About
The Evidence to Recommendations (EtR) frameworks describe information considered in moving from evidence to ACIP vaccine recommendations.
Summary
Policy question: Should 3-doses of Dengvaxia® be administered routinely to persons 9-16 years of age with laboratory-confirmed previous dengue infection and living in endemic areas?
Population: Persons 9 to 16 years of age with laboratory confirmed previous dengue infection living in dengue-endemic areas of the United States, territories, and freely associated states (Puerto Rico, US Virgin Islands, American Samoa, Federated States of Micronesia, Republic of the Marshall Islands and Palau).
Intervention: Three doses of Dengvaxia® with 0.5mL/dose at 0, 6 and 12 months
Comparison(s): No vaccination
Outcome:
- Subsequent virologically confirmed dengue (VCD) (Critical)
- Severe dengue (Critical)
- Hospitalizations from dengue (Critical)
- Deaths from dengue (Critical)
- Serious adverse events related to vaccination (Critical)
Background
Dengue viruses (DENV) transmitted by Aedes spp. mosquitoes present a growing public health challenge.12 Dengue is endemic throughout the tropics and sub-tropics, with an estimated 3.8 billion people (roughly 53% of the global population) living in areas that are suitable for DENV transmission with the majority in Asia, followed by Africa and the Americas3. Global estimates for 2013 suggest a total of 58 million symptomatic DENV infections and 13,600 fatal cases occurred, resulting in an annual global cost of $8.9 billion (95% CI 3.7 billion–19.7 billion).12
DENVs are members of the genus Flavivirus within the family Flaviviridae. The four dengue virus serotypes (DENV-1, DENV-2, DENV-3 and DENV-4), all circulate globally, with most endemic countries reporting circulation of all four serotypes in recent years. The 4 DENV serotypes are serologically and genetically distinct, although they share several structural antigens. Following an infection with one DENV serotype, the antibodies induced are both type-specific and cross-reactive with other DENV serotypes.3
Clinical disease varies from a mild, undifferentiated febrile illness to severe disease with shock, hemorrhage and/or severe organ impairment such as hepatitis and encephalitis. The case-fatality ratio for severe dengue is 10% or higher when untreated but can be reduced to less than 1% with good clinical management. Heterotypic secondary infections are the most prominent risk factor associated with severe dengue.3 Aedes aegypti, the main vector of dengue, is difficult to control, and continues to expand its geographic range. Dengue is a serious and ongoing public health problem in Puerto Rico and in other US territories and US affiliated nations in the Pacific.4
A vaccine to prevent dengue (CYD-TDV, Dengvaxia®) is licensed and available in 20 countries for people ages 9-45 years old. The vaccine manufacturer, Sanofi Pasteur, announced in 2017 that people who receive the vaccine and have not been previously infected with a dengue virus may be at risk of developing severe dengue if they get dengue after being vaccinated.5 After these findings were released WHO updated its guidance to recommend pre-vaccination screening and vaccinating only seropositive persons. In May 2019, Dengvaxia® was approved by the U.S. Food and Drug Administration (FDA) in the United States for use in children 9–16 years old with laboratory confirmed prior dengue virus infection living in an area with endemic dengue.
Problem
| Criteria | Work Group Judgements | Evidence | Additional Information |
|---|---|---|---|
| Is the problem of public health importance? | Yes | Endemic areas in the United States include Puerto Rico, American Samoa, US Virgin Islands, Federated States of Micronesia, Republic of the Marshall Islands and Palau. More than 90% of the population in these territories and affiliated states reside in Puerto Rico. More than 95% of cases in the past 10 years occurred in Puerto Rico. In Puerto Rico, dengue epidemics occur every 3–5 years. The heaviest burden is among 10–19 year-olds, with approximately 10,000 cases and 5,000 hospitalizations in this age group from 2010–2013. Only one death was reported among children. Incidence rates are highest among this age group and varied from 1 to 6 per 1,000 in 2010–2013. In other U.S. territories including the U.S. Virgin Islands and American Samoa, this age group also has the highest dengue incidence.
Population-based dengue seroprevalence data is not available from any of the endemic areas. However, small studies have found dengue seroprevalence estimates in Puerto Rico to range from 50% among adolescents 10–18 years old in 2007 to 56% in 2011 among participants 9–16 years of age in vaccine trials. 6,7
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Benefit and Harms
References in this table:8
| Criteria | Work Group Judgements | Evidence | Additional Information |
|---|---|---|---|
| How substantial are the desirable anticipated effects? | Large | Among seropositive children 9–16 years of age, vaccine efficacy against VCD was 82% (95% CI: 67–90). VCD incidence in unvaccinated and vaccinated seropositive children over 25 months was 5.2% and 1.0%, respectively. Efficacy was higher for serotype 4 (89%, 95% CI: 80–94) and lowest for serotype 1 and 2 (67% for each, 95% CI 46–80). Among 9–16 year old seropositive participants, the vaccine was protective against hospitalization (relative risk [RR] 0.21, 95% CI:0.14–0.31) and severe dengue (RR 0.16, 95% CI: 0.07–0.37). The five-year incidence of hospitalization for VCD among unvaccinated and vaccinated children was 1.88% and 0.38%, respectively. | Additional information on the age-specific seroprevalence in US territories would be helpful but is not available at this time. |
| How substantial are the undesirable anticipated effects? | Small | Unsolicited adverse reactions occurred in 1.2% of vaccinated children and 0.8% of controls. There were no differences in severe adverse events at 28 days (0.6%) and deaths (<0.1%) in the vaccine and control arms.
