Working Feverishly to Fend Off Dengue

While the world is facing the growing threat of the Zika virus and its devastating consequences, a cousin to the vector-borne virus is wreaking even more havoc.

By Mary Rushton

When scientists isolated the first serotype of dengue virus in 1943—a mere four years before the Zika virus surfaced in a Ugandan rainforest—this mosquito-borne virus already had a lengthy history.

The first record of a disease that is clinically compatible with that caused by the dengue virus dates all the way back to 10th century China. Reports of outbreaks spread by the Aedes aegypti mosquito that caused high fever, headaches, severe muscle and joint pains, and a skin rash characteristic of dengue had been reported for centuries (Trends Microbiol. 22(3), 138, 2014).

Then World War II brought the virus to a whole new level. Millions of soldiers from Allied and Axis forces who had never been exposed to dengue were flooding the South Pacific and becoming infected. The situation was so dire that the Malaria and Epidemic Control Board of the South Pacific area classified dengue second only to malaria as a tropical disease of military importance (Emerg. Infec. Dis. Vol. 18, No. 4, 2012).

Around 90,000 US troops had been hospitalized for dengue infection by the time Japanese scientists Ren Kimura and Susumu Hotta identified the first serotype of the virus in 1943 while investigating an epidemic in Nagasaki (Dengue Matters, Issue 11, 2014). US scientists Walter Schlesinger and Albert Sabin (best known for his work on the oral polio vaccine) made the same discovery, independently, in Hawaii the following year.

The ecological disruption caused by World War II that encouraged dengue’s spread was soon followed by decades of rapid urbanization Aedes-Aegypti-Mosquitoesand increased globalization due to more transient populations. Together, these factors encouraged the spread of dengue, including the emergence of multiple strains circulating simultaneously, which in turn contributed to more serious disease outcomes. The discontinuation or reduction in mosquito control programs also worsened the situation. What was once an occasional outbreak in a small number of tropical countries where mosquitoes persist year-round, became a pandemic with multiple serotypes co-circulating in the same regions (Clin. Microbio. Rev. 11, 3, 480, 1998).

Today, dengue infects as many as 390 million people worldwide by some estimates (Nature 496, 504, 2013). The World Health Organization (WHO) refers to dengue as the “fastest spreading vector-borne viral disease in the world.” The virus is now endemic in over 100 countries, with the heavily urbanized countries of Brazil and Indonesia being the most affected, and the countries and regions impacted by dengue are growing. The US, for instance, battled a major outbreak of dengue in Hawaii last year that resulted in 260 cases, and cases occur in the state of Florida almost every year. The most dangerous form of dengue disease—a hemorrhagic fever that causes bleeding under the skin, frequent vomiting, abdominal pain, and in some cases death—is also occurring with greater frequency.

“Dengue is spreading steadily but consistently,” says Oliver Brady, an epidemiologist with the London School of Hygiene & Tropical Medicine, who uses maps and models to evaluate epidemics, including dengue and malaria. Brady was part of the research study led by Oxford epidemiology professor Simon Hay, now with the Institute for Health Metrics and Evaluation in Seattle, who shocked the world with estimates that up to 10 percent of people living in the tropical world could be infected by dengue each year. “We’re having real success in reducing malaria, but with dengue, no one has been able to stop it with any amount of resources,” Brady says. “It’s become a huge burden in middle-income countries in South America and some parts of Asia and is a huge drain on productivity.”

The good news is that dengue finally made it onto the list of vaccine-preventable diseases with Dengvaxia, the first vaccine approved for a vector-borne virus since the yellow fever vaccine was introduced in 1937. In December, three tropical hotspots—Mexico, the Philippines, and Brazil—approved Dengvaxia, made by Sanofi Pasteur, the vaccine division of pharmaceutical giant Sanofi, for use in children and adults ages 9 to 45. A fourth country, El Salvador, has recently licensed it as well and the WHO endorsed it in April. The company has filed for regulatory approval of its vaccine in over 20 countries, including several in Europe, and expects to add another 15 countries to the list before the end of this year.

It also has filed a fast-track designation for its vaccine with the US Food and Drug Administration—an option for drug and vaccine makers that allows them to have portions of their application considered before the full application is submitted, which in Sanofi’s case is expected to occur by early 2017. The fast-track designation helps expedite the approval process and is reserved for experimental products that address unmet medical needs.

