Kat Kelley

Photo: National Institute of Allergy and Infectious Diseases (NIAID) Gavi, the Vaccine Alliance, signed an advanced purchase commitment, pledging to spend US$5 million on an Ebola vaccine currently under development by pharmaceutical company Merck & Co. The vaccine candidate was tested on 4,000 people in Guinea last year, and the results were promising: despite all participants having close contact with at least one Ebola patient, none developed the disease more than ten days after vaccination (several days are required for a vaccine to confer protection). The vaccine candidate—VSV-EBOV—was developed and tested in partnership with the Canadian and US governments, however, without the urgency of an outbreak, public-sector support moving forward is limited. The agreement guarantees that there will be a market for the vaccine, assuring Merck & Co. that they can recover investments in advanced development and manufacturing. This move will also enable Gavi to establish a stockpile of the vaccine so that it can be rapidly deployed in future outbreaks. New research suggests that 2.6 million stillbirths occur each year, 420,000 of which are attributable to malaria or syphilis infections. These results underscore the need for testing and treatment of malaria and syphilis in pregnant women, particularly in endemic regions. Fortunately, there are low-cost interventions that could drastically reduce adverse pregnancy outcomes attributable to malaria and syphilis infections. The malaria parasite is able to reside in the placenta, even when undetectable in the mother’s blood, and thus, preventative treatment for malaria is critical. The antimalarial sulphadoxine-pyrimethamine, which costs a mere $0.20 per patient, is recommended for use in pregnant women in endemic areas. In east and southern Africa, an estimated 5 percent of pregnant women are infected with syphilis and in Tanzania, up to half of stillbirths are caused by syphilis. However, one dose of penicillin can cure both maternal and congenital syphilis and prevent stillbirth—at just $1.40 per person. While malaria- and syphilis-related stillbirths can be prevented with the scale-up of existing medicines, many more could be prevented with interventions that are not appropriate for low-resource settings, which is particularly concerning as 98 percent of stillbirths occur in low- and middle-income countries. Further, the cause of stillbirth is often unknown, according to the Global Alliance to Prevent Prematurity and Stillbirth, and additional research is needed to determine and address these causes. There is little incentive for pharmaceutical companies to invest in antimicrobial research and development (R&D): antibiotics are prescribed for short periods of time and competition among antibiotics keeps prices low. However, with the spread of drug resistance, the “[financial] value assigned to antibiotics and diagnostics often does not reflect the benefits they bring to society,” according to a declaration authored by 80 pharmaceutical and diagnostic companies and released at this year‘s World Economic Forum in Davos, Switzerland. The declaration calls on governments to work with the pharmaceutical industry to spur antimicrobial R&D, identifying innovative financing mechanisms, including prizes (a Market Entry Rewards initiative) and intellectual property–related incentives. In response, the companies pledge to invest in R&D for new antibiotics, as well as improved diagnostics to prevent the unnecessary use of antibiotics (i.e., for viral conditions).

