Document text
Centers for Disease Control and Prevention
National Center for Emerging and Zoonotic Infectious Diseases
Partial Evidence to Recommendations
Framework for Dengue Vaccine TAK -003
Joshua Wong, MD
ACIP June 22, 2023
Dengue Branch, CDC
Goals for Partial EtRPresentation
•Summarize the extent of the Work Group deliberations to date
•Present three Evidence to Recommendations ( EtR) domains*
•Prepare ACIP for the next meeting which will include a full EtRpresentation,
proposed recommendation, and vote.†During the full EtRpresentation:
•Domains presented today will be summarized.
•Work Group opinions and relevant summaries of straw polls will be presented.
*Data from ND/CDC Modeling are preliminary and subject to change
†Subject to change
Evidence to Recommendations ( EtR) Framework
EtR Domain Question
Public Health Problem •Is the problem (dengue) of public health importance?
Benefits and Harms•What is the overall certainty of this evidence for the critical outcomes?
•How substantial are the desirable anticipated effects of the intervention ( TAK-003
dengue vaccine )?
•How substantial are the undesirable anticipated effects?
•Do the desirable effects outweigh the undesirable effects?
Values•Does the target population feel the desirable effects are large relative to the
undesirable effects?
•Is there important variability in how patients value theoutcomes?
Acceptability •Is the intervention acceptable to keystakeholders?
Feasibility •Is the intervention feasible to implement?
Resource Use •Is the intervention a reasonable and efficient allocation ofresources?
Equity •What would be the impact of the intervention on health equity?
Public Health Problem
Is the problem (dengue) of public health
importance?
Is dengue a problem of public health
importance in dengue -endemic areas?
1.Should two doses of TAK -003 be administered routinely to seropositive*
persons aged 4 –16 years living in dengue -endemic areas?
2.Should two doses of TAK -003 be administered routinely to seronegative
persons aged 4 –16 years living in dengue -endemic areas?
3.Should two doses of TAK -003 be administered routinely to seropositive*
persons aged 17 –60 years living in dengue -endemic areas?
4.Should two doses of TAK -003 be administered routinely to seronegative
persons aged 17 –60 years living in dengue -endemic areas?
*Recommendations for seropositive individuals only will require prevaccination screening for previous dengue virus infection.
Dengue is endemic in six U.S. territories and
freely associated states .
Puerto Rico has the largest population
among territories with endemic dengue.
2020 data -census.gov Territory Population (%)
Puerto Rico 3,285,874 (96.0%)
US Virgin Islands 87,146 (2.5%)
American Samoa 49,710 (1.5%)
Total population at risk 3,422,730 (100%)
020004000600080001000012000
1 2 3 4 5 6 7 8 9 10 11Number of cases
Series1 Series2 Series3
024681012
1 2 3 4 5 6 7 8 9 10 11Incidence per 1,000 population
Series1 Series2 Series3Dengue cases and rates per 1,000 population
in Puerto Rico , American Samoa , and USVI , 2010 –2020
Ryff KR, Rivera A, Rodriguez DM, Santiago GA, Medina FA, Ellis EM, Torres J, Pobutsky A, Munoz -Jordan J, Paz -Bailey G, Adams
LE. Epidemiologic Trends of Dengue in U.S. Territories, 2010 -2020. MMWR Surveill Summ . 2023 May 19;72(4):1 -12.
Seropositive Seronegative
4–16 years
Children/Adolescents
17–60 years
AdultsIs dengue a problem of public health importance
for children/adolescents living in endemic areas?
*Immunogenicity in seropositive adults is expected to be at least as high as in seronegative adults.
Dengue cases and hospitalizations by age group in
Puerto Rico , 2010 –2020
Highest case rates occurred among children 10 –19 years old
Ryff KR, Rivera A, Rodriguez DM, Santiago GA, Medina FA, Ellis EM, Torres J, Pobutsky A, Munoz -Jordan J, Paz -Bailey G, Adams
LE. Epidemiologic Trends of Dengue in U.S. Territories, 2010 -2020. MMWR Surveill Summ . 2023 May 19;72(4):1 -12.
