Virus World

A massive upsurge in dengue cases marked by multiple outbreaks is occurring worldwide and raising new questions about who is at elevated risk of severe forms of the mosquito-transmitted disease. Incidence of the infection has increased by orders of magnitude throughout the so-called dengue belt, which encompasses Central and South America, Sub-Saharan Africa, Southeast Asia and swaths of the South Pacific, home to densely populated islands. Dengue, without question, is the most widespread and rapidly increasing vector-borne disease in the world, according to the World Health Organization. In the Americas alone, more than 5.2 million cases have been documented and more than 1,000 deaths were reported within the first three months of 2024, the Pan American Health Organization reported in April, noting a marked surge over the same period in 2023. The story is similar in other dengue-affected areas of the world where lapses in vector control have conspired with global climate change to create an explosion of bloodthirsty mosquitoes, swarms of them moving into regions once considered dengue-free. Only female mosquitoes feed on blood, they're in constant need of the nutrients in it to nurture their eggs. Now, more than two decades of dengue surveillance in Thailand is answering a slew of questions at a time when the world needs guidance most. Findings from the research have revealed how various subgroups—what virologists call subtypes—of the dengue virus influence future risk of severe infection. It has been known for years that those who become infected in subsequent outbreaks, after a usually mild bout with a first-time infection, are at significant risk of severe disease in later dengue exposures. New research finally has analyzed more than 15,000 cases to discern why that is so.

Writing in Science Translational Medicine, a global team of scientists has explained how the four dengue viral subtypes—DENV-1, 2, 3, and 4—influence the risk of repeated severe infections. The findings provide a new framework for disease monitoring and lay the foundation for vaccination strategies as the new dengue immunizations emerge. The team also underscored how dengue, a pernicious tropical malady, can be understood within the context of other common viral diseases that circle the globe. "The ability of viruses, such as SARS-CoV- 2 and influenza, to continuously change their genetic structure in response to the selective pressure of population immunity complicates control efforts," said Dr. Lin Wang, lead author of the dengue study. "In the case of dengue virus, an arbovirus that infects more than 100 million people each year, the situation is even more complex," Wang continued. "Individuals with high dengue virus antibody titers are protected from infection and developing severe disease. "However, individuals with sub-neutralizing antibody titers have been shown to have the highest risk of severe disease, through multiple hypothesized mechanisms including antibody-dependent enhancement," emphasized Wang, a researcher in the genetics department at the University of Cambridge in England. A dengue infection can be tricky. Some patients who have weathered an infection but get infected in a subsequent outbreak can have more severe symptoms the second time around. Yet, most research on repeat dengue infections has regarded each of the serotypes as no different from the other, Wang and colleagues contend, noting that an assessment of each serotype's genetic differences was needed to provide a clearer picture of potential risks.

To develop that clearer picture, researchers studied each serotype in more than 15,000 patients' infections as a way to peel away much of the mystery surrounding why first-time dengue illnesses are traditionally milder than subsequent ones. Working with Wang were collaborators from two centers in Bangkok, Thailand; multiple research institutes in the United States and one in France. To determine how each of the viral serotypes affects the risk of severe disease, Wang and colleagues analyzed viral genetic data. The team also studied cases of patients hospitalized for dengue to determine which viral subtype caused their infections. Researchers gathered data from 21 years of dengue surveillance, ranging from 1994 to 2014, in a children's hospital in Bangkok, encompassing 15,281 individual cases. This allowed them to find repeat cases and each viral subtype in all infections. Based on the pediatric patients' hospital records, researchers discovered a link between hospitalization and the order in which patients became infected with different dengue-virus serotypes. They were also able to determine which combinations of viral subtypes pointed to mild or severe forms of dengue. For instance, people who became infected with serotypes that were very similar, such as DENV-3 and DENV-4, or very different serotypes as in the case of DENV-1 and DENV-4, tended to have a lower risk of severe disease during the second infection.  That said, patients who were infected with serotypes that were only moderately different had a higher risk of severe symptoms in subsequent infections. The highest risk group in this category involved patients who had an initial infection with DENV-2 followed by a subsequent infection triggered by DENV-1.

The new research adds clarity to a disease risk that may seem paradoxical to the lay public. For example, most people infected with dengue virus for the first time develop extremely mild signs of the disease or none at all. But for those who do get sick, soaring fever, headache, body aches, nausea and rash are the primary symptoms, and they intensify in severe manifestations of the infection. For more than a century a severe bout with dengue has been known as breakbone fever because of the intensity of the pain and accompanying muscle spasms. The virus is carried in the tropics and subtropics by Aedes aegypti and Aedes albopictus mosquitoes, which are endemic in the dengue belt. But while the belt, which runs through latitudes 35-degrees North and 35-degrees South, has traditionally been home to dengue-carrying mosquitoes, the arthropods have been extending their range northward as global climate change intensifies, scientists say. Wang, meanwhile, reports that the collaborative research has set the stage to better understand immune system function in subsequent, severe dengue infections. "These findings suggest that immune imprinting helps determine dengue disease risk and provides a pathway to monitor the changing risk profile of populations and to quantifying risk profiles of candidate vaccines," Wang concluded. "This will become increasingly important as dengue vaccines begin to get used."

Research published in Science Translational Medicine (April 24, 2024):

https://doi.org/10.1126/scitranslmed.adk3259 

A single-dose dengue vaccine produced by Butantan Institute in São Paulo state (Brazil) prevents development of the disease in 79.6% of those vaccinated, according to an article published in The New England Journal of Medicine . Called Butantan-DV, the vaccine contains attenuated versions of all four dengue virus serotypes. The results of the ongoing Phase 3 trial show that it is safe and effective for all age groups between 2 and 59, and for people with or without a prior history of infection by dengue virus. "Publication of the article in the world's leading medical journal attests to the rigor and quality of the work done by researchers at 16 Brazilian centers located in all five regions of the country, and coordinated by Butantan Institute," infectious disease specialist Esper Kallás, first author of the article, told Agência FAPESP. "In June, we'll complete the five-year follow-up period. Once the data has been consolidated, we'll know how long the protection induced by the vaccine will last." Also according to Kallás, who heads Butantan Institute, the researchers plan to submit a report to ANVISA, Brazil's health surveillance agency, in the second half of this year in order to apply for registration of the vaccine.

"If all goes well, we'll win definitive approval for the vaccine in 2025. We already have the infrastructure to produce it at Butantan Institute, although it can still be perfected. After all, it's tetravalent, corresponding to four vaccines in one," he said. The article published today describes the results of the first two years of the Phase 3 clinical trial, which began in February 2016 and involves 16,235 participants in 13 states. Preliminary data disclosed by Butantan Institute in December 2022 pointed to overall efficacy of 79.6%. The results for each subgroup evaluated have now been detailed. Vaccine efficacy was 80.1% for participants aged 2-6, 77.8% for those aged 7-17, and 90.0% for 18-59 age group. Stratification by serological status showed protection for 73.6% of participants with no evidence of prior infection by dengue virus and 89.2% of those previously exposed to the virus. Efficacy was 89.5% against dengue serotype 1 (DENV-1) and 69.6% against serotype 2 (DENV-2). It was not possible to assess the vaccine's efficacy against serotypes 3 and 4 because they were not circulating during the follow-up period. Most adverse side effects were classified as mild or moderate. The main reactions were pain and redness at the injection site, headache, and fatigue. Severe adverse events relating to the vaccine were recorded for under 0.1% of all those vaccinated, and all of them recovered. "Findings from Phase 2 [the previous clinical trial] showed that the four attenuated viral serotypes in Butantan-DV multiply in the human organism and induce a balanced response in terms of antibody production. This leads us to conclude that its efficacy against DENV-3 and DENV-4 will also be good," said virologist Maurício Lacerda Nogueira, one of the coordinators of the trials.

