Global rise in dengue warrants improved prevention, control methods

As a leading cause of serious illness and death among Latin American and Asian children and with more than 40% of the world’s population at risk for the disease, dengue is becoming an increasingly prevalent and significant public health issue.

There are four distinct serotypes of virus that cause dengue fever (DEN-1, DEN-2, DEN-3 and DEN-4), which are transmitted by several species of mosquitoes, most notably Aedes aegypti. The disease presents simply enough, with fever, headache, muscle and joint pain and a characteristic measles-like rash, but can develop into more severe illness. Hemorrhagic dengue fever can be fatal, as it may be accompanied by plasma leaking, fluid accumulation, respiratory distress, severe bleeding and organ impairment, according to WHO.

WHO reported there are between 50 million and 100 million dengue infections annually worldwide, with an estimated 500,000 patients — including a large proportion of children — requiring hospitalization. Approximately 2.5% of patients die from severe dengue infection.

However, more recent estimates suggest dengue disease burden is much greater, with an estimated 400 million dengue infections per year, of which 100 million are symptomatic, according to Donald S. Shepard, PhD, a professor at the Schneider Institutes for Health Policy at the Heller School of Brandeis University.

Recovery from infection with one dengue virus serotype confers lifelong immunity against that particular serotype. Immunity against other serotypes after recovery, however, is only partial and temporary, according to WHO.

“In terms of risk for death, the most vulnerable group is infants aged between 5 and 8 months,” Kristy O. Murray, DVM, PhD, an associate professor of pediatric tropical medicine at Baylor College of Medicine, told Infectious Diseases in Children. “Infants are the most susceptible to hemorrhagic fever, likely due to the transfer of maternal antibodies. A mother who has been previously infected with dengue passes those antibodies to her child. This can lead to a more severe clinical picture if the child becomes infected with dengue.”

Maternal antibodies against dengue are unable to neutralize the virus if the serotype of the virus infecting the infant is different from that of the motherbecause the child has not actually experienced the illness; each serotype of.E virus is different enough that it can successfully evade the host immune response, according to Murray.

Overall, the chances of developing hemorrhagic dengue fever are low, Hyeryun Choe, PhD, an associate professor in the department of infectious diseases at The Scripps Research Institute in Jupiter, Florida, told Infectious Diseases in Children.

“However, it is generally believed that dengue hemorrhagic fever is more likely to occur when a person is infected for the second time. This is because immunity generated against dengue virus can enhance the second infection if the serotypes of the first and the second viruses are different,” Choe said.

In areas considered endemic for dengue, the disease is a part of life. Infection with all four dengue serotypes is to be expected by the time an individual reaches adulthood, according to Shepard.

“Everyone is exposed in endemic areas; it is simply that children develop symptomatic disease because they are exposed early on while adults have already had the disease and are immune,” Shepard said in an interview.

Essentially, dengue incidence is more pronounced among children because they are at higher risk for severe disease, which is more likely to be noticed, diagnosed, documented and treated. If patients survive subsequent dengue infections during childhood, they reach adulthood with immunity against the majority of, if not all, dengue virus serotypes.

Just a faraway problem?

Dengue incidence has increased 30-fold during the past 50 years, according to WHO. Before 1970, nine countries had experienced severe dengue epidemics. Since then, dengue has become endemic in more than 100 countries in Africa, North America, the Eastern Mediterranean, Southeast Asia, South America and the Western Pacific.

In 2008, the Americas, Southeast Asia and the Western Pacific regions experienced more than 1.2 million cases of dengue, followed by 2.3 million cases in 2010, marking them as the most seriously affected areas.

In 2013, the Americas had 2.3 million reported cases of dengue, of which 37,687 were severe dengue, according to WHO.

Disease incidence continues to increase, as trends in 2014 indicated greater case counts in the Cook Islands, Malaysia, Fiji and Vanuatu. After a lapse of more than 10 years, Pacific Island countries were recently affected by dengue serotype 3.

Why has dengue incidence increased so dramatically in recent years? The most simplistic explanation begins where the disease starts: A. aegypti mosquitoes.

“These mosquitoes need approximately a tablespoon of water to hatch eggs in,” according to Angelle Desiree LaBeaud, MD, MS, an associate professor of pediatrics and infectious diseases at the Lucile Salter Packard Children’s Hospital, Stanford School of Medicine. “We call them container breeders. They love to live in and around human habitation, so they are often found in urban and semi-urban settings. It is very difficult to control this mosquito in all of its life stages because it is so entrenched around human households and can breed in such small amounts of water.”

