05 Dengue Wong 508

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

Summary: 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…


01 Chikungunya Bell 508

CHIKUNGUNYA VACCINES
Beth Bell, MD, MPH
Chair, ACIP Chikungunya Vaccines Work GroupACIP Meeting
June 22, 2023
Background
In February 2023, FDA accepted Valneva’s Biologics License Application
(BLA) for their chikungunya vaccine and granted priority review, with
licensure possible in August 2023
No chikungunya vaccine ever licensed in United States or globally
No existing ACIP chikungunya vaccine recommendations
Chikungunya Vaccines Work Group is developing policy options for ACIP’s
consideration for use of chikungunya vaccine among U.S. persons at risk of
chikungunya, including
–Travelers
–Laboratory workers
–Residents of U.S. territories and states with, or at risk of, transmission
Recap of previous Work Group presentations to ACIP
October 2022
–Overview of chikungunya virus disease and vaccines
–Immunogenicity and safety of Valneva’s chikungunya vaccine
February 2023
–Global epidemiology of chikungunya
–Chikungunya among U.S. travelers
–Persistent arthralgia following chikungunya
Overview of today’s session
Value and preferences for chikungunya vaccine among U.S. travelers and
healthcare providers
–Ms. Nicole Lindsey (CDC/NCEZID)
Chikungunya virus infection among laboratory workers
–Dr. Susan Hills (CDC/NCEZID)
Update and observations on large chikungunya outbreak in Paraguay
–Dr. Susan Hills (CDC/NCEZID)
Plans and timelines for Work Group activities
–Dr. Susan Hills (CDC/NCEZID)
ACIP Ex Officio Invited Consultants
Beth Bell, Univ Washington (Chair) Robin Levis, FDA Alan Barrett, Univ Texas Galveston
Wilbur Chen, Univ Maryland Sixun Yang, FDA Carina Blackmore, Florida Dept Health
Lesley Dupuy, NIH Alan Lam, DoD
CDC Leads Margaret Ryan, DoD
Susan Hills, DVBD (Lead) ACIP Liaisons Steven Schofield, CATMAT
Nicole Lindsey, DVBD (Deputy Lead) Elizabeth Barnett, ISTM David Shlim, Jackson Hole Travel & Trop Med
James Campbell, AAP Nestor Sosa, Uni New Mexico Hospital
Mary Pat Friedlander, AAFP Sanet Torres, San Jorge Children & Women's Hospital
Kirsten Vannice, Bill & Melinda Gates FoundationMary Wilson, Univ California San FranciscoChikungunya Vaccines Work Group members
DVBD DGMQ ISD
Erin Staples Sarah Guagliardo Elisabeth Velazque z
Ann Powers
Laura Adams DHQP GRADE/ETR consultants
Joshua Wong Michael McNeil Doug Campos -Outcalt
Rebecca Morgan
NCEZID GID
Rita Helfand Rebecca Casey ACIP Secretariat
Jessica MacNeil, NCIRD
Leslie Lee, NCIRDChikungunya Vaccines Work Group CDC participants

Summary: CHIKUNGUNYA VACCINES Beth Bell, MD, MPH Chair, ACIP Chikungunya Vaccines Work GroupACIP Meeting June 22, 2023 Background In February 2023, FDA accepted Valneva’s Biologics License Application  (BLA) for their chikungunya vaccine and granted priority review, with  licensure possible in August 2023 No chikungunya vaccine ever licensed in United States or globally No existing ACIP chikungunya vaccine recommendations Chikungunya Vaccines Work Group is developing policy options for ACIP’s …