Publication cired in N.E.J.M. (Feb. 1, 2024):

https://doi.org/10.1056/NEJMoa2301790 

Dengue disease is highly prevalent in tropical and subtropical regions worldwide. However, its pathogenesis is still incompletely understood, particularly in comparison to other endemic viruses. Antibody-dependent enhancement (ADE) is a well-known phenomenon for dengue viruses. Given the recent surge in dengue cases and potential cross-reactivity with SARS-CoV-2 antibodies, this study explores the impact of anti-SARS-CoV-2 antibodies on DENV-2 infection. The study assessed the cross-reactivity of SARS-CoV-2 antibodies with the DENV-2 Virus. Human convalescent plasma samples collected during different waves of COVID-19 and monoclonal and polyclonal antibodies raised against SARS-CoV-2 were examined for their potential to cause ADE of DENV-2 infection using cell-based assays.

The study found that anti-SARS-CoV-2 antibodies acquired from natural infection in humans or through experimental immunization in animals were cross-reactive with DENV-2 and had the potential to enhance DENV-2 infection in K562 and U937 cells. In-silico and in-vitro studies indicated a strong interaction between SARS-CoV-2 antibodies and DENV-2 E-protein, providing a molecular basis for these findings. This study is the first to demonstrate that anti-SARS-CoV-2 antibodies can cross-react with DENV-2 and can enhance its infection through ADE. These findings have implications for SARS-CoV-2 vaccine development and deployment strategies in regions where dengue is endemic.

Preprint available in bioRxiV (Oct. 10, 2023):

https://doi.org/10.1101/2023.10.09.557914 

Climate change is shifting the ranges of many disease-carrying species like ticks and mosquitoes. Scientists warn that the U.S. is underprepared for a potentially devastating surge in infections. In the summer and fall of 2021, West Nile virus spread rapidly through Arizona’s Maricopa County and other areas of the state. The outbreak, with more than 1,700 cases reported and 127 deaths. was the largest in the United States since the mosquito-borne virus first emerged in this country in 1999. But with the nation facing a far larger public health crisis with the Covid-19 pandemic, it went almost unnoticed. Even before Covid-19 arrived, the public health response to diseases transmitted to humans by vectors like fleas, ticks and mosquitoes — including West Nile, Zika, dengue fever, Lyme disease, and others — was muted, perhaps because the number of reported cases has been relatively low, and the public largely unaware of the health risks such diseases pose. With climate change accelerating, however, shifting the ranges of many disease-carrying species and sharply increasing infections, scientists and others warn that the nation’s public officials, as well as hospitals and doctors, are underprepared for a potentially devastating surge in infections. Research on vector-borne diseases and disease surveillance, they note, are underfunded by federal and local governments, leaving the country vulnerable to outbreaks.

“Without sustained funding in local vector control and surveillance, it ends up stymieing that response of looking for the threats before they become really huge causes for concern for local public health,” said Chelsea Gridley-Smith, director of environmental health for the National Association of County and City Health Officials (NACCHO). In the United States, cases of 17 different vector-borne diseases have been reported to the Centers for Disease Control and Prevention, and nine pathogens new to the country have been identified since 2004, according to a 2020 report by the agency, which noted that the data for 2019 and 2020 might be incomplete due to underreporting during the Covid-19 pandemic. Reported cases of vector-borne diseases more than doubled from 2004-2019, to more than 800,000 cases. But those figures are almost certainly an undercount, CDC officials said in a presentation to Congress last year. Only 2% to 3% of West Nile cases and about 10% of Lyme disease cases are reported, said Lyle Petersen, the director of the CDC’s Division of Vector-Borne Diseases in Fort Collins, Colo. Overall, cases of vector-borne diseases are probably underreported by 10-fold to 80-fold, according to Benjamin Beard, the CDC division’s deputy director.

Petersen noted that addressing vector-borne disease involves formidable challenges, including a lack of vaccines for diseases found in the continental United States; the difficulty in diagnosing some diseases in their early stages; and the sheer number of emerging pathogens. Tick-borne diseases comprise the largest share of vector-borne diseases by far — over 80% of reported cases are caused by ticks. Longer summers, rising temperatures, and the expanding ranges of tick species such as Ixodes scapularis, the black-legged tick, and Amblyomma americanum, the lone star tick, are leading to an increased chance of human exposure to pathogens over a larger geographic area. The range of Ixodes scapularis, a tick that transmits Lyme and other diseases, expanded greatly over two decades, with the number of counties with established populations more than doubling from 1996 to 2015.

Similarly, milder year-round temperatures mean that some mosquitoes may overwinter or emerge earlier in the spring. In the case of West Nile, this affects not just the mosquitoes carrying the virus but the virus itself, which replicates faster in warm temperatures. “So the mosquitoes actually are more infectious to people when they bite them,” Beard said. Nelson Nicolasora, medical director for the infectious disease program at Banner University Medical Center in Phoenix, said that while the 2021 West Nile virus outbreak was “nothing like” the Covid-19 pandemic, the illness was “life-changing” for people who suffered debilitating neurological disease. West Nile usually causes mild, flu-like symptoms, but about 1 in 150 people who are infected will develop severe neuroinvasive disease. “It can be devastating,” Nicolasora said. Two of his patients died during the 2021 outbreak, he said, and others faced serious short-term and longer-term effects: Some required a ventilator to breathe, or rehabilitation to regain the ability to walk. Irene Ruberto, vector-borne and zoonotic disease program manager at the Arizona Department of Health Services, said that even though public health officials in the state were aware of the cyclical nature of West Nile virus infections from year to year, they had no idea the infection rate would be so high in 2021. It’s difficult to predict how many infections will occur in a given year, Ruberto said, because many factors are involved, including mosquito density, local environments, and the climate.

“We do know that birds play a role,” acting as an amplifying host for the virus, Ruberto said, which adds complexity to understanding virus transmission. While West Nile is transmitted to humans by mosquitoes, mosquitoes get the virus through biting an infected wild bird. And different species of birds vary in their ability to transmit the virus once they’re infected. Ruberto said the state health department in Arizona doesn’t on its own have the funding or the capacity to analyze the 2021 outbreak to understand the factors that drove it. Instead, she said, the department is working with the CDC and universities to study the 2021 data and develop a model to predict future outbreaks. However, Ruberto said she’s even more concerned about the emergence in her state of another vector-borne disease: dengue fever. In 2022, two locally transmitted cases of dengue were discovered in Arizona, the first appearance of the disease in the state in modern times. Though dengue — known colloquially as “breakbone fever” because of the severe joint pain and muscle spasms it can cause — is also transmitted by mosquitoes, it differs from West Nile in an important way: The virus can be spread from one infected person to another person through a mosquito bite...

The MCPDH announced that they will offer free, at-home blood testing for residents after a person tested positive for dengue. The Maricopa County Department of Public Health announced on Monday that they have identified a person who recently tested positive for the mosquito-borne viral disease known as dengue. According to the MCDPH, the person who tested positive might have been exposed by an infected mosquito in Maricopa County. "Routine mosquito surveillance performed by Maricopa County Environmental Services Department (MCESD) has detected the dengue virus in a mosquito trap in one neighborhood in the county," the MCDPH said in a news release. According to Mayo Clinic, dengue is common in tropical and subtropical areas of the world with millions of cases reported each year. It is rare in the United States, however, with an average of less than 20,000 cases per year. The World Health Organization notes that while some cases are asymptomatic, symptoms from dengue fever can range from severe flu-like symptoms to severe bleeding, organ impairment, plasma leakage and death. The MCDPH has not revealed who was infected or the severity of their infection, however.