Last week, an oral cholera vaccine receivedWorld Health Organization (WHO) prequalification, a process of regulatory review which paves the way for procurement by United Nations agencies and international organizations. Up to 4.3 million cases and 142,000 deaths from cholera are reported annually, primarily in low- and middle-income countries, and the vaccine—Euvichol®—is 65 percent effective against the bacteria. Euvichol® was developed by GHTC member the International Vaccine Institute (IVI), and has been licensed to the Korean company Eubiologics, which plans to produce 6 million doses in 2016. The vaccine is a reformulated version of Shanchol™, which is licensed to Shantha Biotechnics in India, and was prequalified in 2011. According to the WHO, prequalification of Euvichol® could double the global supply of cholera vaccines. Euvichol® produced by EuBiologics. Photo: IVI Scientists have identified three compounds that could serve as the basis for a vaccine against onchocerciasis (river blindness). More than 17 million people globally are affected by river blindness, 70 percent of whom experience skin conditions, including itching and lesions, and 10 percent of whom develop eye conditions, leading to visual impairment. Without a vaccine, river blindness control programs use the antiparasitic drug ivermectin to treat the disease, however, ivermectin is not recommended for use in children under five. Additionally, in Central and Western Africa, where coinfection with Loa loa worms is common, use of ivermectin can lead to fatal brain inflammation. The team hopes to initiate safety and efficacy trials for a potential vaccine candidate by 2020 and 2025, respectively. The Global Fund to Fight AIDS, Tuberculosis and Malaria is launching an “e-marketplace” through which global health product procurers (i.e., governments and nongovernmental organizations) can purchase everything from drugs and diagnostics to condoms and cars. The e-marketplace will be an online platform utilizing the Global Fund’s pooled procurement mechanisms. Through this mechanism, the Global Fund negotiates with manufacturers and purchases large quantities of global health commodities; governments and other organizations are then able to purchase products directly from the Global Fund, reducing product and transaction costs. This approach also improves demand forecasting and ensures a sustainable supply of products. The launch of the e-marketplace will be phased: while in the first quarter of 2016, only bednets will be available, artemisinin combination malaria medicines, malaria and HIV and AIDS diagnostics, and antiretrovirals will be available by the end of the year. The e-marketplace will initially be limited to Global Fund grant recipients, and 10 to 20 countries are expected to utilize the platform in 2016. The Global Fund hopes to open the e-marketplace to more buyers in the future and eventually offer products that are not part of Global Fund agreements, enabling procurers to independently compare quotes from different manufacturers.

A recent clinical trial found that convalescent plasma therapy, a treatment in which the blood plasma is taken from survivors of a disease and used to treat current patients, did not prove to be effective against Ebola. The blood plasma of survivors includes antibodies against the pathogen, in this case the Ebola virus, which can boost a patient’s immune response. Convalescent plasma therapy has been used for more than 100 years, and was first used against Ebola in 1976. In the trial, plasma therapy was used to treat 84 patients, and an additional 418 patients that had been treated at the same facility served as the control group. The treatment reduced death rates by a mere 2.6 percent, and the result was not statistically significant. However, the trial did demonstrate that the collection and transfusion of blood plasma from survivors to patients was safe and feasible in low-resource settings. During the trial, the therapy did appear to be particularly effective in pregnant women and infants, however, the sample size was too small to confirm. Plasma samples from the trial will now be sent to a facility in France where researchers will assess the concentration of antibodies in the samples to determine if the quantity of antibodies affected survival rates. A recent study suggests that the antimalarial artesunate/amodiaquine (ASAQ) could be more effective against Ebola than artemether/lumefantrine (AL), an antimalarial previously used to treat Ebola, due to the diseases’ overlapping symptoms. During the outbreak, a Médecins Sans Frontières treatment center in Liberia initially used AL to treat patients, however, after running out of AL, they began to use ASAQ. The death rate for patients receiving ASAQ was 50.7 percent, compared to 64.4 percent of patients on AL. While ASAQ appears to be a promising treatment, additional trials are needed to investigate ASAQ’s efficacy in reducing Ebola mortality. Strains of the bacteria responsible for the sexually transmitted infection gonorrhea are becoming increasingly resistant to antibiotics. In the United States, one-third of gonorrhea cases are resistant to at least one antibiotic. Public officials, both in the United States and Britain, are urging doctors to follow prescription recommendations to prevent the spread of drug-resistant strains. In Britain, many doctors continue to prescribe ciprofloxacin, which has not been recommended for gonorrhea in 10 years. In the United States, doctors have historically prescribed ceftriaxone, however, between 2011 and 2013—after new guidelines led doctors to prescribe ceftriaxone in combination with azithromycin—ceftriaxone-resistant strains decreased by two-thirds from 1.4 percent to .4 percent of cases. Cow standing in a grassy field. (Photo: PATH/Eric Becker) The bacteria Mycobacterium bovis, which causes bovine tuberculosis (TB), is a rising cause of human TB, and while it’s responsible for just 1.4 percent of cases globally (and 1.5 percent of cases in America), up to 44 percent of TB-infected Latino Americans have the bovine version. Bovine TB is found in two dozen mammal species and is usually transmitted to humans through unpasteurized dairy products. In Mexico, 40 percent of dairy products are unpasteurized, and consequently the proportion of bovine TB cases among Americans are highest along the US-Mexico border. Two-thirds of bovine cases in the United States are extra-pulmonary—outside of the lungs—and are consequently undetectable by standard diagnostic techniques. The remaining third, confined to the lungs, could presumably be spread between humans through coughing or sneezing.

