GRADE Analysis: Dengvaxia® Dengue Vaccine

About

CDC vaccine recommendations are developed using an explicit evidence-based method based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Introduction

Dengue viruses (DENV) transmitted by Aedes aegypti mosquitoes present a growing public health challenge (Shepard et al. 2016; Stanaway et al. 2016). DENV is endemic throughout the tropics and sub-tropics, with an estimated 3.8 (95% confidence interval [CI] 3.5–4.1) billion people (roughly 53% of the global population) living in areas that are suitable for DENV transmission with the vast majority in Asia, followed by Africa and the Americas (Messina et al. 2019). Global estimates for 2013 suggest a total of 58 million symptomatic DENV infections (95% CI 24–122) and 13,586 fatal cases occurred (95% CI 4200–34,700), resulting in a total annual global cost of $8.9 billion (95% CI 3.7–19.7) (Shepard et al. 2016; Stanaway et al. 2016).

DENV are members of the genus Flavivirus, within the family Flaviviridae. There are 4 dengue virus serotypes (DENV-1, DENV-2, DENV-3 and DENV-4), all of which circulate globally, with most endemic coun­tries reporting circulation of all 4 serotypes in recent years. The 4 dengue serotypes are serologically and genetically distinct, although they share several of their structural antigens. Following an infection with one DENV serotype, the antibodies induced are type-specific and also cross-reactive with other DENV sero­types (Wilder-Smith et al. 2019).

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. Age, co-morbidities, host genetics, and virus strain are risk factors for severe dengue with heterotypic secondary infections being the most prominent factor associated with severe dengue (Wilder-Smith et al. 2019). Ae. aegypti, the main vector of dengue, has proved highly 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 states.

A vaccine to prevent dengue (CYD-TDV, Dengvaxia®) is licensed and available in 20 countries for people ages 9–45 years old. The World Health Organization recommends that the vaccine only be given to persons with confirmed prior dengue virus infection. 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. 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 living in an area with endemic dengue with laboratory confirmed prior dengue virus infection.

Evidence Retrieval

The US Advisory Committee on Immunization Practices (ACIP) Dengue Vaccine Work Group reviewed Dengvaxia® safety and efficacy data in a systematic literature review in 2018. The search terms included Dengvaxia®, CYD-TDV, or live-attenuated dengue vaccine, and 5 database systems were reviewed (Medline, Embase, Cochrane Library, CINAHL, Scopus). A total of 710 results were identified; of these, 359 met initial inclusion criteria of including human data from clinical trials published after 2000. The remaining 351 findings were reviewed by at least two people to assess possible relevance. The majority of those were excluded as describing different live attenuated dengue vaccines or not including primary trial data. The final analysis included 30 papers that described Dengvaxia® safety or efficacy results from clinical trials. In this document we present the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Table 1: Policy Question and PICO, CYD-TDV Dengue Vaccine

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 to prevent virologically confirmed dengue, hospitalizations and severe dengue?
Population Persons 9 to 16 years of age living in dengue-endemic areas of the United States, territories, and freely associated states
Intervention 3 doses of Dengvaxia® administered at 6-month intervals, at 0, 6 and 12 months
Comparison No dengue vaccination
Outcomes Protection against virologically confirmed dengue, severe dengue, and hospitalization for dengue. The harms considered critical outcomes were serious adverse events, hospitalizations, severe dengue and deaths.

Table 2. Summary of outcomes and rankings, CYD-TDV Dengue Vaccine

Outcome Importance Include in evidence profile
Benefits
Vaccine efficacy for virologically confirmed dengue (VCD) Critical Yes
Vaccine efficacy for severe VCD Critical Yes
Vaccine efficacy for hospitalization for VCD Critical Yes
Harms
Serious adverse events Critical Yes
Injection site reactions Important No
Systemic reactions Important No
Hospitalization Critical Yes
Severe dengue Critical Yes
Death Critical Yes