As a result of the positive test, the department announced that Public Health teams will be visiting neighborhood residents to offer free, at-home blood testing if they are interested. Those teams will also include representatives offering information for preventing bites and mosquito breeding around their homes, the MCDPH said. MCDPH did not specify which neighborhood the department would be testing in. “While previous dengue cases in Maricopa County have been related to travel to countries where dengue commonly occurs, it is important to understand if others could have been exposed or if this is an isolated incident.” said Dr. Nick Staab, MCDPH medical epidemiologist. “This is in addition to our routine investigations of anyone suspected to have dengue or other mosquito-borne diseases.” The MCDPH said that Maricopa County will field teams of staff and volunteers to conduct the free testing for residents five years and older and provide mosquito prevention kits as well. The tests will identify if any person has been infected in the last several months even if the person is asymptomatic, the MCDPH said.

“This simple test can provide information that is valuable to our residents and, on a neighborhood level, to Public Health,” Staab said. “When we look at results of this testing and mosquito testing across the county, we can determine if there is any risk to others and what Public Health, Environmental Services, and other partners can do to prevent illness.” The department said that they will send postcards to homes in the specific neighborhood to their door, to notify them about their upcoming visit before field teams go door-to-door over the next week to offer the testing, prevention kits and information on how the test results will be shared with those tested or their legal guardians.

Scientists sent mice on scented chases and swabbed the armpits of people infected with dengue to pinpoint an odor that attracts mosquitoes. Being bit by a mosquito carrying dengue or Zika virus can make you sick. The infection can also make you even more attractive for other mosquitoes, new research finds. It’s an itchy concern for anyone infected, but also poses a major risk to communities at large: Mosquitoes that aren’t already carrying the viruses could be more drawn to sick humans, become infected, and go on to infect more humans. The spread of dengue, in particular, is a threat, with about half the world’s population at risk and hundreds of millions of cases each year. Most cases are asymptomatic, but serious cases can lead to fever and vomiting, and in some instances, organ failure or death. The study, published Thursday in Cell, identifies a specific scent emitted from both Zika- and dengue-infected mice that makes them more attractive to mosquitos than those without the viruses. It also points to a potential route to neutralize the olfactory flag. “This is a highly, highly influential study,” said Nikolaos Vasilakis, a professor of pathology at the University of Texas Medical Branch in Galveston who was not involved with the research. “I’m pretty sure it’s going to foster or spin off several new lines of experimentation to get a better understanding of what’s happening in humans.” In the experiments, performed at Tsinghua University in Beijing, mosquitos in a cage could enter a chamber with virus-infected mice or one with healthy mice. The mosquitos had no preference among the mice when the experimental group was newly infected, but on days four and six of infection, around 70% of the mosquitos flew to the infected group.  “An essential scientific question is how mosquitoes effectively orient to viremic hosts with a high frequency,” lead author Gong Cheng wrote in an email. Body temperature, carbon dioxide levels, and scent are all known factors in attracting mosquitos to a host. The researchers isolated each factor in repeated experiments to systematically eliminate temperature and carbon dioxide and identify scent as the attractant.

To determine exactly what caused the change in scent, they analyzed hundreds of potential volatile compounds emitted from the sick mice and narrowed it down to one, called acetophenone. The amount of acetophenone on the infected mice was found to be 10 times higher than on the uninfected ones. “Regarding virus-induced changes in behavior, this study is like a unicorn because of how in-depth they were able to go on all these levels,” said Megan Wise de Valdez, an associate professor of biology at Texas A&M in San Antonio, who was also not involved. She said the study’s methodology was so rigorous she plans to teach it in the classroom. Still, when it comes to results, “a mouse is a mouse is a mouse is a mouse,” said Vasilakis — meaning the stronger insights come from looking at humans. So the researchers took it a step further.  They applied acetophenone to human hands and found it had a similar effect in attracting mosquitos. And after finding that dengue patients were putting out higher levels of acetophenone than healthy people, they collected odors from the armpits of both and applied the scent extracts to filter paper. The perfumed papers were stuck to a human volunteer’s hand in the trapping chambers. Those with the odors of dengue patients attracted more mosquitos. After pinpointing the cause of the increased attraction, the researchers tested a possible solution. They’d found that when viruses like Zika or dengue invade the body, they suppress a particular antimicrobial protein on the skin that controls acetophenone. Researchers were able to reactivate that protein and stop the overproduction of acetophenone by feeding the mice isotretinoin, a vitamin A derivative often used as acne medication. After that, mosquitos fed on the treated mice less than the untreated mice. “If that holds in longitudinal studies, then there is hope that this is going to be an extremely effective tool in the arsenal that we have against infectious diseases,” said Vasilakis. The researchers will focus their next studies on both the host — by testing potential treatments to suppress acetophenone in human dengue patients — and the vector, by searching for the genetic key in mosquitos that identifies and seeks the acetophenone, and attempting to remove it. In the global effort to fight the viruses, this research lays new groundwork. But it will likely take years to decades before we have a solution as simple as a pill for patients to ward off hungry mosquitos.

Research Published in Cell (June 30, 2022):

https://www.sciencedirect.com/science/article/abs/pii/S0092867422006419 

Researchers have developed a potent inhibitor of the dengue virus, which causes roughly 100 million cases of symptomatic cases of dengue fever annually. There are no antiviral agents available to prevent or treat the approximately 96 million symptomatic cases of dengue fever, annually. But the need for new treatments is growing. The disease is caused by the mosquito-borne dengue virus, which is found in nearly all (sub)tropical regions, but especially in Latin America and Asia. The frequency of outbreaks continues to grow, and the virus is expected to impact billions more in the coming decades as the virus spreads to other regions due to climate change and other global trends. Now, a group from the KU Leuven Rega Institute and Centre for Drug Design and Discovery (CD3) have developed an ultrapotent inhibitor of the dengue virus. The antiviral molecule is exceptionally effective against all known dengue variants and could be used for therapeutic and prevention purposes. This work is published in Nature in the paper, “A pan-serotype dengue virus inhibitor targeting the NS3–NS4B interaction.” 

The highly potent dengue virus inhibitor (JNJ-A07) has a unique mechanism, explained Johan Neyts, PhD, professor of virology at the Rega Institute at KU Leuven. “Together with the research group of Ralf Bartenschlager, PhD, from Heidelberg University, we demonstrated that our inhibitor prevents the interaction between two viral proteins that are part of a kind of copier for the genetic material of the virus. If this interaction is blocked, the virus can no longer copy its genetic material. As a result, no new virus particles are produced.” The antiviral exerts nanomolar to picomolar activity against a panel of 21 clinical isolates that, the group reported, “represent the natural genetic diversity of known genotypes and serotypes.” The molecule, they said, reveals a previously undescribed mechanism of antiviral action by preventing the formation of the viral replication complex by blocking the interaction between two viral proteins (NS3 and NS4B), In addition, the antiviral has a high barrier to resistance.  Research in mice suggests that the inhibitor could also be used for prevention purposes. These findings are cause for optimism, as the existing dengue vaccine only offers partial protection.

“Even a low dose of the drug administered via the oral route proved to be very effective,” noted Suzanne Kaptein, PhD, biological group leader at the Rega Institute at KU Leuven. “What is more, the treatment is still effective when the infection is already at its peak. In these cases, the number of virus particles in the blood dropped drastically within 24 hours after the start of the treatment. This goes to show how extremely potent the antiviral drug is.” “Potent and safe dengue drugs that can be easily taken as tablets could offer anyone effective protection for a certain period of time,” explained Neyts. “Think of people living in areas with an ongoing dengue outbreak, for instance: they could take a dengue drug for a couple of days or weeks. The tablets could also protect travelers or NGO workers during their stay in high-risk regions.” The antiviral drug will be developed in an easy-to-administer formulation that can be optimized for the treatment and prevention of the disease in dengue-endemic tropical and subtropical regions. The development of the antiviral was a long haul, said Neyts. “We started this project in 2009. First, we examined many thousands of molecules in a compound library of the CD3 to find one or more molecules that inhibit the virus in lab-grown cells. In other words: we started looking for a needle in a haystack. As soon as we were able to identify such molecules, the medicinal chemists at CD3 could start to work with them. They created many versions of the molecules to boost their efficacy against the virus.” There are four types of dengue viruses, and the molecule needed to be equally effective against all four of them, added Patrick Chaltin, PhD, managing director, CD3. “It was no easy feat to reach that goal: the optimization process involved about 2,000 steps. Years of intensive collaboration have now resulted in an ultra-potent dengue inhibitor that we are proud to present.”

