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Photo: CDC Vaccines The US National Institutes of Health (NIH) is ramping up research for a vaccine against Zika, a mosquito-borne virus which is “spreading explosively” throughout the Americas and can cause birth defects, including microcephaly, which is associated with stunted head and brain development in newborns. The NIH will be offering new funding for Zika research and supplementary funding will be available for researchers studying similar viruses, including West Nile, dengue, and yellow fever. The NIH plans to initiate clinical trials of a Zika vaccine by the end of this year, and currently has two potential candidates, one resulting from research into West Nile virus. The Brazilian government is also supporting Zika vaccine research and development (R&D), but despite its commitment to developing a vaccine “in record time,” the process will take at least three to five years. GlaxoSmithKline is conducting feasibility studies to determine if its existing vaccine technology could be used to develop a Zika vaccine, however, the company warns it could take ten to fifteen years. Inovio Pharmaceuticals and GeneOne Life Science are initiating research to develop and test a DNA-based Zika vaccine, building on their current partnership for Ebola and MERS vaccine R&D. Treatment There are currently no available therapies for Zika disease and the US Centers for Disease Control advises treating the symptoms by resting, hydrating, and taking medicines for the fever and pain. The National Institute of Allergy and Infectious Diseases (NIAID) at NIH is testing Zika drug candidates. In light of the paucity of treatment options, NIAID Director Dr. Anthony Fauci is calling for a shift in the drug development “one-bug–one-drug approach,” noting that recent pandemics have demonstrated the need for antivirals effective against entire classes of viruses. Diagnostics Point-of-care diagnostics are “the first line of defense in these outbreaks,” according to FIND Chairman Mark Kessel, as rapid, accurate diagnosis is needed to “identify, treat and track the outbreaks to minimize the deaths and costs to the world economy.” Currently, the standard approach for diagnosing Zika takes place in laboratory settings, and involves looking for the virus’ RNA in a blood sample, however the RNA only remains in the blood for a short period of time, and by the time the symptoms begin (3 to 12 days after infection), it may be too late. As exposure to Zika virus during pregnancy can lead to birth defects, scientists are also interested in diagnostic approaches that can test for past infections in newborns, however the leading method requires access to the live virus and advanced safety conditions not found in most labs. When testing for antibodies against the virus in blood samples, differentiating between related viruses can be difficult, and Zika is primarily found in areas in which the related dengue virus is endemic. Despite these limitations, several diagnostics that test for antibodies against Zika are already on the market. Most notably, the Canadian diagnostic company Biocan launched a rapid Zika test in December that takes just ten minutes, and uses a finger prick to collect blood, making it safe for use in the field. Biocan is also launching the Tell Me Fast Dengue/Chikungunya/Zika Virus Combo Rapid Test, which as the name suggests, can detect dengue, chikungunya, or Zika virus. Researchers at the University of Texas are developing a “cheap, portable box” that detects Zika virus DNA. The team has developed a prototype and is seeking additional funding for continued development and testing. The box structure enables testing of mosquitos for Zika virus, and could allow scientists to detect an outbreak early, rather than relying on reported cases in humans. Vector Control Without approved vaccines or drugs, and limited point-of-care diagnostic options for Zika virus, public health officials are calling for heightened mosquito control efforts. British biotechnology company Oxitec is testing genetically modified mosquitos to reduce the population of the Aedes aegypti mosquitos which transmits Zika, as well as dengue and chikungunya. Oxitec’s mosquitos are engineered to produce larvae that are unable to mature to adulthood, and in an ongoing trial in Piraciaba, Brazil, the introduction of the engineered mosquitos has resulted in an 82 percent decrease in A. aegypti larvae in just nine months. In response to the Zika outbreak, Oxitec is expanding its trial and building a new facility to produce the mosquitos. Oxitec is currently seeking approval from the US Food and Drug Administration to conduct additional trials in the Florida Keys. The US government is taking the spread of Zika seriously, and President Barack Obama has called for research into Zika vaccines, drugs, and diagnostics. However, the White House is also emphasizing that the threat from Zika is distinct from that of Ebola. While the risk to women who are or may become pregnant is significant, for others, “the impact of the virus is relatively mild." Are there additional Zika R&D initiatives that we’ve missed? Please send tips to Kat Kelley (kkelley@ghtcoalition.org).

