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A DNA vaccine candidate expressing dengue-3 virus prM and E proteins elicits neutralizing antibodies and protects mice against lethal challenge

24 Nov 2008

Marcia Triunfol

Source: Archives of Virology (see original article)

Citation: De Paula SO, Lima DM, de Oliveira França RF, Gomes-Ruiz AC, da Fonseca BA (2008). A DNA vaccine candidate expressing dengue-3 virus prM and E proteins elicits neutralizing antibodies and protects mice against lethal challenge. Arch Virol. [Epub ahead of print]

Dengue is a severe public health problem in many countries and shows no signs of slowing down. Controlling the spread of dengue requires a coordinated approach involving much more than actions taken in individual villages. All small pans and pots that may retain rainwater and serve as repositories for the mosquito vector to grow and reproduce need to be eliminated. This is not always feasible. Other alternatives include spaying large areas with insecticide, or adding it to the water.

Another alternative would be the development of a vaccine that could protect individuals against the several forms of dengue, from mild cases to dengue haemorrhagic fever. However, all the vaccines tested so far have presented many problems that have included the development of a series of symptoms – such as febrile illness, headache, myalgia, and malaise – in vaccinated individuals The development of these symptoms is most likely because these vaccines were all live vaccines that used modified strains as the main vehicle of inoculation. In some circumstances modified strains in live vaccines can convert themselves to the original strain and cause the same or even bigger damage than the pathogen which the vaccine was originally designed to combat. The alternative is therefore a DNA vaccine that does not use live strains but instead is based on the construction of small circular DNAs called plasmids. These plasmids, or constructs, carry target nucleotide sequences of the virus antigens that are expected to trigger an immunological response against them.

The work of De Paula and colleagues represents the initial steps of what may become a DNA vaccine against dengue. The authors built three recombinant plasmids based on DENV-3. These recombinants were pVAC1DEN3, pVAC2DEN3 and pVAC3DEN3, and included two proteins of the Flavivurus genus that causes dengue. These two proteins, the E protein and prM, were chosen for different reasons. The E protein is the sequence that contains the main epitopes, which are important regions for triggering the host immune response. Previous studies have shown that the host’s antibodies that act against the E protein are conformation dependent, so the E protein needs to be present in the right shape for the antibodies to detect it. Therefore, the researchers added prM to the construct, which is a second protein that needs to be expressed together with the E protein in order for the latter to be in the right shape.

The researchers first analyzed the ability of these constructs in generating an immune response. To do so, they extracted the spleens of immunized animals and cultivated the immune cells to evaluate the cytokines, which are secreted by immune cells and indicate the occurrence of an immune response. Only cells immunized by the pVAC2DEN3 construct did not show the production of any of the cytokines tested. The other two constructs generated the production of cytokines.

Next, animals were inoculated with the constructs and the immune response analyzed. In 100% of the cases the animals produced antibodies against DENV-3. When challenged by intracerebral injection with lethal doses of DENV-3, the animals vaccinated with pVAC3DEN3 showed the highest survival rate (80%).

The immune response obtained with pVAC3DEN3 is promising. The researchers inform us in their discussion that it is going to be further analyzed in a tetravalent DNA vaccine that includes DNA from other dengue viruses. Indeed, it seems worth a trial!

2008 Springer Science + Business Media.

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