See also original findings published in Nature (Oct. 6, 2021):

https://doi.org/10.1038/s41586-021-03990-6 

Singapore has just begun to get its second wave of coronavirus under control. Now, it's on track to face its worst-ever outbreak of another viral infection: dengue. More than 14,000 dengue cases have been reported in the city-state since the start of the year, according to the National Environment Agency (NEA). The total number for the whole year is expected to exceed the 22,170 cases reported in 2013 -- the largest dengue outbreak in Singapore's history, the agency said.

Dengue is a viral infection transmitted by the Aedes mosquito, the same insect responsible for spreading Zika, chikungunya and yellow fever. It is commonly found in hot, wet regions of the tropics and subtropics during the rainy months. Only about 25% of those infected show symptoms, which include high fever, severe headaches, muscle and joint pains. Extreme cases can bring bleeding, breathing difficulties, organ failure, and potentially death. In Singapore, 16 people have died of dengue this year -- twice the death toll of 2013. The warmer months from June to October are traditionally peak dengue season in the city state, due to accelerated development of the Aedes mosquito and the shorter incubation period of the Dengue virus. 

Recover from dengue once, and you’re not necessarily free and clear. The mosquito-borne disease marked by fever, rash, and debilitating pain results from any of four genetically distinct versions of the dengue virus. Previously infected people who get hit with a second of these “serotypes” can face more severe, even life-threatening symptoms. Now, by endowing a line of mosquitoes with an antibody against the virus, researchers have for the first time made insects that—at least in lab tests—appear unable to spread any form of the disease. In theory, these mosquitoes could be released into the wild to suppress the circulation of the virus. “This is right on the money,” says Alexander Franz, a biologist at the University of Missouri, Columbia, who studies insect-borne viruses. “This is what you need to do if you really want to have a strong effect on dengue prevalence.”

Conventional control strategies for dengue, such as removing stagnant water where mosquitoes breed, spraying insecticides, and protecting people with bed nets, have failed to defeat the virus, which infects up to 400 million people a year in regions near the tropics. So some researchers are trying to defeat dengue from inside the mosquito that has just drunk infected blood. The goal is to keep the virus from spreading to the insect’s saliva, where it can be injected into the next person bitten....

Mosquitoes don’t make antibodies to target pathogens like we do, but giving them the ability to make one of these immune proteins could help them fight off an infection that they would otherwise pass on to people. In previous studies, researchers endowed mosquitoes that carry the malaria parasite Plasmodium with an antibody that kept the pathogen out of their saliva.

The new study applies a similar principle to the dengue virus. Molecular biologist Omar Akbari of the University of California, San Diego, and colleagues reengineered the human antidengue antibody to simplify its structure, making its gene easier to insert into the mosquito genome. They injected the slimmed-down antibody gene into the embryos of Aedes aegypti mosquitoes, which spread dengue. Then, they bred the resulting insects to make offspring with two copies of the new gene, which is activated only when blood enters the gut. After the engineered mosquitoes drank blood infected with any one of the four dengue serotypes, they had no detectable dengue virus in their saliva, the researchers report today in PLOS Pathogens.

In the lab, these genetically engineered mosquitoes could mate and produce healthy offspring. They developed slightly slower than typical mosquitoes, and the females had slightly shorter life spans, but it’s hard to gauge from these initial tests how fit these mosquitoes will be compared with their wild counterparts, Akbari says.

Overall, the work is promising, Franz says. But future tests will need to demonstrate that the dengue virus doesn’t quickly mutate and evade the antibody’s grip, and that the inserted gene is stable—able to produce the antibody in the mosquito gut generation after generation. If it does, he says, “I think this probably a winner.”

Original report Published in PLOS Pathogens (January 16, 2020):

https://doi.org/10.1371/journal.ppat.1008103

By folding snippets of DNA into the shape of a five-pointed star using structural DNA nanotechnology, researchers have created a trap that captures Dengue virus as it floats in the bloodstream. Once sprung, the trap—which is non-toxic and is naturally cleared from the body—lights up. It's the most sensitive test for the mosquito-borne diseases yet devised. Published today in Nature Chemistry, this detection technique could be expanded to other viruses and adapted to kill the viruses it snares.

"This is more sensitive than any other way of detecting Dengue, beating the clinical test by more than 100 fold," said Xing Wang, the corresponding author of the study, an assistant professor of chemistry and member of the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselaer Polytechnic Institute at the time of the research. "The binding is tight and the specificity is high, enabling us to distinguish the presence of Dengue on the first day of infection." A trap could be effective against many different viruses because, in order to infect their host, all viruses must first latch onto a cell wall and disgorge their genetic instructions into the cell. In 2016 research conducted at CBIS, Rensselaer chemist Robert Linhardt and Rensselaer chemical engineer Jonathan Dordick constructed a synthetic polymer configured to match a sequence of sialic acid latch points on the influenza virus. In the lung, influenza must bind to sialic acid to invade lung cells. The synthetic trap worked as a decoy, catching influenza before it latched onto lung cells.

The treatment reduced influenza A mortality in mice from 100% to 25% over 14 days. However, Linhardt and Dordick, who are both co-authors on the new study, expected that the synthetic polymer they had used as framework for the trap might prove toxic to the body and was unlikely to be accepted as a therapeutic. Structural DNA nanotechnology—an established method of folding strands of DNA into designed, customized geometric shapes and objects—offered the research team a non-toxic, biodegradable alternative on which to construct a new trap, said Wang. The spherical surface of Dengue, like the closely related Zika virus, are studded with multiple latch points to catch a cell surface.

By superimposing various DNA nanostructural shapes onto images of the virus, the team settled on a five-pointed star—they call it a "DNA star"—as the best match between points on the DNA shape and latch points on the virus. Wang took the lead on producing the DNA star. He also attached specific aptamers—molecules the viral latches will bind to—precisely to the tips and vertices of the star so that they would align with the distribution of the latches on the virus. "You could overlay the star onto the virus and target a whole hemisphere of the sphere precisely," said Wang, now at the University of Illinois at Urbana-Champaign. "All the ligands that would target the antigens of this virus would overlay perfectly with a DNA star. If we were only able to make a connection in one place it would be a weak binder, but with ten aptamers connecting the virus to the star, we have a tight hold on the target." Once bound to the virus, the DNA star starts to fluoresce, making it easily visible in a blood test....

Published in Nature Chemistry (November 25, 2019):

https://doi.org/10.1038/s41557-019-0369-8

Mosquitoes zapped with radiation to make them sterile are set to be released into the wild in a bid to fight outbreaks of dengue fever.  The World Health Organization has announced that from next year it will start large-scale studies of what is known as the sterile insect technique. This involves irradiating male Aedes mosquitoes, the species responsible for the spread of diseases such as dengue, Zika and chikungunya. The scientists hope that the sterile males will be released in such large numbers that they will overwhelm the native male population and then go on to mate with females. But they will produce no offspring so the insect population will reduce over time, alongside the number of cases of the disease. The technique has been used for about 50 years in the management of agricultural pests, such as the Mediterranean fruit fly, and experts are confident that it poses no risk to either human health or the environment. 