Photo: PATH/Teresa Guillien A new vaccine against Middle East Respiratory Syndrome (MERS) could save human lives by boosting immunity in camels. MERS, a virus that causes an innocuous cold in camels but kills nearly one-third of human patients, is primarily found in the Arabian Peninsula, where camels are common and 12 percent are infected at any given time. While the virus does spread between humans, camel-to-human transmission is believed to be a significant driver of new cases. Not only are camels an important host for the virus, but developing a vaccine for animals is cheaper, and the regulatory review is usually less burdensome than for a human vaccine. The vaccine uses a virus engineered to display the spike protein that defines MERS, prompting the immune system to create antibodies that will protect against MERS. The team vaccinated four camels and used an additional four camels as the control group. Three weeks after vaccination, all eight camels were exposed to the virus. While the camels in the control group all became infected, three of the four vaccinated were protected; it is unclear why the fourth was not. Nature took an in-depth look at the development and testing of Ebola vaccine candidate rVSV-ZEBOV and how it could serve as a model for accelerating the research and development (R&D) of tools for other emerging threats. In less than two years, rVSV-ZEBOV went through multiple rounds of testing, culminating in a successful phase III clinical trial. In the typical timeline, it would take years to obtain regulatory approval for the trial, let alone to conduct it, and it would be performed in a setting with greater existing research capacity. The trial design was significant: the team enrolled nearly 4,000 individuals that were close personal contacts of Ebola patients, and those vaccinated were completely protected, while 16 percent of the control group became infected. By using patients’ contacts, they were able to identify and enroll at-risk individuals quickly. The researchers were also able to review preliminary results in real time, and after the vaccine proved to offer a significant advantage, the team immediately began to vaccinate all participants. The White House released a National Action Plan for Combating Multidrug-Resistant Tuberculosis (MDR-TB) last week, with clear actions to be implemented by the US government over the next five years. The Plan is comprised of three goals: (1) Strengthen domestic capacity to combat MDR-TB; (2) Improve international capacity and collaboration to combat MDR-TB; and (3) Accelerate basic and applied Research and Development to combat MDR-TB. The first two goals call for increased diagnosis and treatment of MDR-TB patients while the third calls for R&D for new vaccines, drugs, and rapid diagnostics. Within the third goal, the plancalls for R&D of new products as well as research to improve the use of existing drugs; the development of strategies to identify the "most promising drug and vaccine candidates" within a given portfolio; and the identification of biomarkers (which are an early sign indicating whether a drug or vaccine will be successful) to accelerate clinical trials. Scientists have genetically engineered male mosquitoes whose female offspring will be infertile in order to reduce the population of mosquitoes that transmit malaria in sub-Saharan Africa. Normally, only half of an organism’s offspring inherit a non-dominant gene, however, the team used an approach called “gene drive” to ensure the trait—infertility—will be passed on at a rate of 90 percent. Gene drive involves using an endonuclease—a molecule that literally cuts DNA—to damage the original gene; the cell then duplicates the remaining, engineered gene, which results in two copies of the gene with the desired trait. While vector control is a cornerstone of existing malaria programs, there are concerns that this technique of drastically reducing the mosquito population could have unintended ecological consequences.