A close-up of packets of pills. (Photo: PATH/Christopher Nelson) In November 2015, United Nations (UN) Secretary-General Ban Ki-moon convened a High-Level Panel on Access to Medicinesto discuss and develop solutions to promote innovation and access to essential medicines, vaccines, diagnostics, and other health technologies needed to ensure health and well-being around the world. This panel comes on the heels of the UN General Assembly formally adopting the Sustainable Development Goals (SDGs)—goal three of which is to “ensure healthy lives and promote well-being for all at all ages”—and is designed to consider ways in which intellectual property (IP) protections, trade rules, and international human rights law might affect global access to medicine and the ability of the international community to achieve SDG three by 2030. The panel also comes at a time when the United States and the international community are considering one of the most ambitious trade agendas in the last several years. The Trans-Pacific Partnership (TPP), the largest regional trade agreement in history, linking 11 Pacific-rim countries that make up 40 percent of the world’s economy, was finalized in October 2015 and is currently under review by the US Congress. The agreement has stronger IP protections for pharmaceutical products than those included in previous regional and bilateral trade agreements—including twelve years of data protection for new biologics and the ability to evergreen certain pharmaceutical patents—which may impact timely access to generic medicines in TPP countries. The US is also in the process of negotiating the Trans-Atlantic Trade and Investment Partnership (TTIP), which would reduce tariffs and codify trade-related standards between the United States and the European Union. Details of this agreement have not yet been made public. (To read more about the potential impact of TPP on access to medicine, visit GHTC’s blog .) Though minimum standards for patents and IP protections have been included in trade agreements since 1995, when the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) was approved by the World Trade Organization (WTO), certain actions have carved out exceptions to protect public health and support low- and middle-income countries. The Doha Declaration on TRIPS and Public Health formally clarified that TRIPS IP protections for pharmaceuticals should not prevent countries from protecting public health and promoting access to medicine. It also affirmed flexibilities for least developed countries (LDCs), as designated by the UN, to gradually enforce IP protections for pharmaceuticals, including provisions around compulsory licensing of generic medications, and established January 1, 2016, as the deadline for LDCs to implement enforcement of pharmaceutical patents. The US May 10th Agreement established congressional intent for TRIPS flexibilities, as expressed in the Doha Declaration, to be reflected in all US trade negotiations. With the on-ramp for LDCs to enforce pharmaceutical patents set to expire at the start of the new year, in November, the WTO committee on IP rights agreed to extend the provision allowing LDCs to avoid applying and enforcing IP rights on pharmaceutical products until 2033. In a June 2015 letter to the WTO, advocates argued that, “Many LDCs (at least 25 countries) have relied on the…pharmaceutical product [exemption] to declare patents unenforceable as well as to exempt pharmaceutical products from patent and test data obligations, thereby allowing them to import critical treatments such as medicines for their national HIV and AIDS treatment programs” at affordable prices. Because “the public health crisis in LDCs is a long-term challenge that will endure at least as long as these countries remain LDCs,” an extension of the on-ramp is critical to “provide suppliers, procurers and donors of affordable medicines in LDCs the clarity and certainty to confidently manufacture, export and import generic medicines.” Countries with strong pharmaceutical industries, like the United States, negotiated to make the extension time-bound to 2033 in lieu of the permanent extension sought by LDCs and their advocates. It is with this backdrop that the UN High-Level Panel on Access to Medicines begins its work. The UN Secretary-General has appointed members of the panel—with representatives from both developed and low- and middle-income countries. Further, a group of expert advisors—from civil society, the private sector, and academia—has been established to help guide the Panel’s work. Several documents including a Report on HIV and the Law are cited as background for the Panel’s work. After the first in-person meeting of the panel in December, the group opened a call for contributions by interested stakeholders “that address the misalignment between the rights of inventors, international human rights law, trade rules and public health where it impedes the innovation of and access to health technologies.” The panel will discuss these contributions at two public hearings in March, which will help to guide the development of their formal report to the Secretary-General, expected to be finalized in early June. To ensure that essential global health technologies get into the hands of populations in need, promoting access to medicines and global health tools is just as critical as supporting the research and development that drives these new innovations. GHTC will be closely monitoring the work of the High-Level Panel and looks forward to contributing to the public hearings in March.