Dengue cases and hospitalizations by age group in
US Virgin Islands and American Samoa , 2010 –2020
Highest case rates occurred among children 10 –19 years old
Ryff KR, Rivera A, Rodriguez DM, Santiago GA, Medina FA, Ellis EM, Torres J, Pobutsky A, Munoz -Jordan J, Paz -Bailey G, Adams
LE. Epidemiologic Trends of Dengue in U.S. Territories, 2010 -2020. MMWR Surveill Summ . 2023 May 19;72(4):1 -12.
Seropositive Seronegative
4–16 years
Children/Adolescents
17–60 years
AdultsIs dengue a problem of public health importance
for adults living in endemic areas?
Fatal dengue cases (N = 68) by age group in
Puerto Rico , 2010 –2020
Higher mortality rates occurred among adults
*All fatal dengue cases reported during 2010 –2020 were from Puerto Rico. No deaths were reported fro m the other territories
Ryff KR, Rivera A, Rodriguez DM, Santiago GA, Medina FA, Ellis EM, Torres J, Pobutsky A, Munoz -Jordan J, Paz -Bailey G, Adams LE. Epidemiologic Trends of Dengue in U.S. Territories, 2010 -2020. MMWR Surveill Summ . 2023 May 19;72(4):1 -12.
Summary –Public Health Problem
•Dengue is endemic in six US territories and freely associated
states.
•Puerto Rico has the largest population among US territories where
dengue is endemic.
•The highest case and hospitalization rates occur in individuals
aged 10 –19 years.
•The highest mortality rates occur in adults aged ≥20 years.
Public Health Problem
Is the problem (dengue) of public health
importance?
Options: ○No ○Probably no ○Probably yes ○Yes ○Varies ○Don't know
Benefits and Harms
Benefits and Harms
What is the overall certainty of the
desirable anticipated effects?
Outcomes: desirable anticipated effects
Outcome Importance*
Virologically confirmed dengue due to any serotype Critical
Hospitalization for dengue due to any serotype Critical
Dengue hemorrhagic fever due to any serotype Critical
Severe dengue (trial definition) due to any serotype Critical
*Options are critical, important but not critical, not important for decision -making
Systematic review
•Systematic search identified 370 articles
•17 met inclusion/exclusion criteria including data on outcomes of interest
from phase 1 –3 trials.
•However, 0 articles contained the 57 month follow -up time of interest
that has been presented to and discussed by Work Group and ACIP .
•All vaccine efficacy and safety data provided by Takeda.*
*One article regarding safety outcomes used in systematic review has been published (Patel, CID, 2022), but
data stratified by PICO populations was provided by Takeda in personal communications with WG lead.
Multiple GRADE domains do not change for
the populations assessed or outcomes.
Outcome№ of
studiesStudy
designRisk of bias Inconsistency Indirectness ImprecisionOther
considerationsCertainty
VCD
Hospitalization
DHF
Severe Dengue
Indirectness and imprecision varied by population/outcome
assessed and determined final certainty level.
Outcome№ of
studiesStudy
designRisk of bias Inconsistency Indirectness ImprecisionOther
considerationsCertainty
VCD
Hospitalization
DHF
Severe Dengue
SAE
Deaths
Seropositive Seronegative
4–16 years
Children/Adolescents•Phase 3 Trial data •Phase 3 Trial data
17–60 years
AdultsHow certain are the desirable effects in
children/adolescents?
*Immunogenicity in seropositive adults is expected to be at least as high as in seronegative adults.