02 Chikungunya Lindsey 508

National Center for Emerging and Zoonotic Infectious Diseases
Value of a vaccine to prevent travel -related
chikungunya for US persons
Nicole Lindsey, MS
CDC Deputy Lead , Chikungunya Vaccines Work Group
Arboviral Diseases Branch
Centers for Disease Control and PreventionJune 22, 2023
Potential value of a chikungunya vaccine among
international travelers (Valneva survey)
2021 online survey of 2,002 US residents aged ≥ 18 years who either
travelled internationally in last 3 years or planned to do so in next 3 years
–Excluded anyone who self -identified as ‘anti -vaccination’
Limited information provided about the surveyed population
Participants provided basic information about chikungunya disease
–Disease distribution, symptoms of disease, rarely joint pain/fatigue that lasts
for months or years, and lack of treatment
–No information on risk of infection, potential adverse events, costs of vaccineAwareness of chikungunya and value of a chikungunya
vaccine among travelers
9
Only 18% had heard of chikungunya prior to survey
After participants provided information about chikungunya, asked two
questions:
–How likely would you be to ask a healthcare professional about a vaccine to
protect yourself against chikungunya? 72% Likely
–If a doctor or health care provider recommended the chikungunya vaccine for you, how likely would you be to get vaccinated?   81% LikelyAwareness of chikungunya and value of a chikungunya
vaccine among travelers
10
Low awareness of chikungunya virus disease among traveler population
Most would likely ask healthcare provider about a chikungunya vaccine
and be vaccinated if their provider recommended vaccination
Limitations
–No info rmation provided to participants about risk of disease or
risks/benefits of vaccination
–No information about co sts
–Although traveler population, unknown if representative of traveler
population to areas at risk for chikungunyaAwareness of chikungunya and value of a chikungunya
vaccine among travelers: Summary
11
Potential value of a chikungunya vaccine among U.S.
persons (CDC survey)
Method: Porter Novelli Consumer Styles surveys
Online panel representative of non -institutionalized U.S. population
–Members randomly recruited using probability -based sampling by address
–Provided with a laptop or tablet and access to internet if needed
–Receive small monetary rewards for participation
2022 Summer Styles respondents included 4,156 invited adults (69%
response rate)
Core questions capture demographic information in addition to consumer attitudes, values, and behaviors
Data weighted to U.S. Population Survey proportions for sex, age, household income, race/ethnicity, household size, education, census region
13
Questions on value of a chikungunya vaccine
1.Imagine you are going on a trip to another country. You have a 1 in 150
chance of getting a disease. About 1 in 4 people who get the disease
suffer from long -term joint pain. A vaccine is available that costs $350
and is not covered by insurance. How likely would you be to get the
vaccine?
2.Now imagine you are going on the same trip, but your chances are 1 in
15,000 of getting the disease. About 1 in 4 people who get the disease
suffer from long -term joint pain. The vaccine costs $350 and is not
covered by insurance. How likely would you be to get the vaccine?
3.Which factors are most important to you in deciding whether or not to get the vaccine?
14
50% female; median age 54 years (range: 18- 94 years)
72% identified as white, non- Hispanic
Education
–5% with less than high school education
–25% with high school education
–70% with at least some college or higher education
Household income
–<$25K: 10%
–$25- <$75K: 30%
–≥$75K: 60% Demographics of survey participants (N=4,156)
15
Imagine you are going on a trip
to another country. You have a
1 in 150 chance of getting a
disease. About 1 in 4 people who get the disease suffer from
long -term joint pain. A vaccine
is available that costs $350 and is not covered by insurance. How likely would you be to get
the vaccine? (n=4,146)
*Includes very and somewhat likely responses
**Includes very and somewhat unlikely responses42%
26%32%
Likely* Unsure Unlikely**
16
Likelihood of chikungunya vaccination by age group
where disease risk is 1 in 150
45%43%43%35%
26%26%24%28%
30%31%33%37%
70+50-6930-4918-29
Likely Not Sure Unlikely
17
Likelihood of chikungunya vaccination by sex where
disease risk is 1 in 150
39%44%
29%22%
32%33%
FemaleMale
Likely Not Sure Unlikely
18
Likelihood of chikungunya vaccination by
race/ethnicity where disease risk is 1 in 150
51%42%36%42%
26%21%35%25%
24%37%29%33%
OtherHispanicBlackWhite
Likely Not Sure Unlikely
19
Likelihood of chikungunya vaccination by education
where disease risk is 1 in 150
54%41%31%
19%26%32%
27%33%38%
College and higherSome collegeHigh school or less
Likely Not Sure Unlikely
20
Likelihood of chikungunya vaccination by household
income where disease risk is 1 in 150
51%38%31%22%
22%29%27%36%
27%33%42%42%
75K+50-74K25-49K<25K
Likely Not Sure Unlikely
21
Likelihood of chikungunya vaccination where disease
risk is 1 in 150: Summary
42% respondents likely to be vaccinated when disease risk is high
–About a third unlikely to be vaccinated even in high -risk scenario
–About a quarter unsure
Main differences by group
–Lower likelihood of vaccination among youngest age groups, those with lower
education and household income levels
–Blacks less likely to be vaccinated and more likely to report ‘unsure’
22
Now imagine you are going on
the same trip, but your
chances are 1 in 15,000 of
getting the disease. About 1 in 4 people who get the disease
suffer from long -term joint
pain. A vaccine is available that
costs $350 and is not covered
by insurance. How likely would
you be to get the vaccine?
(n=4,138)27%
24%49%
Likely* Unsure Unlikely**
