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Just one case of yellow fever in an unvaccinated population is considered an outbreak, according to the World Health Organization (WHO). And now, an outbreak in Angola has spread to Kinshasa, a city of 12 million in the Democratic Republic of Congo. Health experts are calling it the worst yellow fever outbreak in Africa in decades. The outbreak in Angola has resulted in nearly 350 deaths, and unrelated outbreaks are ongoing in Uganda and Peru. Meanwhile, the WHO’s emergency stockpile of the yellow fever vaccine—the only available countermeasure against the virus—has been depleted twice this year, and is currently running low at only 6 million doses, raising concerns about global ability to respond to growing outbreaks.Background: The illness and impact of a historic virus Yellow fever is a mosquito-borne disease—spread by both the Aedes and Haemogogus species—found in both urban and rural settings. The disease is endemic in forty-seven countries across Africa and Latin America, and each year results in anywhere from 84,000 to 170,000 severe cases and 29,000 to 60,000 deaths. Many cases of yellow fever are asymptomatic, and when they manifest, initial symptoms are nonspecific: fever, fatigue, aches and pains, nausea, and vomiting. Fifteen percent of cases progress to a more severe illness  characterized by high fevers, liver and kidney damage, jaundice—thus the name yellow fever—and even hemorrhaging. Half of those who enter this toxic stage of infection die. While the yellow fever virus has plagued the world since the 17th Century, it was first isolated in 1900 by American pathologist Walter Reed, earning it the distinction of being the first human virus ever to be discovered. A safe and effective vaccine was first introduced in 1936; however, in the eight decades since, few new tools against the virus have been developed. Below, we break down the status of research and development (R&D) for vaccines, drugs, and diagnostics for yellow fever.Status of R&D and access to yellow fever countermeasures Vaccines Yellow Fever vaccine manufacturing facility Val de Reuil Sanofi Pasteur site, France (Photo: Sanofi Pasteur / Patrick Boulen)The yellow fever vaccine is effective, safe, and affordable. Just one dose provides lifetime protection from the virus for 99 percent of those vaccinated. However, the vaccine contains live virus, and in extremely rare cases, can result in illness. Since 2000, the price of the vaccine has risen 30 percent annually. However, this increase has not incentivized manufacturers to scale up production. There are only four manufacturers of the vaccine, and it’s notoriously difficult to produce. Consequently, the global demand for the vaccine surpasses availability by 42 percent. Yellow fever vaccine production relies on eggs from pathogen-free chickens flocks, which are hard to come by. The embryos are infected with the yellow fever virus, and after three to four days, the embryos are harvested under sterile conditions. Each egg can provide anywhere from 100 to 300 doses of the vaccine. The entire production process takes about one year. A vaccine candidate with an inactivated version of the virus completed successful phase 1 clinical trials in 2011. However, since GE Healthcare acquired the intellectual property for the vaccine in 2012, no additional clinical trials have been undertaken. Fortunately, last month PnuVax Incorporated entered into an agreement with GE Healthcare, under which PnuVax will advance the vaccine through clinical trials and will partner with GE Healthcare for manufacturing. In the meantime, the WHO is recommending that the vaccine be administered in fractional doses, using just one-fifth of the standard amount. Studies suggest that this approach still confers at least 12 months of protection from the virus, however, booster shots would be required to sustain immunity when a global shortage is no longer imminent. Additionally, fractional dosing has not been tested in children, raising concerns that this approach might not be sufficient for kids, whose immune responses, including to vaccines, are typically weaker. Drugs There are no specific therapies for yellow fever. Current treatment involves supportive care (i.e., addressing the symptoms). Animal studies suggest that the widely-used antiviral ribavirin and an active carboxamide drug reduce mortality in hamsters, and the molecule interferon-α, used in some cancer therapies, effectively treats the disease in monkeys. However, these treatments were only effective when administered within a few days of infection. Thus, even if they were to prove effective in humans, their application would be limited. The yellow fever virus incubates for three to four days in the body before symptoms appear, and as aforementioned, initial symptoms are nonspecific and easily confused with anything from malaria to dengue fever or leptospirosis to poisoning. Diagnostics As yellow fever is hard to distinguish from other illnesses based on initial symptoms alone, the development of rapid, point-of-care diagnostics is critically needed. Currently, cases can only be confirmed in laboratory settings. Diagnosis requires examining blood or serum for either the virus itself or antibodies against the virus. However, researchers at the Massachusetts Institutes of Technology are currently developing a paper-based diagnostic that simultaneously tests for Ebola, dengue fever, and yellow fever. The test is designed for use in low-resource settings, requiring no electricity or specialized lab equipment and the results are easy to interpret. Testing requires a small amount of blood, and colored nanoparticles appear—red for Ebola, orange for yellow fever, and green for dengue—based on the proteins in the blood. While this new tool is showing promise, it could be some years before testing is completed and regulatory approval is secured. With a limited pipeline of countermeasures against yellow fever, the global community is scrambling to ramp up vaccine production, expand vaccination coverage, and scale up vector control efforts. However, R&D for rapid, point-of care diagnostics; lifesaving treatments; and a safe, affordable, easy-to-produce vaccine is critical to combat this virus after a centuries-long battle.