Overall VE
61.2% (56.0, 65.8%)
VE in Seropositives
64.2% (58.4, 69.2%)VE in Seronegatives
53.5% (41.6 –62.9%)
VE in Seropositives by Serotype
DENV -1 56.1% (44.6, 65.2%)
DENV -2 80.4% (73.1, 85.7%)
DENV -3 52.3% (36.7, 64.0%)
DENV -4 70.6% (39.9, 85.6%)VE in Seronegatives by Serotype
DENV -1 45.4% (26.1, 59.7%)
DENV -2 88.1% (78.6, 93.3%)
DENV -3 -15.5% (-108.2, 35.9%)
DENV -4 -105.6% (-628.7, 42.0%)Vaccine Efficacy* Outcome: Virologically Confirmed Dengue
*57 months after first dose, s ignificant results bolded. Number for seropositive placebo
participants 4,855 and vaccine 9,666; Seronegative placebo 1,832 and vaccine 3,714. Paz-Bailey. ACIP , February 17, 2023.
Overall VE
84.1% (77.8, 88.6%)
VE in Seropositives
85.9% (78.7, 90.7%)VE in Seronegatives
79.3% (63.5, 88.2%)
VE in Seropositives by Serotype
DENV -1 66.8% (37.4, 82.3%)
DENV -2 95.8% (89.6, 98.3%)
DENV -3 74.0% (38.6, 89.0%)
DENV -4 100% (NE, NE)†VE in Seronegatives by Serotype
DENV -1 78.4% (43.9, 91.7%)
DENV -2 100% (NE, NE)§
DENV -3 -87.9% (-573.4, 47.6%)¶
DENV -4 100 % (NE, NE)**Vaccine Efficacy* Outcome: Hospitalization
†DENV -4 Placebo events: 3 TAK-003 events: 0§DENV -2 Placebo events: 23 TAK -003 events: 0
¶DENV -3 Placebo events: 3 TAK-003 events: 11
**DENV -4 Placebo events: 1 TAK-003 events: 0
*57 months after first dose, s ignificant results bolded. Number for seropositive placebo
participants 4,855 and vaccine 9,666; Seronegative placebo 1,832 and vaccine 3,714.Paz-Bailey. ACIP , February 17, 2023.
Overall VE
84.1% (77.8, 88.6%)
VE in Seropositives
85.9% (78.7, 90.7%)VE in Seronegatives
79.3% (63.5, 88.2%)
VE in Seropositives by Serotype
DENV -1 66.8% (37.4, 82.3%)
DENV -2 95.8% (89.6, 98.3%)
DENV -3 74.0% (38.6, 89.0%)
DENV -4 100% (NE, NE)†VE in Seronegatives by Serotype
DENV -1 78.4% (43.9, 91.7%)
DENV -2 100% (NE, NE)§
DENV -3 -87.9% (-573.4, 47.6%)¶
DENV -4 100 % (NE, NE)**Vaccine Efficacy* Outcome: Hospitalization
†DENV -4 Placebo events: 3 TAK-003 events: 0§DENV -2 Placebo events: 23 TAK -003 events: 0
¶DENV -3 Placebo events: 3 TAK-003 events: 11
**DENV -4 Placebo events: 1 TAK-003 events: 0
*57 months after first dose, s ignificant results bolded. Number for seropositive placebo
participants 4,855 and vaccine 9,666; Seronegative placebo 1,832 and vaccine 3,714.Data insufficient to rule
out an increased risk
Paz-Bailey. ACIP , February 17, 2023.
Overall VE
70.0% (31.5, 86.9%)
VE in Seropositives
80.9% (46.3, 93.2%)VE in Seronegatives
-3.4% ( -464.7, 81.1%)Dengue Hemorrhagic Fever
(1997 Definition)
*57 months after first dose, s ignificant results for vaccine efficacy bolded. Number for seropositive
placebo participants 4,855 and vaccine 9,666; Seronegative placebo 1,832 and vaccine 3,714.Overall VE
70.2% ( -24.7, 92.9%)
VE in Seropositives
90.2% (16.4, 98.9%)VE in Seronegatives
-999.0% (NE, NE)Severe Dengue
Trial -specific Definition
Events by Serotype
Placebo TAK-003
DENV -1 <10 <10
DENV -2 <10 <10
DENV -3 <10 <10
DENV -4 <10 <10
Total 13 5Events by Serotype
Placebo TAK-003
DENV -1 <5 <5
DENV -2 <5 <5
DENV -3 <5 <5
DENV -4 <5 <5
Total 2 4Events by Serotype
Placebo TAK-003
DENV -1 <5 <5
DENV -2 <5 <5
DENV -3 <5 <5
DENV -4 <5 <5
Total 5 1Events by Serotype
Placebo TAK-003
DENV -1 <5 <5
DENV -2 <5 <5
DENV -3 <5 <5
DENV -4 <5 <5
Total 0 2
Paz-Bailey. ACIP , February 17, 2023.