*Includes very and somewhat likely responses
**Includes very and somewhat unlikely responses 23
Likelihood of chikungunya vaccination where disease
risk is 1 in 15,000: Summary
Level of risk is important factor in determining likelihood of vaccination
with 27% being likely to vaccinate in low -risk scenario compared to 42% in
higher risk scenario
About a quarter of respondents unsure for both risk level scenarios
Similar trends for different demographic factors between high and low risk scenarios, with responses more towards ‘unlikely’ end of scale
24
Which factors are most important to you in deciding
whether or not to get the vaccine? (n=4,130)
6%11%36%41%43%57%
I do not get any vaccinationsOther factors not listedChance of getting long-term joint painCost of the vaccineChance of side effects from the vaccineChance of getting the disease
25
Not many differences by age
–Youngest age group more concerned about costs and less about long -term
joint pain
–Middle aged (45 -59 years) most concerned about vaccine side effects
No meaningful differences by sex or race/ethnicity
Importance of risk of disease and risk of long -term joint pain following
infection increased with both education level and household income
Conversely, proportion of respondents that do not receive vaccination
decreased by increasing education and incomeDifferences in factors influencing vaccination by
demographics
26
Factors influencing vaccination in high- risk scenario
by likelihood of vaccination
71%
51%
40%
33%
1%44%
21%42%51%
14%
Chance of getting
diseaseChance of long-term
joint painChance of side
effects from vaccineCost of the vaccine I do not get any
vaccinationsLikely
Unlikely
27
Factors influencing vaccination in lower risk scenario
by vaccine acceptance
68%
53%
40%
27%
1%55%
28%43%51%
9%
Chance of getting
diseaseChance of long-term
joint painChance of side
effects from vaccineCost of the vaccine I do not get any
vaccinationsLikely
Unlikely
28
Factors influencing likelihood of vaccination:
Summary
Most commonly reported factor was risk of getting disease, which is
consistent with findings for high and low risk scenario questions
Also important are risk of side effects, vaccine cost, and risk of long -term
join pain following infection
Significant differences between those likely and unlikely to be vaccinated in importance of factors, with exception of concern about side effects
–For “likely to be vaccinated” key factors were chance of disease and chance of
long -term joint pain
–For “unlikely to be vaccinated”, key factors were vaccine cost and chance of disease
29
Survey limitations
Not a traveler population
–Unknown how well these responses reflect attitudes of a traveler population
Only very basic disease information provided
No information on likelihood or type of side effects from vaccination
Vaccine cost was estimate based on typical travel vaccine not actual cost
30
Potential value of a chikungunya vaccine among U.S.
persons: Summary
42% of respondents likely to be vaccinated when disease risk is high; 27%
when disease risk is low
–About a quarter of participants were unsure in both scenarios
Lower likelihoods of vaccination than reported in Valenva survey (81%),
but were important differences in methods
–Traveler vs general population
–Different background information provided – more general information on
chikungunya vs. information focusing on disease risks, sequela, and costs
–Response to question on “likelihood of getting vaccine if recommended by
healthcare provider” vs “likelihood of getting vaccine”
31
Awareness of chikungunya and value of a
chikungunya vaccine to U.S. travel healthcare
providers (Valenva survey)
Online survey conducted in 2021 of 158 US travel healthcare providers
–All participants routinely preform pre -travel health counseling and prescribe
and/or administer relevant travel vaccines
–Mix of provider types and practice settings relevant to travel health
How familiar, if at all, are you with chikungunya disease?
–Familiar with disease and have clinical knowledge of it (30%)
–Have heard of it but don’t know what it is (20%)
–Majority not familiar (51%)Awareness of chikungunya and value of a vaccine to
U.S. travel healthcare providers
33
Value of chikungunya vaccine to U.S. travel
healthcare providers
Participants provided information:
–Disease epidemiology, clinical presentation, types and duration of sequelae
–Chikungunya vaccines likely available within few years
Asked to indicate likelihood to recommend/prescribe a vaccine for
chikungunya if recommended by ACIP
–15% Very likely
–73% Somewhat likely–11% Neither likely nor unlikely
–1% Unlikely
34
Low awareness of and familiarity with chikungunya among U.S. healthcare
providers, even among those who work in travel medicine
Following minimal education, 88% of providers surveyed would be likely to  recommend/administer vaccine to travelers if recommended by ACIP
–Explicit in question that vaccination would be recommended by ACIP
–No estimates of risk of disease or possible risks of vaccination Awareness of chikungunya and value of a vaccine to
U.S. travel healthcare providers: Summary
35
Value of chikungunya vaccine to U.S. travelers and
healthcare providers: Summary
Awareness of chikungunya low among travelers and healthcare providers
Healthcare providers likely to prescribe vaccination as recommended by
ACIP and travelers interested in vaccination if recommended by provider
Independent of healthcare provider recommendation, about 30– 40% of
U.S. persons interested in vaccination and remainder unsure or unlikely to
be vaccinated
–Variability in population perception of whether potential desirable effects
outweigh undesirable effects
–Risk of disease, vaccine cost, vaccine side effects, and risk of chronic arthralgia are influential factors in deciding on chikungunya vaccination
36