Sanofi already had a track record in making vaccines against flaviviruses, namely yellow fever and Japanese encephalitis, so scientifically it made sense for them to focus on dengue. But tropical diseases don’t always attract a lot of commercial investment, and dengue, in particular, was challenging. The brewing public health crisis drew Sanofi in.

“Dengue is a major and growing public health issue threatening almost half the world’s population and cases have been reported in the US and Europe,” says Guillaume Leroy, vice president of Sanofi Pasteur’s Dengue Business Unit. “The fact that dengue is so well adapted to spread in urban centers of the tropical and sub-tropical world makes it a real threat to global growth and economic stability in these emerging countries.”

Sanofi invested an estimated €1.5 billion to develop its vaccine. The company is not alone in making substantial investments in this area. Another promising vaccine candidate is undergoing efficacy trials in Asia and Latin America that was developed by the US National Institutes of Health (NIH), and Merck and GlaxoSmithKline both also have candidates in early clinical trials. There are also discussions underway to develop a combined dengue and Zika vaccine candidate. And while there are no antiviral drugs to treat dengue on the horizon, work is being conducted in earnest to develop therapeutics that could help quell symptoms.

“Zika and Ebola are teaching us that infectious diseases know no borders and can rapidly become global public health threats that require innovative solutions in terms of both vaccine development and timely access to curb further geographic spread,” says Leroy.

With so much attention fixated on what to do about Zika—a virus once thought to be relatively benign but now, almost overnight, linked to severe fetal birth defects (primarily microcephaly) and the rare autoimmune disorder, Guillain-Barré Syndrome (NEJM 374, 1981, 2016; Lancet 387, 1531, 2016)—dengue provides important insights, some fleshed out below, into how quickly vector-borne viruses can spread and how challenging it can be to control and prevent them when they do.

Dengue’s family

Considering how much damage they cause, viruses are pretty simple creatures. The retrovirus HIV’s genome encodes for consists of a mere nine proteins; Ebola, a filovirus, encodes for seven. Dengue, a flavivirus, consists of a single strand of RNA that is referred to as positive-sense RNA because it can be directly translated into proteins. The viral genome is translated as a single, long polypeptide that is cut into ten proteins (Cell 108, 717, 2002).

There are four confirmed serotypes of dengue. In 2013, a researcher from the University of Texas Medical Branch reported on the discovery and characterization of a possible fifth serotype in Malaysia—the first new subtype in over 40 years—however, the work has not been published yet, and so its existence remains a topic of some debate (See sidebar, below).

A Fifth Serotype?  

Designing vaccine candidates that effectively target four separate serotypes of dengue virus is difficult enough, but a 2009 outbreak in Malaysia suggests there may be a fifth serotype. Nikos Vasilakis, a virologist at the University of Texas Medical Branch in Galveston, reported three years ago at the Third International Conference on Dengue and Dengue Hemorrhagic Fever in Thailand that a fifth serotype had been discovered and characterized in an adult male with acute dengue fever. The man lived on the Malaysian island of Borneo. The four recognized serotypes of dengue are genetically similar—about 65% of their sequences are homologous—while the virus identified in the Malaysian male, though 40% similar to dengue serotype 4, was thought to be phylogenetically distinct (Med. J. Armed Forces India 71, 67, 2015).

Vasilakis reported at the time that he thought the virus isolated in the Malaysia man may have been circulating in nonhuman primates (the only known animal reservoir of Dengue) and made its way into humans (Science 345, 415, 2013). However, Vasilakis and his colleagues who identified the new serotype have not formally described or published their work. “Official ratification of a separate serotype awaits the recovery of an isolate, which should be characterized by performing a series of rigorous identification tests to confirm, or indeed conversely to refute, its uniqueness,” writes Andrew Taylor-Robinson, a virologist with Central Queensland University in Australia, in a commentary earlier this year (Int. J. Clin. Med. Microbiol. 1, 101, 2016). —M.R.

Flaviviruses belong to the Flaviviridae family, which got its name from yellow fever—flavus being the Latin word for yellow. At least 53 flaviviruses have been identified, a third of which are medically important human pathogens (D. Gubler, K. Goro, L. Markoff, Flaviviruses. Fields Virology, 4th Edition. Eds. B. Fields, D. Knipe, P. Howley, Philadelphia: Walters Kluwer Health/Lippincott Williams & Wilkins, 2007). West Nile Virus, also transmitted by mosquitoes, is asymptomatic in most people but can cause fatal neurological disease. Yellow fever virus got its name because in the most severe forms it causes jaundice and hepatitis. Dengue, thought to be named for the Swahili term “Ka-dinga pepo”—cramp-like seizures caused by an evil spirit—does indeed cause debilitating joint pain that takes weeks and even months to recover from.