Outcomes: desirable anticipated effects
Outcome Importance*
Virologically confirmed dengue due to any serotype Critical
Hospitalization for dengue due to any serotype Critical
Dengue hemorrhagic fever due to any serotype Critical
Severe dengue (trial definition) due to any serotype Critical
*Options are critical, important but not critical, not important for decision -making
What is the overall certainty of the desirable anticipated
effects in children/adolescents aged 4 –16 years?
Outcome (Desirable) Vaccine Efficacy Imprecision Indirectness Certainty
Virologically confirmed dengue 64.2 (58.4, 69.2) Not serious
Hospitalization 85.9 (78.7, 90.7) Not serious
Dengue hemorrhagic fever 80.9 (46.3, 93.2) Not serious
Severe dengue (trial definition) 90.2 (16.4, 98.9) Not serious
Outcome (Desirable) Vaccine Efficacy Imprecision Indirectness Certainty
Virologically confirmed dengue 53.5 (41.6, 62.9) Not serious
Hospitalization 79.3 (63.5, 88.2) Not serious
Dengue hemorrhagic fever -3.4 ( -464.7, 818.1) Serious
Severe dengue (trial definition) NE (NE, NE) SeriousSeropositive children/adolescents aged 4 –16 years
Seronegative children/adolescents aged 4 –16 years
Does the study population differ
from the population of interest?
DENV -1 and DENV -2 were the most common
serotypes in the TAK -003 Phase 3 trial.
Takeda –ACIP WG presentation September 13th230
193
113
23
050100150200250
1 2 3 4VCD case counts in Placebo group
All four serotypes have circulated in PR from
2010 –2020 .
Ryff KR, Rivera A, Rodriguez DM, Santiago GA, Medina FA, Ellis EM, Torres J, Pobutsky A, Munoz -Jordan J, Paz -Bailey G, Adams
LE. Epidemiologic Trends of Dengue in U.S. Territories, 2010 -2020. MMWR Surveill Summ . 2023 May 19;72(4):1 -12.
The VE for all serotypes combined
from the phase 3 trials
does notdirectly apply to our
population of interest and their
future risk of dengue if
it does not protect against one or
more of the 4 serotypes. VE in Seropositives
80.9% (46.3, 93.2%)
VE by Serotype
DENV -1
DENV -2
DENV -3
DENV -4
The VE for all serotypes combined
from the phase 3 trials
is only directly applicable to our
population of interest and their
future risk of dengue if there is
significant protection against all 4
serotypes. VE in Seropositives
80.9% (46.3, 93.2%)
VE by Serotype
DENV -1
DENV -2
DENV -3
DENV -4
What is the overall certainty of the desirable anticipated
effects in children/adolescents aged 4 –16 years?
Outcome (Desirable) Vaccine Efficacy Imprecision Indirectness Certainty
Virologically confirmed dengue 64.2 (58.4, 69.2) Not serious Not serious High
Hospitalization 85.9 (78.7, 90.7) Not serious Not serious High
Dengue hemorrhagic fever 80.9 (46.3, 93.2) Not serious Serious Moderate
Severe dengue (trial definition) 90.2 (16.4, 98.9) Not serious Serious Moderate
Outcome (Desirable) Vaccine Efficacy Imprecision Indirectness Certainty
Virologically confirmed dengue 53.5 (41.6, 62.9) Not serious Serious Moderate
Hospitalization 79.3 (63.5, 88.2) Not serious Serious Moderate
Dengue hemorrhagic fever -3.4 ( -464.7, 818.1) Serious Serious Low
Severe dengue (trial definition) NE (NE, NE) Serious Serious LowSeropositive children/adolescents aged 4 –16 years
Seronegative children/adolescents aged 4 –16 years
Seropositive Seronegative
4–16 years
Children/Adolescents
17–60 years
Adults•Outcomes assessed through
immunobridgingHow certain are the desirable effects in
adults?
