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In this guest post, Dr. Claire Huang, a researcher with the Centers for Disease Control and Prevention’s (CDC) Division of Vector-Borne Diseases, describes a dengue vaccine candidate developed by her team. The vaccine is now being clinically evaluated in field trials. This is the final blog in a four-part series by experts from CDC’s National Center for Emerging and Zoonotic Infectious Diseases. Dengue, a painful and sometimes deadly viral disease transmitted by mosquitoes, threatens more than 2.5 billion people, or 40 percent of the world’s population. Dengue is endemic in at least 100 countries in Southeast Asia, the Pacific Islands, the Caribbean, Central America, South America, and parts of Africa. A recent report in the journal Nature estimated that there are 390 million dengue infections yearly; 96 million of those infections cause moderate to severe illness, and 294 million cause no or mild symptoms. Previous reports also suggested that 500,000 severe dengue hemorrhagic fever cases and 22,000 deaths occur annually, mostly among children. In 2013, the World Health Organization ranked dengue as the fastest spreading vector-borne viral disease. The mosquito vectors of the virus have adapted to living in urban areas, so changes in demographics favor transmission. Puerto Rico, for example, had one of its largest recorded epidemics in 2010, with more than 21,000 reported cases. Several years ago, Florida reported its first cases of locally acquired dengue in 75 years, and the Republic of the Marshall Islands currently is experiencing its first epidemic since 1989. New outbreaks in Angola and Kenya are also being investigated right now by our Division staff. As the world has become more accessible and travel becomes more frequent, the risk from dengue viruses has increased. Large numbers of travelers return from dengue-endemic areas to the United States each year, increasing the possibility of introducing the virus to those parts of this country where the mosquitoes capable of transmitting dengue virus still thrive. Claire Huang (center) and her team (L-R), Janae Stovall, Betty Luy, and Karen Boroughs, in their CDC laboratory in Fort Collins, Colorado. Credit: CDC. I was born and raised in Taiwan, and I saw first-hand how devastating the disease can be. In 1987, South Taiwan had a dengue outbreak. Now, dengue is a common infection, and dengue cases are reported every year. This is how I became interested in dengue research. Vaccination is the best way to protect against mosquito-borne diseases, and it has been my lifelong passion to create a vaccine that will protect people against the crippling illness I witnessed. Despite decades of effort by many scientists to develop a vaccine for dengue, no licensed vaccine is available. Dengue is caused by infection with any of four distinct but related dengue viruses, and a successful dengue vaccine must offer immunity against all four types of the virus. Infection with one type of the virus produces lifelong immunity—but only to that dengue type. Infection with another type of dengue virus increases the chance of developing life-threatening dengue hemorrhagic fever. Typically, an epidemic caused by one dengue virus type is followed a few years later by an epidemic caused by one of the other three types. In most dengue-endemic countries, most teenagers have already been exposed to multiple dengue viruses. My team in the Division of Vector-Borne Diseases in Fort Collins, Colo., has developed a tetravalent dengue vaccine candidate active against all four types of the virus that is now being clinically evaluated in the United States, Colombia, Puerto Rico, Thailand, and Singapore for safety and efficacy. The vaccine is showing promising results in these human clinical trials. The novel technology invented at CDC and used to create the vaccine has been awarded multiple US and international patents. My team has partnered with Inviragen, Inc., a Colorado-based vaccine company, to conduct collaborative research, development, and licensure agreements. Inviragen is manufacturing the vaccine, named DENVax, and is conducting clinical development and testing of the vaccine for human use. The goal is to provide a safe, effective, and affordable dengue vaccine to protect billions of people living in or traveling to dengue-endemic countries. As my team’s efforts to develop this potentially lifesaving vaccine demonstrate, more research in dengue is needed to fully understand the disease and develop effective strategies to prevent and control the disease.

