Diseases (NIAID) Researchers at Tulane University successfully tested an experimental aerosol tuberculosis (TB) vaccine in monkeys, demonstrating that the candidate was more effective in protecting against infection than BCG—the only TB vaccine on the market. To create the vaccine, the researchers genetically modified the TB bacterium, removing a gene that plays a key role in infection. The vaccine was then administered to seven monkeys, while another seven each received either an aerosol version of BCG or no vaccine. After eight weeks, the monkeys were exposed to TB at a lethal level. The experimental vaccine not only was more protective than BCG, but it also induced a stronger immune response in the lungs, which is thought to be key to preventing infection. A new formulation and coating for existing HIV and AIDS medicines could significantly decrease the frequency with which the drugs must be taken. Researchers at the University of Nebraska Medical Center used a process called nanoformulation, which involves modifying drugs at the most basic level (i.e., atomic or molecular level) in order to convert them into nanoparticle crystals. In this experiment, the antiretroviral medicine crystals were coated with fat and protein, allowing them to last much longer in the body. In the lab, the drug proved to be effective in combatting HIV and AIDS. The team hopes its findings could eventually lead to the development of an HIV and AIDS treatment that could be administered once or twice per year, rather than daily. Resistance to the leading antimalarial—artemisinin—was first reported in Cambodia in 2008, and a new study in Nature Communications suggests that the drug-resistant parasite has the ability to infect African mosquito species. A team of researchers at the US National Institute of Allergy and Infectious Disease infected two Asian and one African mosquito species with the drug-resistant malaria parasite, and all three species proved to be susceptible. Furthermore, the African species were no less vulnerable to infection, which came as quite a surprise as the species have evolved independently for more than 30 million years. Health officials from the United States and Saudi Arabia are considering a collaboration for the development of a vaccine against Middle East Respiratory Syndrome (MERS), which has infected more than 1,500 people across 27 countries. There are currently a number of MERS vaccines in development and several have yielded promising results in animal studies. The Saudi Ministry of Health has US$70 million available for the project; however, the proposed role of the US government remains unknown.

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.