In May 2019, Dengvaxia® became the first dengue vaccine to be approved by the U.S. Food and Drug Administration (FDA). The FDA approved its use specifically for children 9 to 16 years old with laboratory-confirmed previous dengue virus infection and who live in an area with endemic dengue. In June 2021, the U.S. Advisory Committee on Immunization Practices (ACIP) recommended use of Dengvaxia in the approved group.

This month, when the Centers for Disease Control and Prevention (CDC) released the “2022 Recommended Child and Adolescent Immunization Schedule for Ages 18 Years and Younger,” dengue vaccine had been added to the schedule. So, let’s take a closer look at this virus with which many of us are unfamiliar.

Where might we find dengue-infected patients?

At present within the United States and its related areas, dengue is endemic only in Puerto Rico, American Samoa, the U.S. Virgin Islands, the Federated States of Micronesia, the Republic of Marshall Islands, and the Republic of Palau (See the map on the CDC website). Although vaccination is not currently recommended for those of us who live outside of the endemic areas, having at least a nodding acquaintance with dengue and the vaccine to prevent it would be prudent for several reasons:

  • We may see patients who live in areas where dengue is endemic. After all, about 100 million to 400 million people throughout the world are infected by dengue each year.
  • We may see patients who will soon travel to or have recently traveled from areas where dengue is endemic. In the pre-COVID-19 era, dengue was cited as the leading cause of fever in recent travelers.
  • Studies on the potential effects of climate change suggest that the geographic regions suitable for transmission are likely to expand during this century.

Biology of dengue viruses

Dengue virus infections cause about 22,000 deaths each year; most are among children. Viral particles include a single-stranded-RNA genome surrounded by a protein capsid. The RNA codes for 10 proteins. Three are structural proteins (capsid, pre-membrane and envelope), and seven are non-structural proteins. The envelope protein, found embedded in the capsid, is crucial from the  perspective of the virus because it enables viral entry into susceptible cells, where the virus multiplies. From the human perspective, the envelope protein is key to immunity and vaccination strategies.

Four related viruses cause dengue, so a person can be infected four times with each infection caused by a different form of the virus.

Dengue viruses spread to humans through infected mosquitoes, in fact, the same accursed mosquitoes that carry Zika virus — the Aedes species, which includes Ae. aegypti and Ae. albopictus. About one of every four or five infected people will become symptomatic about four to 14 days after exposure. Symptoms, which usually last about two to seven days, consist of fever accompanied by one or more of the following:

  • Pain in muscles, joints, bones, head, or behind the eyes
  • Nausea
  • Vomiting
  • Rash

Among those who become symptomatic, about 1 in 20 will develop severe disease, an outcome that is more common among those who previously had dengue.

The case definition of severe dengue includes any sign of severe plasma leakage leading to shock or fluid accumulation (in the abdomen or around the heart or lungs) with respiratory distress, severe bleeding, or severe organ impairment. Patients with severe dengue require hospitalization for supportive care. Unfortunately, no dengue-specific antiviral therapy is currently available.

Antibody-dependent enhancement (ADE) and dengue viruses

Severe dengue is thought to be the result of an immunologic phenomenon, known as antibody-dependent enhancement (ADE), which has made creation of a safe vaccine much more difficult. In the case of dengue virus, infection with two different types of the virus sets the stage:

  1. Imagine that I am infected with dengue virus (DENV). This is my first DENV infection.
  2. I develop antibodies to DENV, but they are only effective against that specific DENV serotype (one of the four types).
  3. Later, I am infected with a second dengue serotype.
  4. The antibodies from my first infection bind to, but cannot neutralize, the second type of DENV.
  5. The antibody–virus complexes can then attach to immune system cells by means of the antibody-immune cell interaction. The immune cells involved are a type of white blood cell, known as monocytes. Although monocytes normally seek and destroy invaders, in this situation, the antibody-virus complex acts like a Trojan horse, tricking the monocytes into inviting the second type of DENV in, where it takes over the cell and reproduces like a lie on the internet.
  6. New viral particles are then released into the body to start at step 4 again.

The increased viral replication caused by the “Trojan horse” effect leads to a greater risk of experiencing severe dengue.

In addition to the effects of ADE, other factors are also hypothesized to contribute to the increased severity of a second dengue infection, including induction of pro-inflammatory immune responses, inhibition of normal host defense mechanisms, and dysregulated cytokine production.

It should be noted that the risk of developing severe dengue is highest for a second infection with a different DENV serotype, but it can occur following infection with another virus from the same family (flavivirus), such as Zika virus.

Prevention of dengue virus infections

Preventing dengue virus infections involves community-based and individual approaches to protection:

Mosquito control. Ridding dengue-infested areas of the vector mosquito has met with limited success. In fact, over time, the geographic range has expanded. The mosquito breeding sites are difficult to locate, and insecticide resistance is widespread. Community action to interrupt mosquito breeding has been successful in some areas, but the triumphs have often been transient.

Personal protection from mosquito bites. The mosquitos that carry dengue virus are most active for about two hours after sunrise and for several hours before sunset, but they also bite at night in well-lit areas. Wearing clothing that minimizes skin exposure and using personal household protection measures, such as window screens, are recommended.

Vaccination. One dengue vaccine, Dengvaxia, is FDA approved and available in the U.S. It is a live weakened viral vaccine that protects against all four dengue virus serotypes. The vaccine is made using recombinant DNA technology. Specifically, the genes for each dengue virus pre-membrane and envelope protein are incorporated into yellow fever virus. The strain of yellow fever virus used is the same one used for the yellow fever vaccine (i.e., attenuated 17D). To learn more about ADE and dengue vaccine development, check the VEC’s ADE webpage.

Vaccine recommendations

Please consult the CDC’s published recommendations for complete information; however, we have included some key background information.

Who should get it? Dengvaxia is approved for use in children 9 to 16 years old who previously had a laboratory-confirmed dengue virus infection and live in areas where dengue is endemic.

Important clinical note: Lab-confirmed, previous DENV infection is required because persons not previously infected with DENV who receive Dengvaxia might be at risk for developing severe dengue due to ADE if infected with DENV after vaccination. This is also why the age recommendations are for older children, rather than younger children who are more likely to be dengue naive.

The vaccine is not approved for use in U.S. travelers visiting, but not living, in an area where dengue is common.

What is the schedule? Dengvaxia is recommended as a three-dose vaccination series with dose two administered six months after dose one, and dose three administered 12 months after dose one.

What side effects were found? Common side effects included headache, pain at the injection site and general muscle pains. Severe side effects may rarely include anaphylaxis, so patients should remain at the vaccination site for 15-30 minutes after receipt of the vaccine.

Who should not get this vaccine? Those with a history of severe allergic reaction to any component of the vaccine or a previous dose of the vaccine and those with severe immunodeficiency or immunosuppression due to underlying disease or therapy, including children with symptomatic HIV infection or CD4+ T-lymphocyte count of < 200/mm3, should not get this vaccine.

Several other dengue vaccine candidates are in clinical development (See “Anti-dengue Vaccines: From Development to Clinical Trials”). It is wonderful to enter an era of more reliable dengue prevention.

Resource alert!

Materials in this section are updated as new information and vaccines become available. The Vaccine Education Center staff regularly reviews materials for accuracy.

You should not consider the information in this site to be specific, professional medical advice for your personal health or for your family's personal health. You should not use it to replace any relationship with a physician or other qualified healthcare professional. For medical concerns, including decisions about vaccinations, medications and other treatments, you should always consult your physician or, in serious cases, seek immediate assistance from emergency personnel.