Appendix 1: Studies included in Evidence Review

Last name first author, Publication year Study design Country Age in years Total population N Intervention N comparison Outcomes Funding source
Capeding, 2014 RCT (phase 3) Indonesia, Malaysia, Philippines, Thailand, and Vietnam (CYD14) 2-14 10,275 6,851 3,424 Virologically confirmed dengue (VCD) Sanofi Pasteur
Villar, 2015 RCT (phase 3) Colombia, Brazil, Mexico, Honduras, Puerto Rico (CYD15) 9-16 20,869 13,920 6,949 VCD Sanofi Pasteur
Sabchareon, 2012 RCT (phase 2b) Thailand (CYD23-57) 4-11 4,002 2,669 1,221 VCD Sanofi Pasteur
Hadinegoro, 2015 2 RCT Combined (CYD14/CYD15) 9-14 30,063 20,046 10,017 VCD, hospitalization, severe dengue Sanofi Pasteur
Gailhardou, 2016 18 clinical trials (phase 1, 2, 3) USA, Philippines, Mexico, Australia, Colombia, Honduras, Mexico, Puerto Rico, Vietnam, Peru, Singapore, Brazil, India, Thailand Malaysia, Australia, Indonesia 2-60 38,918 26,356 12,562 Serious adverse events, deaths Sanofi Pasteur
Sridhar, 2018 Case-cohort Combined (CYD14/CYD15/CYD23-57) 9-16 3,578 2,384 1,194 VCD, hospitalization, severe dengue Sanofi Pasteur

Table 3a: Summary of studies reporting virologically confirmed dengue (VCD), CYD-TDV Dengue Vaccine

Authors last name, pub year Age; DENV Serotype Serostatus n/N intervention n/N comparison Comparator vaccine Efficacy/Relative Risk Study limitations (Risk of Bias)
Capeding, 2014 2-14 Seropositive 18/1811 34/880 Placebo 74.3 (53.2, 86.3) Not serious
Capeding, 2014 2-14 Seronegative 23/838 18/423 Placebo 35.5 (-26.8, 66.7) Not serious
Villar, 2015 9-16 Seropositive 8/2116 23/994 Placebo 83.7 (62.2, 93.7) Not serious
Villar, 2015 9-16 Seronegative 9/500 9/284 Placebo 43.2 (-61.6, 80.0) Not serious
Sabchareon, 2012 4-11 Combined 45/2522 32/1251 Placebo 30.2 (-13.4, 56.6) Not serious
Hadinegoro, 2015 9-16 Seropositive 15/1560 40/763 Placebo 81.9 (67.2, 90.0) Not serious
Hadinegoro, 2015 9-16 Seronegative 16/387 17/208 Placebo 52.5 (5.9-76.1) Not serious
Hadinegoro, 2015 9-16; Serotype 1 Combined 135/17230 161/8596 Placebo 58.4 (47.7, 66.9) Not serious
Hadinegoro, 2015 9-16; Serotype 2 Combined 117/17230 110/8596 Placebo 47.1 (31.3, 59.2) Not serious
Hadinegoro, 2015 9-16; Serotype 3 Combined 66/17230 124/8596 Placebo 73.6 (64.4, 80.4) Not serious
Hadinegoro, 2015 9-16; Serotype 4 Combined 42/17230 124/8596 Placebo 83.2 (76.2, 88.2) Not serious
Sridhar, 2018 9-16 (MI) Seropositive 192.7/1441.4 372.1/697.3 Placebo 76 (64, 84) Not serious
Sridhar, 2018 9-16 (MI) Seronegative 174.3/353.6 148.9/193.7 Placebo 39 (-1, 63) Not serious
Sridhar, 2018 9-16 (MI); Serotype 1 Seropositive 71/1441.4 103.5/697.3 Placebo 67.4 (45.9, 80.4) Not serious
Sridhar, 2018 9-16 (MI); Serotype 2 Seropositive 57.1/1441.4 83.1/697.3 Placebo 67.3 (46.7, 79.9) Not serious
Sridhar, 2018 9-16 (MI); Serotype 3 Seropositive 40.5/1441.4 96/697.3 Placebo 80.0 (67.3, 87.7) Not serious
Sridhar, 2018 9-16 (MI); Serotype 4 Seropositive 20.9/1441.4 91.9/697.3 Placebo 89.3 (79.8, 94.4) Not serious
Sridhar, 2018 9-16 (MI); Serotype 1 Seronegative 23.6/365.4 23.6/365.4 Placebo 1.37 (0.59, 3.19) Not serious
Sridhar, 2018 9-16 (MI); Serotype 2 Seronegative 21.2/365.4 21.2/365.4 Placebo 2.41 (0.65, 8.95) Not serious
Sridhar, 2018 9-16 (MI); Serotype 3 Seronegative 10.1/365.4 10.1/365.4 Placebo 0.86 (0.23, 3.3) Not serious
Sridhar, 2018 9-16 (MI); Serotype 4 Seronegative 3.4/365.4 3.4/365.4 Placebo 0.94 (0.11, 8.1) Not serious