GMR DENV -1 6 months 607 353 0.62 (0.51, 0.76) Yes
GMR DENV -2 6 months 607 355 0.66 (0.57, 0.76) Yes
GMR DENV -3 6 months 607 355 0.98 (0.84, 1.14) Yes
GMR DENV -4 6 months 607 354 1.01 (0.86, 1.18) YesAntibody titers in seronegative adults (18 –60) were
noninferior* at 1 and 6 months for almost all serotypes
compared to participants aged 4 –16.
Outcome (desirable) Time after 2nd
doseN (4–16
years)N (18–60
years)Geometric Mean Ratio Met noninferiority
objective*
GMR DENV -1 1 month 641 367 0.69 (0.58, 0.82) Yes
GMR DENV -2 1 month 641 367 0.59 (0.52, 0.66) Yes
GMR DENV -3 1 month 641 367 1.77 (1.53, 2.04) No
GMR DENV -4 1 month 641 367 1.05 (0.92, 1.20) Yes
*Non -inferiority was defined as a geometric mean ratio (GMR) with the upper bound of the 95% CI below 2.0.
Rivera L, Biswal S, Sáez -Llorens X, Reynales H, López -Medina E, Borja -Tabora C, et al. Three years
efficacy and safety of Takeda's dengue vaccine candidate (TAK -003). Clin Infect Dis. 2021 Oct 4.
What is the overall certainty of the desirable
anticipated effects in adults aged 17 –60 years?
Outcome (Desirable) N (4–16
years)N (18–60
years)Met noninferiority
objectiveIndirectness Certainty
VCD, hospitalization,
DHF, severe dengue
(assessed with
immunobridging )607-641 353-367 Yes for all serotypes,
except for DENV -3
assessed at 1 monthSerious* ModerateSeronegative adults aged 17 –60 years
*Downgraded once for indirectness due to immunobridging.
Seropositive Seronegative
4–16 years
Children/Adolescents
17–60 years
Adults•Outcomes assessed through
immunobridging in
seronegatives *•Outcomes assessed through
immunobridgingHow certain are the desirable effects in
adults?
*Immunogenicity in seropositive adults expected to be at least as robust as in seronegative adults; downgraded twice for indi rectness.
What is the overall certainty of the desirable
anticipated effects in adults aged 17 –60 years?
Outcome (Desirable) N (4–16
years)N (18–60
years)Met noninferiority
objectiveIndirectness Certainty
VCD, hospitalization,
DHF, severe dengue
(assessed with
immunobridging )607-641 353-367 Yes for all serotypes,
except for DENV -3
assessed at 1 monthSerious ModerateSeronegative adults aged 17 –60 years
Outcome (Desirable) Indirectness Certainty
VCD, hospitalization, DHF, severe dengue (assessed with
immunobridging in seronegative adults)Very Serious* LowSeropositive adults aged 17 –60 years
*Downgraded twice for indirectness, because outcomes are assessed with immunobridging data from seronegative
adults and assumption of equal or greater immunogenicity in seropositive adults
Seropositives Seronegatives
4–16 years
Children/Adolescents
17–60 years
AdultsSummary of Desirable Outcomes
Outcome VE Certainty
VCD 64.2 (58.4, 69.2) High
Hospitalization 85.9 (78.7, 90.7) High
DHF 80.9 (46.3, 93.2) Moderate
Severe dengue 90.2 (16.4, 98.9) Moderate
Outcome (Desirable) Certainty
All outcomes
(assessed with
immunobridging )ModerateOutcome (Desirable) Certainty
All outcomes
(assessed with immunobridging in
seronegatives *)Low
*Immunogenicity in seropositive adults is expected to be at least as high as in seronegative adults.Outcome VE Certainty
VCD 53.5 (41.6, 62.9) Moderate
Hospitalization 79.3 (63.5, 88.2) Moderate
DHF -3.4 ( -464.7, 818.1) Low
Severe dengue NE (NE, NE) Low
Seropositives Seronegatives
4–16 years
Children/Adolescents
17–60 years
AdultsSummary of Certainty for All Desirable Outcomes
*Immunogenicity in seropositive adults is expected to be at least as high as in seronegative adults.High –Moderate Moderate –Low
Moderate Low
Benefits and Harms
How substantial are the desirable
anticipated effects?