Summary: National Center for Emerging and Zoonotic Infectious Diseases Value of a vaccine to prevent travel -related  chikungunya for US persons Nicole Lindsey, MS CDC Deputy Lead , Chikungunya Vaccines Work Group Arboviral Diseases Branch Centers for Disease Control and PreventionJune 22, 2023 Potential value of a chikungunya vaccine among  international travelers (Valneva survey) 2021 online survey of 2,002 US residents aged ≥ 18 years who either  travelled internationally in last 3 years or planned…


03 Chikungunya Hills 508

National Center for Emerging and Zoonotic Infectious Diseases
CHIKUNGUNYA VIRUS INFECTIONS
AMONG LABORATORY WORKERS
Susan Hills, MBBS, MTH
CDC Lead , Chikungunya Vaccines Work Group
Arboviral Diseases Branch
Division of Vector -Borne Diseases
Fort Collins, Colorado
ACIP meeting, June 22, 2023
Chikungunya virus management in the laboratory
Handled at biosafety level (BSL) -3
High viral loads in blood samples increase risk for
l
aboratory -acquired infections1
1. Simmons G et al, Emerg Infect Dis 2016; Appassakij H et al, Transfusion 2013
2
Information on laboratory worker infections
Summary article published in 1980 by Subcommittee on
Arb
ovirus Laboratory Safety (SALS)1
Case report in a publication on exposures to pathogens in a U
.S. laboratory2
Cases reported to the U.S. national arboviral disease s
urveillance system
1.The Subcommittee on Arbovirus Laboratory Safety of the American Committee on Arthropod -B orne Viruses. Am J Trop Med Hyg 1980
2.Rusnak JM, et al. J O ccup Environ Med 2004 3
SALS report1
Methods
–Conducted literature review and two surveys
–Surveys sent to national and international labs in 1976 and 1978
39 chikungunya virus disease cases or infections
–38 (97%) disease cases, no deaths
–1 (3%) asymptomatic infection
Route of transmission
–7 (18%) aerosol
–32 (82%) not identified/unknown
1. The Subcommittee on Arbovirus Laboratory Safety of the American Committee on Arthropod -Borne Viruses. Am J Trop Med Hyg 1980
4
Case report from worker in a U.S. laboratory
Occurred during 1989 –2002
Needlestick injury
Full recovery after slow convalescence with intermittent joint
p
ains, headaches, and blurred vision for several months
Rusnak JM, et al. J Occup Environ Med 20045
Reports to national arboviral disease surveillance
system, 2015 –2022
Four disease cases
–One case hospitalized for observation
–No deaths
Route of transmission
–Needlestick (n=2)
–Other percutaneous (n=1)
–Unknown (n=1)
Photo credit: Getty Images
6
Reported cases likely underrepresent all infections in
laboratory workers
Underreporting of cases to national arboviral disease surveillance system
Asymptomatic infections not reportable to surveillance system
No formal laboratory surveillance system
Reluctance to publish
7
Summary
Laboratory workers at risk for chikungunya virus infections
a
nd disease
–At least 44 reports, including 4 cases during last 8 years
Documented modes of transmission include aerosol and pe
rcutaneous routes
Likelihood of disease vs. asymptomatic infection probably h
igh
8
Thank you
Getty
Images

