Dengue Immunization

Dengue impacts millions of children every year. High-risk areas of transmission are in tropical and subtropical climates of the Americas, Africa, Asia, the Middle East, and the Pacific Islands, although the geographical range and transmission rates are rising rapidly because of a complex interplay of social and environmental factors. There are effective vaccines available, and this article highlights vaccination as an important and emerging strategy to reduce the global burden of this disease.Dengue is a mosquito-borne illness caused by 1 of 4 flavivirus serotypes (DENV-1, DENV-2, DENV-3, and DENV-4). Transmitted primarily by the Aedes aegypti mosquito, it infects an estimated 390 million individuals per year, resulting in 50 to 100 million symptomatic infections and 10 000 deaths per year. Individuals at highest risk are those residing in, or visiting, tropical and subtropical areas. It is endemic to several US territories, including Puerto Rico, American Samoa, the US Virgin Islands, the Federated States of Micronesia, the Republic of Marshall Islands, and the Republic of Palau. There is a wide clinical spectrum in symptoms, and 75% of infections are asymptomatic. Dengue is classified based on severity of clinical symptoms, with severe disease being associated with secondary infections from a different viral serotype.The 2009 World Health Organization (WHO) classification of dengue classifies dengue illness as patients who live in or have traveled to a dengue-endemic area in the last 14 days that recover without major complications. Although patients can be asymptomatic, primary infection tends to have nonspecific symptoms of fever (lasting between 3 to 7 days), rash, myalgias, and arthralgia. However, a small subset of the patients may progress to severe disease. Those classified as having severe dengue includes those with presence of shock, respiratory distress, severe bleeding, or severe organ impairment. Warning signs that portend an increased risk for progressing to severe dengue include abdominal pain or tenderness, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy, restlessness, and hepatomegaly. Secondary infection often results in severe presentations.Treatment of dengue is largely supportive, and there have not been head-to-head trials of management schema. Adjunctive therapies like antivirals, steroids, and immunomodulators have not shown clinical benefit. Thus, there is considerable focus on prevention strategies.Prevention of dengue infections surrounds population control of its arthropod vector, mosquito bite prevention, and immunization. Although the goal of this article is to discuss dengue immunization, there is a lot of exciting work done in controlling mosquito populations outside of the scope of this review.Dengue immunization is included in the Centers for Disease Control and Prevention (CDC) 2024 Recommended Child and Adolescent Immunization Schedule for children aged 9 to 16 years living in areas with endemic dengue and with laboratory confirmation of previous dengue infection. The recommended immunization schedule involves giving a 3-dose series administered at 0, 6, and 12 months of the CYD-TDV vaccine. The CYD-TDV dengue vaccine (this is the only one currently approved by the Food and Drug Administration [FDA]) should not be administered to children traveling to or visiting endemic dengue areas or among those who are dengue antibody seronegative. When seronegative individuals are immunized with CYD-TDV and later infected with dengue, patients can experience more severe infections.Globally, there are 2 commercially available dengue vaccines, CYD-TDV and TAK-003. Access to these vaccines within the United States is limited, and there have not been head-to-head trials between these vaccines.CYD-TDV is a live attenuated tetravalent vaccine given in a 3-dose series at 0-, 6-, and 12-month intervals. Although it was studied in individuals aged 2 years and older, younger patients had higher rates of severe disease; thus the CDC recommendation is to start the immunization series between 9 and 16 years of age. CYD-TDV can only be given in seropositive individuals, and thus, serological status is assessed before beginning the vaccination series. For seropositive individuals that completed the vaccine series, there was a significantly decreased risk of hospitalization. Vaccine efficacy was found to be between 80% to 95% effective against severe disease leading to hospitalization.Because of a lack of global demand, Sanofi-Pasteur is no longer manufacturing CYD-TDV. Despite it no longer being actively manufactured, the CDC recommends CYD-TDV as part of its routine immunization schedule as discussed previously. In a memo released in the CDC Health Alert Network, they announced that there is an available supply in Puerto Rico that will be used for routine immunization until available doses expire in 2026.TAK-003, also a tetravalent live, attenuated vaccine, can be given to children aged 4 years and older at 0- and 3-month intervals, although age recommendations vary by country and regulatory authority. Although in clinical trials it was given to recipients regardless of serological status at first immunization, there is limited data on its potential to increase the risk of more severe infections.Overall, it was found to be 84.1% effective against hospitalization due to dengue infection. This benefit is higher in individuals that are seropositive at time of immunization. Particularly, the vaccine is effective against the DENV-1 and DENV-2 serotypes, but low circulation of the DENV-3 and DENV-4 serotypes made extrapolation of data difficult. It was also found to not provide strong protection against the Dengue-3 and -4 serotypes in seronegative recipients. As of 2023, Takeda has voluntarily withdrawn its US Biologics License Application for TAK-003 because of the FDA’s request for additional data outside of the original trial protocol and thus is not commercially available in the United States. It is available in several countries in Asia, Europe, and the Americas, and has been prequalified by the WHO.Although not yet commercially available, the newest vaccine to be introduced and