Kat Kelley

The dapivirine ring (Photo: International Partnership for Microbicides) GHTC member the International Partnership for Microbicides (IPM) announced last week the results of two phase 3 clinical trials demonstrating that a monthly vaginal ring filled with the antiretroviral drug dapivirine can reduce the risk of HIV infection in women. The dapivirine ring is the first long-acting HIV prevention method designed for women, and IPM plans to seek regulatory approval for the product. The trials, conducted by IPM and the Microbicide Trials Network (MTN), enrolled 1,959 and 2,629 HIV-negative women and reduced infection rates by 31 and 27 percent, respectively. Efficacy rates were affected by participant age and adherence: for women over 21—who reportedly used the ring more consistently—the dapivirine ring reduced HIV infections by 37 and 56 percent in the trials led by IPM and MTN, respectively. As IPM Founding Chief Executive Officer Dr. Zeda Rosenberg stated, “These findings give new hope to many women at high risk who need more and different options to effectively protect themselves from HIV.” Researchers at the Scripps Research Institute (TSRI) and the US Army Medical Research Institute of Infectious Diseases have discovered potent antibodies against Ebola that could play a critical role in the research and development (R&D) of Ebola vaccines and treatment. The team identified 300 different antibodies against Ebola in the blood of a survivor, using molecules developed by TSRI to hunt for antibodies. Seventy-seven percent of the antibodies were able to combat the virus in mice, providing protection rates ranging from 60 to 100 percent. The three strongest antibodies all targeted distinct vulnerable spots on a certain protein found on the virus’ surface. Anti-Ebola antibodies have been used before, including in ZMapp™, an experimental treatment deployed during the 2014 Ebola outbreak. However, the number of known, effective antibodies was previously limited. This research also revealed a weak spot on the base of the aforementioned Ebola surface protein. As the virus mutates, so do the surface proteins. However, the base of these proteins remains largely the same, and thus, a weak spot on the base of the protein could be a potential target for manifold strains of the virus. US President Barack Obama is calling on Congress to allocate an additional US$200 million for the President’s Malaria Initiative (PMI), a 30 percent increase that would bring the Initiative’s budget to US$874 million. The funding would enable PMI to expand into three new countries—Sierra Leone, Cote D’Ivoire, and Cameroon; eliminate malaria in Zambia and Cambodia; scale up the use of bed nets; and advance R&D for vaccines, drugs, diagnostics, and vector control methods. As resistance grows to both malaria treatments and insecticides, the need for R&D remains critical. Further, resistance to the leading antimalarial was first reported in Cambodia and the most virulent strains are found on the border between Cambodia and Thailand. Thus, eliminating malaria in Cambodia would impede the global spread of drug resistance. With this new funding, PMI would be able to reach an additional 70 million people, ultimately reaching 92 percent of those in malaria endemic regions.

