Dengue double punch: combo controls

Scientist performing a study
A mosquito control technician performs targeted indoor residual spraying in Merida, Mexico. Credit: Gonzalo Vazquez-Prokopec.

New research published this week in PNAS predicts the most strategic combination of dengue control methods to drastically curtail, if not eliminate, dengue from the Mexican state of Yucatán. Interventions analyzed included two different vaccines and targeted indoor residual insecticide spraying.

An international team collaborated on the study, including Ira Longini, a professor of biostatistics in UF’s College of Public Health and Health Professions and College of Medicine, and Tom Hladish, a research scientist in UF’s College of Liberal Arts and Sciences biology department. Lead author Hladish, and senior author Longini, are both affiliated with UF’s Emerging Pathogens Institute.

The team used 37 years of historical data on dengue in the Yucatán to create a model from which they tested how various combinations of vaccine and vector control measures would affect dengue incidence in a region with a long history of dengue outbreaks.

“In a disease system, you generally expect that when two interventions are stacked together, you will see  a synergistic relationship that works even better than you’d expect from the performance of the individual interventions,” Hladish says. “We wanted to test which combination of dengue interventions work best, and see just how strong that synergy may be.”

Other team members include former UF postdoctoral researchers Carl A. B. Pearson, now with the London School of Hygiene &Tropical Medicine; and Diana Patricia Rojas, now at James Cook University; Kok Ben Toh, UF School of Natural Resources and Environment; Pablo Manrique-Saide, Universidad Autonoma de Yucatán; Gonzalo Vazquez-Prokopec, Emory University; and Elizabeth Halloran, University of Washington.

Testing a double punch

Although insecticides are recognized as a vital dengue management tool, in the long run, they don’t pack enough punch.

“Insecticides can initially be very powerful,” Longini says, “But they tend to drop from 80 percent initial effectiveness to just 20 percent as the susceptibility to dengue builds up in the human population due to successful dengue control.”

But using indoor residual spraying in a targeted fashion, in combination with a vaccination campaign, could bolster the effects of each — in theory — packing a double punch that knocks transmission down to very low levels.

The team first modeled how each intervention would perform alone. When targeted indoor residual spraying and vaccines were used individually against dengue in this region, they were predicted to lose effectiveness over a 15 to 40 year time period down to about 20 percent for spraying and between 20 and 50 percent for vaccines, depending upon which vaccine was deployed.

Next, they modeled a scenario that combined targeted indoor residual spraying with the only commercially-available licensed vaccine, Dengvaxia, but found that these interventions did not perform as well together as expected. In fact, the measures appeared to interfere with each other.

A second combination scenario looked at matching targeted indoor residual spraying with an in-development vaccine and found, assuming the vaccine reaches a target of 70 percent effectiveness, that the combination of these two control measures worked in a way that amplified the other, magnifying their effectiveness. The model predicted that their combined use could eliminate dengue regionally, even if new cases are introduced to the area.

Combining an investigational vaccine with indoor spraying had an amplifying effect on decreasing dengue prevalence. Chart provided courtesy of the study authors.

The upper graph above shows how targeted indoor residual spraying may combine with both the theoretical in-development vaccine (top blue-shaded trend line with closed circles descending from 100 percent to 60 percent effectiveness over 40 years), and with the Dengvaxia vaccine (blue-shaded trendline with closed diamonds descending from 100 percent effectiveness to 40 percent effectiveness over 40 years.

The lower graph shows how the Dengvaxia vaccine and targeted indoor residual spraying perform worse than expected together, leveling off at below 40 percent after 40 years. (This is the black line with diamonds compared to green line with diamonds.) In contrast, the in-development vaccine and TIRS perform better than expected together in the simulated model, leveling off at 80 percent after 40 years. (This is the black trend line with circles compared to green trend line with circles.)

The reason Dengvaxia and spraying interfered with each other has to do with how the vaccine works. It most effectively prevents new dengue cases when administered to people who have already had at least one natural dengue infection. It essentially relies on prior infection in order to prevent future infection. But because spraying reduces the mosquito population, which in turn reduces dengue transmission, fewer people become ill. And if there are fewer cases of people acquiring their first case of dengue, there are fewer people to whom the vaccine can be offered.

“It was surprising that by adding Dengvaxia to spraying you can actually do worse compared to only spraying,” Hladish says.  Worse, severe outcomes can result when it is given to people who have not had a prior dengue infection.

The researchers also determined that timing the strategies did not matter; results varied little if the vaccine campaign started in lock step with the targeted indoor residual spraying, or if they were staggered by a few years.

“Understanding how these combinations play out ultimately informs economic decisions, for choices about where to allocate resources in public health,” Hladish says. “And what our study shows is to be careful with combining interventions where one may undermine the other.”

Dengue expanding globally

Dengue is caused by a virus that spreads to people through mosquito bites. Also known as breakbone fever, dengue has traditionally been endemic to tropical regions. It causes fever, muscle and joint pain, headache and rash. Climate change, and a host of other factors, threaten to sweep dengue into new areas across the globe.

Latin America saw a surge in dengue incidence in 2019, with more than two million people sickened, likely due in part to lingering immune effects from the Zika epidemic in 2015-2016. Although it is an age-old disease, it is emerging as a novel disease as it makes its way to southern Florida and even Spain, mostly through cases imported with tourism.

Given dengue’s potential global reach, this type of research will be of increasing interest to public health policy makers seeking solutions to curb breakbone fever in their jurisdiction.

“Eventually we hope also to test some of these vaccines in conjunction with vector control in randomized community trials to see if we can verify the theoretic results that are in this paper,” Longini says.

By: DeLene Beeland