For severe adverse events at 6 months there were fewer in the vaccine arm (RR 0.86, 95% CI: 0.75–0.99).
Seronegative individuals could be misclassified as seropositive when using tests with imperfect specificity to determine prior infection with dengue virus. There was an overall excess hospitalization (RR 1.41, 95% CI: 0.74–2.68) and severe dengue (RR 2.44, 95% CI: 0.47–12.56) among 9–16 year old seronegative children vaccinated with Dengvaxia® but this excess risk with small sample size was not statistically significant. The cumulative 5-year incidence of dengue hospitalization among seronegative vaccine recipients was 1.57% and 1.09% among controls.
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| Do the desirable effects outweigh the undesirable effects? | Favors intervention | The desirable effects are protection against clinical dengue infection, hospitalization, and severe disease in children with a prior dengue infection. The major undesirable effect is more severe illness among seronegative children inadvertently vaccinated because of false positive pre-vaccination screening tests for prior dengue infection. The balance can be modeled on a population basis. One model predicts that at a moderate transmission scenario with prior dengue infection prevalence of 50% in the target age group for vaccination, using a serologic screening test with a sensitivity of 80% and a specificity of 95% over 10 years (vaccinating 9 year-olds with 80% of 9 year-olds screened), 3,415 hospitalizations would be prevented, and an additional 184 hospitalizations would occur, or 18.6 hospitalizations prevented for every one additional hospitalization.8 In this scenario there would be 1.6 vaccine induced hospitalizations for every 1,000 total vaccinees. In a lower transmission scenario of 30% prevalence at 9 years, an estimated 1,162 hospitalizations would be averted and an additional 14 hospitalizations would occur, or 7.8 hospitalizations averted per every one additional hospitalization. In this scenario there would be 3 vaccine-induced hospitalizations for every 1,000 total vaccinees. Vaccination in the moderate transmission scenario (50%) would avert 1.8% of symptomatic cases and 5.5% of hospitalizations; in the low transmission scenario (30%), vaccination would avert 0.8% of symptomatic cases and 3.2% of hospitalizations. | |
| What is the overall certainty of this evidence for the critical outcomes? | Effectiveness of the intervention is Level 1 (high)
Safety of the intervention is Level 2 (moderate)
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The overall certainty of the evidence was high among seropositive children with no evidence of harm. For the outcome of virologically confirmed dengue, the final evidence was rated as 1. For hospitalization and severe dengue the final evidence level was 2.
The overall certainty of the evidence for safety with regard to serious adverse events and deaths was high (level 1).
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Among seronegative children, the certainty is low (level 4) for the evidence of increased risk of hospitalization and severe dengue. |
Values
| Criteria | Work Group Judgements | Evidence | Additional Information |
|---|---|---|---|
| Does the target population feel that the desirable effects are large relative to undesirable effects? | Probably yes | If the screening test has a specificity of 95% or higher, survey data, focus groups, and stakeholder interviews in Puerto Rico suggest that the perception would be yes, that desirable effects are large relative to undesirable effects. | |
| Is there important uncertainty about or variability in how much people value the main outcomes? | Probably important uncertainty or variability | In a parent survey (n=1,139) conducted in southern Puerto Rico in 2018, 30% of parents surveyed were unsure or would not vaccinate their children against dengue. The reason given most frequently (38%) was concern about side effects. Pediatricians who were unsure about (21%) or would not vaccinate (6%) needed more information about the vaccine and were concerned about the risks of vaccinating persons with falsely positive dengue laboratory test results. |
Acceptability
| Criteria | Work Group Judgements | Evidence | Additional Information |
|---|---|---|---|
| Is the intervention acceptable to key stakeholders? | Probably yes | A parent survey conducted in southern Puerto Rico showed 75% of parents were interested in having their children vaccinated against dengue. Of those uncertain or not interested, side effects were the most frequently mentioned concern. In focus groups, most parents would agree to have their children vaccinated with Dengvaxia® once they have received sufficient information about the vaccine. Pediatricians surveyed in Puerto Rico in 2019–2020 (n=115) think dengue is a significant public health problem. Most pediatricians (73%) would recommend use of the vaccine if a laboratory test with acceptable specificity is available to document prior dengue infection. Key stakeholders interviewed including pediatricians, school principals and school nurses were all favorably disposed to a Dengvaxia® vaccination program for children with laboratory confirmed prior dengue infection. |