Last monPhoto: PATH/Mike Wangth, the World Health Organization (WHO) convened experts to determine which emerging diseases could become “the next Ebola”—those pathogens most likely to cause the next major epidemic. The panel focused on diseases for which there are limited medical countermeasures, with the goal of galvanizing research and development (R&D) for the tools needed to prevent and control future outbreaks. Many have lauded the acceleration of Ebola R&D since the onset of the West Africa outbreak, with experimental treatments made available through emergency use authorizations, and stages of vaccine development and manufacturing progressing in months, rather than years. However, these last minute investments are costly and will not always be successful—underscoring the importance of having tools to prevent, detect, and treat these emerging pathogens before we need them.The list of emerging diseases identified by the WHO includes Crimean Congo hemorrhagic fever (CCHF), Ebola and Marburg, Lassa fever, Rift Valley fever (RVF), Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS), and Nipah virus. There are some striking similarities between these eight pathogens: all eight are viral, zoonotic, and there are no approved vaccines, point-of-care diagnostics, or treatments for any of the eight diseases.Below, GHTC provides an overview of the eight diseases and the state of R&D for diagnostics, drugs, vaccines and other technologies against them.Crimean-Congo hemorrhagic fever Why should we be concerned? CCHF is tick-borne virus that is fatal in up to 40 percent of cases. First reported in Tajikistan in the 12th century, CCHF is now endemic in the Balkans, the Middle East, central and south Asia, and Africa. A hemorrhagic fever, CCHF affects many parts of the body and can weaken blood vessels. Initial symptoms are often nonspecific—fever, headache, muscle and back pain, vomiting, diarrhea—but as the disease progresses, patients may experience light sensitivity, redness of the face and throat, jaundice, depression, exhaustion, and mood swings.CCHF can be found in a myriad of both wild and domestic animals, including cattle, sheep, goats, horses, hedgehogs, and even ostriches. While most human cases are attributable to either tick bites or interactions with livestock, it can be transmitted between humans through contact with body fluids.Where does R&D stand? There are several laboratory tests to diagnose CCHF, however, diagnosing the disease in low-resource settings presents challenges. Blood and tissue samples are contagious and should not be handled outside of “maximum biological containment conditions,” according to the WHO.There are currently no vaccines or drugs approved to treat CCHF. Current treatment involves managing the symptoms, including the provision of fluids and electrolytes. Ribavirin, an antiviral hepatitis C medicine, is often used to treat CCHF, although clinical trials to demonstrate its efficacy have been inconclusive. There is a vaccine candidate in early-stage development which has proved effective in mice.Ebola and Marburg virus disease Why should we be concerned? It is possible that Ebola could literally be the “next Ebola” outbreak. Marburg virus, a close relative of Ebola, is another leading contender. Both Ebola and Marburg viruses reside in monkeys and bats and can jump from animals to humans, however, most cases result from human-to-human transmission, through exposure to bodily fluids.Ebola and Marburg are also hemorrhagic fevers, and the symptoms—fever, headache, malaise, diarrhea, abdominal pain, nausea, vomiting—are easily confused with malaria, typhoid fever, or meningitis, depending on the local disease burden. Cases of Marburg and Ebola can only be confirmed in laboratory settings, and similar to CCHF, patient samples are a major biosafety risk if handled inappropriately. In late 2014, the WHO Prequalification Program instated an emergency mechanism to allow for rapid review of Ebola diagnostics, resulting in the approval of six diagnostics for emergency use. The WHO, in partnership with Médecins Sans Frontières and FIND, also convened diagnostic companies to plan for the accelerated development of rapid, point-of-care diagnostics.Where does R&D stand? The recent West African outbreak galvanized US$165 million for Ebola R&D, and several Ebola vaccine and drug candidates in development are also intended to prevent and treat Marburg. However, to stymie the next outbreak, sustained investment in Ebola and Marburg R&D is needed for the advanced development, regulatory review, introduction, and roll-out of promising vaccines, drugs, and diagnostics.Lassa fever Why should we be concerned? Lassa fever is primarily transmitted to humans through the bodily fluids of either rats or other humans. While 80 percent of those infected are asymptomatic, 20 percent experience the standard set of symptoms associated with hemorrhagic fevers, and in severe cases, swelling