Table 3b: Summary of studies reporting hospitalization, CYD-TDV Dengue Vaccine

Authors last name, pub year Age Serostatus n/N intervention n/N comparison Comparator vaccine Efficacy/Relative Risk Study limitations (Risk of Bias)
Hadinegoro, 2015 9-16 Combined 27/17,230 70/7,596 Placebo 80.8 (70.1, 87.7) Not serious
Sridhar, 2018 9-16 (MI) Seropositive 58.8/1502.9 137.7/729.8 Placebo 0.21 (0.14–0.31) Not serious
Sridhar, 2018 9-16 (MI) Seronegative 64.2/375.1 25.3/207.2 Placebo 1.41 (0.74–2.68) Not serious
Sridhar, 2018 9-16 (MI); Serotype 1 Seropositive 15.4/1495.6 32.9/708.1 Placebo 0.22 (0.11, 0.45) Not serious
Sridhar, 2018 9-16 (MI); Serotype 2 Seropositive 15.8/1495.6 42.1/708.1 Placebo 0.18 (0.09, 0.34) Not serious
Sridhar, 2018 9-16 (MI); Serotype 3 Seropositive 14.9/1495.6 18.6/708.1 Placebo 0.38 (0.17, 0.82) Not serious
Sridhar, 2018 9-16 (MI); Serotype 4 Seropositive 3.6/1495.6 21.1/708.1 Placebo 0.07 (0.01, 0.38) Not serious
Sridhar, 2018 9-16 (MI); Serotype 1 Seronegative 23.6/365.4 9.1/196.9 Placebo 1.37 (0.59, 3.19) Not serious
Sridhar, 2018 9-16 (MI); Serotype 2 Seronegative 21.2/365.4 4.9/196.9 Placebo 2.41 (0.65, 8.95) Not serious
Sridhar, 2018 9-16 (MI); Serotype 3 Seronegative 10.1/365.4 6.4/196.9 Placebo 0.86 (0.23, 3.3) Not serious
Sridhar, 2018 9-16 (MI); Serotype 4 Seronegative 3.4/365.4 1.9/196.9 Placebo 0.94 (0.11, 8.1) Not serious

