Future Dengue Fever Treatments

As dengue has become a greater threat to public health, scientists have made progress in their search for dengue fever treatments. What strides have scientists made in developing vaccines and antiviral drugs to treat and protect people from dengue infections?

Vaccines are an important way to protect people from viral infections. How does a vaccine work? Vaccines are prepared from weakened or inactive viruses or microorganisms that cause diseases. When a healthy person is given a vaccine, that person's immune system responds to the virus or microorganism with an adaptive immune response. Vaccination stimulates the body to produce antibodies against the disease-causing agent, which increases the individual's immunity to the disease. When a vaccinated individual comes in contact with the disease-causing agent again, the immune system will readily recognize it and "remember" how to destroy it.

Scientists have been attempting to produce a safe, effective dengue vaccine since the 1940s. Why is it so difficult to develop a suitable dengue vaccine? One challenge is that there are four distinct types (serotypes) of dengue virus that cause dengue, and an effective vaccine must successfully protect people against all four virus serotypes. Once a person has immunity against one dengue serotype, the individual will never be infected with that same serotype again. If the person is subsequently infected with a different dengue serotype, however, he or she will have an increased risk of developing a more severe dengue illness. Therefore, a safe vaccine must provide immunity against all four dengue viruses to protect people from severe dengue successfully.

Despite these concerns, scientists have made considerable progress in developing dengue vaccines. Scientists are testing candidate vaccines for safety and effectiveness and to ensure that they do not have negative side effects. Currently, five types of dengue vaccines are in development: live attenuated vaccines, chimeric live attenuated vaccines, inactivated vaccines, subunit vaccines, and nucleic acid-based vaccines. What are these vaccine types, and what are the differences between them?

Live attenuated vaccines are made of weakened versions of the dengue virus (Figure 1A). An ideal live attenuated vaccine would produce a robust immune response similar to that of natural infection — but without the disease or symptoms of natural infection. Because the weakened virus does not replicate well, an ideal live attenuated vaccine would produce low levels of the virus in the blood and only minimal symptoms of infection. The low levels of virus in the blood would make it unlikely that mosquitoes could transmit the attenuated virus. Live attenuated vaccines are generally inexpensive to produce, which makes them widely available. In addition, because there are four dengue viruses, the ideal vaccine should provide balanced immunity to all four dengue serotypes.

Chimeric live attenuated vaccines are designed by combining genes from different sources to create a live attenuated virus (Figure 1B). Scientists are currently studying vaccines in which dengue viral genes have been genetically engineered into either a live attenuated vaccine for yellow fever or an attenuated dengue virus from a single serotype. Ideal chimeric live attenuated vaccines should have the same characteristics that are described above for live attenuated vaccines.

Two additional vaccines are the inactivated and the subunit vaccines. How do scientists make these vaccines? Inactivated vaccines are made of virus particles that have been destroyed (Figure 1C), and subunit vaccines are made of dengue proteins (Figure 1D). In both vaccines, the dengue antigens are able to produce an immune response. The inactivated and subunit vaccines generally have a high level of safety because the virus does not replicate. They may, however, require booster vaccinations to provide long-term immunity, and they may be more expensive to produce than live attenuated vaccines.

What are the characteristics of the nucleic acid-based vaccines? Nucleic acid-based vaccines are designed by introducing DNA copies of specific dengue viral genes into cells (Figure 1E). The dengue genes are expressed as dengue proteins, which produce an immune response. This type of vaccine is relatively simple to produce, but may require multiple doses to provide immunity. Therefore, this option may not be practical for widespread vaccinations.

Researchers continue to make progress toward developing safe, effective vaccines against dengue. In preclinical and clinical trials, a large number of vaccine candidates are currently being evaluated for their safety and effectiveness. It is possible that a safe and economical dengue vaccine will be commercially available in the next few years.

In addition to developing dengue vaccines, scientists are working to design antiviral drugs against dengue. Antiviral drugs are an alternative to vaccinations, but research on antivirals is a relatively new field. Once effective antiviral drugs are developed, they could potentially be administered to people with or without a fever to decrease or prevent disease symptoms at the first sign of a dengue outbreak.

Antiviral drugs work by reducing the level of virus in an infected person. Who would benefit from antiviral drugs? Patients who have very high levels of the dengue virus circulating in their blood have a greater risk of developing severe dengue disease than other patients. Scientists believe that reducing viral levels by administering antiviral drugs during the early stage of the dengue infection could decrease the risk of severe dengue diseases.

How are antiviral drugs developed? The development of antiviral drugs involves screening libraries of thousands of potential antiviral compounds to see if they can interfere with the dengue viral proteins necessary for viral replication. One example is using an antiviral drug called a nucleoside analogue to block a dengue infection. This compound works by preventing synthesis of the viral RNA genome so that the dengue virus cannot replicate. Scientists are currently testing and identifying nucleoside analogues to find those that can inhibit dengue but have no adverse side effects or toxicity.

As scientists have learned about the structures and functions of various viral proteins, they have been able to consider new targets for antiviral drugs. Research on the disease pathway of dengue infections can give scientists new avenues to develop dengue therapies. Viral replication can be difficult to prevent because there is a short timeline for treatment. Instead, scientists may also be able to target other steps in the disease pathway to prevent dengue at later stages. Once scientists develop safe antiviral therapies, they can administer them to people with or without a fever during dengue epidemics to decrease dengue symptoms.

Researchers are making substantial progress in developing safe and effective vaccines against the dengue virus. Currently, a large number of dengue vaccine candidates are being tested in preclinical and clinical trials for safety and effectiveness, and within the next several years, a safe, economical vaccine for dengue may be commercially available. Scientists are also examining antiviral drugs to decrease the risk of severe dengue diseases. Once scientists develop safe antiviral therapies, they can administer them to people with or without a fever during dengue epidemics to decrease dengue symptoms.

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