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 cites research indicating there are between 284 million and 528 million dengue infections annually worldwide, with an estimated 67 million to 136 million cases showing symptoms.

However, more recent estimates indicate that while the number of symptomatic cases is probably at the bottom end of the range reported by WHO, the growth is worrying, with several countries reporting record outbreaks within the last 5 years, 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 Disease News. “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 because the child has not actually experienced the illness; each serotype of 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, according to Hyeryun Choe, PhD, an associate professor in the department of infectious diseases at The Scripps Research Institute in Jupiter, Florida.

“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 an interview.

In areas considered endemic for dengue, the disease is a part of life.

“Everyone is exposed in the most heavily impacted endemic areas, such as Thailand and Cambodia,” Shepard told Infectious Disease News. “More symptomatic cases occur in children there because children are first exposed early on while adults are more likely to have been previously infected with the circulating serotype and be immune.”

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 recently were 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, peri-urban and densely populated rural areas are the most hospitable,” Shepard said. “As more and more of the population moves into these 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 mosquitoes 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.”

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 was 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.

Increased surveillance identified 24 additional cases of dengue in Key West in 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 Florida Department of Health.

“Why dengue has re-emerged in Florida is unknown,” researchers wrote in MMWR. “The re-emergence of dengue in Florida as well as the threat posed 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 Disease News. 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. population.

“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 these measures:

• 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 virtually 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.

“This bacterium doesn’t naturally infect A. aegypti, but if you infect them, this microorganism actually changes in a mysterious and almost God-given way — it changes the ability of the mosquito to transmit viruses,” Scott B. Halstead, MD, an adjunct professor at the department of preventive medicine and biometrics, Uniformed Services of the University of Health Sciences in Bethesda, Maryland, told Infectious Disease News. “So this bacterial infection actually suppresses the ability of the mosquito to transmit dengue.”

Additionally, the characteristic Wolbachia produced in A. aegypti carries over into the next generation, according to Shepard.

Another approach to vector control has been the genetic modification of mosquitoes, rendering the insect incapable of producing viable offspring. While the release of genetically modified mosquitoes has been shown to markedly reduce A. aegypti populations in small field trials, larger trials have not yet been conducted to determine the scalability of this approach and its effect on human dengue incidence, according to Lyle R. Petersen, MD, MPH, director of the CDC’s Division of Vector-Borne Diseases and an Infectious Disease News Editorial Board member.

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

“Mathematical models indicate that the best approach is some combination of effective vector control and a human vaccine,” Petersen said.

A loss of morale

While increased urbanization and international travel are no doubt factors in the rise of dengue cases over the past 50 years, there also is a basic human element to the problem, according to Halstead.

“The brutal truth is that we, human beings, are just simply growing less competent,” Halstead said. “Yellow fever, another disease that is transmitted by the A. aegypti mosquito, was a huge scourge, mostly in the American tropics, from the 1700s until the mid-1900s. Around the turn of the 20th century, people rolled up their sleeves and figured out how to control A. aegypti, and they did such a good job that the mosquito was eradicated from huge parts of the whole American hemisphere, and all of Brazil.”

Those eradication efforts ended in about 1970, according to Halstead.

“Of course, the corresponding benefit was that there was no dengue,” he said. “But then everybody just laid back and quit.”

Halstead said that after the A. aegypti control programs stopped in the 1970s, the mosquito was re-exported from the U.S. to South America, and from there, it moved very quickly. By this time, he said, the medical and scientific communities had begun to experience a loss of morale in battling the problem.

“There was, in all of these countries in South America, a whole collection of really competent people who were not replaced,” he said. “The people who ultimately replaced them were sort of infused, embedded with a feeling of pessimism.”

Halstead said that during a 10-year period, the whole of Brazil had become reinfested with the mosquito. While the reinfestation spurred renewed efforts in vector control, these measures were inadequate to keep pace with the mosquito, or with the increases in population, urbanization and international travel.

“Everybody could see that the programs weren’t working, and they became very discouraged,” he said. “Every country that has dengue has a national program, and they have all of these insecticide sprays. But when they actually roll up their sleeves and try to apply it and then measure the results, they find that they don’t get very far, because A. aegypti is extremely efficient at transmitting [dengue]. That’s why in 2015, it seems everyone has decided that we’re not going to succeed at mosquito control, so we’d better focus on a vaccine.”

Advancements in vaccine development

A combination of vector control methods and a safe tetravalent dengue vaccine that has equal efficacy against all four virus serotypes may be the key to eliminating dengue, according to experts. Finding a vaccine that is safe and effective against all dengue disease, however, 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 their 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 to the rise in dengue.

CYD-TDV 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. Results from the Asian trial indicated an overall vaccine efficacy of 56.5% after three injections and 80.8% efficacy against severe dengue.

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

The 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 in rates of adverse events. Study results were published in The Lancet and the New England Journal of Medicine.