Editor’s note: This is the second post in a two-part series on the history of GHTC and lessons learned by the organization in coalition building. The series coincides with the launch of a case study examining GHTC as a model of successful coalition building in the global health space. The first post explores the history of GHTC. "If everyone is moving forward together, then success takes care of itself." ~ Henry Ford Inspiring words. But if you have ever worked with a group before, you know, getting everyone moving forward together is a task that is easier said than done. Through our over a decade of experience building and operating a coalition for global health research and development (R&D) advocacy, GHTC staff and members have learned a lot about what it takes to enable a group of organizations to work together effectively as a coalition to enact policy change. While there is no silver bullet that guarantees smooth sailing in building a coalition, there are value systems and operating structures that can be put in place from the start to make the journey less choppy. From interviews with current and former staff and members, we’ve pulled together a list of what we think are the top eight keys to success for building an effective coalition. 1. Establish a core set of shared principles  You can only move forward together if you first agree on what direction to take. GHTC learned this early in our coalition’s formation. As GHTC achieved initial success and membership ballooned, it became increasingly challenging for the coalition to achieve consensus and agree on areas of advocacy to pursue. To counter this paralysis, GHTC established terms of reference to define the principles that would guide the coalition’s advocacy agenda and a membership application requiring all members to endorse those terms. “Having terms of reference and a clear vision for members is key,” said Kaitlin Christenson, former founding director of GHTC. “It helps members understand what they can expect from the secretariat of [the] coalition and agree on issues of focus—what the coalition’s purpose is and is not and what it will and will not pursue.” Establishing these principles early ensured that GHTC’s work could move forward in areas of agreement, rather than stagnating around sources of dissension. 2. Pursue membership diversity While it is important to agree to a set of common principles, it is equally as critical to ensure that a wide range of perspectives is represented among a coalition’s membership. GHTC has benefitted from a broad membership base of global health R&D actors and stakeholders who have experience in different health and technology areas and across the continuum of product development. Not only does this ensure that GHTC truly represents the voice of the global health R&D community, but it expands the coalition’s understanding of complex policy issues, enabling GHTC to knowledgably speak to and advocate for policies that could strengthen global health R&D. 3. Identify the right convening organization It is critical to choose a convening organization or secretariat that not only has resources to serve as a convener, but also one whose interests are best aligned with the coalition’s mission and best insulate the coalition from internal schisms.As GHTC’s founding members worked to transition from an ad-hoc group of collaborators to a formalized coalition, PATH was selected to serve as secretariat. This choice was strategic. PATH was the only member that conducts R&D across a large number of technology platforms and health and disease areas. Thus, the selection of PATH as convener helped protect the coalition from fracturing along the lines of disease or health area and has ensured that its activities do not promote the importance of one member’s perspective or area of R&D over another. This has helped engender critical trust between the secretariat staff and coalition members. 4. Elect a representative steering committee Establishment of a representative steering committee has been critical to GHTC’s ability to make informed decisions and translate those decisions quickly and efficiently into action. GHTC’s steering committee is elected by members with seats on the committee reserved for different types of GHTC member organizations (product developers, advocacy organizations, etc.), thus ensuring it is representative of the breadth of the coalition’s membership. The committee is a critical forum and mechanism for strategy development and guidance without depending on consensus from every coalition member for every decision. 5. Remain transparent and member driven Decision-making within GHTC’s organizational structure is an intentionally transparent process—every GHTC member has the opportunity to offer an opinion on a decision or policy position through surveys, calls for feedback, or open discussion, even if it means that GHTC avoids taking a stance in an issue area in response to member disagreements. As a result, members have remained engaged and invested in GHTC’s work, preserving the strength of the coalition’s collective voice. “GHTC is very good at giving its members a chance to provide input,” said Jodie Curtis, executive vice president at District Policy Group and a consultant who works closely with GHTC. “There are no hidden agendas, no sense that GHTC [secretariat staff] wants to hold all the power; it is a very transparent organization.” To remain member driven, GHTC staff prioritize regular communication with members through regular meetings and more informal interactions. 