A vaccine candidate against Rift Valley Fever appears to be safe and effective for livestock and has the potential for use in humans. Rift Valley Fever—which was recently identified by the World Health Organization (WHO) as a leading culprit for the next major pandemic—is often asymptomatic, or manifests with nonspecific symptoms that are easily confused with malaria. However, severe cases can involve vision impairment, brain swelling (encephalitis), hemorrhagic fever, or death. The disease is caused by a virus and transmitted to humans through mosquito bites or contact with infected animal tissue. While there is a veterinary vaccine against Rift Valley Fever used throughout Africa, it does not provide complete protection from the disease and can induce abortion. The vaccine uses a virus that causes cold-like symptoms in chimpanzees, an approach that is generally safe for humans. The candidate will next be tested in animal trials across East Africa, which will be followed by human clinical trials in the region. Middle East Respiratory Syndrome Coronavirus (Photo: National Institute of Allergy and Infectious Diseases (NIAID)) Last week, the Walter Reed Army Institute of Research (WRAIR) initiated the first-ever human clinical trials for a vaccine against the Middle East Respiratory Syndrome (MERS). The DNA-based vaccine was developed by Inovio Pharmaceuticals and GeneOne Life Sciences Inc., and the two companies are also partnering to develop vaccines against Ebola and Zika. MERS is endemic in the Middle East, however, an outbreak last spring in South Korea resulted in 186 cases and 36 deaths. The United States currently has 35,000 and 27,000 troops in the Middle East and South Korea, respectively, and as 40 percent of MERS cases are fatal, “low prevalence doesn’t mean low risk” according to Dr. Kayvon Modjarrad, associate director of the Emerging Infectious Disease Research Program at WRAIR. Meanwhile, a team of researchers at Erasmus Medical Center in Rotterdam is testing a MERS vaccine in camels in Saudi Arabia, where 12 percent of camels are infected at any time and camel-to-human transmission is a significant driver of new cases. Inovio Pharmaceuticals and GeneOne Life Sciences Inc. are also conducting animal studies of their vaccine against Zika, and announced last week that the candidate successfully prompted an immune response in mice, including the development of antibodies against Zika. The partners will next test the candidate in primates and begin Phase 1 human clinical trials by the end of the year. However, vaccine candidates developed by Bharat Biotech in India and the US National Institutes of Health (NIH) are farthest along, according to the WHO. Bharat Biotech will launch animal studies within the next few weeks and the NIH plans to start human clinical trials of at least one of their two vaccine candidates by the end of this summer. As more than 15 groups across government, industry, and academia have joined the hunt for a Zika vaccine, US Congressman Curt Clawson (R-FL) has introduced legislation to further incentivize Zika research and development (R&D), providing companies a 10 percent tax credit for any Zika vaccine R&D costs. The legislation was accompanied by two additional bills, the first of which would reauthorize a program—at US$200 million per year for five years—to support states with mosquito control and prevention. Clawson’s third piece of Zika-related legislation would allow supplemental funding for the Ebola response to be used for Zika, however, leaders at the NIH and US Centers for Disease Control have stated that the remaining Ebola funding has already been reprogrammed and that the agencies have had to take funding away from other programs to kickstart the Zika response.

Seated woman holding baby bundled in a blanket East London, Tutura Clinic, Sep 29, 2009 (Photo: PATH/Wendy Stone) Many of the 15 million babies born premature each year struggle with hypothermia and need help to stay warm. To address this problem, researchers at Johns Hopkins University and George Mason University developed a thermal blanket that uses the chemical substance found in hand warmers and pain patches. The International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) is currently testing the blanket to determine its acceptability and feasibility among mothers and health care providers in Bangladesh and initial results suggest that it is easy-to-use, portable, and can be affordably produced using local materials. Next, the team will incorporate feedback on the blanket’s design and use from the study and a stakeholder’s workshop and will test the efficacy of the blanket in reducing newborn mortality. In India, where there are only seven doctors for every 10,000 people—compared to a global average of 13.9—and where nearly six times as many critical care doctors are needed, electronic intensive care units (eICUs) are expanding access to quality, intensive care. In these eICUs, critical care specialists monitor patients and their vital signs and as needed, provide instructions to local physicians—who may not have any intensive care experience—remotely. Across the country, there are currently 3,000 eICU “beds,” and a 15–20 percent is expected annually. Fortis Healthcare, a chain of hospitals that currently monitors 350 patients, estimates that they save 25 lives per month. While the cost of monitoring patients remotely is only US$10–30 per day, the standard cost of critical care within the hospital ($200 per day) remains, and thus, access to the technology remains limited to those who can afford it. The United States, European Union, and World Health Organization (WHO) are seeking to expedite Zika virus research and development (R&D) through financing and innovative regulatory mechanisms. The White House is calling on the US Congress to provide $1.8 billion in funding to combat Zika, including $200 million specifically for vaccine and diagnostic R&D. The request also includes funding for the US Agency for International Development to incentivize R&D through public-private partnerships, advanced market commitments, or volume guarantees. Meanwhile, legislation has been introduced in both the House and Senate to add Zika virus to the list of diseases eligible for the US Food and Drug Administration’s Priority Review Voucher program, through which a pharmaceutical company is granted a voucher (worth up to $350 million) for expedited review of a future drug as a reward for successfully sponsoring the review of a drug for a neglected disease. Meanwhile, the European Medicines Agency has established a task force to advise on scientific and regulatory issues—including clinical trial design, manufacturing, and post-market surveillance—for tools to prevent, detect, and treat Zika. The European Commission is offering $10 million for Zika vaccine R&D, using existing funding for vaccine development through Horizon 2020, which promotes research and innovation across sectors. The WHO plans to use its Emergency Use Assessment and Listing procedures to rapidly evaluate Zika products for quality, efficacy, and safety. This mechanism is particularly invaluable as United Nations agencies and many nongovernmental organizations rely on WHO evaluations when making procurement decisions.

