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Current Development and Challenges of Tetravalent Live-Attenuated Dengue Vaccines

Dengue is the most common arboviral disease caused by one of four distinct but closely related dengue viruses (DENV) and places significant economic and public health burdens in the endemic areas. A dengue vaccine will be important in advancing disease control. However, the effort has been challenged by the requirement to induce effective protection against all four DENV serotypes and the potential adverse effect due to the phenomenon that partial immunity to DENV may worsen the symptoms upon subsequent heterotypic infection. Currently, the most advanced dengue vaccines are all tetravalent and based on recombinant live attenuated viruses. CYD-TDV, developed by Sanofi Pasteur, has been approved…

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 A problem with dengue virus vaccine

A dengue virus vaccine was recently developed not only to prevent first infections, but to avoid severe disease that may occur upon second and third infections. This consequence, called antibody dependent enhancement (ADE), now appears to be caused by the vaccine itself.

 Challenges on the development of a dengue vaccine: a comprehensive review of the state of the art

h. There is currently no specific treatment for dengue and only one licensed vaccine (Dengvaxia) for children 9 through 16years of age in just a few countries. Despite its licensure for clinical use, Dengvaxia has performed with low efficacy in children and dengue naïve individuals and critically has resulted in increased risk of developing severe dengue in young, vaccinated recipients. Currently, there are various novel strategies for the development of a dengue vaccine.

 Dengue Vaccines: An Update

Dengue vaccine development has been challenging because of the need to provide protection against all four dengue serotypes to avoid potentially causing antibody-dependent enhancement in further infections. Denvaxia® is currently the only licenced vaccine, but phase III clinical trials with two other vaccines, TV-003/TV-005 and TAK-003, are currently ongoing, with promising results.

 What vaccine is available to prevent dengue?

Dengvaxia (Sanofi Pasteur) is a live-attenuated, chimeric tetravalent dengue vaccine built on a yellow fever 17D backbone. It is designed to protect against all four DENV serotypes. It was licensed by the FDA in May 2019 for children and adolescents age 9 through 16 years with a confirmed history of previous dengue infection. The recommendation for vaccination is restricted to people with confirmed previous DENV infection because Dengvaxia is associated with an increased risk for severe dengue in those who experience their first natural infection (i.e., primary infection) after vaccination.

Articles of Interest

Dengue Vaccine Could Increase or Worsen Dengue in Some Settings

The only approved vaccine for dengue may actually increase the incidence of dengue infections requiring hospitalization rather than preventing the disease if health officials aren’t careful about where they vaccinate, Dengue typically causes a mild first infection but a far worse one if someone is infected with the virus a second time. There are four types of dengue virus, and it is thought that the body’s response to the first infection leads to more severe disease upon a second infection. This has long posed challenges to scientists developing a vaccine, who worried that any candidate that failed to protect fully could raise the risk of making people sick rather than keeping them well.

A new dengue vaccine should only be used in people who were previously infected, WHO says

The World Health Organization (WHO) in Geneva, Switzerland, put the brakes on implementation of the world's first dengue vaccine today when it recommended it only be used in people who have previously been infected with the disease—a move that will shrink the potential market for the vaccine's producer, Sanofi Pasteur.

Dengue Vaccine: What Pharmacists Need to Know

The development and approval of a dengue vaccine is a critical step in combatting this global public health challenge. Although not indicated as a travel vaccine, the availability of Dengvaxia in the United States to those who qualify may be important as travel increases and travelers may be exposed to diseases regional to their destination

Dengue vaccines: where are we now and where we are going?

Only one tetravalent dengue vaccine, CYD-TDV (Dengvaxia; Sanofi Pasteur), has already been licensed in endemic countries. Its antigens consist of chimeric viruses, in which genomic sequences encoding envelope proteins of the yellow fever virus were replaced by those of each of the four serotypes of dengue virus.

Half the world is at risk of dengue. Why is there no universal way to prevent it?

Aside from the Dengvaxia vaccine (which is still approved in over a dozen countries, including the US, for those with a laboratory-confirmed prior dengue infection), there are approximately five other dengue vaccines in development as of 2018. The Japanese pharma company Takeda’s vaccine, TAK-003, is showing promising results. It’s a live-attenuated vaccine like Dengvaxia’s shot, but rather than using the yellow fever virus as its backbone, it uses the dengue serotype 2 virus.

Scientists Discover How Dengue Vaccine Fails to Protect Against Disease

Several vaccines have been in clinical development for years, and most show that they induce neutralizing antibodies against all four serotypes. Yet, research has also shown that the creation of neutralizing antibodies alone does not correlate to protection against clinical disease. The de Silva lab conducted experiments to compare the properties of antibodies against wild-type Dengue viruses and the properties of antibodies produced by a leading vaccine candidate – Dengvaxia – which the pharmaceutical company Sanofi Pasteur created using all four dengue virus serotypes in one formulation.

Resources

Dengvaxia

For the prevention of dengue disease caused by dengue virus serotypes 1, 2, 3 and 4. DENGVAXIA is approved for use in individuals 6 through 16 years of age with laboratory-confirmed previous dengue infection and living in endemic areas.

CDC

A new dengue vaccine is approved for use in children aged 9–16 years with laboratory-confirmed previous dengue virus infection and living in areas where dengue is endemic (occurs frequently or continuously). Endemic areas include some U.S. territories and freely associated states. The vaccine is not approved for use in U.S. travelers who are visiting but not living in an area where dengue is common.