Breakthroughs Blog: Antimicrobial resistance

Authored by Elodie Jambert & Elizabeth Poll, Medicines for Malaria Venture, Switzerland; Panayota Bird, GSK; and Dr Marcus Lacerda, Fiocruz, Brazil  The Amazon is a renowned hotspot for biodiversity, but it’s also a hotspot for malaria. Brazil is one of the Latin American countries with the heaviest burden of malaria, with its Amazon region accounting for 99.5 percent of all national cases. Tackling malaria in Brazil is complicated by the fact that the vast majority of the burden is caused by the malaria parasite Plasmodium vivax. After causing an initial bout of malaria symptoms, this species of parasite has the ability to hide dormant in the liver of infected people, only to re-emerge and cause symptoms again several weeks to several months after initial infection. Another compounding issue is that the only medicine currently available to stop such relapse is primaquine–a medicine approved in the 1950s that must be taken for at least seven days. Given this lengthy course of treatment, many patients fail to complete the full course. It’s a challenge to explain to patients why they should take seven days of pills to treat something that appears to have resolved after the third day (the duration of treatment of the initial acute P. vivax malaria bout). As a result, the medicine often doesn’t work, and transmission of relapsing malaria is perpetuated. In Brazil, over the last 20 years, the burden of the more deadly Plasmodium falciparum has fallen from 50 to 10−15 percent. Yet, progress against P. vivax is yet to see the same success; this parasite now causes 89 percent of malaria cases. While P. vivax doesn’t kill as many people as P. falciparum, it is still debilitating, can also be lethal, and has substantial economic impact on families and nations. As such, it’s important to keep the attention of policymakers focused on malaria even in the face of other pressing public health issues, such as Zika and chikungunya viruses.A new solution for relapsing P. vivax in sightChildren in the village of Boa Vista, on the border of the Juma Reserve in the Brazilian Amazon. Photo: Neil Palmer/CIATFortunately, a new solution to tackle relapsing P. vivax malaria could be in sight. Medicines for Malaria Venture (MMV) and GSK have collaborated to develop a new, single-dose anti-relapse medicine, tafenoquine. The medicine was submitted for regulatory review to the US Food and Drug Administration and Australian Therapeutic Goods Administration at the end of 2017. If approved, it could be an important new treatment for individuals suffering from relapsing malaria, and could help to eliminate the disease in the Amazon.MMV and GSK have developed an access strategy together with in-country partners and are preparing the ground for the medicine’s potential launch in endemic countries. Country-level briefings are ongoing with the National Malaria Control Programmes (NMCP) in Brazil and six other endemic countries (Thailand, Ethiopia, Vietnam, Cambodia, Peru, and Colombia); their goal is to assess interest in introducing the new medicine into national practice and to understand what type of evidence NMCPs would need to support policy adoption. Developing diagnostics to make anti-relapse medicines safer for allPATH rapid diagnostic test to support treatment and elimination of P. vivax. Photo: PATHIntroduction of tafenoquine faces one additional challenge: As is the case with primaquine, people with a genetic deficiency in a specific enzyme known as glucose-6-phosphate dehydrogenase (G6PD) can suffer potentially serious side effects. On average, 8 percent of people in malaria-endemic countries are deficient in this enzyme. To reduce the risk of patients suffering this side effect, PATH is supporting development of a point-of-care diagnostic test to identify patients’ G6PD status and determine whether tafenoquine or primaquine can be safely administered. Concomitant use of this point-of-care diagnostic test will be critical for the correct and well-tolerated use of tafenoquine. Despite the World Health Organization’s recommendation that G6PD tests guide the use of primaquine, few endemic countries routinely use such testing today. In Brazil, the prevalence of G6PD deficiency varies depending on the immigration profile of the region. Most published papers on the subject estimate that the average prevalence among men in Brazil is around 5 percent, a statistic recently confirmed with preliminary data from a government-supported prevalence survey in endemic areas of the Brazilian Amazon.In light of this, additional data is being gathered. Initial preparations for an implementation study are underway in Brazil to demonstrate how a quantitative G6PD test would work in practice, prior to use of tafenoquine in the healthcare system. It is planned for the study to begin after regulatory approval of tafenoquine is granted. The team is also working with academics to model the cost effectiveness of the medicine paired with a G6PD test compared to current standard of care (primaquine without a test), as well as the potential impact of tafenoquine on malaria transmission and elimination. The Brazilian government will use these findings as it considers broader deployment of the intervention throughout malaria-endemic areas.Tafenoquine has potential for significant impact both for the individuals that suffer from this disease as well as for the regions focused on malaria elimination. We await the regulatory decisions on the medicine and will continue to work together as a team of partners to prepare the ground in the Brazilian Amazon to help make it malaria-free for all.

