The CDC’s Advisory Committee on Immunization Practices (ACIP) has now recommended the use of Sanofi’s dengue vaccine Dengvaxia in the United States, with certain limitations. The vaccine is only for use in children aged 9 to 16 years living in endemic areas and in whom a specific diagnostic test indicates a previous dengue infection.

Dengue is a mosquito-borne virus found throughout the world, primarily in tropical or subtropical climates. The number of cases rose steadily to 5.2 million in 2019, and the geographic spread of cases is widening with climate change and urbanization. About half of the world’s population is at risk today.

Dengue virus has four serotypes. The first infection can be mild or asymptomatic, but the second can be life-threatening due to a phenomenon called antibody-dependent enhancement.

The lead author of the new recommendations is Gabriela Paz-Bailey, MD, PhD, Division of Vector-Borne Diseases, Dengue Branch, CDC. She told Medscape Medical News that during the second infection, when “there are low levels of antibodies from that first infection, the antibodies help the virus enter cells. There the virus is not killed and this leads to an increased viral load and then this can lead to more severe disease and plasma leakage syndrome which can lead to shock, severe bleeding and organ failure. The mortality rate for severe dengue is as high as 13%.

Previous Zika virus infections, common in the same areas where dengue is endemic, may also increase the risk of symptomatic and severe dengue in subsequent infections.

In the US, Puerto Rico is at the center of control efforts as 95% of native dengue cases originate there — nearly 30,000 cases between 2010 and 2020, with 11,000 cases and 4,000 hospitalizations in children ages 10-19.

Because Ae aegypti, the primary mosquito vector of dengue, is resistant to all common insecticides in Puerto Rico, preventive efforts have shifted from insecticides to vaccination.

Antibody testing pre-vaccination

The main concern of Sanofi’s dengue vaccine is that it could act as an asymptomatic primary dengue infection and prepare the body for a severe response through antibody-dependent amplification with subsequent infection. For this reason, it is important that the vaccine is only given to children with signs of a pre-existing condition.

Paz-Bailey said: “The CDC has made recommendations as to what the performance of the test used for pre-vaccination screening should be. And it was 98% specificity and 75% sensitivity… specificity of 98%, and that’s why we recommend the “two-test algorithm” where two different assays are run on the same blood sample taken at a pre-vaccination visit.

If the child has evidence of previous dengue fever, they can proceed with vaccination to protect themselves from reinfection. Dengvaxia is given as a series of three injections over a period of 6 months. The effectiveness of the vaccine is 82% – so not everyone is protected, and what’s more, that protection wears off over time.

There is concern that achieving compliance with such a complex regime will be difficult. Paz-Bailey said: “But I think confidence in vaccines is very widespread [Puerto] Rico and the confidence in the healthcare system and the importance dengue is given by providers and parents based on previous outbreaks and past experiences will help us.” She added, “I think the COVID experience has been very enlightening. And what we’ve learned is that Puerto Rico has a very strong healthcare system, a very strong network of vaccine providers… Coverage for COVID vaccines is higher than other parts of the US.”

One of the interesting things about dengue is that the initial infection can range from asymptomatic to life-threatening. The second infection is generally worse due to this antibody-dependent amplification phenomenon. Eng Eong Ooi, MD, PhD, Professor of Microbiology and Immunology, National University of Singapore told Medscape Medical News: “After you have two infections, you seem to be quite protected against the remaining two [serotypes]. The vaccine serves as another episode of infection in those who previously had dengue, so any natural infection after vaccination becomes seropositive as if it were the result of a third or fourth infection.

Vaccination alone will not solve dengue. Ooi said: “There is no one method that would completely control dengue fever. They need both vaccines and control measures, be it Wolbachia or something else. At the same time, I think we need antiviral drugs because hitting this virus in just one part of its life cycle wouldn’t have a big, lasting effect.” Ooi added that “the spread of the virus and the immunity of the population is going down, you actually now are more susceptible to dengue outbreaks when they are introduced So suppressing transmission alone is not the answer They also need to maintain herd immunity So if we can reduce virus transmission either by controlling the mosquito population or by controlling transmission while vaccinating, to keep immunity high, then I think we have a chance of controlling dengue.”

Paz-Bailey concluded, “I would like to emphasize that we are very excited about these tools as we have had very limited ability to prevent and control dengue for years. It is an important addition that the vaccine will be approved for use in the US and will pave the way for future vaccines.”

Paz-Bailey and Ooi report no relevant financial relationship.

MMWR Morb Mortal Wkly Rep. Published online December 17, 2021. Full text

Judy Stone, MD, is an infectious disease specialist and the author of Resilience: One Family’s Story of Hope and Triumph Over Evil and of Conducting Clinical Research, the essential guide on the subject. You can find her at drjudystone.com or on Twitter @drjudystone.

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