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. Additionally, Takeda’s chimeric dengue vaccine is expected to advance to phase 3 testing in the near future, and GlaxoSmithKline is conducting a phase 1 study to evaluate new methods of vaccine administration.

The ‘ideal vaccine’

Halstead emphasized that while some of the vaccines currently in development are promising, a truly optimal vaccine may still be some years away.

“The efficacy of the Sanofi vaccine was only a little bit better than 50%, which isn’t good,” he said. “I think for the next 5 or 10 years, we’re going to have a vaccine that will be somewhat protective, but suboptimal. Meanwhile, there are other, better vaccines coming along.”

For example, the CYD-TDV vaccine is intended to be administered as three doses, while the NIH vaccine would protect against all four serotypes with a single dose.

“That’s the ideal vaccine, one that protects against all four in one dose. It looks like the NIH vaccine is going to achieve that. The Sanofi vaccine is not,” Halstead said.

Eugene D. Shapiro, MD, professor of pediatrics at Yale School of Medicine and an Infectious Disease News Editorial Board member, agreed that while the ‘ideal’ vaccine has not yet been introduced, significant strides are being made.

“One of the concerns about dengue vaccine has been that if you get vaccinated against one type and then a person gets another type, this might be putting people at risk,” he said. “But I think there’s a lot of progress being made on the vaccines. There have already been clinical trials that have indicated a pretty substantial degree of protection, even if it’s not ideal. So, if we can get a safe and effective vaccine, that will be great.”

Lifestyle factors and climate change

Although vector control and vaccines are important pieces of the puzzle, there remain significant socioeconomic and lifestyle factors driving dengue prevalence.

“We’ve looked at outbreaks that have occurred right on the border, and what we see is that there are lots of dengue cases on the Mexican side, and much fewer cases on the American side,” Petersen said. “Yet the number of mosquitoes are the same; if anything, there are more mosquitoes on the American side.”

Petersen said these differences are likely related to the presence or absence of air conditioning and the extent of urbanization and close living quarters.

“The studies we have done have shown that the presence of air conditioning seems to be a major protective factor, and people living further apart in larger lot sizes seems to be a major protective factor,” he said. “It makes sense — if the virus spreads from mosquito to person to mosquito, people who aren’t living in as close proximity to each other have a lower risk of outbreaks, and air conditioning provides a barrier to Aedes aegypti mosquitoes, which typically bite indoors.”

While Petersen said he would not rule out the possible role of climate change in the dengue uptick, he said it is difficult to establish a correlation between the two.

“I think we really don’t know for sure,” he said. “What we know is that the recent huge increases in dengue incidence have largely been due to a sociological phenomenon — urbanization, poor sanitation, globalization, demographic shifts. These are the really overwhelming factors and they are happening really quickly.”

In contrast, climate change, by definition, is a slow process.

“So, it’s hard to sort out what effect climate change has, if any, on dengue incidence given these other major factors that are happening much more rapidly,” he said. “I wouldn’t discount climate change having an effect, but I think it’s hard to tell in light of these other factors.”

Halstead said improvements in water sanitation will likely also be essential in permanently controlling dengue.

“A lot of people say, ‘What’s the secret of controlling A. aegypti?’ The answer is two words — piped water,” he said. “If you have adequate and reliable piped water, you don’t store water on the premises. If you store water on your premises, A. aegypti will get into it. The problem is that most of these poor urban communities don’t have adequate piped water; some don’t have any piped water. So, it’s a whole lot of different things that ultimately reflect the way people live.”

Halstead said correcting these problems at a societal level would probably be very effective — but very challenging.

“For example, if Brazil has success in their control of A. aegypti, it would mean cleaning up all of those favelas,” he said. “You’d have to get them electricity and piped water. Unfortunately, that’s a big job.”

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 and 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 a heavy dengue disease burden simply do not have the necessary tools, according to Murray.

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

In order to minimize the spread of dengue and chikungunya in the U.S. — both which are spread by the same mosquito — Petersen advised clinicians to consider the possibility that returning international travelers may be infected with either of these diseases, or both.

“It’s important to recognize the possibility of dengue in travelers coming back from endemic areas, because with prompt recognition and effective treatment, the mortality from this disease could be lowered substantially,” he said.