In this guest post, Jessie L. Dyer, MSPH, in the Centers for Disease Control and Prevention’s (CDC) Rabies Program, writes about the agency’s work with partners in Haiti to fight the disease. She focuses here on the implementation of a low-cost rabies diagnostic test that could make better use of scarce resources and save lives in this developing Caribbean nation. This is the third in a four-part series by experts from CDC’s National Center for Emerging and Zoonotic Infectious Diseases. Often the shred of truth behind legends, rabies is an ancient disease that has inspired countless stories and cautionary tales throughout the world. The Caribbean island nation of Haiti is no different. Historical records warn of rabid man-eating dogs brought to the island by French colonist as early as 1791. Fast-forward more than 200 years, and you’ll find that rabies is now endemic in Haiti—meaning it is commonly found in dogs, mongooses, and possibly bats. Haiti also reports the highest number of suspected human rabies cases of all Latin American and Caribbean countries. Children are the most vulnerable age group for rabies exposure throughout the world. Credit: Michael Niezgoda, CDC. For the past 2 years, while working with the CDC’s Rabies Program in Haiti, I’ve heard many personal stories about “mad” dogs and learned first-hand about the large-scale collaborative effort that is needed to prevent and control rabies. Rabies is a terrifying disease, and once symptoms present, death is inevitable. Yet, most people do not know how to protect themselves. Without the appropriate post-exposure prophylaxis (PEP) after a suspected rabies exposure (usually a dog bite), rabies is almost always fatal.PEP consists of: Wound care (washing with soap) Administration of rabies immune globulin (antibodies that protect you until your body can produce its own antibodies against the rabies virus) Multiple doses of the rabies vaccine (given in the arm). Proper application of PEP can prevent the onset of rabies and death. CDC is one of many partners collaborating with the Haitian government to develop and implement a One Health approach to rabies prevention and control—an approach that encourages physicians, veterinarians, community workers, laboratory professionals, and public health and agriculture officials to work together to prevent and control this horrifying disease. Because rabies is a zoonotic disease, a disease spread between animals and humans, partnerships between human and animal health agencies are vital for successful implementation. For example, we work with Haiti’s Ministry of Public Health and Population (for human rabies prevention) and the Ministry of Agriculture, Natural Resources, and Rural Development (for animal rabies prevention and laboratory diagnostics). Our goal is to cut the incidence of human and canine rabies cases in half by 2015. We know we cannot do it alone, and that it will require efforts in many different areas, including laboratory diagnostics, surveillance, and community outreach. A crucial part of our efforts in Haiti is a push to expand laboratory capacity to quickly and accurately diagnose rabies. One promising new tool is the direct rapid immunohistochemistry test (DRIT), a low-cost test developed at CDC that can be used for initial diagnosis of rabies. The DRIT requires a light microscope, which is far less expensive than the fluorescence microscopes needed to perform the current world standard for rabies laboratory diagnoses—the direct fluorescent antibody test. Research has also shown that the DRIT has a higher specificity for the rabies virus than the test routinely used in Haiti—the Sellers staining method—which was developed in the 1920s and cannot confirm that the resulting stained inclusion is, for sure, the rabies virus (for example, it also stains inclusions caused by the canine distemper virus). Another benefit of accurate diagnostics is that it will strengthen rabies surveillance, which is a critical component for the control and elimination of canine rabies in Haiti. Our hope is that one day, through improved laboratory diagnostics, enhanced surveillance, and growing partnerships, we will better understand the true impact of this tragic and deadly disease in Haiti. The enormous potential of the DRIT gives hope for rabies prevention and control programs in resource-scarce countries such as Haiti.

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. The National Institutes of Health has released a fact sheet on the impact of sequestration. The fact sheet states that, due to budget cuts, approximately 700 fewer research project grants will be awarded this year compared to fiscal year 2012. New statistics show that the vaccine MenAfriVac™—developed through a partnership between the World Health Organization and PATH—has significantly reduced the number of cases of meningitis A in Africa. The most recent meningitis season marks the lowest number of cases in ten years. Scientists at Virginia Tech and the University of Florida are making progress in developing a new species-specific insecticide that would be lethal only to insects that carry malaria. Though they have seen positive results, the scientists still think it will be four to five years before they are ready to submit the compound for federal approval. Drugmakers in Japan have agreed to release data on experimental compounds for possible use to create drugs to combat malaria, tuberculosis, and neglected tropical diseases. The pharmaceutical companies are part of a five-year partnership called the Global Health Innovative Technology Fund.