The population level effects of TAK -003
implementation will vary by…
seroprevalence of past infection AND serotype circulation.
Anti-DENV IgG
1 2 3 4
Preliminary Modeled Estimates of Population -
level Impacts in San Juan, PR* over 10 years
Recommendation Reduction in VCD† Reduction in hospitalizations†
4–16, seropositive ( screening‡) 1% 3%
4–16, all serostatuses (no screening) 3% 3%
17–60, seropositive ( screening‡) 6% 10%
17–60, all serostatuses (no screening) 8% 13%
4–60, seropositive ( screening‡) 7% 12%
4–60, all serostatuses (no screening) 9% 15%
España . ACIP , June 22, 2023.*The model assumes a seroprevalence of 40% at age 9, a vaccine coverage increasing from 0 to 40% over 10 years in all ages el igible, and
serotype distribution simulated from 20 years of historical data (1996 –2016) from San Juan, Puerto Rico (PR).
†Averted symptomatic and hospitalizations are for all ages in San Juan and include direct and indirect effects.
‡Screening test with 80% sensitivity and 98% specificity
Summary of Desirable Anticipated Effects
•Modeling* shows a reduction in VCD and hospitalizations following
implementation of TAK -003 in all populations explored in the policy
questions.
•Reductions in VCD and hospitalizations are higher when vaccination is
implemented in broader age ranges and for both seropositive and
seronegative individuals.
*Model based on preliminary data from Dr. España presented to ACIP on June 22, 2023.
Benefits and Harms
How substantial are the desirable
anticipated effects?
Options: ○Minimal ○Small ○Moderate ○Large ○Varies ○Don't know
Benefits and Harms
How substantial are the undesirable
anticipated effects?
What is the overall certainty?
Outcomes: undesirable anticipated effects
Outcome Importance*
Serious adverse events (SAEs) Critical
Deaths Critical
Systemic reactions†Important
Local reactions†Important
Interference with co -administered vaccines†Important
*Options are critical , important but not critical, not important for decision -making
†Not assessed in GRADE analysis
Seropositive Seronegative
4–16 years
Children/Adolescents•Phase 2 and 3 trials •Phase 2 and 3 trials
17–60 years
AdultsHow certain are the undesirable effects in
children/adolescents?
*Immunogenicity in seropositive adults is expected to be at least as high as in seronegative adults.
What is the overall certainty of the undesirable anticipated
effects in children/adolescents aged 4 –16 years?
Seropositive children/adolescents aged 4 –16 years
Seronegative children/adolescents aged 4 –16 yearsOutcome
(Undesirable)n/N TAK -003 n/N placebo Hazard Ratio Imprecision Indirectness Certainty
SAEs 826/9725 (8.5%) 503/4944 (10.2%)* 0.82 (0.74, 0.92) Not serious Not serious High
Deaths† 14/9725 (0.14%) 6/4944 (0.12%) 1.18 (0.45, 3.07) Not serious Not serious High
Outcome
(Undesirable)n/N TAK -003 n/N placebo Hazard Ratio Imprecision Indirectness Certainty
SAEs 323/3984 (8.1%) 183/1979 (9.3%)*0.88 (0.73, 1.05) Not serious Not serious High
Deaths† 2/3984 (0.05%) 1/1979 (0.05%) 1.00 (0.09, 11.04) Not serious Not serious High
*Higher dengue SAEs in placebo (n=100) compared to TAK -003 (n=51) resulted in HR <1 for all SAEs in TAK -003 compared to placebo.