Increases in urbanization and international travel have created a multitude of opportunities for A. aegypti mosquitoes to breed, transmit and introduce dengue virus to new and susceptible populations.

“The A. aegypti mosquito likes to breed in man-made containers and does not travel very far. Thus, urban areas are the most hospitable,” Shepard said. “As more and more of the population moves into urban areas, we are creating an environment that is amenable to these mosquitoes. The movement of people facilitates dengue virus being introduced into new areas, as well as new strains of dengue introduced into already endemic settings.”

Additionally, A. aegypti do not just spread one specific virus, but rather four virus serotypes, all of which do not confer protective immunity to each other.

“The fact that there are four serotypes of dengue virus is a significant explanation of recent increases in disease burden,” LaBeaud noted. “Most of the world is hyperendemic for dengue, meaning all four serotypes coexist together. Instead of having outbreaks of one virus, you have outbreaks of four viruses, which can increase incidence and risk for more severe disease.”

‘Coming to a mosquito near you!’

International travel has undoubtedly led to the re-emergence of dengue virus in the United States. Cases of dengue in returning U.S. travelers have steadily increased in the past 20 years, according to the CDC.

From 1947 to 1980, no cases of dengue acquired in the continental U.S. were reported to the CDC. However, there have been seven localized outbreaks of dengue along the Texas-Mexico border since 1980, all of which were associated with large outbreaks in neighboring Mexican cities.

The CDC has confirmed that the A. aegypti mosquito inhabits the southern and southeastern U.S., and noted that a secondary mosquito vector, A. albopictus, has spread throughout the southeastern U.S. since its introduction in 1985. A. albopictus is responsible for a dengue outbreak in Hawaii in 2011, which likely stemmed from a Hawaiian resident returning from Tahiti, according to the CDC.

A suspected case of dengue in a New York resident — whose only recent travel had been to Key West, Florida — was reported to the Florida Department of Health in September 2009. Within the next 2 weeks, two dengue infections in Key West residents without recent travel were reported and confirmed, according to the CDC.

Increased surveillance identified 24 additional cases of dengue in Key West during 2009. Another Key West dengue case was reported in April 2010, bringing the case count to 28.

Florida experienced another outbreak of locally acquired dengue in 2013. The state Department of Health identified 28 cases of dengue in Rio and Jensen Beach in August and September 2013. Of these, six required hospitalization.

Inspection of affected areas revealed A. aegypti mosquito breeding activity in 33% of Rio and 100% of Jensen Beach sites. After intensive mosquito control efforts, signs of A. aegypti breeding decreased and were detected in 18% of inspected areas in Rio and nearly none of inspected areas in Jensen Beach, according to a report from the state Department of Public Health.

“Why dengue has re-emerged in Florida is unknown,” researchers from the CDC wrote in MMWR. “The re-emergence of dengue in Florida, as well as the threat posited to the U.S. from other emerging mosquito-borne arboviruses (ie, chikungunya) emphasizes the necessity for strong vector-borne surveillance and mosquito control infrastructure to rapidly identify and control outbreaks of dengue and other mosquito-borne diseases.”

LaBeaud echoed this sentiment in an interview with Infectious Diseases in Children. While recognizing that major disease burden occurs outside of the U.S., she emphasized the reality that dengue, in addition to all mosquito-borne diseases, can easily and quickly affect the U.S.

“Although dengue seems like a faraway problem in the tropics, it can be a problem here in the United States too,” she said. “This mosquito vector is moving around the world, and so are these viruses. All it takes is one person who does not recognize they are sick with dengue to return from their island vacation and infect their local mosquito to potentially start an outbreak.”

Current prevention methods

As disease spreads from typically affected areas in tropical climates to areas considered less likely to harbor dengue virus, the importance of dengue prevention methods increases.

Currently, dengue prevention and control depends solely on effective vector control methods, according to WHO.

To prevent dengue and control its spread, WHO recommends:

• conduct environmental management and modification to prevent mosquitoes from accessing egg-laying habitats;
• dispose of solid waste properly and remove artificial man-made habitats;
• cover, empty and clean domestic water storage containers on a weekly basis;
• apply appropriate insecticides to outdoor water storage containers;
• use personal household protection, including window screens, long-sleeved clothes, insecticide-treated materials, coils and vaporizers;
• improve community participation and mobilization for sustained vector control;
• apply insecticides via space spraying as an emergency vector control measure during outbreaks; and
• actively monitor and conduct surveillance of vectors to determine effectiveness of control methods. 