But in more serious cases dengue can also damage the overall vascular system, leading to increased vascular leakage and abnormal blood clotting, and interfering with the body’s ability to repair itself. Widespread bleeding may accompany this condition, which is why it is referred to as dengue hemorrhagic fever (DHF). The most severe form of DHF is Dengue Shock Syndrome (DSS), characterized by severe vascular leakage, multi-organ failure, and a complete breakdown of the circulatory system. People with DHF, and particularly DSS are at risk of dying from dengue.

The culprit

Many viruses that cause tropical diseases are transmitted to humans by mosquitoes. About 3,000 different species of mosquitoes have been described in the scientific literature, according to the Entomological Society of America, but only a small percentage are vectors for pathogens that sicken and kill humans. Female Anopheles mosquitoes spread malaria, and various species of Culex mosquitoes are the primary chauffeurs for West Nile virus, and Japanese, Eastern Equine, and St. Louis encephalitis.

The Aedes aegypti mosquito spreads a number of different viruses, but its reputation as a vector seems to hinge mostly on the transmission of a quartet of viruses that include dengue, yellow fever, Zika, and chikungunya, which is an alphavirus. Aedes albopictus, also known as the Asian Tiger mosquito, may also spread these viruses, though Aedes aegypti is the most common carrier.

Many mosquitoes live and feed outdoors. According to the US Centers for Disease Control and Prevention (CDC), the Anopheles mosquito lays its eggs in fresh- or salt-water marshes, mangrove swamps, rice fields, grassy ditches, the edges of streams and rivers, and small, temporary rain pools. They generally breed outdoors, in open, sun-lit pools or shaded breeding sites in forests. A few species breed in tree holes or the leaf axils of some plants. They are active at dusk, dawn, and at night.

Aedes aegypti mosquitoes are different. They are highly domesticated insects that like to lay their eggs in flower vases, automobile tires, rain buckets, cisterns, and other containers in and around homes, and prefer to feed on humans during daylight hours. They weren’t always this “friendly,” says Duane Gubler, Founding Director of the Emerging Infectious Diseases research program at the Duke-NUS Medical School in Singapore and formerly chief of the CDC’s dengue branch. Gubler, who has studied dengue since the 1970s, says the yellow fever and dengue-spreading mosquitoes used to be feral insects that lived in forests and didn’t mix much with humanity. “But thousands of years ago, Aedes aegypti started moving into the villages of Africa and over time have become highly adapted to their human surroundings.”

The feeding habits of Aedes aegypti have, inadvertently, also made the spread of disease more efficient. Gubler notes that the female mosquitoes tend to be very nervous feeders that are easily distracted by the slightest movement. This peripatetic behavior means that females often feed on several individuals during a single blood meal, greatly increasing the rate of transmission when their hosts are infected with dengue or other viruses.

Man-made calamity

Scientists generally agree that dengue would not have spread so rapidly in recent years were it not for a succession of events that began during the Second World War. Prior to WWII, dengue viruses circulated throughout the tropics, but the relatively small urban populations and the fact that viruses and mosquitoes relied primarily on boats to move around the world meant that epidemics were sporadic (Trop. Med. Health 39 (Suppl), 3, 2011). Most regions had only one or two dengue serotypes circulating at any one time.

This changed when millions of soldiers descended on the South Pacific—US and Japanese enforcements alone totaled around 10 million. These soldiers transported viruses and their vectors across the region. By the end of the war, many countries in Asia were endemic with all four circulating serotypes of dengue, says Gubler.

Major shifts in population from rural areas to cities during and after the war further fueled dengue’s spread. Rapid industrialization began in earnest in post-war Asia, causing millions of people to move into cities ill-prepared or too poor to accommodate them. As an example, the mean population in the Asian cities of Dhaka, Bangkok, Jakarta, Manila, and Saigon grew from about 1 million to over 12 million between 1950 and 2010. Families lived in overcrowded houses with poor sanitation and poor mosquito control. This enabled dengue to thrive.

It was in the 1950s and 1960s that epidemics of DHF began occurring across southeastern Asia, the first one being in the Philippines in 1953-54. It is still not entirely clear what mechanisms provoke DHF, which seems to occur slightly more often following infection with serotype 2 of the virus but can occur, nonetheless, following infection with all four serotypes. Gubler says co-circulation of multiple serotypes doesn’t just increase the probability of infection. “It increases genetic mutations, which in turn increases the probability of a more virulent strain of virus emerging.

