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Simple idea to dramatically improve dengue vaccinations

March 30, 2006

An innovative new study explains, for the first time, the failure of previous attempts to vaccinate against the four known Dengue viruses, and it suggests a very simple solution - injecting the four vaccines simultaneously at different locations on the body.

A mosquito-born disease, Dengue kills tens of thousands of people per year and sickens 100 million more. Known as "bone-break disease," Dengue is characterized by excruciating pain and was "the most important mosquito-borne viral disease affecting humans" in 2005 according to the U.S. Centers for Disease Control.

The study, from bioengineers and physicists at Rice University, appears in the March 24 issue of the journal Vaccine. The study suggests that the multi-site vaccination strategy, termed polytopic vaccination, may be effective against other diseases as well, including HIV and cancer.

Dengue infection occurs from one of four closely related viruses. Previous exposure to one of the four - either by prior infection or by vaccination - makes people significantly more likely to develop a potentially lethal hemorrhagic infection if they are later infected by one of the other three viruses.

"This is a classic case of something called 'original antigenic sin,' which happens when our immune system becomes overly reliant upon memory when recognizing diseases similar to those that it has seen before," said lead researcher 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. This starts when 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 available T-cells in its arsenal. 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 pre-programmed 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 co-existent versions of Dengue by developing a vaccine against all four versions simultaneously. Doctors found that patients who got a four-component vaccine wound up only being protected against one or two versions at most, 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, the immune system may respond preferentially against the version for which it has T-cells with the strongest affinity, which is immunodominance," Deem said.

He said 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. Each person has hundreds of lymph nodes. 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 said. "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 is also a problem for researchers working on vaccines for both the AIDS virus and cancer, each of which mutate quickly and occur in multiple strains.

Rice University