GRADE Analysis: Dengvaxia® Dengue Vaccine

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

Table 1: Policy Question and PICO

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

Table 2. Summary of outcomes and rankings

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

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

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

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

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

Table 3d: Summary of studies reporting severe adverse events

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

Table 3e: Summary of studies reporting deaths

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

CI: Confidence interval; RR: Risk rati0

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. Dayan GH, personal communication. 2019.
11. 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

Table 5: Summary of Evidence for Outcomes of Interest

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

References

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Gailhardou S, Skipetrova A, Dayan GH, et al. Safety Overview of a Recombinant Live-Attenuated Tetravalent Dengue Vaccine: Pooled Analysis of Data from 18 Clinical Trials. Plos Negl Trop Dis; 2016.

Hadinegoro SR, Arredondo-García JL, Capeding MR, et al. Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. N Engl J Med. 2015 Sep 24;373(13):1195-206.

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