Summary: National Center for Emerging and Zoonotic Infectious Diseases CHIKUNGUNYA VIRUS INFECTIONS  AMONG LABORATORY WORKERS Susan Hills, MBBS, MTH CDC Lead , Chikungunya Vaccines Work Group Arboviral Diseases Branch Division of Vector -Borne Diseases Fort Collins, Colorado ACIP meeting, June 22, 2023 Chikungunya virus management in the laboratory Handled at biosafety level (BSL) -3  High viral loads in blood samples increase risk for  l aboratory -acquired infections1 1. Simmons G et al, Emerg…


04 Chikungunya Hills 508

National Center for Emerging and Zoonotic Infectious Diseases
UPDATE AND OBSERVATIONS ON A LARGE
CHIKUNGUNYA OUTBREAK IN PARAGUAY
Susan Hills, MBBS, MTH
CDC Lead , Chikungunya Vaccines Work Group
Arboviral Diseases Branch
Division of Vector -Borne Diseases
Fort Collins, Colorado
ACIP meeting, June 22, 2023
Chikungunya notifications*
October 1, 2022 –June 3, 2023
167,239 cases
Source: Ministry of Public Health and Social Welfare, Paraguay
Epidemiologic weekNo. notifications
*Confirmed and probable cases and suspected arboviral infection 11
Chikungunya notifications*
by district
January 1 –June 3, 2023
Source: Ministry of Public Health and Social Welfare, Paraguay
No cases
<200 cases200– 1,000 cases
1,001– 4,000 cases
4,001– 8,000 cases
19,324 cases
*Confirmed and probable cases and suspected arboviral infection12
Morbidity and mortality among persons with probable or
confirmed chikungunya (N=90,709)
~8,600 (9%) hospitalizations *
*As of June 3, 2023263 (<1%) deaths *
13
Chikungunya virus transmission in 2023
in new areas of South America
Uruguay
–First autochthonous transmission
r
eported April 2023
Argentina and southern Brazil
–Transmission in new locations
U.S traveler cases reported with
t
ravel to this regionUruguayArgentinaParaguayBrazil
14
Observations on the outbreak of relevance to vaccine recommendations:
Explosive nature of outbreaks
<10,000
notifications* by
end of 2022
>50, 000
n
otifications* by
week 6, 2023
Source: Ministry of Public Health and Social Welfare, Paraguay *Confirmed and probable cases and suspected arboviral infection15
Observations on the outbreak of relevance to vaccine recommendations:
Impact on young infants and older persons
Torales M, et al. MMWR Weekly Rep 2023Number of hospitalizations (N=4,604) and case fatality rate among probable and
confirmed chikungunya cases by age group, October 1, 2022 –March 11, 2023
16
Observations on the outbreak of relevance to vaccine recommendations:
Impact on young infants and older persons
Torales M, et al. MMWR Weekly Rep 2023About three
quarters of all
patients who
died had
comorbiditiesNumber of hospitalizations (N=4,604) and case fatality rate among probable and
confirmed chikungunya cases by age group, October 1, 2022 –March 11, 2023
17
Observations on the outbreak of relevance to vaccine recommendations:
Impact on neonates

Observations on the outbreak of relevance to vaccine recommendations:
Impact on health services
Patient loadHealthcare
staff
absenteeism
Summary of observations from outbreak in Paraguay
Outbreak has been explosive and extensive
Groups at risk for severe disease include infants, older adults,
a
nd persons with comorbidities
Case fatality rate highest among neonates
Impact on health services from patient load and sick staff
20
Acknowledgements
Staff of the M inistry
of Public Health
and Social Welfare, Paraguay
Amy Beeson, CDC

Summary: National Center for Emerging and Zoonotic Infectious Diseases UPDATE AND OBSERVATIONS ON A LARGE  CHIKUNGUNYA OUTBREAK IN PARAGUAY Susan Hills, MBBS, MTH CDC Lead , Chikungunya Vaccines Work Group Arboviral Diseases Branch Division of Vector -Borne Diseases Fort Collins, Colorado ACIP meeting, June 22, 2023 Chikungunya notifications* October 1, 2022 –June 3, 2023 167,239 cases Source: Ministry of Public Health and Social Welfare, Paraguay Epidemiologic weekNo. notifications *Confirmed and…