WHO has been working with organisations including the International Atomic Energy Agency (IAEA) and the Food and Agriculture Organisation on preliminary studies in countries including Bangladesh, Cuba, Brazil and Mauritius. Dengue fever has become a major health threat with 110 countries around the world suffering outbreaks this year. WHO believes that as many as five million cases may be reported by the end of 2019 - up from an average of three million in previous years. Urbanisation and climate change are expected to see the mosquito responsible for transmitting the disease spread to new areas.  Raman Velayudhan, coordinator of WHO’s department of neglected tropical diseases, said there was a desperate need for new tools to control the Aedes mosquito which lives in urban areas, bites during the day and whose eggs are able to survive for long periods. 

“It’s a unique mosquito which has silently expanded and today is present in over 130 countries,” he told a press conference, where the trial was announced. Experts insist the technique is safe - the mosquitoes are not “radioactive” and there is no genetic mutation. WHO also stresses that the technique will not harm the wider eco-system. There are more than 3,500 different types of mosquito that serve as food for animals so removing one species will have little impact. The IAEA is looking at refining the technique for malaria-carrying mosquitoes, although Dr Velayudhan said there were already control tools for this mosquito, such as bed nets and indoor residual spraying. 

Takeda has laid out considerable time, effort and money on its dengue vaccine program despite Sanofi's trouble with its earlier entrant. Now, the Japanese drugmaker is touting phase 3 data showing the vaccine was 80% effective at preventing dengue.

In a study called Tides, investigators tested the Takeda vaccine, TAK-003, against placebo in more than 20,000 participants aged four to 16 in dengue-endemic countries in Latin America and Asia. Twice as many participants received the vaccine as those who received placebo. In those who received both doses, the vaccine was 80.2% effective, the team reported Wednesday. Investigators tracked 61 cases of dengue in the vaccine group versus 149 in the placebo group, according to results published in The New England Journal of Medicine. 

Importantly, efficacy varied among dengue serotypes. The vaccine was 73.7% effective against dengue serotype 1, 97.7% effective against serotype 2 and 62.6% effective against serotype 3. The investigators didn't track enough serotype 4 cases to reach an efficacy determination. The shot was 95.4% effective in preventing dengue that required hospitalization; there were five hospitalizations in the vaccine group versus 53 in the placebo group. The company has said it expects phase 3 studies to form the basis for regulatory submissions. Derek Wallace, Takeda’s dengue vaccine program chief, told FiercePharma the company is “encouraged by the data” as the results demonstrate the vaccine “has a potential to have a very big impact” on the dengue burden worldwide.

Takeda is particularly pleased about the vaccine’s performance in participants who hadn't had a prior dengue infection, Wallace said. In that group, the vaccine was 74.9% effective in preventing dengue. Pharma watchers may remember that Sanofi's dengue vaccine, the world's first, tripped up because of safety problems in those who hadn't had prior infections. The French drugmaker rolled out the shot in 2016, but in late 2017, the company said a new analysis had found it could cause more serious disease in those who’d been infected before. The disclosure triggered outrage in the Philippines, where officials had started a vaccination campaign. All told, the scandal knocked Sanofi’s vaccine off its launch trajectory and the company faced numerous questions about the vaccine's safety and its rollout in the Philippines. Dengvaxia originally had blockbuster expectations, but in 2018, its sales weren’t significant enough for Sanofi to disclose. Still, Takeda isn't backing down from the dengue vaccine challenge. The company just this week opened a €130 million plant in Germany to meet global demand for the shot once it launches. The drugmaker plans to employ up to 200 workers at the plant. 

Clinical Study published in New England Journal of Medicine (November 6, 2019):

https://doi.org/10.1056/NEJMoa1903869

A study led by Brazilian researchers shows that people who have had the Zika virus run a higher risk of subsequently having severe dengue and being hospitalized. The finding is highly relevant to the development of a Zika vaccine.According to the scientific literature, a second infection by any of the four known dengue serotypes is known to be typically more severe than the first, but until now no correlation between this fact and the occurrence of other diseases had been investigated. The study is published in the journal PLOS Neglected Tropical Diseases. The mechanism that exacerbates dengue infection following a case of Zika differs from that of two consecutive infections by the dengue virus, the authors conclude. The viral load is higher in the second dengue episode, with high levels of inflammatory cytokines not seen in Zika. Detection of other markers suggested that the increase in severity may be due to activation of T cells, key parts of the immune system that help produce antibodies, in a pathogenic immune response that has been termed the "original antigenic sin." The process involves so-called T-cell memory, a response in which T cells produced during a previous infection stimulate the production of more T cells to combat a new infection. Because these new cells are not specific to the virus, they trigger an excessive release of inflammatory cytokines, which attack the organism's proteins and tissues, potentially leading to hemorrhage.

The researchers analyzed samples from 1,043 laboratory-confirmed dengue patients, identifying those with prior Zika and dengue infections. The cases occurred in 2019 in São José do Rio Preto, a large city in São Paulo state, Brazil, considered hyperendemic for dengue since more than 70% of the population has had the disease. Its climate and geography favor the circulation of arboviruses throughout the year. Dengue epidemics occurred there in 2010, 2013, 2015, 2016 and 2019, with a record number of cases involving serotype 2. "We concluded that a prior dengue infection was not a risk factor for severity, probably because the patients were already into their third or fourth infection. Prior Zika infection, however, was important and an aggravating factor in a second dengue episode. This led us to suggest novel mechanisms and renew our knowledge of the natural history of the disease," Cássia Fernanda Estofolete, an infectious disease specialist at the São José do Rio Preto Medical School (FAMERP) and first author of the article, told Agência FAPESP. "Our findings confirmed the results of a previous study involving children who had Zika in Nicaragua. Later, when they had dengue, the risk of severity increased. We showed the same thing [risk of severe dengue increased by prior Zika or dengue] for adults in Brazil. We also showed that ADE [antibody-dependent enhancement, in which—instead of providing protection—antibodies enhance viral entry into host cells and can exacerbate the disease] is non-classical," said corresponding author Maurício Lacerda Nogueira. "This raises questions about the type of Zika vaccine that should be used and the optimal timing: should it be administered with a dengue vaccine in order to avoid this problem of one following the other, for example? There are various possibilities, which need to be understood to ensure correct prescription. In Brazil, it's still more important to give the dengue vaccine first because of the number of cases," added Nogueira.

Published in PLOS Neglected Diseases:

https://doi.org/10.1371/journal.pntd.0011710

The global failure to reduce fossil fuels is leaving small island states trapped in a never-ending cycle of fightback against disease and extreme weather. In the summer of 2023, the world recorded the highest temperature in 100,000 years. All continents were affected and even the gentle breeze often felt in the tropics did little to cool the sweltering heat experienced by small island developing states (Sids). Our latest Lancet Countdown report, tracking the connections between health and the climate crisis, showed that Sids experienced 103 health-threatening heat days each year between 2018 and 2022 – equating to almost a third of the year being above the threshold whereby heat-related deaths are likely to increase. Aside from the direct dangers of exposure to health-threatening heat such as heat stress, heatstroke, and, in severe circumstances, death, increased heat improves the climate suitability for the spread of infectious diseases such as dengue fever, malaria and vibrio by expanding their climatic boundaries, our most recent data shows. Our mathematical models of dengue fever show an increase in the frequency of outbreaks with an increase in heat, and the evidence suggests that the climate crisis has exacerbated the frequency of these outbreaks.