of the face and brain, shock and seizures, and deafness.Where does R&D stand? Cases can only be confirmed in the lab, and there are no vaccines or drugs approved to specifically treat or prevent Lassa. The aforementioned hepatitis C drug—ribavirin—is also used to treat Lassa fever, with again only limited data available on its efficacy. The primary method of Lassa prevention and control involves promoting hygiene and protecting homes and food from rodents.Rift Valley Fever Why should we be concerned? RVF is found in sub-Saharan Africa and the Arabian Peninsula. Most cases are either asymptomatic or mild with nonspecific symptoms, including fever, muscle and joint pain, and headache. Eight percent of patients experience more severe symptoms which can include lesions in the eye and loss of vision; swelling of the brain (encephalitis); or a hemorrhagic fever.Sheep, cattle, camels, and goats can all become infected with RVF and most human cases are attributable to contact with infected animal tissue, through slaughter, disposal, or veterinary care. It is believed that humans can also become infected through consumption of unpasteurized dairy products or mosquito bites. No cases of human-to-human transmission have been reported.Where does R&D stand? RVF can only be diagnosed in the lab, and the range of symptoms makes it difficult to detect. Treatment is supportive, and is tailored to the patients’ symptoms. The US Centers for Disease Control and Prevention have developed an experimental vaccine against RVF for use in animals. Initial studies have been encouraging, suggesting that the vaccine is safe, effective, and inexpensive.Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome coronaviruses Why should we be concerned? MERS and SARS affect the upper respiratory and gastrointestinal systems, and the two coronaviruses have similar symptoms, including fever, cough, and shortness of breath. While MERS is less contagious than SARS, it is four times more deadly, killing up to 40 percent of those infected."Camels in the kingdom [of Saudi Arabia] are like dairy cows, beef cows, racehorses, pulling horses, beloved Labradors, and living daily reminders of holy scripture, all in one." Cynthia Gorney, National Geographic (Photo: PATH/Teresa Guillien)SARS was first identified in 2002, infecting 8,000 people, primarily in China, Hong Kong, and Taiwan. However, the outbreak lasted less than a year, and there have been no new cases since 2004. Since the 2012 emergence of MERS, more than 1,600 cases have been reported in 26 countries. Most cases, however, are found in the Arabian Peninsula, and all other cases are attributed to Middle East travel.While both viruses are found in bats, most cases of these airborne diseases come from human-to-human transmission. MERS is also found in camels and camel-to-human transmission is believed to be a significant source of new cases. In the Arabian Peninsula, 12 percent of camels are infected with MERS at any given time, however, the virus merely causes an innocuous cold in camels.Where does R&D stand? There are no approved vaccines or drugs for either SARS or MERS, and both must be confirmed in the lab. Without effective antivirals against the coronaviruses, treatment involves addressing the symptoms. Convalescent blood plasma therapy—in which the blood plasma of survivors, containing antibodies against the virus, is provided to patients—has been used experimentally for both diseases, and decreased the SARS fatality rate by 23 percent. A number of treatments for MERS are in development, however, none have progressed to human trials. There are several MERS vaccine candidates, and human trials are planned for at least one. Additionally, a MERS vaccine for camels has undergone an initial, promising round of testing. GHTC member Sabin Vaccine Institute is also working on a vaccine for SARS.Nipah Why should we be concerned? Nipah virus was first identified in 1999, during an outbreak of the illness in Malaysia and Singapore, in which nearly 300 cases and 100 deaths were recorded, primarily among pig farmers. To stop the spread of Nipah, more than 1 million pigs were slaughtered. Since then, regular outbreaks have occurred in Bangladesh and India.Nipah impacts the nervous and respiratory systems, causing inflammation of the brain, sluggishness, disorientation, and encephalitis. Nipah kills 40 percent of those infected, and survivors often experience long-term effects, including convulsions and personality change.Where does R&D stand? Diagnosing Nipah virus requires multiple laboratory tests. As is the case with CCHF and Lassa fever, the drug ribavirin has been used to treat Nipah, however, its efficacy has not been confirmed. While there is no vaccine to prevent Nipah, human antibodies against it have been tested in ferrets, and results suggest that these antibodies could provide protection against the virus.

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).