As 2015 draws to a close, the Global Health Technologies Coalition is reflecting on the past year in global health innovation. Below, in no particular order, are our picks for the top global health research and development (R&D) news and stories that shaped 2015. First ever vaccine against dengue virus approved The world’s first vaccine against dengue fever was approved by the national regulatory authority of Mexico, marking an important initial step in preventing this mosquito-borne infection, which is spreading worldwide. Nearly half the world’s population now lives in dengue-endemic countries, and an estimated 390 million infections occur each year. The vaccine’s developer Sanofi spent over 20 years and US$1.65 billion developing the vaccine and is now pursuing regulatory approval in 19 other countries. Sanofi has stated it will make the vaccine available for sale at a “fair, affordable, equitable, and sustainable price.” NIH finally receives funding boost Christmas came early for the US National Institutes of Health (NIH). After years of stagnated funding, NIH—the world’s leading public funder of neglected disease R&D—will finally receive a funding boost in 2016. In the fiscal year 2016 omnibus spending package, Congress approved a $2 billion—nearly 7 percent—increase in funding for NIH from $30 billion to $32 billion. NIH has lost 22 percent of its purchasing power since 2003 due to inflation, so this boost will provide critically-needed funding for the agency to continue to build upon its record of leadership in global health R&D. Photo: PATH/Satvir Malhotra Availability of the first child-friendly, appropriately-dosed TB medicines announced Health workers will soon have a critically-needed new tool to improve treatment for the one million children infected with tuberculosis (TB) each year. In November, TB Alliance and partners announced that the first-ever appropriate, child-friendly tuberculosis (TB) medicine in the correct dose will be available in early 2016. At the moment, TB medicines are not available in appropriate doses for children, so parents must crush or cut the pills to administer. This arduous process—combined with the bitter taste—leads to poor adherence. The new treatments are strawberry- and raspberry-flavored, appropriately-dosed versions of the three most commonly used TB medicines. These new treatments are expected to significantly improve TB treatment and adherence among children. Global Health Innovation Act passes House An important new piece of global health legislation championed by GHTC—the Global Health Innovation Act—passed the US House of Representatives earlier this month. This legislation would strengthen global health R&D programming at the US Agency for International Development (USAID) by directing USAID to incorporate R&D across its global health programming and requiring the agency to report annually to Congress on its R&D programs and activities. In 2016 the hard work will begin again to get the Senate to introduce and pass companion legislation so the bill can move another step closer to becoming US law. Ebola product development advanced at lightning speed After years of slow and stunted progress in the development of drugs, vaccines, and diagnostic tools to fight Ebola, product development jumped forward by leaps and bounds in 2015. Thanks to the collaboration of developers, regulatory agencies, and the World Health Organization, six Ebola diagnostics were developed and deployed in West Africa under emergency measures, early-stage clinical trials are underway for at least two Ebola drug candidates with others in development, and at least 15 vaccine candidates are in development with two candidates undergoing Phase II/III trials. The most advanced vaccine candidate VSV-EBOV was shown to offer near-total protection, according to preliminary data analysis from the trials. While these products arrived too late to have a major impact during the epidemic, the accelerated development approaches and mechanisms used may be able to be emulated to speed product development in the future. New pediatric malaria treatment receives positive scientific opinion paving path for regulatory approval A new pediatric malaria medicine— Pyramax® Granules—will soon be available for children worldwide. In November, Pyramax® Granules received a positive scientific opinion from the European Medicines Agency (EMA) under Article 58, a mechanism which facilitates regulatory approval of the product in malaria-endemic countries. The medicine, which was developed by Medicines for Malaria Venture (MMV) in partnership with Shin Poong Pharmaceutical Co. Ltd, is a combination of two antimalarials and is designed to be easy for children to consume. It is taken in liquid form and is flavored to mask the bitter taste. 