†None of the deaths in the trial were due to dengueCommunication with Takeda. April 25, 2023.
Seropositive Seronegative
4–16 years
Children/Adolescents•Phase 2 and 3 trials •Phase 2 and 3 trials
17–60 years
Adults•Phase 2 and 3 trials •Phase 2 and 3 trialsHow certain are the undesirable effects in
adults?
What is the overall certainty of the undesirable
anticipated effects in adults aged 17 –60 years?
Seronegative adults aged 17 –60 years
Seropositive adults aged 17 –60 yearsOutcome
(Undesirable)n/N TAK -003 n/N placebo Hazard Ratio Imprecision Indirectness Certainty
SAEs 9/488 (1.8%) 3/84 (3.6%) 0.499 (0.14, 1.84) Not serious Not serious High
Deaths 0/488 0/84 N/A Not serious Not serious High
Outcome
(Undesirable)n/N TAK -003 n/N placebo Hazard Ratio Imprecision Indirectness Certainty
SAEs 3/83 (3.6%) 0/31 N/A Serious Not serious Moderate
Deaths 0/83 0/31 N/A Serious Not serious Moderate
Communication with Takeda. April 25, 2023.
Seropositives Seronegatives
4–16 years
Children/Adolescents
17–60 years
AdultsSummary of Undesirable Outcomes Certainty
Outcome
(Undesirable)n/N TAK -003 n/N placebo Certainty
SAEs 3/83 (3.6%) 0/31 Moderate
Deaths 0/83 0/31 ModerateOutcome
(Undesirable)n/N TAK -003 n/N placebo Certainty
SAEs 826/9725
(8.5%)503/4944
(10.2%)High
Deaths 14/9725
(0.14%)6/4944
(0.12%)HighOutcome
(Undesirable)n/N TAK -003 n/N placebo Certainty
SAEs 323/3984
(8.1%)183/1979
(9.3%)*High
Deaths 2/3984
(0.05%)1/1979
(0.05%)High
Outcome
(Undesirable)n/N TAK -003* n/N placebo Certainty
SAEs 9/488 (1.8%) 3/85 (3.6%) High
Deaths 0/488 0/85 High
Seropositives Seronegatives
4–16 years
Children/Adolescents
17–60 years
AdultsSummary of Certainty for All Undesirable Outcomes
High High
High Moderate
Dengue vaccine outcomes of interest can be a
desirable and an undesirable outcome.
Desirable Effects Undesirable EffectsPrevent Dengue Enhance Dengue?
Desirable Effects Undesirable EffectsSeropositives
DENV -1
DENV -2
DENV -3
DENV -4Seronegatives
DENV -1
DENV -2Prevent Dengue
Seronegatives
DENV -3*The effects differ by vaccinee serostatus
and serotype.
“Data insufficient to
rule out an increased
risk among vaccine
recipients.”
*for outcome of hospitalization.Enhance Dengue?
Benefits and Harms
Do the desirable effects outweigh the
undesirable effects?
*Hospitalizations among vaccinees in a no screening scenario represent hospitalizations among seronegative persons who are in fected by
DENV -3 post -vaccination. In the screening scenario, they represent hospitalizations among seronegative persons with false positi ve test results
who are infected with DENV -3 and are subsequently hospitalized. Model based on 40% seroprevalence at 9 years old. Other model
assumptions described by Dr. España (ACIP , June 22, 2023).Screening decreased the ratio of averted to additional hospitalizations compared to no pre -
vaccination screening but may lead to lower absolute hospitalizations averted.