05 Chikungunya Hills 508

National Center for Emerging and Zoonotic Infectious Diseases
WORK GROUP PLANS AND TIMELINES
Susan Hills, MBBS, MTH
CDC Lead , Chikungunya Vaccines Work Group
Arboviral Diseases Branch
Centers for Disease Control and Prevention
ACIP meeting
June 22, 2023
Work Group timeline (tentative)
Jun May Apr Mar Feb Jan Sept Jul Aug2024
Present EtRs (Today) Perceptions
of chikungunya vaccine, Laboratory workers, Paraguay outbreakACIP vote on vaccine recommendations for adult travelers and laboratory workersOct Nov Dec Jan Feb Mar Apr2023
FDA accepted BLA and
granted Priority ReviewPossible licensure
Consideration of
chikungunya vaccine use among residents
of U.S. territories and states at risk for outbreaks
Longer term Work Group plans and activities
Future presentations on topics relevant to consideration of vaccine use in
U
.S. territories and states with risk of transmission
Possibly additional vaccine data in younger age groups and/or additional chi
kungunya vaccines
24
Thank you

Summary: National Center for Emerging and Zoonotic Infectious Diseases WORK GROUP PLANS AND TIMELINES Susan Hills, MBBS, MTH CDC Lead , Chikungunya Vaccines Work Group Arboviral Diseases Branch Centers for Disease Control and Prevention ACIP meeting June 22, 2023 Work Group timeline (tentative) Jun May Apr Mar Feb Jan Sept Jul Aug2024 Present EtRs (Today) Perceptions  of chikungunya vaccine, Laboratory workers, Paraguay outbreakACIP vote on vaccine recommendations for adult travelers and laboratory…


01 RSV Mat Ped Long 508

1
Centers for Disease Control and Prevention
National Center for Immunization and Respiratory Diseases
Centers for Disease Control and Prevention
National Center for Immunization and Respiratory Diseases
Centers for Disease Control and Prevention
National Center for Immunization and Respiratory Diseases
Centers for Disease Control and Prevention
National Center for Immunization and Respiratory Diseases
Maternal/Pediatric Respiratory Syncytial Virus (RSV)
Work Group
Sarah S. Long, MD
Chair, Maternal/Pediatric RSV Work Group
ACIP General Meeting
June 22, 2023

2Work group members (External)
ACIP Members
Sarah Long (chair)
Pablo Sanchez
Oliver Brooks
Camille Kotton
Ex Officio Members
Rachel Zhang (FDA -CBER)
Nicholas Geagan (FDA -CBER)
Judy Beeler (FDA -CBER)
Yodit Belew (FDA -CDER)
Prabha Viswanathan (FDA -CDER)
Sonnie Kim (NIH -NIAID)
April Killikelly (Public Health Agency of Canada)
Winnie Siu (Public Health Agency of Canada)
Valerie Marshall (OIDP/OASH)
Jessica Lee (CMS/CMCS)
Terry Dalle -Tezze (HRSA)
Lucia Lee (FDA -CBER)Consultants
Cody Meissner (Dartmouth Geisel School of Medicine)
Helen Chu (University of Washington)
Natasha Halasa (Vanderbilt University)
Denise Jamieson (Emory University School of Medicine)
Daniel Feikin (World Health Organization)
Carol Baker (University of Texas Health Science Center)
Kevin Ault (Western Michigan University)Liaisons
James McAuley (IDSA)
Patsy Stinchfield (NFID)
Brenna L. Hughes (ACOG)
Nicole Chaisson (AAFP)
Sean O’Leary (AAP)
Jennifer Schuster (PIDS)
Molly Howell (AIM)
GRADE/ EtRconsultants
Doug Campos -Outcalt
Rebecca Morgan
3Work group members (CDC)
Lauren Roper
Amber Winn
Chris Taylor
Tami Skoff
Angie Campbell
Michael Melgar
Amanda Payne
Nicole Dowling
Noelle MolinariClaire Midgley
Fiona Havers
Pragna Patel
Andrea Sharma
Amadea Britton
Ruth Link -Gelles
Danielle Moulia
Megan Wallace
Monica GodfreyCDC ACIP Staff
Melinda Wharton
Stephanie Thomas
Jessica MacNeilKaren Broder
Naomi Tepper
Hannah Rosenblum
Heidi Moline
Derrell Powers
Raigan Wheeler
Sally Ezra
Elizabeth GreeneCDC
Katherine Fleming -Dutra (co -lead)
Jefferson Jones (co -lead)
Meredith McMorrow
Mila Prill
Natalie Thornburg
Aron Hall
Ismael Ortega -Sanchez
Melissa Coughlin
Jamison PikeA. Patricia Wodi
Neil Murthy
Christine Olson
Anne Hause
Andrew Leidner
David Shay
4▪Epidemiology and burden of RSV in infants
▪Virology and immunology of RSV
▪Safety and efficacy of nirsevimab
▪Cost effectiveness analysis for nirsevimab –CDC model
▪Cost effectiveness analysis for nirsevimab –Comparison to manufacturer model
▪Evidence to Recommendations framework for nirsevimab
▪Clinical considerations for nirsevimab
▪Safety and Efficacy of RSV Bivalent PreF Maternal VaccinePrevious maternal/pediatric RSV ACIP presentations
5Agenda: Thursday June 22, 2023
▪Economic Analy sis of RSVpreFin
Pediatric Popul ations
▪Evidence to Recommen dations
Frame work f or Pfizer Maternal  RSVpreF
Vaccine
▪Economics of combi ned use of Pfizer
maternal  RSVpreFvaccine and
nirsevimab
▪Clinical considerations for
RSVpreFmaternal vaccine and
nirsevimabDr. David Hutton (University of
Michigan)
Dr. Kather ine Fleming-Dutra (CDC)
Dr. David Hutton (University of
Michigan)
Dr. Jefferson Jones (CDC)
6