Interested in more global health innovation news? Every week GHTC scours media reports worldwide to deliver essential global health R&D news and content to your inbox. Sign-up now to receive our weekly R&D News Roundup email. In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. Researchers discovered that the meal times of malaria-infected organisms may impact the rate at which the malaria parasite multiplies in the host’s blood. A team at the University of Edinburgh studied the parasitic rhythms of reproduction and invasion of red blood cells in malaria-infected mice and found that the parasites timed their daily multiplication rhythms to match when the animals were fed. When the mice’s feeding time changed, the parasites altered the timing in which they invaded red blood cells. Researchers believe that interfering with the biological processes that link eating to these parasite rhythms—through diet, drugs, or other approaches—could reduce the spread of malaria infection A team of scientists recently created a prototype oral flu vaccine that does not need to be temperature controlled—paving the way for potential new oral vaccines that do not require refrigeration or freezing. Unlike traditional biological vaccines, which are made from part of a virus or bacteria and must be temperature controlled to remain stable, this oral vaccine prototype contains manmade peptides that mimic peptides in real viruses. Scientists found the prototype triggered a strong immune response when tested in human cell cultures and in mice. While more research is needed, these early results are promising. A heat-stable oral vaccine would be easier to transport and store, which could improve care in low-resource, hard-to-reach communities were immunization supply chains may be insufficient. Scientists at the Jena and Friedrich Schiller University Hospital are working to develop a rapid antibiotic resistance test. Current diagnostics for drug-resistant infections can take up to 72 hours to deliver results—a long amount of time for these infections, which can be acutely life-threatening. Using light-based analytical methods combined with microfluidic sample processes—which the researchers colloquially referred to as a miniature Lab-on-a-Chip system—the scientists were able to clearly identify bacterial strains and their resistances in fewer than three hours. New rapid tests for antibiotic-resistant infections could help get patients on treatment more quickly and reduce the overprescription of antibiotics.

Interested in more global health innovation news? Every week GHTC scours media reports worldwide to deliver essential global health R&D news and content to your inbox. Sign-up now to receive our weekly R&D News Roundup email.  In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. Using a new research platform that extracts DNA directly from soil, researchers at Rockefeller University have discovered a new class of antibiotics. Scientists have long seen soil as a potential untapped source for new antibiotics; however, tapping this resource has proved challenging because only about 1 percent of bacterial species in soil can be cultured in labs. This new discovery platform is culture-independent. It allows scientists to extract, clone, and sequence DNA from the soil without growing bacteria in the lab. Researchers are hopeful this new platform can be scaled to systematically search for new antibiotics in the environment. With recent advances in gene therapy techniques, researchers are looking at the potential of these techniques to improve treatment for those living with AIDS and cure the disease. Scientists have used gene-editing tools to cut DNA at the exact spot to disable the HIV entryway gene both in immune T cells and blood stem cells. While the results of these initial experiments were less promising than researchers had hoped, there was a silver lining: Patients saw a decrease in the number of cells where the HIV virus lurked in a dormant state. Thus, researchers are looking at the potential to pair altered cells with existing antiretroviral medicines to improve the body’s ability to eliminate the virus. Scientists are also looking at the potential to use gene editing to introduce new genes that would help T cells recognize and kill HIV, similar to therapy introduced last year to treat cancer. Aeras announced resultsfrom an innovative clinical trial that provides new encouraging evidence that tuberculosis (TB) vaccines could prevent sustained infections in high-risk adolescents. A prevention-of-infection phase 2 trial in South Africa demonstrated that revaccination with the Bacille Calmette-Guerin vaccine significantly reduced sustain TB infections in adolescents. Another experimental vaccine candidate, H4:IC31, also reduced sustained infections, although not at statistically significant levels. However, these results mark the first time a subunit vaccine has shown any indication of ability to protect against TB infection or disease in humans.

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. Novartis has launched patient testing of a new anti-malaria compound with the hopes of staving off the development of further drug-resistance. The experimental compound—KAF156—will be tested in combination with another medicine in children and adults across nine countries in Africa and Asia over the next few months. In recent years, there have been increasing reports of malaria parasites that have become resistant to the standard treatment regimens against malaria, spurring the need for new treatment options from different classes of antimalarial compounds. Novartis expects to complete phase 2b studies of the compound by late 2019. It remains too early to tell whether the product will eventually reach market. A strain of gut bacteria taken from the diaper of a baby could hold promise in saving the lives of thousands of newborns in poor regions. Scientists conducting a large clinical trial in India found that babies who were fed a probiotic strain of Lactobacillus bacteria for a week were 40 percent less likely to develop a deadly infection called sepsis, which kills 600,000 newborns per year in India and other nearby nations. Babies who took the probiotic also had fewer cases of pneumonia, diarrhea, and ear infections. Researchers believe this probiotic—which costs only US$1—could be a “game changer” in advancing the health of infants in poor nations. Scientists at Harvard University are genetically engineering relatives of Mycobacterium tuberculosis (TB) in the hopes if speeding development and clinical trials to develop a better TB vaccine. The only currently available TB vaccine is partially effective in children and performs poorly in adults, so scientists are working to develop other vaccine candidates. However, performing clinical trials on vaccines is challenging because a typical clinical trial involves observing large numbers of people over long periods of time to monitor results in a small subset of people that naturally come into contact with the microbe. Alternatively, “challenge studies” infect people on purpose, so are faster and less expensive, but these studies are only possible if the disease can be detected and treated easily. TB can take time to detect and many months to treat, so is not appropriate for this type of study. The team at Harvard is working to genetically modify TB so it can be safely given to people as part of challenge trials, and thus help speed vaccine development.