Dengue fever is a climate-sensitive disease that is spread through the saliva of an infected female Aedes mosquito when it bites an uninfected person. Dengue fever presents with high fever, severe headache, flu-like symptoms, intense joint and muscle pain, and other flu-like symptoms. It is usually a mild disease that can be adequately treated with rest, hydration and acetaminophen/paracetamol. However, it can also be severe, requiring hospitalisation and, in rare cases, causing death. Its most severe form is dengue haemorrhagic fever. The virus has four strains: Denv-1, Denv-2, Denv-3, and Denv-4. These strains are distinct, and immunity to one does not provide protection from the others. Denv-2 is the most severe strain. Exposure to one strain after being infected with another increases the severity of the disease, and repeated infection increases the risk of acquiring dengue haemorrhagic fever. Before 2007, the frequency of dengue outbreaks in Jamaica was once every 10 years; after 2007, the frequency increased to one every three to four years. The last epidemic was in 2019. While other risk factors such as behaviour and environment are implicated in the spread of dengue, the climate crisis is believed to be a significant contributor to the frequency of outbreaks, with the increase in temperature being the primary reason. The Jamaican summer of 2023 provided the perfect conditions for an increase in mosquito proliferation. First, there was a drought, which led to an increase in the storage of water, often in containers ideal for mosquito breeding. The drought was followed by a record-breaking hot and dry summer that ended with rain. Added to the mix is hyperendemnicity, with all four dengue strains circulating.

In September 2023, Jamaica’s ministry of health and wellness declared a dengue fever outbreak. The number of cases reported by health officials as of 6 November was 3,147 (suspected, presumed and tested), with nine deaths, adding pressure on the island’s already burdened health system. The dominant strain in circulation was Denv-2, and the hospitalisation rate was 72 people a week. Children aged between five and 14 were the most affected, with 360 cases per 100,000 people. Children were disproportionately affected because the last dengue outbreak with Denv-2 as the dominant strain occurred in 2010; these children were born after 2010 and did not acquire immunity to Denv-2. The outbreak is ongoing. Small island states often feel as if we are in a constant state of recovery from the impacts of the climate crisis. Recovery from extreme weather events, such as tropical cyclones; recovery from disease outbreaks exacerbated by climate change; recovery from sea level rise causing coastal erosion and salinisation of our water and land. We have repeatedly lost land, lives and livelihoods because of the climate crisis, a phenomenon to which we collectively contribute less than 1%. We should not lose sight of the progress made: the lethality of extreme weather events in Sids has fallen, and we have recorded progressively fewer deaths. This is a result of meteorological early warning systems, better disaster preparedness and management, as well as prompt appropriate health responses.  But we risk exceeding the power of these adaptation efforts, as the world moves in the wrong direction: expanding oil and gas activities, forgoing climate financing commitments, and leaving countries such as Sids behind in the uptake of clean, renewable energy. In October, when I visited my 14-year-old niece, who was in hospital with dengue, I reflected on the children of small island developing states whose lives will continue to be affected by the climate crisis. Urgent action must be taken at the global level to reduce fossil fuel production and consumption to protect the health of all people, especially those living in Sids, who bear the brunt of the climate crisis.

Dr Georgiana Gordon-Strachan is the executive director of the Lancet Countdown Regional Centre for Small Island Developing States, and director of the Tropical Metabolism Research Unit at the Caribbean Institute for Health Research, University of the West Indies in Jamaica

The Antiviral Program for Pandemics (APP) team, along with experts from across the National Institutes of Health (NIH) and Biomedical Advanced Research and Development Authority (BARDA), has drafted Target Product Profiles (TPPs) for potential direct-acting antiviral therapeutics candidates targeting several key viruses of pandemic potential.  These TPPs should be considered ‘living documents’ that are never final but may be useful starting points for consideration by therapeutics developers who are drafting TPPs for their specific candidates.  Also, the example TPPs are not intended to provide details about product requirements for funding or other support from USG or other funders.  Instead, these sample TPPs are being provided as tools for scientists working toward therapeutics product development of direct-acting antivirals for use in potential future outbreaks or pandemics. We are happy to receive feedback on these sample TPPs and may make updates/revisions or add TPPs for additional clinical indications in the future, so please monitor this page for updates and send any feedback to APPSubmissions@mail.nih.gov

LIMA, Peru – Peru on Thursday declared a “health emergency” in 13 departments in the country’s north, center and southeast due to an outbreak of dengue. The emergency would remain in place for 90 days, according to an official notice, after the health ministry recorded more than 11,500 cases and 16 deaths due to the disease so far in 2023. This represented a “considerable increase” of 72 percent from the same period in 2022. Last year, the country had more than 72,800 dengue cases and 84 deaths. Dengue fever is a mosquito-borne tropical disease that can provoke a high fever, headache, vomiting, muscle and joint pain, and sometimes death. Earlier this month, neighbor Bolivia also declared a health alert with a cumulative number of more than 6,800 cases and 26 deaths.

Mosquito-borne viruses increasingly threaten human populations due to accelerating changes in climate, human and mosquito migration, and land use practices. Over the last three decades, the global distribution of dengue has rapidly expanded, causing detrimental health and economic problems in many areas of the world. To develop effective disease control measures and plan for future epidemics, there is an urgent need to map the current and future transmission potential of dengue across both endemic and emerging areas. Expanding and applying Index P, a previously developed mosquito-borne viral suitability measure, we map the global climate-driven transmission potential of dengue virus transmitted by Aedes aegypti mosquitoes from 1981 to 2019. This database of dengue transmission suitability maps and an R package for Index P estimations are offered to the public health community as resources towards the identification of past, current and future transmission hotspots. These resources and the studies they facilitate can contribute to the planning of disease control and prevention strategies, especially in areas where surveillance is unreliable or non-existent.

Preprint in medRxiv (Nov. 5, 2022):

https://doi.org/10.1101/2022.11.04.22281958 

LA JOLLA, CA-;Researchers at La Jolla Institute for Immunology (LJI) have found that Zika virus can mutate to become more infective-;and potentially break through pre-existing immunity.  "The world should monitor the emergence of this Zika virus variant," says LJI Professor Sujan Shresta, Ph.D., who co-led the Cell Reports study with Professor Pei-Yong Shi, Ph.D., of the University of Texas Medical Branch (UTMB). Zika virus is carried by mosquitoes, and the symptoms of Zika infection are usually mild in adults. However, the virus can infect a developing fetus, resulting in birth defects such as microcephaly. Zika virus and dengue virus overlap in many countries worldwide. Like Zika, dengue virus is a mosquito-borne flavivirus, and thus shares many biological properties. In fact, the viruses are similar enough that the immune response sparked by prior dengue exposure can offer protection against Zika.  Unfortunately, both viruses are also quick to mutate. "Dengue and Zika are RNA viruses, which means they can change their genome," explains Shresta. "When there are so many mosquitoes and so many human hosts, these viruses are constantly moving back and forth and evolving.

To study Zika's fast-paced evolution, the LJI team recreated infection cycles that repeatedly switched back and forth between mosquito cells and mice. This work gave the LJI scientists a window into how Zika virus naturally evolves as it encounters more hosts. The researchers found it is relatively easy for Zika virus to acquire a single amino acid change that allows the virus to make more copies of itself-;and help infections take hold more easily. This mutation (called NS2B I39V/I39T mutation) boosts the virus's ability to replicate in both mice and mosquitoes. This Zika variant also showed increased replication in human cells.  "This single mutation is sufficient to enhance Zika virus virulence," says study first author Jose Angel Regla-Nava, Ph.D., former postdoctoral researcher at LJI and current Associate Professor at the University of Guadalajara, Mexico. "A high replication rate in either a mosquito or human host could increase viral transmission or pathogenicity-;and cause a new outbreak." Adds Shresta, "The Zika variant that we identified had evolved to the point where the cross-protective immunity afforded by prior dengue infection was no longer effective in mice.

Unfortunately for us, if this variant becomes prevalent, we may have the same issues in real life." So how can we prepare for this kind of variant? Shresta's laboratory is already looking at ways to tailor Zika vaccines and treatments that counteract this dangerous mutation. She will also continue to work closely with Regla-Nava to better understand exactly how this mutation helps Zika replicate more efficiently. "We want to understand at what point in the viral life cycle this mutation makes a difference," says Shresta.