Table 3c: Summary of studies reporting severe dengue, CYD-TDV Dengue Vaccine

Authors last name, pub year Age Serostatus n/N intervention n/N comparison Comparator vaccine Efficacy/Relative Risk Study limitations (Risk of Bias)
Hadinegoro, 2015 9-16 Combined 3/17,230 22/8,596 Placebo 93.2 (77.3, 98.0) Not serious
Sridhar, 2018 9-16 (MI) Seropositive 11.2/1502.9 33.4/729.8 Placebo 0.16 (0.07–0.37) Not serious
Sridhar, 2018 9-16 (MI) Seronegative 14.8/375.1 3.6/207.2 Placebo 2.44 (0.47–12.56) Not serious
Sridhar, 2018 9-16 (MI); Serotype 1 Seropositive 12.9/1803.3 10.5/856.1 Placebo 0.57 (0.19, 1.74) Not serious
Sridhar, 2018 9-16 (MI); Serotype 2 Seropositive 8.6/1803.3 16/856.1 Placebo 0.24 (0.08, 0.74) Not serious
Sridhar, 2018 9-16 (MI); Serotype 3 Seropositive 10.5/1803.3 6.8/856.1 Placebo 0.72 (0.26, 2.0) Not serious
Sridhar, 2018 9-16 (MI); Serotype 4 Seropositive 1.1/1803.3 9/856.1 Placebo NA Not serious
Sridhar, 2018 9-16 (MI); Serotype 1 Seronegative 13.1/551.7 4.5/294.9 Placebo 1.55 (0.37, 6.56) Not serious
Sridhar, 2018 9-16 (MI); Serotype 2 Seronegative 16.4/551.7 3/294.9 Placebo 3.21 (0.50, 20.68) Not serious
Sridhar, 2018 9-16 (MI); Serotype 3 Seronegative 9.5/551.7 1.2/294.9 Placebo NA Not serious
Sridhar, 2018 9-16 (MI); Serotype 4 Seronegative 0.9/551.7 0/294.9 Placebo NA Not serious

Table 3d: Summary of studies reporting severe adverse events, CYD-TDV Dengue Vaccine

Authors last name, pub year Age; Length of follow-up Serostatus n/N intervention n/N comparison Comparator vaccine Efficacy/Relative Risk Study limitations (Risk of Bias)
Gailhardou, 2016 2-60; 28 days Combined 218/26356 121/12562 Placebo NA Not serious
Gailhardou, 2016 2-60; 6 months Combined 23/26356 499/12562 Placebo NA Not serious
Dayan G., personal communication 9-16; 28 days Combined 123/19102 73/9484 Placebo 0.84 (0.63, 1.12) Not serious
Dayan G., personal communication 9-16; 6 months Combined 534/19102 307/9484 Placebo 0.86 (0.75, 0.99) Not serious

Table 3e: Summary of studies reporting deaths, CYD-TDV Dengue Vaccine

Authors last name, pub year Age Serostatus n/N intervention n/N comparison Comparator vaccine Efficacy/Relative Risk Study limitations (Risk of Bias)
Gailhardou, 2016 2-60 Combined 23/26,356 14/12,522 Placebo NA Not serious
Dayan G., personal communication 9-16 Combined 51/19102 26/9484 Placebo 0.97 (0.61, 1.56) Not serious

Table 4. GRADE assessment for 3 doses of Dengue vaccine administered at 6-month intervals compared to no vaccine for protection against virologically confirmed dengue, severe dengue, and hospitalization among children ages 9-16 yrs with confirmed previous dengue infection, CYD-TDV Dengue Vaccine