In this guest post, Dr. Martin Schriefer, chief of the Diagnostic and Reference Activity in the Bacterial Diseases Branch of the Division of Vector-Borne Diseases (DVBD) in Fort Collins, Colo., writes about his laboratory’s development of a new diagnostic tool, the plague dipstick. DVBD is one of seven divisions in the Centers for Disease Control and Prevention’s (CDC) National Center for Emerging and Zoonotic Infectious Diseases (NCEZID). His blog is the second in a four-part series from experts at NCEZID. Uganda is considered a “hot zone” for emerging infectious diseases that have the potential for far- ranging impact. These diseases include Ebola and Marburg hemorrhagic fevers, yellow fever, chikungunya, West Nile virus disease, and plague. The NCEZID has a number of field programs in Uganda to study this unique ecological environment. I have traveled there several times, learning about the health infrastructure and a critical gap in plague diagnostics that was putting people's lives at risk. Plague is an acute and potentially fatal febrile illness that is harbored in rodents and transmitted by fleas. In its pneumonic form, plague can be transmitted by aerosol from person to person, resulting in local outbreaks and the risk for global spread. Now rare in the United States, plague remains a real threat to human health in sub-Saharan Africa and Madagascar. These regions account for more than 95 percent of the world’s reported plague cases. Fatality rates for untreated infections range from 50 percent to 60 percent for bubonic plague to nearly 100 percent for pneumonic infections. A convalescing plague patient in Uganda. Photo Credit: NCEZID In my laboratory, a team of CDC researchers has developed, manufactured, and field-tested a rapid, affordable diagnostic tool—the plague dipstick. The point-of-care plague dipstick, which works like a pregnancy test, brings the laboratory to the bedside. In September 2012, we delivered a supply of dipsticks to Uganda in anticipation of the 2012-2013 plague season. At the plague field station and several local health clinics, the plague dipsticks are providing significant improvements in terms of time, ease of use, storage, and handling. Healthcare workers have been trained in the collection of blood, lymph node aspirate, or sputum from suspected plague patients and the application of these samples to the dipstick. Results are visualized in 15 minutes. During a recent outbreak involving four patients and three deaths, the dipstick successfully diagnosed a pneumonic plague patient, allowing rapid prevention measures to 130 contacts—as a result, no further cases occurred. Before the dipstick was introduced, early clinical diagnosis of plague was difficult and could delay life-saving treatment. Sending samples away for laboratory verification took weeks. Overcoming barriers to effective diagnosis and timely treatment is a priority for CDC laboratory technicians. Plague dipsticks do not require electricity or refrigeration—a critical issue in an environment where electricity is sporadic. And each test costs less than $1.00 to produce. However, better diagnostics are not useful in Uganda unless people can access and use them with confidence. Many Ugandans living in more rural, remote areas are unable to trek long distances to find a health clinic and visit “traditional healers” instead. CDC has been working with field staff to train local healers to recognize plague symptoms and its effects on rats and to refer cases of plague to local clinics as necessary. Healthcare workers can be quickly trained to apply blood or lymph node aspirate to the dipstick, which yields results in 15 minutes. The dipsticks do not require electricity or refrigeration— important in an environment where electricity is sporadic. Photo Credit: NCEZID By educating healers in plague recognition, CDC is helping them to better protect their villages from this deadly disease. NCEZID’s highly innovative programs in Uganda are saving lives with early detection and response. They serve as an important source to strengthen the country’s public health capacity and better prepare for potential bioterrorism events in the United States. The plague dipstick is now being submitted to the US Food and Drug Administration for 510(k) clearance, which is the next step in showing the dipstick to be a clinically validated, sensitive, and specific test.