To bypass unreliable roads, a project funded by the Bill & Melinda Gates Foundation and the United Nations Population Fund is using drones to deliver contraceptives, condoms, and other health supplies to remote villages in sub-Saharan Africa. A drone operator, located in an urban area, loads the supplies into the machine and guides it to its destination, such as a rural health facility. After a successful pilot in Ghana, the project is expanding into six additional African nations, with several governments themselves offering to foot the bill, at just US$15 per flight. Researchers at Brigham Young University in Utah are developing a mobile vaccine kit, with the hope of making vaccine manufacturing as easy as making a Cup of Noodles. The kit is comprised of a one to three liter package and produces antigens—molecules that elicit an immune response, and can result in immunity against a certain pathogen. A health worker merely adds water and the kit generates a vaccine that can be used that same day. The kit is reusable and can be freeze-dried, and thus can be stored at temperatures up to 77 degrees Fahrenheit, which requires much less energy than storing traditional vaccines. The team has successfully used the kit to produce a cancer-fighting protein, and is currently testing its vaccine production capabilities. GHTC member IVCC is leading a $65 million initiative to expand access to new insecticides in 16 malaria-endemic African countries over four years, with the hope of protecting 50 million people from malaria. The project will focus on spraying indoor walls with insecticides, a practice that despite its efficacy against malaria, has decreased by 40 percent over the past few years as mosquitos have become resistant to older, affordable insecticides and as new insecticides remain expensive. IVCC will be partnering with UNITAID, who will help fund the cost of insecticides, as well as GHTC member PATH and the US President’s Malaria Initiative, among others. Insecticides are a critical tool in malaria control, and up to 80 percent of malaria cases prevented since 2000 are attributable to insecticides. However, if new insecticides are not developed and adopted, malaria deaths could increase by 120,000 annually. Photo: CDC/ Prof. Woodbridge Foster; Prof. Frank H. Collins Last week, the World Health Organization declared the Zika virus outbreak in Latin America a Public Health Emergency of International Concern, calling for expedited research and development for Zika vaccines and diagnostics. Currently, the most promising Zika virus vaccine candidates come from small biotech companies, including the Indian firm Bharat Biotech and Pennsylvania-based Inovio Pharmaceuticals. Bharat Biotech has two vaccine candidates against Zika, one that uses Zika and another comprised of a weakened version of the virus. The company launched its Zika program in November 2014, due to its similarity to dengue and chikungunya, which are endemic in India. The company is on the verge of animal studies, which will take approximately five months. Inovio is developing a DNA vaccine as well, an approach that is much faster but often less effective than using an inactivated version of the virus itself. Inovio is currently testing the vaccine in mice and plans to initiate testing in primates within “the next few weeks.” Meanwhile, Sanofi has initiated a Zika vaccine program, building on its experience developing a vaccine for the related dengue virus. Sanofi, the fourth largest pharmaceutical company worldwide, is joined by five more of the top ten—Pfizer, Merck & Co., Johnson & Johnson, GlaxoSmithKline, and Takeda—who are all currently evaluating their existing vaccine technologies and platforms.

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).

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.