№ of participants (studies) Reference Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Study event rates (%) with no vaccination Study event rates (%) with 3 doses of Dengue vaccine administered at 6-month intervals Relative effect
(95% CI)
Absolute effect/risk difference per 1000
(95% CI)
Certainty Importance
Virologically confirmed dengue among seropositives (follow up: 25 months; assessed with: active follow-up and laboratory testing)
2323
(2 RCTs)
Handinegoro SR, et al.
RCTs not seriousa,b not serious not serious not seriousc none 40/763 (5.2%) 15/1560 (1.0%) VE 81.9
(67.2 to 90.0)
-42.8
(-59.4 to -26.3)
1
HIGH
Critical
Hospitalization for VCD among seropositives (follow up: 6 years; assessed with: hospital surveillance)
2232.7
(Case cohort using data from 3 RCTs)
Sridhar S, et al.
Case cohort using data from 3 RCTs not seriousd not serious not serious not serious Upgrade for strong association 137.7/729.8 (18.9%) 58.8/1502.9 (3.9%) RR 0.21
(0.14 to 0.31)
-149.6
(-179.6 to -119.5)
2
MODERATE
Critical
Severe VCD among seropositives (follow up: 6 years; assessed with: hospital surveillance)
2232.7
(Case cohort using data from 3 RCTs)
Sridhar S, et al.
Case cohort using data from 3 RCTs not seriousd not serious not serious not serious Upgrade for strong association 33.4/729.8 (4.6%) 11.2/1502.9 (0.7%) RR 0.16
(0.07 to 0.37)
-38.3
(-54.19 to -22.5)
2
MODERATE
Critical
Virologically confirmed dengue among seronegatives (follow up: 25 months; assessed with: active follow-up and laboratory testing)
595
(2 RCTs)
Handinegoro SR, et al.
RCTs not seriousa not seriouse not serious seriousf Downgrade for imprecision 17/208 (8.2%) 16/387 (4.1%) VE 52.5
(5.9 to 76.1)
-40.4
(-82.6 to 1.8)
2 MODERATE Critical
Hospitalization for VCD among seronegatives (follow up: 6 years; assessed with: hospital surveillance)
582.3
(Case cohort using data from 3 RCTs)
Sridhar S, et al.
Case cohort using data from 3 RCTs not seriousg not serious not serious serioush Downgrade for imprecision 25.3/207.2 (12.2%) 64.2/375.1 (17.1%) RR 1.41
(0.74 to 2.68)
49.1
(-9.6 to 107.7)
4
VERY LOW
Critical
Severe VCD among seronegatives (follow up: 6 years; assessed with: hospital surveillance)
582.3
(Case cohort using data from 3 RCTs)
Sridhar S, et al
Case cohort using data from 3 RCTs not seriousg not serious not serious seriousi Downgrade for imprecision 3.6/207.2 (1.7%) 14.8/375.1 (3.9%) RR 2.44
(0.47 to 12.56)
22.1
(-4.5 to 48.6)
4
VERY LOW
Critical
Serious adverse events among seropositive and seronegative (follow up: 6 months; assessed with: active surveillance)
28586
(9 RCTs) j
RCTs not serious not serious not serious not serious none 73/9484 (0.8%) 123/19102 (0.6%) RR 0.86
(0.75 to 0.99)
-1.3
(-3.4 to 0.8)
1
HIGH
Critical
Deaths among seropositives and seronegatives (follow up: 6 years; assessed with: hospital surveillance)
28586
(9 RCTs) j
RCTs not serious not serious not serious not seriousk none 26/9484 (0.3%) 51/19102 (0.3%) RR 0.78
(0.40 to 1.52)
-0.1
(-1.4 to 1.2)
1
HIGH
Critical

CI: Confidence interval; RR: Risk rati0

a. Dengvaxia® has been evaluated in two parallel Phase 3 clinical trials, known as CYD14 and CYD15. CYD14 was conducted in 5 countries in Asia (Indonesia, Malaysia, Philippines, Thailand, and Vietnam), with 5,234 participants aged 9-14 years at first vaccination (10,275 participants in the full trial population aged 2-14 years). CYD15 was conducted in 5 countries in Latin America (Brazil, Colombia, Honduras, Mexico, and Puerto Rico (US), with 20,869 participants aged 9-16 years at first vaccination. Participants were randomized to vaccine/placebo in a 2:1 ratio. Because the physical appearance of the vaccine and placebo was different, unmasked trial staff were responsible only for administration and were not involved in the follow-up. For trial endpoints the trials were observer-masked. All serology testing was also performed in a blinded manner. Immune status at baseline was only known for the immunogenicity subset with 2,000 participants per study, 4,000 total.

b. Active surveillance of participants lasted only until study month 25, after which surveillance was hospital-based. Thus, it is not possible to evaluate the duration of protection against virologically-confirmed dengue of any severity.

