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NIAID Scientists Use Reverse Genetics To Develop Potential Dengue Vaccine

Joining the global fight against a disease that threatens approximately 2.5 billion people annually, researchers in the Laboratory of Infectious Diseases (LID) are developing a vaccine against dengue fever.

A female Aedes aegypti mosquito
A female Aedes aegypti mosquito with a fresh blood meal visible through her transparent abdomen. A. aegypti mosquitoes are the principal transmitters of dengue fever.
Credit: CDC

Dengue fever occurs mostly in tropical and subtropical regions of the world. While not usually fatal, the disease can lead to the more severe dengue hemorrhagic fever and dengue shock syndrome. The World Health Organization estimates that dengue fever causes 22,000 deaths annually, mostly in children. This reality, combined with increasing reports of dengue expanding into temperate climates, makes finding an effective, safe, and affordable vaccine an important public health goal.

One major obstacle in the search for such a vaccine is the existence of four distinct but related dengue viruses (DENV), called DENV-1, DENV-2, DENV-3, and DENV-4. When a person is exposed to one virus, he or she builds immunity to only that specific type. If that person is later infected with a different dengue virus, he or she is not only susceptible to dengue fever but is also at a higher risk for developing severe dengue disease. Because the disease is enhanced with re-infection, any vaccine must provide equal protection to all four dengue viruses. Researchers refer to this as a tetravalent vaccine.

LID scientists have created live, attenuated vaccine candidates for dengue using a technique called “reverse genetics.” The technique enables researchers to produce a cloned version of a wild dengue virus that can trigger an immune response but is not strong enough to cause disease. LID developed candidates for DENV-1, DENV-3, and DENV-4 that were safe, did not cause symptoms of dengue fever, and created a high level of immunity to the dengue viruses. Using the candidate for DENV-4, LID researchers were able to create a “chimeric,” or hybrid, vaccine for DENV-2.

The vaccine candidates were found to be safe and to stimulate an immune response in Phase I clinical trials launched in 2010. One vaccine combination, TV003, appeared to induce the most balanced antibody response against all four dengue viruses: a single dose resulted in an antibody response to all four viruses in 45 percent of participants and against at least three virus types in 90 percent of participants.

TV003’s inexpensive production cost—less than $1 per dose—is critical to its potential use in developing countries where dengue viruses are prevalent and effective vaccination is a public health priority. LID’s vaccine technology has been licensed to industry partners in Brazil, India, and Vietnam for further development.

A promising implication of effective dengue virus vaccination would be a reduction in the overall level of virus transmission from humans to mosquitoes. Because dengue circulates from human to mosquito to human, eliminating transmission to the mosquito vector will help ease the burden of disease even among unvaccinated people.

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Last Updated February 09, 2011