Research cited published in Cell Reports (April 12, 2022):

https://doi.org/10.1016/j.celrep.2022.110655 

This is the main finding of a study. The authors analyzed blood samples collected in a town in the Brazilian Amazon before and after the first wave of the pandemic to detect the presence of antibodies against dengue virus and SARS-CoV-2.  A study published this May in the journal Clinical Infectious Diseases suggests that people who have had dengue in the past are twice as likely to develop symptoms of COVID-19 if they are infected by the novel coronavirus. The findings of the study were based on an analysis of blood samples from 1,285 inhabitants of Mâncio Lima, a small town in the state of Acre, part of Brazil’s Amazon region. The principal investigator was Marcelo Urbano Ferreira, a professor at the University of São Paulo’s Biomedical Sciences Institute (ICB-USP) in Brazil. The study was supported by FAPESP.  “Our results show that the populations most exposed to dengue, possibly owing to socio-demographic factors, are precisely those that most risk falling very sick if they’re infected by SARS-CoV-2. This is an example of what has been called a syndemic [synergic interaction between two epidemic diseases so that one exacerbates the effects of the other]. On one hand, COVID-19 has hindered efforts to control dengue. On the other, the latter appears to increase the risk for those who contract the former,” Ferreira told Agência FAPESP. For seven years Ferreira has been conducting research in Mâncio Lima with the aim of combating malaria. In 2018 he began work on a project involving a survey of 20% of the town’s population every six months. His team call on homes, apply questionnaires, and collect blood samples. In early 2020 the project received additional funding from FAPESP so that part of the research effort could be redirected to the monitoring and characterization of SARS-CoV-2 in the region (read more at: agencia.fapesp.br/34728). “In September 2020, a study by another group was published suggesting that areas with many cases of dengue were relatively little affected by COVID-19. Because we already had blood samples collected from inhabitants of Mâncio Lima before and after the first wave of the pandemic, we decided to use the material to test the hypothesis that prior infection by dengue virus conferred some degree of protection against SARS-CoV-2. What we found was exactly the opposite,” Ferreira said.

Methodology

The blood samples analyzed had been collected in November 2019 and November 2020. They were submitted to tests capable of detecting antibodies against all four dengue serotypes and against SARS-CoV-2. The results showed that 37% of the cohort studied had contracted dengue before November 2019 and 35% had been infected by the novel coronavirus before November 2020. Clinical data (symptoms and outcomes) of the volunteers diagnosed with COVID-19 were also analyzed. “We deployed statistical analysis to conclude that prior infection by dengue virus doesn’t alter the risk of being infected by SARS-CoV-2. On the other hand, our study also shows that people who have had dengue are more likely to have symptoms if they’re infected by SARS-CoV-2,” said Vanessa Nicolete, first author of the article. Nicolete is a researcher with a postdoctoral fellowship at ICB-USP. The causes of the phenomenon described in the article are unclear. There may be a biological basis for it, in the sense that antibodies against dengue virus somehow exacerbate COVID-19, or it may simply be due to socio-demographic factors that make certain population groups more vulnerable to both diseases for various reasons.

“The results evidence the importance of reinforcing both the social distancing measures introduced to contain the spread of SARS-CoV-2 and efforts to control the dengue vector, as the two epidemics are occurring at the same time and affecting the same vulnerable population. This should be getting more attention from the federal government,” Ferreira said.

Article published in Clin. Infect. Diseases (May 6, 2021):

https://doi.org/10.1093/cid/ciab410

A study of Nicaraguan children links prior Zika virus infection with aggravated dengue fever symptoms. The 2015–16 Zika virus epidemic that spread through Central and South America was followed last year by a surge in dengue virus cases. While this unfortunate series of diseases battered the region’s populace, it gave scientists, who had been following a cohort of several thousand children in the area, the opportunity to study how these two flaviviruses might jointly affect the immune system. That research has revealed that kids infected with dengue virus are more likely to suffer worse symptoms if they had previously been infected with Zika than if they hadn’t. The findings, reported in Science today (August 27), indicate that antibody-dependent enhancement—a phenomenon known for making a second infection with a virus worse than the first—is not limited to influencing infections by the same pathogen. This raises concerns that such cross-species effects may occur for other types of viruses—including coronaviruses—and may impact vaccine safety, scientists say.

“It’s a pretty amazing story. [It] addresses what I think is the most important question in the field that has emerged following the Zika virus outbreak, and that is, how do Zika virus and dengue virus influence each other?” says virologist Jean Lim of the Icahn School of Medicine at Mount Sinai who was not part of the research team. Dengue and Zika viruses are closely related members of the flavivirus genus and are both transmitted to humans via the bites of infected mosquitoes. Dengue virus infection can be asymptomatic or can cause symptoms such as fever, headache, muscle aches, and rash. In some cases the disease can be severe, causing hemorrhagic fever and even shock (a dangerous drop in blood pressure). Zika virus causes a mostly mild disease—characterized by fever, rash, and joint pain—that resolves within a week, but in adults it can occasionally cause Guillain-Barré syndrome, an autoimmune condition affecting the peripheral nerves, and in pregnant women, the virus can lead to brain defects in the developing fetus including microcephaly. 

There are four strains, or serotypes, of dengue virus and infection by one type has a curious effect on infection by another, explains epidemiologist Isabel Rodriguez-Barraquer of the University of California (UC), San Francisco, who also did not work on the project. While an infection with the same serotype twice will not cause disease the second time around, if a different serotype causes the second infection, the existing antibodies fail to neutralize the virus and actually assist its entry into host cells. “The antibodies that your body builds after that first infection make the second infection worse and that’s often referred to as antibody-dependent enhancement,” Rodriquez-Barraquer says. This phenomenon is also thought to explain the worsening of disease severity seen after dengue vaccination.  Because Zika is closely related to dengue, “when Zika came along there was a question [of whether] there was going to be some sort of immunological interaction,” says UC Berkeley’s Eva Harris. And her group was in a perfect position to provide an answer, she adds, thanks to a long-standing collaboration with scientists in Nicaragua who have been monitoring infections, measuring antibody titers, and collecting other data from a rolling cohort of children since 2004.

In an earlier study, Harris’s group had shown that dengue infections preceding the Zika outbreak that started in 2015 offered a slightly protective effect against Zika severity, at least in children. Then, in 2019, when a major epidemic of dengue infections blew through the region—the worst in Nicaragua’s history—the group looked at the reverse scenario: whether prior Zika infection influenced dengue severity.  A total of 302 children of a cohort of 3,434 were diagnosed with symptomatic dengue fever between 2019 and 2020, confirmed via PCR amplification of the virus’s genetic material. By analyzing the infection history of the cohort, the team then calculated that children who had had a prior Zika infection had a roughly 12 percent chance of developing symptomatic dengue, compared with an only a 3.5 percent chance for children that had had no prior flavivirus exposure. Children who had had one prior dengue infection had a roughly 9 percent chance of later symptomatic disease. Prior Zika or dengue infection also increased the risk that a child would experience the most severe symptoms of dengue—hemorrhagic fever and shock—compared with children who had not previously had flavivirus disease, the team showed...

Published in Science (August 28, 2020):

https://doi.org/10.1126/science.abb6143

A new study led by scientists at the Walter Reed Army Institute of Research has shown for the first time that a single dose of an experimental Zika vaccine in a dengue-experienced individual can boost pre-existing flavivirus immunity and elicit protective cross-neutralizing antibody responses against both Zika and dengue viruses. Findings were published today in Nature Medicine. Researchers analyzed the antibody responses of a dengue-experienced volunteer who participated in a Phase 1 clinical trial of the WRAIR-developed Zika purified inactivated virus vaccine. They identified a potent cross-reactive antibody called MZ4 that demonstrated a potent ability to neutralize the Zika virus as well as the dengue virus serotype-2 strain. In addition, MZ4 protected against Zika and dengue in a mouse model of infection. 

