20 diciembre, 2021

Dengue Vaccine: Recommendations of the Advisory Committee on Immunization Practices, United States, 2021


Dengue is a vectorborne infectious disease caused by dengue viruses (DENVs), which are predominantly transmitted by Aedes aegypti and Aedes albopictus mosquitos. Dengue is caused by four closely related viruses (DENV-1–4), and a person can be infected with each serotype for a total of four infections during their lifetime. Areas where dengue is endemic in the United States and its territories and freely associated states include Puerto Rico, American Samoa, the U.S. Virgin Islands, the Federated States of Micronesia, the Republic of Marshall Islands, and the Republic of Palau. This report summarizes the recommendations of the Advisory Committee on Immunization Practices (ACIP) for use of the Dengvaxia vaccine in the United States. The vaccine is a live-attenuated, chimeric tetravalent dengue vaccine built on a yellow fever 17D backbone. Dengvaxia is safe and effective in reducing dengue-related hospitalizations and severe dengue among persons who have had dengue infection in the past. Previous natural infection is important 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. Dengvaxia was licensed by the Food and Drug Administration for use among children and adolescents aged 9–16 years (referred to in this report as children). ACIP recommends vaccination with Dengvaxia for children aged 9–16 having evidence of a previous dengue infection and living in areas where dengue is endemic. Evidence of previous dengue infection, such as detection of anti-DENV immunoglobulin G with a highly specific serodiagnostic test, will be required for eligible children before vaccination.


Dengue is a vectorborne infectious disease caused by dengue viruses (DENVs), which are predominantly transmitted by Aedes aegypti and Aedes albopictus mosquitos. DENVs are members of the genus flavivirus in the family flaviviridae. The four dengue virus serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) all circulate globally, and most countries where dengue is endemic have reported circulation of all four serotypes. These serotypes share structural antigens yet are serologically and genetically distinct.Dengue is a growing public health challenge (1,2). Dengue is endemic throughout the tropics and subtropics, with an estimated 3.8 billion persons (95% confidence interval [CI]: 3.5 billion–4.1 billion), or approximately 53% of the global population, living in areas suitable for DENV transmission (3). The majority of these areas are in Asia, Africa, and the Americas (3). In 2013, an estimated 58 million symptomatic DENV infections (95% CI: 24 million–122 million) and 13,586 deaths occurred worldwide (95% CI: 4,200–34,700), resulting in a total annual cost of $8.9 billion (95% CI: $3.7 billion–$19.7 billion) in direct medical and nonmedical costs and indirect costs associated with time lost because of illness, care, or death (1,2).


Dengue can be caused by any one of the four distinct but related viruses, and a person can be infected with each serotype for a total of four dengue infections during their lifetime (4). After an infection with one DENV serotype, antibodies induced are type specific and cross-react with other DENV serotypes (4). The adaptive immune response that develops with infection by any DENV provides long-term immunity to the homologous virus and short-lived protection against heterologous DENV. Human experimental infection studies indicated that this cross-protection lasts approximately 3 months (5,6), whereas epidemiologic observations suggest that cross-protection might last up to 2 years (7,8). The risk for severe dengue varies on the basis of many factors, including the number of previous dengue infections a person has had. Whereas any dengue infection can lead to severe dengue, a second infection with a dengue virus is the most likely to cause severe dengue compared with the first and post-secondary infections (9,10). Multiple mechanisms likely contribute to increased disease severity during a second DENV infection. Cross-reactive or non-neutralizing antibodies binding to a heterologous DENV facilitates uptake in Fc receptor–bearing monocytes and results in both higher magnitude and prolonged viremia (i.e., antibody-dependent enhancement). Moreover, virus-host interactions during antibody-dependent enhancement enable the virus to evade host antiviral and immune responses that would otherwise limit infection (11).An accompanying enhanced immune response also occurs in which activated natural killer cells and memory T-cells trigger inflammatory mediators that contribute to intravascular leakage (12). The dengue nonstructural protein 1 (NS1) is secreted from infected cells and is independently associated with vascular leakage by damaging the endothelial glycocalyx and disrupting endothelial cell junctions. This phenomenon might be worsened during a second infection in association with increased viremia (13). Although this risk for severe dengue is highest for a second infection with a different DENV serotype, it can occur after post-secondary infection. Previous infection with Zika virus (another flavivirus commonly co-circulating in areas where dengue is endemic) has been demonstrated to increase the risk for symptomatic and severe dengue for subsequent DENV-2 infections occurring several years after Zika infection (14). Interactions between dengue and other flaviviruses are less clear (15,16).

