Breakthroughs Blog: Guest post

Malaria has infected humans for a very long time and in more places than many realize. There’s evidence that 3,000 years ago, malaria killed King Tut. It stalked the marshlands and fens of Great Britain and was common in the American South until the middle of the 20th Century. Yet for this disease that has taken many turns over many millennia, the first 15 years of the 21st century are exceptional. During that time, deaths from malaria—which are primarily concentrated in young, African children—fell dramatically, from 839,000 in 2000 to 438,000 in 2015. But progress is not inevitable. Over the last two years, malaria deaths and infections have plateaued. In some areas they are rising, and not just in Africa. For example, amidst the deteriorating infrastructure of Venezuela, malaria infections have surged by 69 percent. Some of the problem involves a failure to invest the resources required to sustain the fight. But there are also other long-term challenges, including growing resistance among malaria-carrying mosquitoes to the insecticides used in bednets and indoor spraying campaigns—control measures that have been very effective at reducing infections. Malaria parasites are spreading in Southeast Asia that are resistant to the lifesaving malaria medicine artemisinin—and to other malaria drugs as well. There are reports along the Cambodian border of “triple mutant” malaria parasites that are resistant to artemisinin and two other once-reliable malaria drugs. The biggest fear is that these superbugs could spread into India and then into the malaria strongholds of Africa. Our goal at PATH’s Malaria Vaccine Initiative (MVI) is to help develop vaccines to aid in fighting malaria. If you look at the battle against infectious diseases that once spread death and misery, like smallpox, polio, measles, and whooping cough, vaccines helped turn the tide. Vaccines could do the same for malaria. However, malaria-causing parasites, like all parasites that cause disease, are biologically complex in ways that have made them notoriously hard to subdue with vaccines. But despite the challenge, and because of substantial investments made over the last couple of decades, we are closer than ever to a world where malaria vaccines can join the battle. The malaria vaccine closest to deployment is called RTS,S/AS01, and was developed by GSK. No vaccines are currently in use against human parasitic diseases, including against Plasmodium, the mosquito-transmitted parasite responsible for causing malaria. RTS,S will be the first, rolled out next year through a pilot introduction that will make it available to 750,000 young children living in areas of Ghana, Kenya, and Malawi, where malaria is common. This is the first step to possible wider use across Africa, where, alongside currently used interventions like bednets, indoor residual spraying, and drugs, it could help save thousands of lives. Yet, even as RTS,S is rolled out, which is a huge achievement, we continue to develop the next generation of malaria vaccines. MVI is working with partners on creative ways to optimize the use of RTS,S that could translate to increased public health impact against disease and death in young African children, and potentially support its use in community-wide campaigns to accelerate parasite elimination. A few years ago, we looked closer at what was originally seen as a fluke finding from more than a decade ago: that delaying and reducing the third dose of RTS,S might boost its protection against malaria. The small trial in 2014 provided intriguing evidence that this approach does indeed improve the quality of the immune response from RTS,S. A series of larger trials are now underway to explore whether different dosing approaches could positively impact efficacy. These studies are being further leveraged, in concert with advances in medicine that enable isolation and testing of individual antibodies with a strong affinity for targeting a disease. These monoclonal antibodies (mAbs) are driving exciting new therapies targeting certain cancers and autoimmune conditions. We are at the cutting-edge of efforts to perform proof-of-concept studies with mAbs to answer critical scientific questions and determine their applicability, as a potential supplemental tool, to preventing infection by malaria-causing parasites. We’re also excited about the potential to fight malaria with transmission-blocking vaccines (TBVs). A TBV could prevent mosquitoes that feed on malaria-infected humans from passing along their parasites to new victims. While not providing immediate protection from infection, high coverage with a TBV in a community where malaria is common would steadily reduce the risk of getting malaria from a mosquito bite—as the parasite’s survival is pegged to a continuous cycle, moving between humans and mosquito. A successful TBV could prevent malaria from returning to areas where it has been eliminated. Malaria has been plaguing humans for thousands of years and the parasites that cause the disease are constantly evolving to evade our attempts at control. But while the current fight may have plateaued, the lesson of the last decades is that a unified, well-funded assault on malaria—one committed to developing a variety of tools and making them widely available—can produce substantial progress. If we continue to invest in malaria vaccine development, and fund other promising work now underway to create a new generation of drugs, insecticides, diagnostics, and other tools, while strengthening the programs and systems that deliver them, we can turn the tide. And from there, we can confidently set our sights on eliminating and eradicating the disease forever.