“Most places where we see dengue are lower-resource countries; and they just do not have the type of resources to implement strict control policies,” Murray said. “In many areas people do not have mosquito repellent or screens on their windows. Mosquitoes are an everyday part of life.”

Mosquito breeding sites are endless, according to Shepard, and can range from flowerpots, to birdbaths or a water tank on the roof of someone’s home.

“The logistics of trying to mount an effective vector control are very formidable,” he said. “Some sites are deemed ‘cryptic,’ where even the most vigorous program could not detect breeding. This could be an underground drain beneath someone’s garden, for example.”

Although insecticide is a recommended control measure, many countries’ approaches do not have lasting, long-term effects on mosquito populations.

“Many countries conduct outdoor fumigation, where a truck drives down the street spraying insecticide. This will kill adult mosquitoes and thus temporarily suppress the number of mosquitoes, but does not address the issue of breeding sites,” according to Shepard. “Mosquitoes can reproduce quickly, so within a few weeks the population can return.”

As these traditional vector control methods continue to demonstrate only partial effectiveness, other approaches to reducing vector counts and transmission have shown recent promise.

Researchers from the University of Melbourne discovered that inserting a bacteria called Wolbachia— a naturally occurring bacteria often found in fruit flies — into A. aegypti mosquitoes significantly reduced their ability to transmit dengue disease.

Additionally, the characteristic Wolbachia produced in A. aegypti carries over into the next generation, Shepard noted. Similarly, genetically modified mosquitoes have emerged as a successful method of vector control.

“The mosquito’s genetics are altered so that mosquito breeding is unable to produce female mosquitoes,” LaBeaud told Infectious Diseases in Children. “So within a certain number of generations, female mosquitoes stop being produced, abruptly stopping the natural cycle of mosquito-borne disease transmission.”

Genetically modified mosquitoes also can be engineered to be incapable of transmitting certain pathogens, according to WHO.

After field trials indicated significant reductions in wild adult populations of A. aegypti mosquitoes, Brazil became the latest country to authorize use of genetically modified mosquitoes in vector control programs.

So how successful can an approach that relies exclusively on mosquitoes be? With a significantly diverse gene pool and vast populations of A. aegypti circulating globally, experts say, other prevention tactics must be developed to successfully inhibit dengue disease burden.

Advancements in vaccine development

Perhaps a combination of vector control methods and a safe tetravalent dengue vaccine that has equal efficacy against all four virus serotypes is the key to eliminating dengue. But finding a vaccine that is safe and effective against all dengue disease poses a serious challenge to manufacturers.

“I have heard people use the baseball analogy ‘like trying to hit a home run vs. a single’ when trying to explain challenges to dengue vaccine development,” Shepard said. “The vaccine must provide comparable protection against all four virus serotypes. There is also an additional concern for risk: if a vaccine protects against one serotype and not against the other, will the vaccinated patient have a higher risk for severe disease?”

The nature of dengue disease, with each serotype offering immunity solely to itself, complicates vaccine development. Since secondary infection is associated with increased risk for severe disease, if a dengue-naive individual is vaccinated against one serotype and they then contract dengue, their immune system may recognize the infection as secondary and thus, increase risk for severe disease.

Despite these challenges, one vaccine candidate, a live-attenuated tetravalent vaccine from Sanofi Pasteur that recently completed phase 3 trials in Latin America and Asia, may provide a suitable response for the rise in dengue.

CYD-TDV (Sanofi Pasteur) is a chimeric vaccine that uses yellow fever virus as a replicative backbone but carries structural proteins of dengue virus, WHO reports.

Twin phase 3 clinical trials were conducted in Latin America and Asia to assess efficacy and safety of CYD-TDV. Preliminary results from the Asian trial indicated an overall vaccine efficacy of 56.5% after three injections and 80.8% efficacy against severe dengue, according to study findings published in the New England Journal of Medicine.

Researchers followed study participants, aged 2 to 14 years, for 25 months after vaccination. No significant adverse events have been reported.

The current Latin American study was conducted in Brazil, Colombia, Honduras, Mexico and Puerto Rico. Researchers randomly assigned 20,869 children aged 9 to 16 years to receive three injections of CYD-TDV or placebo at months 0, 6 and 12. Study participants were followed for 25 months.

