Vaccination Technique Might Combat Fearsome Diseases

Dengue fever may be less well known than malaria, but it’s a lot more dangerous. A mosquito-born disease, dengue kills tens of thousands of people per year and sickens 100 million more.

Michael Deem

Known as “bone-break disease,” dengue is characterized by excruciating pain and was “the most important mosquito-born viral disease affecting humans” in 2005, according to the U.S. Centers for Disease Control and Prevention.

Dengue infection is caused by one of four closely related viruses. Previous exposure to one of the four by prior infection makes people significantly more likely to develop a potentially lethal hemorrhagic condition if they are later infected by one of the other three viruses. And, unfortunately, attempts to vaccinate against the four known dengue viruses have been failures precisely because vaccination also counts as a previous exposure.

“This is a classic case of something called ‘original antigenic sin,’ which happens when our immune system becomes overly reliant on memory when recognizing diseases similar to those that it has seen before,” explains Michael Deem, the John W. Cox Professor in Biochemical and Genetic Engineering and professor of physics and astronomy. “With diseases like HIV, influenza, and dengue, our acquired immune system’s tendency to go with what it knows can leave us more vulnerable to infection from a mutant strain or a related virus. The immune system may respond less favorably in these cases than if it had never been exposed to the disease in the first place.”

Original antigenic sin, or immunodominance, arises out of the procedure the immune system uses to target infection. The immune system identifies infected cells and brings pieces of them into the lymph node for targeting. Within a few days of infection, the immune system completes a massive scan of the 100 million cells—called “T-cells”—available to orchestrate an immune system response. Through a complex trial-and-error process, it identifies three to five T-cells that best recognize and attack the components of the sickened cells. Once the cells are selected, they are produced by the millions and sent out to clear the infection. After the infection is gone, thousands of these preprogrammed T-cells remain in the body, lying in wait should the disease return.

In recent years, public health officials have documented the disturbing co-existence of two or more dengue viruses in Brazil, Cuba, Thailand, and other tropical and subtropical countries. Because sequential infection by multiple dengue viruses can lead to increased likelihood of deadly infections, public health officials have attempted to counter the threat of coexistent versions of dengue by developing a vaccine against all four versions simultaneously. Doctors found that patients who were given a four-component vaccine were being protected against only one or two versions of the disease, due to immunodominance.

Intrigued by these results, Deem and graduate student Hao Zhou developed a precise computer model of the immune system’s biochemical scanning process to see if they could recreate the effect and find out what caused it. Their program conducts statistical calculations about the likelihood of specific interactions at the atomic level. They conducted trillions of calculations and gradually built up a bigger picture of what occurs in dengue immunodominance.

“When faced with more than one version of the virus,” Deem says, “the immune system may respond preferentially against the version for which it has T-cells with the strongest affinity, which is immunodominance.”

He says that polytopic vaccination—giving different vaccines simultaneously at different locations on the body—could help overcome immunodominance by taking advantage of the relative isolation of lymph nodes throughout the body. Deem believes vaccinations at four different sites, served by four different lymph nodes, could allow the body to simultaneously develop immune responses against all four versions of dengue.

“The literature about immunodominance is new and growing,” Deem says. “Ours is the first model that can predict immunodominance, and when we compare our results with experimental data from dengue vaccination trials, they match quite closely. There may be other factors at work, but we appear to be explaining a significant portion of the effect that occurs in dengue immunodominance.”

Immunodominance also is a problem for researchers working on vaccines for both the AIDS virus and cancer, each of which mutate quickly and occur in multiple strains. Deem’s study, however, suggests that the multisite vaccination strategy may be effective against these other diseases as well.

The research is supported by the National Institutes of Health and the National Science Foundation and was published in the March 24 issue of the journal Vaccine.

—Jade Boyd