Dengue Clinical Disease

Dengue clinical disease ranges from a mild, undifferentiated febrile illness to severe disease complicated by shock, bleeding, or severe organ impairment. Approximately 75% of dengue infections are mild or asymptomatic (17). The most common presentation of symptomatic disease is sudden onset of fever accompanied by headache, retro-orbital pain, generalized myalgia and arthralgia, flushing of the face, anorexia, abdominal pain, and nausea. A generalized erythematous, macular rash developing within 3–4 days of fever onset frequently is observed. Laboratory-detected findings can include leukopenia, hemoconcentration, transaminitis, and thrombocytopenia. The World Health Organization (WHO) classifies dengue illness as 1) dengue with or without warning signs for progression toward severe dengue and 2) severe dengue (18). Warning signs of severe dengue include abdominal pain or tenderness, persistent vomiting, clinical fluid accumulation (e.g., ascites, pericardial effusion, and pleural effusion), mucosal bleeding, lethargy or restlessness, postural hypotension, liver enlargement of >2 cm, or an increased hematocrit level concurrent with a rapid decrease in platelet count (18). Criteria for the case definition of severe dengue include any sign of severe plasma leakage leading to shock or fluid accumulation with respiratory distress, severe bleeding, or severe organ impairment.Patients with severe dengue need in-hospital medical treatment to mitigate poor clinical outcomes commonly due to vascular permeability, which results in plasma leakage and leads to hypovolemic shock or clinically significant ascites or pleural effusions, and less commonly, to severe bleeding due to various host or viral factors (19). Because of the risk for complications due to plasma leakage and bleeding, severe dengue requires monitoring and treatment in intensive care settings. Although rare, dengue can affect the liver, heart, central nervous system, kidneys, eyes, muscles, or bone marrow (4,20,21). These severe manifestations of dengue carry a high risk for death and must be recognized and appropriately managed in a timely manner. Age, comorbidities, host genetics, and the infecting virus strain are risk factors for severe dengue, and heterotypic secondary infections are the most prominent factor associated with severe dengue (4).

Dengue Treatment

No effective antiviral treatments against dengue are available; therefore, the mainstay for preventing severe disease and death is timely and supportive management with volume replacement, particularly among patients with severe dengue. The case-fatality ratio for severe dengue has been reported to be as high as 13% (22,23) and can be <1% with access to timely diagnosis and appropriate treatment (24,25).

Dengue Immune Response and Diagnostics

Typically, immunoglobulin M (IgM) antibodies directed against DENV develop during the first week of illness (26) and persist for several months to as long as 1 year (27). Neutralizing antibodies develop shortly after IgM antibodies and consist primarily of immunoglobulin G (IgG) antibodies. Type-specific neutralizing antibodies persist for many years after dengue and other flavivirus infections (e.g., Zika) and usually confer lifelong immunity to the infecting virus serotype (28). In persons previously infected with or vaccinated against a flavivirus, subsequent infection with another flavivirus (i.e., second flavivirus infection) can cause both a diminished IgM response and a rapid increase to high titers of neutralizing antibodies against multiple different flaviviruses, which might prevent conclusive determination of which virus was responsible for the person’s recent infection using serological methods (29).Acute dengue diagnosis can be achieved using blood or serum collected ≤7 days after symptom onset by detection of viral RNA through nucleic acid amplification tests, by detection of viral antigens such as dengue NS1 by enzyme-linked immunosorbent assay (ELISA) or rapid diagnostic tests, and by detection of IgM antibodies through serologic testing. Dengue IgM antibodies start to increase from day 4, with levels peaking between days 10–14 and then declining. In primary dengue infections (i.e., first infection), anti-dengue IgG can be detected at low concentrations by the end of the first week of illness; the antibody concentration increases slowly thereafter and is thought to persist for life. In patients with a previous dengue infection (i.e., had dengue at least once before), anti-dengue IgG titers rise rapidly within the first week of illness (30).Cross-reactivity with Zika virus is reported for all serological assays. Plaque reduction neutralization tests (PRNTs) are quantitative assays that can measure virus-specific neutralizing antibody titers for dengue, Zika, and other flaviviruses to which the patient might have been exposed. For diagnostic testing, CDC uses a PRNT with 90% reduction in the input virus (PRNT90) with a cutoff value titer of ≥10 in serum to define positive specimens (30). PRNTs can resolve false-positive IgM antibody results caused by nonspecific reactivity in primary infections and, in certain cases, can help identify the infecting virus, particularly in specimens collected ≥3 months after illness onset. However, in many dengue secondary infections, patients have neutralizing antibody titers that do not allow previous DENV and Zika virus infections to be distinguished (30).