Epidemiological evidence suggested that DHF was provoked by an immune response. Many of the individuals infected with DHF had a secondary antibody response to dengue and lived in regions where there were two or more serotypes of the virus in circulation. Researchers concluded that the course of infection with a second dengue virus of a different serotype was worse because it was adversely affected by the immune response against the first infection (Yale Journal of Biology and Medicine 42, 262, 1970).

Steven Whitehead, a dengue researcher at the National Institute of Allergy and Infectious Diseases (NIAID)—part of the NIH—says antibodies elicited to the virus serotype in the primary infection are able to bind a second infecting virus, “but they do not effectively neutralize the new serotype and, in fact, may enhance entry of the new dengue serotype into susceptible cells, such as monocytes, through Fc receptors,” says Whitehead. “This, in turn, leads to increased viral replication, increased viral load, and enhanced disease.” Whitehead says cross-reactive antibodies from one’s first dengue infection are therefore more problematic than helpful during the next encounter with a different virus serotype. The WHO now warns that cross-immunity between serotypes following recovery from dengue is temporary and subsequent infections increase the risk of developing DHF or DSS. “Of course, you always have good protection against infection with the same serotype,” says Whitehead.

People do gradually build up immunity as they are progressively infected with other serotypes. Young children are much more vulnerable to infection and severe disease because they haven’t been around dengue long enough to be exposed to different serotypes.

Mosquito control

Along with urbanization and globalization, inconsistent and sporadic mosquito control operations also fostered the spread of disease. Concerned more with yellow fever than dengue, an effort led by the Rockefeller Foundation’s International Health Division (IHD) sought to destroy mosquito breeding grounds in key communities or “seedbeds,” where the Aedes aegypti mosquitoes thrived. During the early 1900s, the IHD established campaigns in South America and Africa, with the aim of reducing house infestation of Aedes aegypti to 5 percent, enough to break the virus’ transmission cycle.

The Pan American Sanitary Organization (later re-named the Pan American Health Organization) followed up in the late 1940s with a successful campaign that actually eradicated Aedes aegypti from 18 countries in Latin America and several Caribbean nations. The campaigns were carried out by semiautonomous groups who sprayed urban buildings, including residential homes, with the inexpensive but controversial insecticide DDT that would later be banned for health reasons. These efforts and the introduction of the vaccine helped eliminate urban yellow fever from the Americas.

But even before the DDT ban, some countries wouldn’t participate in the eradication efforts, and those that did eventually lost interest, political will, or lacked funds. Surveillance efforts were scaled back, which helped mosquito populations to return and re-establish habitats.

Robert Tesh, a pathology professor at the University of Texas Medical Branch who studies the epidemiology, pathogenesis, and natural history of arthropod-borne and zoonotic viral diseases, says this door-to-door spraying would likely be pretty unpopular today, even in countries that once embraced such tactics. “When I was living in Panama they used to come door to door and spray the walls with insecticide in a kerosene base. The house would reek of it,” says Tesh. “Can you imagine trying to do that in a residential neighborhood in the US?”

More innovative approaches to stop mosquitoes from transmitting viruses are now being pursued. Researchers at the University of Melbourne have developed two strains of the bacteria Wolbachia—an organism that infects arthropods—that reduce the ability of Aedes aegypti mosquitoes to transmit dengue and Zika (PLoS Pathogens 2016, doi:10 1371/journal.ppat.1005434 2016). In superinfected mosquitoes, pathogens appear to lose their ability to replicate, and if abundant enough are able to out-compete the disease-bearing mosquitoes until the cycle of transmission is broken. Studies are ongoing in Australia, Columbia, Vietnam, and Brazil using Wolbachia-infected mosquitoes to control dengue. Several other efforts to alter moquitoes to inhibit their ability to transmit viruses are also being explored to control mosquito populations and prevent diseases such as malaria.

The promise of vaccines

One of the most promising technologies for stopping dengue is an effective vaccine, which thanks to years of effort is now available. The earliest dengue vaccine development efforts date back to during and just after World War II when pioneering microbiologist Albert Sabin used mouse brains to passage wild-type dengue viruses to develop a live-attenuated dengue vaccine containing two different serotypes. Sabin found that as the virus became adapted to the mice, it became less pathogenic. He later gave the vaccine candidate based on this live-attenuated dengue virus to humans to show that the virus was indeed attenuated and that it caused only mild symptoms. Subsequently, the volunteers were found to be protected following challenge with wild-type virus, and the protection was shown to be generally due to neutralizing antibodies (Antiviral Therapy 14, 739, 2009). Further testing of the candidate was not pursued, however, over concerns that the mouse-brain preparations might be contaminated.