Summary: 1 Centers for Disease Control and Prevention National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention National Center for Immunization and Respiratory Diseases Maternal/Pediatric Respiratory Syncytial Virus (RSV)  Work Group Sarah S. Long, MD Chair,…


02 RSV Mat Ped Hutton 508

Economics of Pfizer maternal
RSVpreF vaccine
David W. Hutton, PhD, MS
Associate Professor, Health Management and Policy, School of Public Health
Associate Professor of Global Public Health, School of Public Health
Associate Professor, Industrial and Operations Engineering, College of Engineering
University of MichiganPresentation to the ACIP
June 22, 2023

Research team
University of Michigan
•David Hutton, PhD
•Lisa Prosser, PhD
•Angela Rose, MPH
•Kerra Mercon , MSCDC
•Jefferson Jones, MD, MPH,
FAAP
•Mila Prill, MSPH
•Meredith McMorrow, MD,
MPH, FAAP
•Jamison Pike, PhD
•Katherine Fleming -Dutra, MD,
FAAP
•Ismael Ortega -Sanchez, PhD
•Fiona Havers, MD
•Betsy Gunnels, MSPH
•Andrew Leidner , PhD
2
Conflicts of interest statements
–Authors have no known conflict of interests.
3
Methods: Study question
•Determine the cost -effectiveness of RSVpreF by:
•Evaluating the population impact in terms of
•annual resource utilization
•total cases
•total costs
•deaths
•quality -adjusted life -years (QALYs)
•Comparing the incremental cost -effectiveness ratio (ICER) of
RSVpreF to natural history/no vaccine.
•Running scenario analyses outcomes that explore key areas of
uncertainty.
•Perspective: Societal
4
Methods: Intervention(s)
•Target population: US pregnant persons
•Interventions:
1.No vaccination (Natural history)
2.RSVpreF against RSV illness
•Timeframe: 1 year (1 RSV season)
•Analytic horizon: infant’s lifetime
•Discount rate: 3%
5
Methods: Decision tree model
6Natural
History
RSVpreFInfection Hospitalization
ED
None of the aboveOutpatientAlive
DeadInfection
Adverse
EventsPrematurity
Injection site reaction
None of the aboveSerious adverse eventInfection Infection
Methods: Epidemiology
Hospitalization
7Base Case Range Source
Respiratory syncytial virus (RSV)
incidence, per 100,000 See Above See AboveCDC NVSN,
December 2016 to September 2020
Proportion with LRTI
Age 0 -5 months 1.0 0.5-1.0 Rainisch, 2020
Age 6 -11 months 1.0 0.5-1.0 Rainisch, 2020
CDC New Vaccine Surveillance Network (NVSN) hospitalization rates for children under 2 years of age from December 2016 to Sep tember 2020 - 1,000 2,000 3,000 4,000
0246810121416182022Hospitalization
rate  per 100,000
children
Age in months
Methods: Epidemiology
ED and Outpatient
8Respiratory syncytial virus
(RSV) incidence, per 100,000 Base
CaseRange Source
Emergency Department
Age 0 -5 months 7,500 5,500 –7,500 Lively 2019 (base case and range),
Hall 2009 (range)
Age 6 -11 months 5,800 5,700 –5,800 Lively 2019 (base case and range),
Hall 2009 (range)
Age 12 -23 months 3,200 3,200 –5,300 Hall 2009 (base case and range),
Lively 2019 (range)
Proportion with LRTI
Age 0 -5 months 0.65 0.25-1.0 Rainisch , 2020
Age 6 -11 months 0.5 0.25-1.0 Rainisch , 2020
Outpatient
Age 0 -5 months21,60013,200 –
21,600Lively 2019 (base case and range),
Hall 2009 (range)
Age 6 -11 months24,60017,700 –
24,600Lively 2019 (base case and range),
Hall 2009 (range)
Age 12 -23 months18,4406,600 –29,620 Jackson 2021 (base case and
range), Hall 2009 (range)
Proportion with LRTI
Age 0 -5 months 0.65 0.25-1.0 Rainisch , 2020
Age 6 -11 months 0.3 0.1-1.0 Rainisch , 2020
LRTI= Lower respiratory tract infection
Methods: Epidemiology
Mortality
9Base
CaseRange Source
RSV mortality per
hospitalization
Age 0 -5 months 0.04% 0.03-0.05% Doucette 2016
Age 6 -11 months 0.04% 0.03-0.05% Doucette 2016
Age 12 -23 months 0.3% 0.28% -
0.34%Gupta 2016
Seasonality
100%5%10%15%20%25%30%
Apr May Jun JulAug Sep Oct Nov Dec Jan Feb MarFraction of Annual Infections
Source: National Respiratory and Enteric Virus Surveillance System (NREVSS) (2015 -2019)
110%20%40%60%80%100%
0 3 6 9 12Efficacy
Month
Against medically-attended RSV-associated LRTI
Against hospitalizationMethods: RSVpreF efficacy
average 6 -month efficacy
= trial efficacy
Zero efficacy
Source: Kampmann et al 2023
LRTI= Lower respiratory tract infection
0%20%40%60%80%100%
0 3 6 9 12Efficacy
Month
Against medically-attended RSV-associated LRTI
Against hospitalization
12Methods: RSVpreF efficacy
alternate scenario
average 6 -month efficacy
= trial efficacy
Zero efficacy
Source: Kampmann et al 2023
LRTI= Lower respiratory tract infection
Methods: Efficacy
13Variable Base case
valueRange for
sensitivity
analysisSource
RSVpreF
Initial efficacy (months 0 -5)
against medically -attended
RSV-associated LRTI 51.3% 29.4% -66.8%Kampmann
et al, 2023
Initial efficacy (months 0 -5)
against hospitalized RSV -
associated LRTI 56.8% 10.1% -80.7%Kampmann
et al, 2023
Efficacy months 6 -12 0
Assumed 0% efficacy against upper respiratory tract infections
LRTI= Lower respiratory tract infection
Methods: Provision of RSVpreF
14•Base case:
–Year round
•Scenarios
–During June -February (no vaccine given in
March -May)
–During May -February (no vaccine given in
March -April)
–During April -February (no vaccine given in
March)
•Mother vaccinated
–During 24 -36 weeks gestation, based on
distribution of Tdap vaccination by week in
that time period
•Birth
–Must be >2 weeks after vaccination for
protective efficacy to pass to infant, based on
historical gestational age
15 TDAP vaccination timing from internal CDC analysis of 2018 -2021 MarketScan data.Methods: Provision of RSVpreF
16100
Pregnant
persons50
Not
vaccinated
50
Vaccinated
47
Vaccinated
in time3
Not
vaccinated
in timeMethods: Provision of RSVpreF
Uptake
Timing
Timing= >2 weeks prior to delivery
Methods: Medical Costs
Variable Value Range Source
Disease -specific
hospitalization costs
(per hospitalization)
Age 0 -11 months $11,487 4,804 -86,646
Bowser 2022Age 12 -23 months $11,469 4,804 -86,646
Disease -specific ED
costs (per ED visit)$563 544 -581 Bowser 2022
Disease -specific
outpatient costs (per
outpatient visit)$82 46 -118 Bowser 2022
17•Bowser, 2022 is a systematic review using studies from 2014 -2021
•Funded by Sanofi
•All numbers updated to 2022 dollars using GDP Deflator
Methods: Productivity costs
Variable Value Range Source
Productivity burden of
RSV disease (caregiver
losses)
Days of lost productivity
Outpatient* 2.5 0-5Fragaszy, 2018; Petrie,
2016; Van Wormer, 2017
ED* 2.5 0-5Fragaszy, 2018; Petrie,
2016; Van Wormer, 2017
Hospitalization^ 7.4 0-14
Lifetime productivity for
those <1 year old (lost
from death)1,795,936 1,346,951 -
2,244,919Grosse, 2019
18*Productivity for outpatient and ED based on adult influenza
^Hospitalization productivity loss = length of hospitalization + 2 days
Methods: Intervention cost
Variable Value Range Source
Immunization -related
costs
RSVpreF , per dose $200 50 –300Assumption: Manufacturer
costs for adult vaccine
RSVpreF administration $16.96 15 -22 Medicare: HCPCS 90460
19Both assume no additional visits, but do include costs of administration
Methods: Adverse event costs
Variable Value Range Source
RSVpreF Maternal
Adverse Events
Rate of injection site
reaction0.41 0.38 –0.44 Pfizer Phase 3 Trial
Probability of healthcare
visit, given injection site
reaction0.02 0.015 –0.025 Curran, 2020
Cost of outpatient visit $367.76 23.15 –1,758 (Deluca, 2023)
Recipient time, physician
office for injection site
reaction (hours)2 1 -3 Assumption
Hypothetical serious
adverse event0.000001 0 -0.0002Base: Prosser, 2006
High: 95% CI Phase 3 data for
RSV adult vaccines
20
21Kampmann B, Madhi SA, Munjal I, Simões EA, Pahud BA, Llapur C, Baker J, Pérez Marc G, Radley D, Shittu E, Glanternik J.
Bivalent prefusion F vaccine in pregnancy to prevent RSV illness in infants. New England Journal of Medicine. 2023 Apr 5.Methods: Prematurity?
1% Difference?