Analysis demonstrated CYD-TDV was 60.8% (95% CI, 52-68) effective against symptomatic virologically confirmed dengue among children who received three doses, and 64.7% (95% CI, 58.7-69.8) effective among those who received at least one dose.

CYD-TDV was 95.5% effective in preventing severe dengue and 80.3% effective in preventing hospitalization. Serotype-specific efficacy was 50.3% for serotype 1, 42.3% for serotype 2, 74% for serotype 3 and 77.7% for serotype 4. CYD-TDV had similar safety to placebo, with no significant difference rates of adverse events.

The Latin American study results highlight two interesting points, according to WHO. First, vaccine efficacy was greater among children who had serological evidence of previous dengue exposures. Further, estimated vaccine efficacy for the per protocol and intention to treat analyses were quite similar, raising the question of whether three doses of the vaccine are required to provide lasting protection in endemic settings. Because the majority of study participants received three doses, longer-term protection after less than three doses could not be evaluated.

Several other dengue vaccine candidates are in the pipeline. These include: a live-attenuated vaccine from the NIH, an adjuvanted recombinant envelope protein vaccine from Merck, a purified inactivated vaccine with novel adjuvants from GlaxoSmithKline and a dengue DNA vaccine from the U.S. Naval Medical Research Center. GlaxoSmithKline also is conducting a phase 1 study to evaluate new methods of vaccine administration.

Future goals and recommendations

WHO has established a global strategy to reduce dengue disease burden, which calls for at least a 50% reduction in dengue mortality by 2020, a minimum of a 25% reduction in dengue morbidity by 2020, and an estimate of the true burden of disease this year.

The 2015 goal has proven to be difficult, according to Murray. Some areas have flawless surveillance programs, while others struggle to find the resources to conduct good disease surveillance.

“Estimating the true burden of dengue is a big question,” Murray said. “A lot of that has to do with the way surveillance is conducted country by country. Some areas have really great dengue surveillance — they can determine exactly how many cases they have because they are testing and monitoring for dengue transmission and will know how severe an outbreak can be once it gets started. In other areas, namely low-resource countries, this just is not happening. Dengue cases that do get reported are those severe enough to stand out. Oftentimes these areas subjectively report cases instead of conducting diagnostic testing to confirm a case of dengue.”

Effective surveillance requires resources and significant manpower, and many countries with significant dengue disease burden simply do not have the necessary tools.

“I think one thing that could really help is having defined guidelines on disease surveillance, so that all countries are doing the same thing,” Murray suggested. “There is no consensus right now among different countries on how to identify and report cases.”

As prevention methods continue to develop, the CDC recommends educating the public and health care providers to raise awareness about dengue. The greater awareness the world has, the easier a case can be identified and transmission halted. – by Amanda Oldt

References:

CDC. MMWR. 2010;59:576-581.
Dengue Vaccine Initiative. Live attenuated vaccines. http://www.denguevaccines.org/live-attenuated-vaccines. Accessed January 28, 2015.
Dengue Vaccine Initiative. Subunit, inactivated vaccines and DNA vaccines. http://www.denguevaccines.org/subunit-and-inactivated-vaccines. Accessed January 28, 2015.
Florida Department of Health. Martin County dengue outbreak and serosurvey. http://www.floridahealth.gov/diseases-and-conditions/dengue. Accessed January 28, 2015.
Villar L, et al. N Engl J Med. 2015;372:113-123.
WHO. Dengue vaccine research. http://www.who.int/immunization/research/development/dengue_vaccines/en. Accessed January 28, 2015.
WHO. Global strategy for dengue prevention and control 2012-2020. http://www.who.int/denguecontrol/9789241504034/en. Published August 2012. Accessed January 28, 2015.
WHO. Questions and answers on dengue vaccines: Phase III study of CYD-TDV in Latin America. http://www.who.int/immunization/research/development/QA_Dengue_vaccine_LA_phIIIstudy_final.pdf. Accessed January 28, 2015.

For more information:
Hyeryun Choe, PhD, can be reached at The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458.
Angelle Desiree LaBeaud, MD, MS, can be reached at 300 Pasteur Drive, Stanford, CA 94305.
Kristy O. Murray, DVM, PhD, can be reached at Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.
Donald S. Shepard, PhD, can be reached at Brandeis University, 415 South Street, Waltham, MA 02453.