Since then, multiple vaccine candidates have been developed and tested, with Sanofi Pasteur’s Dengvaxia vaccine the first and thus far only one to cross the finish line. The live-attenuated recombinant tetravalent vaccine was designed by scientists from Acambis, a vaccine company acquired by Sanofi Pasteur eight years ago. Dengvaxia uses the licensed yellow fever vaccine YF-17D as a backbone, but replaces certain genes that contain neutralizing epitopes for yellow fever with homologous regions of the four different dengue serotypes. This novel approach was pursued because previous live-attenuated vaccine candidates were associated with a high rate of adverse events, and inactivated vaccine candidates didn’t induce broad enough or durable enough responses.

The Acambis scientists produced four live-attenuated vaccine viruses based on the yellow fever 17D strain, one per dengue serotype. Each recombinant virus was constructed by swapping yellow fever genes with dengue genes, a strategy made possible because of the similarities in the virus Dengue-virus-2genus (Vaccine 29, 7229, 2011). “Because dengue is also a flavivirus, it made it easier for molecular biologists to take out the pre-membrane and envelope genes of yellow fever and insert the corresponding genes from dengue fever,” says Stanley Plotkin, a vaccinologist and emeritus professor at the University of Pennsylvania who serves as an executive advisor to Sanofi Pasteur. “The same strategy also works for Japanese encephalitis, and possibly may work for Zika.”

Two large international studies conducted in children and adolescents found that a three-dose regimen of Dengvaxia administered over 12 months was safe and effective in reducing severe disease, and that the vaccine candidate induced neutralizing antibodies against all strains. However, efficacy data by age was mixed.

The first study was conducted in about 20,900 healthy children ages 9-16 from Brazil, Colombia, Puerto Rico, Honduras, and Mexico. The second was conducted in 10,000 healthy children ages 2-14 from Malaysia, Vietnam, Thailand, the Philippines, and Indonesia. Overall, efficacy was around 60 percent in the Latin America trial and 57 percent in the Asia trial, though the vaccine provided greater protection against serotypes 3 and 4 than against serotypes 1 and 2 (NEJM 372 (2) 113, 2015; Lancet 384, 1358, 2014). The studies also found that efficacy increased with age and that previous exposure to dengue prior to vaccination also increased efficacy. The results also varied considerably by country. An exploratory analysis found that in the Latin America study, vaccine efficacy was 83.7 percent among those with a prior exposure to dengue, but as low as 43.2 percent among seronegative participants. Efficacy was as high as 78 percent in Brazil, and as low as 31.3 percent in Mexico.

Pooled results of both studies found an efficacy of around 65 percent for ages 9 and older, but only 44 percent for those under age 9, the group most vulnerable to infection. Long-term follow-up of vaccines recipients found that the risk of hospitalization among individuals aged 9 years or older was less than 1 percent three years after the start of the study. Among vaccinated children under 9 years old it was 1.5 percent and among 2-5 year olds it was as high as 7.4 percent.

Why the hospitalization rates were so high among this group isn’t entirely clear, though some believe the candidate isn’t balanced enough. If the immunization in very young children elicits only partial or transient immunity, it predisposes them to infection later on for which hospitalization is required, wrote Cameron Simmons, a microbiologist and immunologist at the Peter Doherty Institute for Infection and Immunity in Melbourne, who was not involved in the study (NEJM 373, 1263, 2015).

Peter Hotez, president of the Sabin Vaccine Institute in Houston, Texas, and Washington, DC, and a leading advocate for the treatment and prevention of neglected tropical disease (NTDs), says designing vaccine candidates for dengue is so challenging because it has four serotypes that are co-circulating. “What this means is that in a vaccine you have to get equal immunity to all four serotypes at the same time.”

Sanofi is still evaluating the value of vaccinating children under 9 against dengue as part of its long-term follow-up to the two Phase III studies. This analysis will be finalized in 2018. “We can, however, anticipate that large-scale dengue immunization programs in endemic countries could provide indirect protection for unvaccinated younger age groups by lowering the pool of infected individuals and, thus, the transmission risk for all,” said Leroy.