Resource Use
| Criteria | Work Group Judgements | Evidence | Additional Information |
|---|---|---|---|
| Is the intervention a reasonable and efficient allocation of resources? | Probably yes | Two cost effectiveness studies, one from Notre Dame8 and another from Sanofi Pasteur, looked at routine dengue vaccination among children in Puerto Rico. The base cases were as follows. The Notre Dame study looked at screening (test sensitivity 80% and specificity 95%, seroprevalence 50%) and vaccinating seropositive 9-year-old children over 10 years. The Sanofi Pasteur study looked at screening (test sensitivity 91% and specificity 95%, seroprevalence 52%) and vaccinating seropositive 11-year-old children over 10 years. For the base case scenario, the Notre Dame study found ICERs for hospitalizations averted of $16,000 and $122,000 (95% CI: 74,000––182,000) per QALY gained, while Sanofi found ICERS of $9,300 (95% CI: 6,100–16,100) and $21,200 (95% CI 10,200–46,700) for these outcomes, respectively. At a lower transmission scenario (30% prevalence at 9 years), the Notre Dame estimated ICER was higher at $32,000 per hospitalization averted and $240,000 USD per QALY gained. | Neither model is an outlier among a summary of 7 cost effectiveness studies published by WHO in terms of averted cases and averted hospitalizations in Asia. Cost estimates varied depending on transmission intensity (more cost effective at higher intensity), vaccine cost, and serological screening test cost. |
Equity
| Criteria | Work Group Judgements | Evidence | Additional Information |
|---|---|---|---|
| What would be the impact of the intervention on health equity? | Probably increased | The majority (~92%) of the population at risk for dengue in U.S. states and territories is located in Puerto Rico, with 95% of reported locally-acquired cases from 2010–2019. Dengue vaccination in Puerto Rico could increase health equity by reducing the burden of disease experienced by Puerto Ricans compared to other residents of U.S. states and territories. Limited data are available on dengue burden among different racial or ethnic groups in dengue-endemic regions. Health disparities could be increased if costs associated with the serodiagnostic test decrease vaccine availability or discourage vaccination for groups unable to afford the test. In Puerto Rico, the multiple visits required to physicians, testing laboratories, and vaccine providers could be a greater burden for low-income families due to transportation costs and missed days of work, potentially reducing health equity. Covering the cost of the serodiagnostic test and reducing the number of visits required to start the vaccine series could mitigate concerns of reducing health equity by making the vaccine more accessible to all groups. |
Feasibility
| Criteria | Work Group Judgements | Evidence | Additional Information |
|---|---|---|---|
| Is the intervention feasible to implement? | Probably yes | Dengvaxia® presents significant feasibility issues for a vaccination program in older children and adolescents. A pre-vaccination laboratory screening test for prior dengue infection ideally would be a rapid test with high specificity enabling vaccination during the same visit as testing. A school vaccination program might also be considered desirable to achieve vaccination coverage in the target age group of 9–16 years. Neither of these options appears to be available at this time in Puerto Rico, the U.S. territory most highly affected by dengue. A phased implementation to solve logistical issues of pre-vaccination screening in a setting like Puerto Rico would be desirable. |
Balance of consequences
Desirable consequences probably outweigh undesirable consequences in most settings.
Is there sufficient information to move forward with a recommendation? Yes.
Draft recommendation (text)
ACIP recommends 3-doses of Dengvaxia administered 6 months apart at month 0, 6, and 12, in persons 9-16 years of age with a laboratory confirmation of previous dengue infection and living in endemic areas.
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- Messina, J. P., Brady, O. J., Golding, N., Kraemer, M. U., Wint, G. W., Ray, S. E., ... & Hay, S. I. (2019). The current and future global distribution and population at risk of dengue. Nature microbiology, 4(9), 1508-1515.
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- Sridhar S, Luedtke A,Langevin E, et al. (2019) Effect of Dengue Serostatus on Dengue Vaccine Safety and Efficacy. N Engl J. Med.
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- L'Azou M, Assoukpa J, Fanouillere K, Plennevaux E, Bonaparte M, Bouckenooghe A, Frago C, Noriega F, Zambrano B, Ochiai RL, Guy B. Dengue seroprevalence: data from the clinical development of a tetravalent dengue vaccine in 14 countries (2005–2014). Transactions of The Royal Society of Tropical Medicine and Hygiene. 2018 Apr 1;112(4):158-68.
- Espana, G., Leidner, A. J., Waterman, S., & Perkins, A. (2020). Cost-effectiveness of Dengue Vaccination in Puerto Rico. medRxiv.