6. Secure a dedicated staff and source of funding In its earlier days the coalition was constrained because its members were not able to dedicate the consistent amount of time and resources needed to maximize its effectiveness. In 2009, PATH received a grant from the Bill & Melinda Gates Foundation to fund GHTC which enabled it to hire full-time, dedicated staff to manage day-to-day activities. Having this dedicated staff allows GHTC’s members to focus on contributing to the coalition’s overall strategy and advocacy content and amplifying its work and ensures all members have the capacity to remain up to date on and involved in the coalition’s activities. 7. Conduct active education and relationship-building efforts A coalition is only as strong as its connections and relationships. GHTC’s staff prioritizes relationship building with key decision-makers and their staff, meeting regularly with them and organizing meetings and events where they can interface with GHTC members. Members also appreciate the direct access these relationship-building efforts offer them. “As a member, it certainly helped to have others who were strolling the halls of Congress more frequently than we were and who knew how to get a lot of things done in DC,” said Holly Wong, principal deputy assistant secretary for Global Affairs at the US Department of Health and Human Services and former vice president at IAVI—a GHTC member. “It was like having an extra staffer to run those advocacy activities for us.” 8. Stay connected to the broader advocacy community While GHTC maintains its focus on R&D advocacy, its staff and members are constantly working to understand the broader global health landscape, including development aid infrastructure and systemic issues, and to make sure the coalition has a seat at the right tables it needs to exercise influence. GHTC attends external functions and joins other coalitions and working groups as a member, not only to ensure that the voice of global health R&D is heard in these forums, but also to learn more about what is happening in other areas of the field and how it can shape its priorities to better support the changing environment. “To be effective, a coalition needs to make an effort to be an active member of the broader global health sector,” said Christenson.

TB Alliance announced last week a new agreement with Takeda Pharmaceutical Company Limited to advance novel compounds that show promise as potential treatments against tuberculosis (TB). The compounds were first identified through a recent program in which the partners screened the entirety of Takeda’s chemical library, comprised of 20,000 unique compounds. Existing TB treatment regimens can be onerous for both patients and health systems, requiring four pills per day for at least six months, and only 50 percent of patients with drug-resistant TB are cured after a two-year regimen with more toxic drugs. New drugs against TB are critically needed, and TB Alliance has not only developed multiple products, but has the largest pipeline of TB medicines in history. Both the screening program and the research moving forward are supported by the Global Health Innovative Technology (GHIT) Fund, a cross-sector partnership that invests in research and development for neglected diseases. For years, experts have known that mosquitoes are more effective at transmitting disease than a scientist with a needle, and new research suggests that the key is in the insect’s saliva. To study the impact of mosquitoes' saliva, researchers at the University of Leeds first injected a close relative of the chikungunya virus into mice, recording few symptoms and zero deaths. Next, the team allowed uninfected mosquitoes to bite the mice, and then scientists injected the virus into the mice through the site of the bite. The infection proved to be more virulent, and more than a third of the mice died. Molecules in the saliva prompt an inflammatory response, as the immune system sends neutrophils and macrophages—which combat pathogens by consuming them. The team determined that certain viruses are able to infect the macrophages, enabling the virus to replicate and travel throughout the body. Researchers at Harvard University have created a platform for rapidly and prolifically generating macrolides, a class of compounds containing some of the most common antibiotic and antifungal medicines. Macrolides were first developed in the 1950s, by tweaking microorganisms with antimicrobial properties to make them more effective and safe for use in humans. However, reliance on these natural microorganisms has made it difficult to produce new macrolides or adapt existing ones, and past efforts to develop synthetic macrolides have involved more than fifty steps—an arduous process with no guarantee that the final product will be effective. However, the team at Harvard has developed eight synthetic structures and has designed a method for rapidly combining them, and using just these eight structures and their derivatives, have created more than 300 synthetic macrolides. The team has begun to screen these macrolides for activity against different bacteria, and have identified two that are active against a bacterium that has developed resistance to vancomycin, which is considered an antibiotic of last resort. One drug candidate developed using this technique has recently been tested in two phase 3 clinical trials, proving to be effective against advanced intra-abdominal infections but ineffective against complicated urinary tract infections. The team will continue to screen the more than 300 synthetic macrolides, advancing those that prove most promising in the lab.