Another live-attenuated, tetravalent vaccine candidate, this one developed by scientists at the NIH, is now being tested in Phase III clinical trials in Brazil. The TV003 vaccine candidate was recently licensed to the Butantan Institute, a Brazilian research organization in São Paulo, which is also sponsoring the trial. The vaccine candidate is a mixture of all four dengue serotypes. The study is enrolling three age groups: 18-59, 7-17, and 2-6 years old. Each age group will have at least 5,000 volunteers.

An unusual clinical trial—a human challenge study—conducted by Johns Hopkins already suggests that the vaccine candidate may perform well against at least one dengue serotype. The study enrolled 48 healthy adult volunteers from two college campuses—the University of Vermont College of Medicine in Burlington and Johns Hopkins Bloomberg School of Public Health in Baltimore—and randomly assigned them to receive either a vaccine or placebo injection. Six months later, 41 of the volunteers returned for the dengue challenge. The challenge virus used in the trial was a genetically modified version of the serotype 2 virus isolated in the Kingdom of Tonga in 1974. All 20 placebo recipients were infected and 16 of them got a rash. None of the 21 vaccine recipients showed any signs of infection after challenge (Sci. Trans. Med. 8, 330, 2016).

“We chose a strain of dengue 2 that was historically associated with less disease,” says Whitehead, who developed the TV003 candidate. “People who received placebo and who were then challenged did not get ill, but they did have a good virus load and a rash.”

Whitehead said the human challenge studies were conducted to help ask questions that in this case can’t realistically be answered by models. In endemic regions, where there is more than one circulating strain, one inevitably finds large populations with a high degree of partial immunity, which can make it difficult to assess vaccine efficacy against a particular serotype. Challenging animals isn’t feasible because they don’t develop symptoms to dengue. A second human challenge study with the TV003 vaccine candidate is now underway to assess efficacy against serotype 3.

Until the Zika outbreak, Whitehead’s group was planning on adding a Japanese encephalitis component to their TV003 vaccine candidate. Instead, they are now developing several Zika components, which they plan to test in nonhuman primates and humans in the coming months. Then they will select the best one to add to the tetravalent vaccine candidate and test the combination dengue/Zika vaccine candidate. “I think we can have efficacy data in three to four years,” he says.

They have also licensed the TV003 to three different companies in India and a company in Vietnam. Brazil acquired an exclusive license, which means Butantan Institute has sole rights to distribute the vaccine there. India did not, which gives the three companies based there the right to compete for market share in the South Asian country and also export the vaccine candidate to other countries that do not have exclusive licenses. Vietnam also doesn’t have an exclusive license.

Other vaccine candidates in early clinical testing include Illinois-based Takeda Pharmaceuticals’ chimeric tetravalent candidate based on an attenuated dengue 2 serotype backbone, and a purified, inactivated tetravalent dengue candidate containing the adjuvant alum. GlaxoSmithKline has since signed a research agreement to develop the latter vaccine with Brazil’s Oswaldo Cruz Foundation. Meanwhile, Merck is developing a tetravalent recombinant envelope protein vaccine candidate also using an alum adjuvant that was originally designed by Hawaii Biotech.

This is a much different environment than 15 years ago when companies were disinterested in dengue vaccine development. Whitehead likens it to the “little red hen,” who couldn’t get anyone to help her turn wheat into bread until it was baked. “Large pharmaceutical companies looked at it but they didn’t think it would be profitable,” he says. “They weren’t excited about it. But after Sanofi found a path forward for a dengue vaccine candidate and we developed ours and were able to show that you could administer it in one dose and that it wouldn’t be expensive to produce, then it became a little more attractive.”

Sanofi says both governments and physicians in the countries where Dengvaxia is now licensed are excited about the prospect of finally having a biomedical tool to fight the virus. In the Philippines, for instance, over 200,000 public school children have been vaccinated against dengue, with a target to initiate the vaccination of one million school children by the end of the year.

Unfortunately, this scenario is not playing out with other tropical diseases, including the seven most common NTDs (ascariasis, hookworm infection, trichuriasis, schistosomiasis, lymphatic filariasis, onchocerciasis, and trachoma) that are the focus of the non-profit Sabin Vaccine Institute. Hotez says it might be due to the fact that dengue is not just a disease of poverty. “Dengue is widely occurring among wealthy and middle-class populations around the world—it’s become a huge problem in Singapore, Rio de Janiero, São Paulo, all over Jakarta—and so the market is not as depleted as it would be for hookworm or schistosomiasis,” he said. “We are in the midst of a dengue explosion.”

Mary Rushton is a freelance writer based in Cambridge, Massachusetts.