c. Based on the immunogenicity subset, vaccine efficacy among seropositives was 74.3% (95% CI 53.2-86.3) in CYD14, 83.7% (95% CI 62.2-93.7) in CYD15, 78.2% (95% CI 65.4-86.3) in the two trials pooled, and 81% (95%CI 67.2-90.0) in the two trials pooled with the age limited to 9-16 years. Data based on the supplemental analysis (see explanation in d below) affirms high vaccine efficacy in seropositives with point estimates ranging from 71-75%, depending on the method, and tight confidence intervals.

d. Data for long term hospitalization risk comes from a case cohort study using all VCD, hospitalization and severe dengue cases and randomly selected controls that represent 10% of the study cohort (n=3,300). As part of this supplemental study, three methods were used to assign dengue serostatus and re-analyze the Phase 3 trial data: multiple imputation (MI, month 0 onward), targeted minimum loss–based estimation (TMLE, month 0 onward), and measured anti–nonstructural protein 1 (NS1) titer (month 13 onward). Analyses from these methods provided similar results, therefore only results from multiple imputation (MI) are presented in the table. These methods are based on assays and statistical methods that are associated with misclassification of serostatus at baseline, which vary by assay. The false-positive rate (misclassifying seronegatives as seropositives) is high (31%), which would bias the result towards the null. Thus, the protective effect in seropositives may be greater than that estimated in these analyses. About 80% of participants in the case control study are seropositive, therefore the potential bias from the misclassified seronegatives is likely small.

e. Data based on the supplemental analysis provides variable point estimates for seronegatives. In 9-16 year-olds, vaccine efficacy is estimated at 39% (95%CI -1-63) using the multiple imputation method, 45% (95%CI 26-58) using the TMLE method, and 18% (95%CI -18-43) using the NS1 method. The confidence is downgraded for inconsistency.

f. Based on the immunogenicity subset, vaccine efficacy among seronegatives was 35.5% (95% CI -27.0-66.6) in CYD14, 43.2% (95%CI -61.6-80.0) in CYD15, 38.1% (95% CI -3.4-62.9) in the two trials pooled, and 52.5% (95% CI 5.9-76.1) in the two trials pooled with the age limited to 9-16 years. There were few seronegatives in the immune subset, making it hard to estimate vaccine efficacy with precision. The confidence is downgraded in the category of imprecision.

g. Data for long term hospitalization risk comes from a case control study using all VCD, hospitalization and severe dengue cases and randomly selected controls that represent 10% of the study cohort (n=3,300). The methods used for re-analysis of the Phase 3 trial data are based on assays and statistical methods that are associated with misclassification of serostatus at baseline, which vary by assay. The false-negative rate (misclassifying seropositives as seronegatives) is low and for this analysis there is limited bias due to misclassification.

h. Based on analyses of the immune subset for sero-negatives at baseline, the confidence intervals are very wide. All cross zero. The imprecision remains for most supplemental analyses with the longer-term follow-up, with the lower bound of the 95% CI crossing 0 for the multiple imputation method, TMLE and NS1 methods. The confidence is downgraded for imprecision.

i. The number of severe dengue cases among seronegatives was small. Multiple estimation methods were used including multiple imputation, TMLE, and NS1 testing at month 13. The estimates of increased risk of severe dengue among those vaccinated range from 1.4 (95%CI: 0.4-4.5) with TMLE to 6.2 (0.8-48.3), and the confidence intervals are wide and all estimates cross zero. The confidence is downgraded for imprecision.

j. Dayan GH, personal communication. 2019.

k. Did not rate down for imprecision because sample size meets optimal information size.

Table 5: Summary of Evidence for Outcomes of Interest, CYD-TDV Dengue Vaccine

Outcome Importance Included in evidence profile Certainty
Benefits
Vaccine efficacy for virologically confirmed dengue (VCD) Critical Yes High
Vaccine efficacy for hospitalization for VCD Critical Yes Moderate
Vaccine efficacy for severe VCD Critical Yes Moderate
Harms
Serious adverse events Critical Yes High
Injection site reactions Important No
Systemic reactions Important No
Hospitalization Critical Yes Moderate
Severe dengue Critical Yes Moderate
Death Critical Yes High

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