Dengue Prevention

Ae. aegypti, the main vector of dengue, has proven difficult to control and continues to expand its geographic range. Control of Ae. aegypti is complicated by cryptic and inaccessible breeding sites that make it difficult to locate and control a large proportion of the targeted mosquito population (31,32). Furthermore, insecticide resistance to Ae. aegypti is widespread (33,34). New regulatory requirements have resulted in discontinuation of some insecticides and greater difficulty in registering new chemicals. Ae. aegypti is resistant to all commonly used insecticides in Puerto Rico (35,36). Successful broad-scale application of integrated vector control management strategies have been difficult to achieve and sustain. The dichlorodiphenyltrichloroethane (DDT) spraying campaign in the 1950s and 1960s across Central and South America nearly eradicated Ae. aegypti from the region (37), resulting in substantial reductions in disease caused by DENV and yellow fever virus (38,39). Cuba experienced a substantial reemergence of dengue, leading to a concerted vector control effort that included community mobilization and source reduction and resulted in reductions in the per capita risk for dengue (40). However, because of the high cost, such achievements are rare, and their impact in controlling mosquito populations is transient.

Dengue in the U.S. Territories and Freely Associated States

Areas where dengue is endemic in the United States and its territories and freely associated states include Puerto Rico, American Samoa, the U.S. Virgin Islands, the Federated States of Micronesia, the Republic of Marshall Islands, and the Republic of Palau (41). Areas where dengue is endemic are defined as areas with frequent or continuous dengue transmission, with evidence of >10 dengue cases in at least three of the previous 10 years. Dengue epidemics occur in a cyclical pattern every 3–7 years, with all four DENV serotypes reported in the Pacific Islands and in the Caribbean. Of areas where dengue is endemic, Puerto Rico, the U.S. Virgin Islands, and American Samoa report dengue cases to ArboNET (Table 1). Limited surveillance data are available from the Federated States of Micronesia, the Republic of Marshall Islands, and the Republic of Palau.Approximately 90% of the population at risk for dengue in the U.S. territories and freely associated states live in Puerto Rico. During 2010–2020, approximately 95% of locally acquired dengue cases in the United States (n = 31,289) occurred in Puerto Rico (n = 29,779). During the same period, the greatest number of cases and hospitalizations in Puerto Rico occurred among persons aged 10–19 years, with approximately 11,000 reported cases and 4,000 hospitalizations. Incidence rates also are highest among this age group, ranging from 1 to 7 per 1,000 persons during the most recent outbreak years (2010–2013) based on 2010 census data ( and icon). In contrast, during 2010–2020 most dengue deaths in Puerto Rico (88%; 61 of 69) occurred among persons aged 20–89 years (CDC, unpublished data, 2020).Similar to Puerto Rico, during 2010–2020, persons aged 10–19 years experienced the highest dengue incidence and accounted for the largest number of dengue cases in the U.S. Virgin Islands and American Samoa ( Dengue outbreaks were reported from the Federated States of Micronesia in 2011, 2012–2013, 2016, and 2019–2020. In the last outbreak, most cases occurred among persons aged 5–19 years (42). Outbreaks also were reported from the Republic of Marshall Islands during 2019–2020 and the Republic of Palau in 2019. Guam and the Northern Mariana Islands have reported sporadic and travel-associated (imported) dengue cases but do not meet the criteria for areas where dengue is endemic (43). Hawaii, Texas, Florida, and other states have reported sporadic, locally acquired cases and occasional outbreaks but do not meet the definition of endemic areas (43,44). During 2010–2017, Hawaii reported 250 locally acquired dengue cases, Florida 103, and Texas 24 (44).Population-based dengue seroprevalence data are not available from any of the U.S. areas where dengue is endemic. However, small convenience studies estimated dengue seroprevalence in Puerto Rico to range from 50% in 2007 (45) to 56% in 2010 among participants aged 9–16 years in vaccine trials (46). Preliminary results from a community-based study in 2018 in southern Puerto Rico suggested similar seroprevalence in this age group (CDC unpublished data, 2021).