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.

Typhoid may seem like a distant memory in industrialized countries, but for many low- and middle-income countries (LMICs) it continues to cause millions of illnesses and about 150,000 deaths per year in endemic areas and during outbreaks. Spread through contaminated food and water, typhoid typically burdens young children and adolescents under the age of 15. Recently, we have witnessed several outbreaks, including those in Zimbabwe,  Zambia, and Pakistan, where thousands of typhoid cases have been reported. Without treatment, typhoid can cause serious short- and long- term complications, and even lead to death. While antibiotic treatment has greatly improved outcomes in typhoid patients, the effectiveness of antibiotics is becoming increasingly limited. The World Health Organization (WHO) has called antibiotic resistance one of the biggest threats to global health today, and treating typhoid is no exception. Drug and multi-drug resistant typhoid has been increasingly reported in LMICs in Southeast Asia and sub-Saharan Africa where typhoid burdens are highest, and treating drug-resistant typhoid may become prohibitively expensive. As global experts met this week at the International Caparica Conference in Antibiotic Resistance to discuss ways to address this growing issue, I reflected on ways that we can combat this looming threat for typhoid: 1. We need to accelerate the introduction of typhoid vaccines alongside proven water, sanitation, and hygiene (WASH) interventions. Just as we know how to treat typhoid, we also know how to prevent it: WASH precautions are key. However, given the significant burden of typhoid among hard-to-reach populations where WASH progress may be slow, we need an integrated approach to prevention that includes vaccines. Currently, two vaccines are globally available and are effective in preventing typhoid—an oral live attenuated vaccine and an injectable Vi capsular polysaccharide vaccine. In 2008, WHO recommended that both vaccines can be used during outbreaks and in endemic areas, but uptake has been low and neither are used routinely. Newer typhoid conjugate vaccines (TCVs) have the potential to overcome the shortcomings of the current vaccines by allowing for longer-lasting protection, fewer doses, and greater suitability for children younger than two years old in routine childhood immunization programs. The Typhoid Vaccine Acceleration Consortium (TyVAC), a partnership between the Center for Vaccine Development at the University of Maryland School of Medicine, the Oxford Vaccine Group at the University of Oxford, and PATH, an international nonprofit, is committed to ensuring that prevention and control of typhoid is a global health priority. We work with local and global partners to accelerate the introduction of TCVs in LMICs as part of an integrated prevention strategy. 2. We need research and development to advance the typhoid vaccine, drug, and diagnostics pipeline to prevent, accurately diagnose, and treat typhoid. One of the challenges of typhoid is that an infected person presents with symptoms that are often mistaken for other diseases, which leads to frequent misdiagnoses. Current diagnostics require blood or bone marrow and a lab to analyze the results, which is not feasible for many low-resource health facilities. Knowing that a patient has confirmed typhoid allows the physician to provide the proper course of treatment and helps combat antibiotic misuse. A robust vaccine and drug pipeline will help ensure that we continue to have a range of prevention and treatment tools at our disposal for typhoid. There are currently several TCVs in various stages of development. New vaccines provide a mechanism for protection against typhoid that can avert cases that may be drug resistant. As more vaccines and drugs become available, access improves and costs can come down due to healthy market competition. The time is now for us to #TakeonTyphoid. We cannot afford to risk typhoid becoming untreatable—not when we can strengthen prevention through immunization with TCVs and improvements in WASH.