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. Several promising global health products advancing through development The pipeline of global health technologies is growing and maturing with several exciting products moving through critical development stages. For example, a new medicine for drug-resistant TB became the first new TB drug to advance into clinical trials in six years when it entered Phase I trials in February, a vaginal microbicide containing a novel antiretroviral drug to prevent HIV entered Phase I trials in November, a drug candidate with the potential to become the first ever, oral-only, single-dose treatment for sleeping sickness completed Phase I trials in September, and a microbicide vaginal ring is completing Phase II trials with results expected in early 2016. Due to increased attention and investment over the last 15 years, there are now nearly 500 neglected disease product candidates in the pipeline. Global goals recognize importance of health R&D In September, global leaders ratified a new set of global goals, called the Sustainable Development Goals (SDGs), which will guide global development efforts for the next 15 years. GHTC was excited to see these goals recognize the importance of global health R&D with inclusion of a target supporting R&D of vaccines and medicines for diseases primarily affecting developing nations. It’s been broadly recognized that we cannot reach the ambitious SDG health targets—to reduce maternal and child mortality and end the epidemics of HIV/AIDS, TB, and neglected tropical diseases— by 2030 with the health technologies we have today. Now that the goals and targets are in place, accountability is key. We must ensure the SDGs translate into greater investment and political commitment from all nations to catalyze development of the next generation of health technologies needed to transform global health.

Photo: Neil Brandvold/DNDi Global Health Now took an in-depth look at the flesh-eating fungus mycetoma—which enters the body through cuts, and can result in swollen, deformed limbs—in a three-part series on this Untold Global Health Story of 2015. The final installation focuses on GHTC member Drugs for Neglected Diseases initiative (DNDi), a product development partnership that will be initiating a clinical trial in mid-2016 to assess the safety and efficacy of the antifungal Fosravuconazole against mycetoma. Fosravuconazole is currently under development by Japanese pharmaceutical company Eisai, where it has proven more successful at combatting mycetoma in petri dishes than currently used medicines. The leading treatment, itraconazole, is only curative for one in thirteen patients after a year of use. The article notes that DNDi’s entire budget for the study is under US$2 million, compared with the average $1 billion spent by pharmaceutical companies. Eisai has agreed to donate Fosravuconazole pills for the trial which will compare Fosravuconazole, itraconazole, and a placebo. Pharmaceutical company Gilead Sciences has been heavily criticized for “price gouging,” charging Americans $1,000 per pill for their drug sofosbuvir, which, for most patients, cures Hepatitis C in twelve weeks. However, in Egypt, where 10 percent of the population has chronic Hepatitis C—the highest rate worldwide—Gilead is selling them to the government for $10 per pill. The reduced price comes at a cost: to prevent the drugs from entering the black market and undermining Gilead’s sales, the Egyptian government has agreed to several restrictions that some advocates consider humiliating for patients and/or unethical. Not only are the drugs only sold at official government pharmacies, but patients must break the seal and take the first pill on-site to receive their first bottle and must return the original bottle to receive refills. The program has generated interest from other pharmaceutical companies, and the government has entered into similar deals with Bristol-Meyers Squibb and AbbVie, importing their medicines Viekira and Daklinza, respectively. Over the past year, more than 125,000 Egyptians have been treated, and the government hopes to treat another 300,000 each year starting in 2016, with the ultimate goal of reducing prevalence to 2 percent by 2025. Figure 1: Compounds included in the Pathogen Box, by disease (Photo: MMV) GHTC member Medicines for Malaria Venture (MMV) launched the Pathogen Box, a set of 400 compounds, each with proven activity (i.e., in test tubes) against neglected diseases, free for researchers and laboratories around the world. To create the Pathogen Box, MMV's team of chemists, as well as partners with expertise across neglected diseases, evaluated compounds in the European Bioinformatics Institute’s open access database, to determine those with the most potential. The team then acquired fresh samples of each compound to include in the boxes themselves. By expanding access to these samples, the Pathogen Box eliminates a major barrier to drug discovery for malaria, tuberculosis, schistosomiasis, Chagas, and other neglected diseases (See Figure 1).