"Rapid-onset countermeasures are needed to protect military personnel, travelers and residents in areas where emerging infections such as Zika and dengue viruses are already widespread and expanding," said Dr. Kayvon Modjarrad, who leads the U.S. Army Zika vaccine program, directs the Emerging Infectious Diseases Branch at WRAIR and is one of the lead authors on the paper. "These results demonstrate the potential for MZ4 to be part of the prevention toolbox for these diseases." The individual's immune profile was compared to trial volunteers who had no previous exposure to dengue virus. While the volunteer with prior dengue exposure experienced a sharp increase in antibodies that neutralize Zika and dengue viruses, following just one dose of the ZPIV vaccine, the dengue-naïve trial participants required two vaccinations to reach a similar magnitude of Zika antibody responses. Additionally, no cross-reactive antibody response to dengue virus. 

"These new findings indicate that an effective Zika vaccine could both boost dengue virus immune responses and generate potent Zika neutralizing antibodies that might have unique potential as a prevention tool in regions where both dengue and Zika are prevalent," said Dr. Shelly Krebs, a B cell researcher at WRAIR and senior author of the paper....

Published in Nat. Medicine (February 3, 2020):

https://doi.org/10.1038/s41591-019-0746-2

A new technology to produce safer 'hybrid' viruses at high volumes for use in vaccines and diagnostics for mosquito-borne diseases has been developed at The University of Queensland. Researchers from UQ and QIMR Berghofer Medical Research Institute have exploited the benign characteristics of the Binjari  virus—inert to humans—to produce 'dangerous looking' mosquito-borne viruses such as Zika and dengue, but which cannot grow in humans or animals. School of Chemistry and Molecular Biosciences' Dr. Jody Hobson-Peters said the team, led by Professor Roy Hall, began to explore this possibility after discovering new viruses in the lab. "We were originally hoping to gain insights into how mosquito-borne viral diseases evolve—viruses like Zika, yellow fever and dengue," Dr. Hobson-Peters said. "We were also hoping to discover new viruses that might be useful for biotechnology or as biological control agents. "The Binjari virus stood out, and while it grows to very high levels in mosquito cells in the lab, it's completely harmless and cannot infect humans or other vertebrate species. "And it is incredibly tolerant for genetic manipulation, allowing us to swap important genes from pathogenic viruses like Zika, West Nile and dengue into the Binjari genome. "This produces hybrid, or chimeric, viruses that physically appeared identical to the disease-causing viruses under the electron microscope, but were still unable to grow in human or animal cells."

The researchers have effectively developed a new biotechnology platform requiring low biocontainment, to help safely develop vaccines and diagnostics against these mosquito-borne diseases. Professor Andreas Suhrbier, from QIMR Berghofer Medical Research Institute, said the team hoped to push this technology further down the development pathway toward human applications. "The main advantage of this system is that it is safe," Professor Suhrbier said."  "These hybrids cannot infect humans, meaning that manufacture of vaccines and diagnostic reagents don't require the strict and expensive biosecurity infrastructure ordinarily needed to grow these pathogenic viruses." "The research is a testament to collaborative science—this all fell into place, with amazing collaboration within the Australian Infectious Diseases Research Centre. "It's a technology that will truly revolutionise the manufacture of vaccines—supercharging high-volume vaccine development."

Published in Science Translational Medicine (11 December 2019):

https://doi.org/10.1126/scitranslmed.aax7888

An international team of scientists have reported an effective and environmentally sustainable way to block the transmission of mosquito-borne dengue virus, in trials carried out in Malaysia. The breakthrough has major implications for countries with hot climates such as island nations in the South Pacific to Saudi Arabia, Africa and South America, all of which experience dengue, Zika, yellow fever and chikungunya.

Using a strain of the bacteria Wolbachia, which inhibit mosquitoes from transmitting viruses to humans, researchers at the Universities of Melbourne and Glasgow and the Institute for Medical Research in Malaysia were able to successfully reduce cases of dengue at sites in Kuala Lumpur. Their data, published today in Current Biology, shows that mosquitoes carrying the wAlbB strain of Wolbachia, when released into the wild, had the effect of reducing the incidence of dengue cases by 40 per cent. Previously, scientists including Professor Ary Hoffmann from the University of Melbourne, have carried out successful mosquito releases using a different strain of the Wolbachia bacteria, but while this strain was able to invade wild populations in some conditions, it did not appear to be suitable for use in the very hot conditions experienced in equatorial countries such as Malaysia. 

Now, this international team of researchers from Melbourne, Glasgow and Malaysia has shown that the wAlbB strain of Wolbachia is stable and effective, even in daily peak temperatures of 36°Celsius and higher, as commonly experienced in areas of Malaysia where dengue is prevalent. Professor Hoffmann, from Melbourne University's Bio21 Institute, said the findings could make a difference to a number of countries who have dengue. "This study provides us with a new Wolbachia strain for field release and highlights disease impact within a complex urban setting where dengue incidence rates are high. The intervention succeeded despite ongoing pesticide applications and other challenges that can make it hard for the Wolbachia to become established. The approach holds promise not only in Malaysia but also in other countries."

Each year there are around 90 million symptomatic cases of dengue, with severe disease in around 1 per cent of cases, including life-threatening haemorrhage or shock syndrome. In Malaysia alone, over 100,000 dengue cases were reported in 2016, with an annual cost estimated at $US175 million. Researchers released batches of Aedes aegypti mosquitoes carrying the wAlbB strain of Wolbachia into the wild, in six different sites in greater Kuala Lumpur with high levels of dengue transmission. The Wolbachia carrying mosquitoes - both male and female - then went on to mate with the wild mosquito population, resulting in the spread and establishment of the virus-inhibiting bacteria. In some sites, Wolbachia-carrying mosquitoes were measured at over 90 per cent frequency more than a year after the mosquito releases ended....

Published in Current Biology (November 21, 2019):

https://doi.org/10.1016/j.cub.2019.11.007

Spanish health authorities have confirmed a case of a man spreading dengue through sex, a world first for a virus which until recently was thought to be transmitted only by mosquitos. The case concerns a 41-year-old man from Madrid who contracted dengue after having sex with his male partner who picked up the virus from a mosquito bite during a trip to Cuba, said Susana Jimenez of the Madrid region's public health department. His dengue infection was confirmed in September and it puzzled doctors because he had not travelled to a country where the disease, which causes severe flu-like symptoms such as high fever and body aches, is common, she added.

"His partner presented the same symptoms as him but lighter around ten days earlier, and he had previously visited Cuba and the Dominican Republic," she said. "An analysis of their sperm was carried out and it revealed that not only did they have dengue but that it was exactly the same virus which circulates in Cuba." A "likely' case of sexual transmission of dengue between a man and a woman was the subject of a recent scientific article in South Korea, she said.

In an e-mail sent to AFP, the Stockholm-based European Centre for Disease Prevention and Control (ECDC), which monitors health and disease in Europe, said this was "to our knowledge, the first sexual transmission of the dengue virus among men who have sex with men." 

Dengue is transmitted mainly by the Aedes Aegypti mosquito, which thrives in densely-populated tropical climates and breeds in stagnant pools of water. It kills 10,000 people a year and infects over 100 million. The disease is fatal only in extreme cases but the symptoms are extremely unpleasant, including a high fever, severe headaches and vomiting. It also exacts a heavy economic burden on countries as sufferers are unable to work, as well as overwhelming health services when there is a severe outbreak. It is most serious - and deadly - in children, especially young girls. Scientists do not know why. Dengue is most commonly caught by people traveling to hotter climates such as South East Asia, Africa, Australia, the Caribbean and South and Central America.