Meet Grace, Denise, and Sarah. At age 21, Grace is a single mother of two living in South Africa. Because her children need routine check-ups and immunizations, Grace frequently sees pediatricians and nurses, but rarely visits doctors for her own health needs. In Namibia, 19-year-old Denise is a first-time mother. She wants contraceptives but the few times she’s asked, the local pharmacist said they were available only for married women. And in Malawi, 18-year-old Sarah has started having sex, sometimes with male partners twice her age.  These three young women lead very different lives, but they all have one thing in common—they’re at high risk for HIV infection. Although Grace, Denise, and Sarah are not real people, their stories illustrate diverse challenges young women face, particularly in sub-Saharan Africa, where young women ages 15-24 are at least twice as likely to have HIV as men their age—and, in some regions, are more than eight times as likely to get infected. IPM's Sharyn Tenn with workshop participantsExisting HIV prevention strategies are not doing enough to reduce the high rate of infection among women because women still lack a range of options that address their diverse needs. While some women may feel comfortable discussing available HIV prevention options such as condoms with their partners, negotiating safe sex is not a realistic option for many others, including those at risk of sexual violence. In addition, while some women may be able to use a daily oral HIV prevention pill known as PrEP, in the three African countries where it recently become available, others may prefer a long-acting prevention method.The payoff for all of these tools spans far beyond individual women—evidence shows that when women are both empowered and healthy, they are more likely to have healthy families, educate their children, and make positive social and economic contributions to society. New discreet and long-acting HIV prevention tools have the potential to empower women to protect their own health and unlock their potential.My organization, the International Partnership for Microbicides (IPM), has developed one such tool–the monthly dapivirine ring. This flexible, silicone vaginal ring is the first long-acting, self-initiated method shown to safely help prevent new HIV infections in women.Results from two Phase III clinical trials last year—The Ring Study and ASPIRE—found that the ring safely reduced HIV risk among women in four African countries. Data from one study suggests that women who used the ring most consistently saw greater risk reduction, and that the youngest women, who saw little to no protection, appeared to be the least likely to use the product. Such adherence challenges are consistent with studies of other HIV prevention methods and underscore the urgent need to identify and overcome barriers to product-use for young women. The dapivirine ring. (Photo: Andrew Loxley) IPM is committed to doing all we can to understand how to help young women who want to use new HIV prevention technologies, like the monthly dapivirine ring, to do so consistently. Last month, we, along with AVAC, the US Agency for International Development, and Dalberg Global Development Advisors, co-hosted an event during the United Nations Commission on the Status of Women to take a holistic view of young women’s lives. Presenters shared examples of the ways HIV-prevention efforts can be informed by the very people who would benefit leveraging an approach called human-centered design, which places end-users and other key stakeholders at the center of the design and implementation process. This approach is being used to create concepts and materials to increase the adoption and sustained use of the dapivirine ring.Several insights shared at the event could inform future steps for the dapivirine ring, should it be approved for use and added to HIV prevention programs in sub-Saharan Africa. For example, the ring could be offered where women already regularly access health services, whether for themselves or for their children.Doing so would make access to the ring more convenient, and subsequently, may increase its uptake. Participants also suggested that a welcoming, environment may also help facilitate uptake as fear of judgment can be a powerful barrier to accessing and using HIV prevention products and services.We’re encouraged by these discussions, recognizing that they are one step in a long and iterative process of getting new HIV-prevention methods into the hands of women worldwide. Continuing to involve women in additional research on the ring and its possible introduction must continue if we are to realize its potential and pave the way for other technologies in the pipeline such as a three-month dapivirine-only ring and a multipurpose dapivirine-contraceptive ring. We’re currently pursuing regulatory approval for the dapivirine ring and looking to two open-label extension studies—DREAM and HOPE—currently underway, to gain insight into when, why, and how women use the ring now that its safety and efficacy are known, and to collect extended safety data.Expanding the toolkit of HIV prevention options available to young women would lower HIV infection rates, allow healthy women to pursue employment, and help sustain strong and productive workforces.The sooner we reduce the heavy HIV burden young women bear, the sooner we can empower a new generation to lead healthy and productive lives. Sharyn Tenn is the senior director for external affairs at the International Partnership for Microbicides.