0102030405060708090100
1 2 3Ratio ofhospitalizations averted to
additional hospitalizations *
6:115:135:1
18:1102:1
69:1
Summary of Balance of Desirable and
Undesirable Anticipated Effects
•Modeling* shows that the ratio of hospitalizations averted to additional
hospitalizations caused by vaccination increases with screening and
vaccination of seropositive individuals only.
•This ratio is higher in the population aged 17 –60 years compared to the
population aged 4 –16 years under both screening and no screening
scenarios.
•The benefits of screening and vaccinating seropositive individuals will be
weighed against the lower overall reduction in VCD and hospitalizations in
this scenario.
*Models based on preliminary data from Dr. España presented to ACIP on June 22, 2023.
Benefits and Harms
Do the desirable effects outweigh the
undesirable effects?
Options: ○Favors intervention ○Favors comparison ○Favors both ○Favors neither ○Varies ○Don't know
Resource Use
Is the intervention a reasonable and
efficient allocation of resources?
Preliminary Modeled Estimates of Cost -
effectiveness in San Juan, PR over 10 years
Population and Strategy†ICER per hospitalization
averted (USD)§ICER per QALY gained (USD)§¶
4–16 (screening) 16,800 181,918
4–16 (no screening) 46,813 254,751
17–60 (screening) 48,989 396,574
17–60 (no screening) 39,886 314,597
4–60 (screening) 48,305 384,830
4–60 (no screening) 45,495 326,412
España . ACIP , June 22, 2023.Estimates modeled on San Juan, PR, population 326,953. Puerto Rico has a total population of 3.264 million) (US Census Bureau ). For estimates with screening, the model assumes
a test with 80% sensitivity and 98% specificity.
†The model assumes a seroprevalence of 40% at age 9 and a vaccine coverage increasing from 0 to 40% over 10 years.
§Cost of full vaccination was $330 US; cost of a test was $30 with annual retesting for negative individuals.
¶ICER per QALY gained was modeled from a societal perspective with a 3% discounting rate.
Resource Use
Is the intervention a reasonable and
efficient allocation of resources?
Options: ○No ○Probably no ○Probably yes ○Yes ○Varies ○Don't know
Summary
•Presented 3 of 7 EtRdomains:
•Public Health Problem
•Benefits and Harms
•Resource Use
•Certainty assessment of the evidence for outcomes by policy question
ranged from high to low .
•Weighing the risks and benefits of dengue vaccination is complex.
•Work Group discussions will continue this summer.
•Draft recommendation and vote will occur at the next meeting .
For more information, contact CDC
1-800-CDC-INFO (232 -4636)
TTY: 1 -888-232-6348 www.cdc.gov
The findings and conclusions in this report are those of the authors and do not necessarily represent the
official position of the Centers for Disease Control and Prevention.
ACIP Members
Wilbur Chen (Chair)
Kathy Poehling
Beth Bell
Veronica McNally
CDC Co -Leads
Gabriela Paz -Bailey
Laura Adams
Ex Officio Members
Kaitlyn Morabito (NIH)
Ralph LeBlanc (FDA)
Ihid Carneiro Leao (FDA)
Kirk Prutzman (FDA)
Srihari Seshadri (DOD)
Liaison Representatives
Elizabeth Barnett (AAP)
Rob Schechter (AIM)Consultants
Edwin Asturias
Robert Atmar
Alan Barrett
IrisCardona
Anna Durbin
Tony Marfin
Kristen Pierce
Anita Shet
CDC Contributors
Joshua Wong
Nicole Medina
Mimi Eckert
Rachel Eidex
Alfonso Hernandez
Susan Hills
Terri Hyde
Mike McNeilJorge Munoz
Erin Staples
Cindy Weinbaum
Rita Helfand
GRADE Consultants
Doug Campos -Outcalt
Rebecca Morgan
GRADE Analysis Team
Joshua Wong (Co -lead)
Alfonso Hernandez (Co -Lead)
Cameron Adams
Arlene Rivera
Daniel MilanQuestions?ACIP Dengue Vaccines Workgroup and Support Team