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 and Jen Byrne

References:

CDC. MMWR. 2010;59:577-581.
Capeding MR, et al. Lancet. 2015;doi:10.1016/S0140-6736(14)61060-6.
Dengue Vaccine Initiative. Live attenuated vaccines. www.denguevaccines.org/live-atten-uated-vaccines. Accessed January 28, 2015.
Dengue Vaccine Initiative. Subunit, inactivated vaccines and DNA vaccines. www.denguevaccines.org/subunit-and-inactivated-vaccines. Accessed January 28, 2015.
Florida Department of Health. Martin County dengue outbreak and serosurvey. 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 and severe dengue. www.who.int/mediacentre/factsheets/fs117/en/. Accessed April 26, 2015.
WHO. Dengue vaccine research. www.who.int/immunization/research/development/dengue_vaccines/en. Accessed January 28, 2015.
WHO. Global strategy for dengue prevention and control 2012-2020. 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. 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.
Scott B. Halstead, MD, can be reached at 5824 Edson Lane, N. Bethesda, MD 20852.
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.
Lyle R. Petersen, MD, MPH, can be reached at the CDC’s Division of Vector-Borne Diseases, 3156 Rampart Road, Fort Collins, CO 80521.
Eugene D. Shapiro, MD, can be reached at Yale School of Public Health, 33 Cedar St, New Haven, CT 06510.
Donald S. Shepard, PhD, can be reached at Brandeis University, 415 South Street, Waltham, MA 02453.

Are there sufficient data to implement wide-scale dengue vaccination in endemic countries?

Successful vaccination implementation is feasible in endemic countries but comes with significant complications.

It is complicated to try to put all the countries in one category because there are different types of countries within the title “endemic.” In the Americas alone, there are significant differences between Colombia, Brazil and Mexico compared with smaller countries in Central America and even some of the Caribbean islands.

The difficulty we have been trying to address, specifically here in Mexico, is that dengue is a disease that has regional differences within countries; to determine vaccine efficacy in a particular country, you have to define geographical areas that are at risk or communities in which the majority of transmission occurs.

For instance, there are communities within endemic areas that are not necessarily where people transmit and catch dengue. There are hubs — transportation hubs, commercial hubs, educational hubs — in which people from different communities travel and where dengue is transmitted and exchanged.

Additionally, we cannot simply say,  “Let’s incorporate the dengue vaccine and make it part of a universal vaccine.”  The process is not that straightforward. In Mexico, for instance, 26 out of 32 states are endemic with sustained person-to-person transmission through the vector; however, there are parts within states that do not have the vector due to the altitude.

Countries would have to decide whether to use the dengue vaccine only in the communities that lie within the boundaries of mosquito habitats or include other communities that experience a flow of individuals in one of the two directions.

Also, in Mexico, there are different epidemiological profiles in different areas of the country. While most of the country experiences a peak in dengue cases during childhood from first disease exposure, there are some states with patients who experience a second peak in dengue cases around 40 years of age.

Another obstacle to effective dengue vaccine implementation is the distribution of the virus. As we have seen with the Sanofi vaccine, the level of protection varies against each of the four dengue viruses, and Mexico does not have a homogenous circulation of the viruses.

In the case of Mexico, we have realized that we have to be very careful in how to define the geographical area, the levels of dengue transmission, the epidemiological profiles, the virological profiles that we are facing, as well as the flow of people around dengue-transmitting communities, in order to decide how widespread we need to implement the vaccine.

Miguel Betancourt Cravioto, MD, MSc, DrPH, is the director of global solutions at the Carlos Slim Foundation in Mexico City. Disclosure: Betancourt Cravioto reports no relevant financial disclosures.

We need more evidence to know exactly what challenges endemic countries may face when implementing dengue vaccine.

Vaccine implementation is evidence-based. A vaccine schedule needs to be determined — will the vaccine be given in the first year of life, the second year of life? Is catch-up immunization needed? None of these variables has been figured out for a dengue vaccine. Demonstration projects, which examine feasibility and disease prevention, need to be conducted.

Ideally, if we had the perfect vaccine that worked in the first year of life, it could be added into the Expanded Program for Immunization, administered during pre-existing immunization visits and successfully integrated into vaccination programs in endemic countries.

However, if the dengue vaccine turns out to be similar to the tetravalent vaccine from Sanofi Pasteur (CYD-TDV), which is administered in the second year of life or after maternal antibodies have disappeared, it will be more difficult to implement in endemic countries. This is because many countries do not have existing routine immunization visits that match a schedule when CYD-TDV should be administered.

Based on our understanding of the epidemiology of dengue virus transmission, catch-up immunization will likely be necessary for successful dengue vaccine implementation. This brings up the question: How can we reach children in older age groups (eg, aged 2 to 10 years) to vaccinate them? School-based vaccination systems and mass vaccination strategies are possible options.

There have been well-documented demonstration projects conducted in Taiwan, Indonesia and China that addressed operational issues related to the introduction of new vaccines in an existing infrastructure — for example, hepatitis B vaccine and the administration of the birth dose. This will likely need to happen for a dengue vaccine once we have one and know how it performs.

Currently, we have one promising vaccine candidate that has not progressed past controlled efficacy trials, and thus, how it would be used in a community-based program has yet to be determined. This needs to be determined so we can assess feasibility operational issues and disease prevention.

Harold S. Margolis, MD, is the chief of the dengue branch of the CDC, San Juan, Puerto Rico. Disclosure: Margolis reports no relevant financial disclosures.