undergoing study is the Butantan-Dengue Vaccine (Butantan-DV), a live, attenuated tetravalent vaccine. In the recently published results of a double-blind, Phase 3 clinical trial, Butantan-DV was given in 1 dose to individuals aged 2 years and older regardless of serological status. There were no DENV-3 and DENV-4 detected during the trial. The trial assessed overall efficacy against virologically confirmed dengue, but not hospitalization. Butantan-DV had 75.3% efficacy in seronegative patients and 89.2% efficacy in seropositive patients. These were solely against DENV-1 and DENV-2, and it is hard to know the safety and efficacy against DENV-3 and DENV-4 infection. This vaccine is not yet commercially available and will need to be evaluated by regulators in the United States pending its longer-term results in Brazil.Overall, vaccines are an emerging strategy to help protect individuals from severe dengue. Patients who may benefit the most from immunization are those with seropositive status and who live in endemic areas. Choice of vaccine and age at initiating vaccine series should largely be based on local regulatory authority approval and commercial availability. There are both documented and theoretical risks of giving a dengue vaccine to seronegative travelers, thus travel clinic referral should be considered for individuals pursuing long term or frequent travel to endemic areas. Because of the limited availability in the United States, pediatricians should council patients traveling to dengue-endemic areas on mosquito protection.The implementation of these vaccines and other strategies to lessen the burden of dengue is increasingly important as rising global temperatures and population increase the number of individuals at risk of illness. Through changes to temperature and precipitation, climate change is contributing to an increased incidence of dengue, and Messina et al state that the burden of this disease “will intensify in already endemic areas through faster viral amplification, increased vector survival, reproduction and biting rate, ultimately leading to longer transmission seasons and a greater number of human infections, more of which are expected to be severe. Increasing temperatures may further exacerbate this situation by enabling greater spread and transmission in low-risk or currently dengue-free parts of Asia, Europe, North America, and Australia.”Although incidence of dengue in the United States has historically been low compared with other parts of the world, with most cases attributed to individuals traveling from endemic areas, local spread of dengue has been reported in Florida, Hawaii, Texas, Arizona, and California. This burden is predicted to increase as more of this southern region becomes hospitable for the transmission of dengue. Pediatricians must be prepared to adopt adaptation measures such as immunization and mosquito safety counseling to protect their patients from this emerging disease. Pediatricians also must have suspicion of dengue in febrile patients that have returned from travel to a dengue-endemic area in the last 14 days.Dengue is a threat to child health globally, with an increasing number of children in the United States at risk due to the impact of climate change and human travel.Immunization is one approach to reduce the burden of dengue and there are available vaccines: ○ CYD-TDV is safe and effective for seropositive patients but puts seronegative patients at higher risk for severe disease. It has an uncertain future with manufacturing stopping.○ TAK-003 can be given to individuals regardless of serological status but is most effective in seropositive patients. Its efficacy against DENV-3 and DENV-4 has not been demonstrated in larger trials. It is not commercially available in the United States.○ Butantan-DV is a new, single-dose vaccine with encouraging results from a Phase 3 trial. There have not been significant case numbers of DENV-3 and DENV-4 to draw conclusions. It has not yet undergone regulatory approval for commercial availability.Children at risk who may benefit from vaccination include patients with a (laboratory confirmed) history of previous infection and who live in endemic areas.Pediatricians should council patients traveling to dengue-endemic areas on mosquito safety. For questions surrounding special populations like long-term travelers or frequent travelers, they should consider consulting with their local health authority or travel clinic.Comment: Having had the opportunity to work internationally in several tropical areas, I have had firsthand experience witnessing the morbidity from dengue in pediatric patients. Yet, this In Brief skillfully explains how additional populations within the United States have contracted dengue because of the complex equation of increased travel, urbanization, and effects from climate change. I anticipate that the number of those infected is likely to rise. Hence education on prevention is essential, and pediatricians are especially skilled in educating their patients and families. I was fascinated by the vaccine overview, and we are appreciative to Dr Olson for helping the authors navigate this complicated topic. Up until now, there remains little access to the dengue vaccine in the United States. As a general pediatrician, I would need the expertise of colleagues in infectious disease and or travel clinics to assist in providing guidance to patients/families on this topic. Throughout the world, it remains important to report cases of dengue through our public health reporting systems and continue world-wide surveillance to identify high-risk areas to continue prevention through novel mosquito control measures and continued work on immunization development. The Health Alert Network of the CDC is an important resource for pediatricians everywhere. Health Alert Network (HAN) | CDC in addition to the following CDC website: https://www.cdc.gov/mosquitoes/prevention/index.htmlJanet R. Serwint, MDAssociate Editor, In BriefWe would like to thank Dan Olson, MD, PhD, Section of Infectious Diseases, University of Colorado School of Medicine, for his thoughtful suggestions and comments in the review process of this article.