Dengue Vaccines

Dengvaxia is a live-attenuated, chimeric tetravalent dengue vaccine built on a yellow fever 17D backbone. WHO recommends Dengvaxia for persons aged 9–45 years with confirmed previous DENV infection (47). Dengvaxia is licensed in 20 countries. The recommendation is only for persons with confirmed previous DENV infection because the vaccine manufacturer, Sanofi Pasteur, announced that persons not previously infected with DENV who receive Dengvaxia might be at risk for developing severe dengue if they are infected with DENV after being vaccinated (48). In May 2019, Dengvaxia was approved by the Food and Drug Administration (FDA) for use in children and adolescents aged 9–16 years (referred to in this report as children) living in an area where dengue is endemic and having had laboratory-confirmed previous DENV infection. Multiple dengue vaccine candidates are in clinical development. Two live-attenuated, tetravalent vaccine candidates are under evaluation in phase 3 trials (49,50).Before Dengvaxia received FDA approval, the Advisory Committee on Immunization Practices (ACIP) had no recommendations for the use of vaccines to prevent dengue. This report provides ACIP recommendations for use of Dengvaxia for children aged 9–16 living in areas where dengue is endemic and having evidence of a previous DENV infection. These recommendations are intended to guide public health practitioners and laboratorians in designing and testing vaccination strategies in jurisdictions where DENV transmission is endemic.


MethodsThe Dengue Vaccines Work Group met bimonthly from October 2018 through April 2021 to review Dengvaxia data from clinical trials. The work group comprised ACIP members, including the chair; the CDC lead from the Division of Vector-Borne Disease’s Dengue Branch; experts in dengue and flavivirus epidemiology and vaccinology; representatives of the American Academy of Pediatrics and the Association of Immunization Managers; ex-officio representatives from the FDA, the U.S. Department of Defense, and the National Institute of Allergy and Infectious Diseases; and CDC observers from the National Center for Immunization and Respiratory Diseases, the Division of Global Migration and Quarantine, the Division of Healthcare Quality Promotion, and the Division of Vector-Borne Diseases.Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (51), the work group defined the research question (i.e., the patient, intervention, comparator, and outcome question), identified critical patient-centered outcomes, systematically reviewed the evidence, assessed the certainty of the evidence, and developed policy options for ACIP’s consideration. The work group identified prevention of the following critical outcomes as benefits: development of virologically confirmed dengue (VCD) (e.g., using a reverse transcription–polymerase chain reaction [RT-PCR] test), severe dengue, and dengue hospitalizations. Outcomes that were considered critical for harms included serious adverse events, hospitalization, severe dengue, and death.To develop a recommendation using the Evidence to Recommendations Framework (EtR), the work group, assisted by technical experts, reviewed dengue epidemiology, immunology, and pathogenesis; clinical manifestations and management; laboratory diagnostics, including prevaccination screening issues associated with dengue anti-IgG antibody testing; cost-effectiveness; vaccine programmatic implementation and acceptability in Puerto Rico; and health equity issues. Details on the systematic review search and inclusion criteria, summaries of the evidence, and GRADE evidence profiles and the EtR framework are available at and ACIP voting members approved vaccination recommendations for children aged 9–16 years with laboratory-confirmed previous DENV infection living in areas of the United States where dengue is endemic.

Créditos: Comité científico Covid

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