Methods: Prematurity scenario
Variable Value Range Source
RSVpreF infant adverse
events
Higher Rate of Prematurity 0% 0-2% Pfizer Phase 3 Trial
22* All costs updated to 2022 using GDP DeflatorOutcomes, per
prematurity
Lifetime cost of late
prematurity
Medical $ 23,241 $11,621 –
$46,482 Waitzman , Jalali, Grosse, 2021
Productivity $ 11,447 $5,724 –
$22,894 Waitzman , Jalali, Grosse, 2021
QALYs lost from late
prematurity0.03 0 –1.2Werner, Hauspurg , Rouse, 2015
Petrini et al, 2008, Hirvonen et al, 2014, Crump
et al, 2021, Darcy -Mahoney et al, 2016, Carroll
et al, 2009, Payakachat et al, 2014
Methods: RSV
health -related quality of life
23LRTI quality -adjusted life DAYS lost Base Lower (Regnier) Upper (JIVE)
Outpatient: Child 3.1 1.8 16.6
Outpatient: Caregiver 1.5 0 9.1
ED: Child 4.9 2.9 16.6
ED: Caregiver 2.5 0 9.1
Hospitalized: Child 6.2 3.7 26.5
Hospitalized: Caregiver 2.4 0 13.6Measured in
Days Lost
Most
Likely
Methods: Uncertainty analyses
•One-way sensitivity
•Scenarios:
–Prematurity
–Cost
–Month of administration
–Upper respiratory tract infection effect
–Efficacy waning
24
Results: Base case
25•Base case:
–Population of 1,000 births
–50% uptake in the RSVpreF group
–First RSV season
–$200/dose
–RSVpreF only impacts LRTI
Results: Health outcomes
26 Cohort:1,000 births, assuming 50% uptake in RSVpreF group
URTI= upper respiratory tract infection; LRTI= lower respiratory tract infection - 50 100 150 200 250
Natural
HistoryRSVpreF Natural
HistoryRSVpreF Natural
HistoryRSVpreF
Outpatient Emergency
DepartmentInpatientNumber of Events in Cohort
URTI LRTI
Results: Events Averted
27 Cohort:1,000 births, assuming 50% uptake in RSVpreF group12.9
4.5
2.1
0.511.6
1.4
0.02.04.06.08.010.012.014.0
Outpatient ED Inpatient ICU Inpatient Day ICU DayEvents Averted per 1000 births
RSVPreF
Results: Number Needed to
Vaccinate
28 Cohort:1,000 births, assuming 50% uptake in RSVpreF group39 112 234 1,062
43 354
 - 200 400 600 800 1,000 1,200
Outpatient ED Inpatient ICU Inpatient Day ICU DayNumber needed to Vaccinate to avoid
RSVPreF
Results: Costs
29
Base costs of RSVpreF : $200/dose, both natural history and RSVPreF involve palivizumab for high -risk childrenCohort:1,000 births, assuming 50% uptake in RSVpreF group$0$100,000$200,000$300,000$400,000$500,000$600,000
Natural History
RSVPreF
Natural History
RSVPreF
Natural History
RSVPreF
Natural History
RSVPreF
Natural History
RSVPreF
Natural History
RSVPreF
Intervention Outpatient ED Inpatient Deaths TotalTotal Costs in Cohort
Medical Productivity
Results: Cost per Event Averted
30
Base costs of RSVpreF : $200/dose$5,459 $15,722 $32,945 $149,751
$6,101 $49,917
 $- $20,000 $40,000 $60,000 $80,000 $100,000 $120,000 $140,000 $160,000
Outpatient ED Inpatient ICU Inpatient Day ICU DayCost per Event Averted
RSVPreF
Results: QALYs Lost
31Adverse
EventsOutpatient ED Inpatient Deaths Total Grand
Child Caregiver Child Caregiver Child Caregiver Child Child Caregiver Total
Natural
History 1.95 0.98 0.90 0.45 0.22 0.09 0.15 3.22 1.51 4.73
RSVpreF 0.0001 1.85 0.93 0.84 0.42 0.19 0.07 0.12 3.00 1.42 4.42
Cohort:1,000 births, assuming 50% uptake in RSVpreF group
QALY= quality -adjusted life -year
Results: Cost -Effectiveness
32Base costs of RSVpreF : $200/dose
QALY= quality -adjusted life -year; ICER= incremental cost -effectiveness ratioCohort:1,000 births, assuming 50% uptake in RSVpreF group, ICER is not affected by uptakeOverallCosts ($)QALYs
lostICER ($/QALY)
Vs. NH
Natural History 418,556 4.73
RSVpreF 489,038 4.40 214,087
Sensitivity: Tornado RSVpreF
33Base cost of RSVpreF : $200/dose
MA= Medically -attended
LRTI= Lower respiratory tract infection
QALY= Quality adjusted life year$14 million$0 $100,000 $200,000 $300,000 $400,000 $500,000
Probability of Prematurity
Disease-specific inpatient costs (per inpatient case)  Age 0-5
months
RSV QALYS Lost
RSVpreF vaccine cost/dose
Vaccination Efficacy, Hospitalized RSV LRTI through 180 days
Vaccination Efficacy, RSV MA-LRTI through 180 days
Proportion of RSV infections with an LRTI diagnosis Outpatient Age
0-5 months
RSV-related QALYs lost Outpatient Child
RSV-related QALYs lost Outpatient Caregiver
Proportion of RSV infections with an LRTI diagnosis ED Visits Age
0-5 monthsIncremental Cost -Effectiveness Ratio
Low High
 $- $500,000 $1,000,000 $1,500,000 $2,000,000 $2,500,000 $3,000,000 $3,500,000 $4,000,000 $4,500,000 $5,000,000
0.0% 0.5% 1.0% 1.5% 2.0%ICER
Excess PrematurityScenario: Prematurity
34Base Case
 $- $50,000 $100,000 $150,000 $200,000 $250,000 $300,000 $350,000
$0 $50 $100 $150 $200 $250 $300ICER
Cost of RSVpreFSensitivity: Cost RSVpreF
35Base Case
Results: RSVpreF timing
scenarios
36•Scenarios
–Base: vaccine given year -round
–During April -February (no vaccine given in
March)
–During May -February (no vaccine given in
March -April)
–During June -February (no vaccine given in
March -May)
Results: RSVpreF timing
scenarios
214,087
162,136
137,871
119,398
 - 50,000 100,000 150,000 200,000 250,000
Base Apr-Feb May-Feb Jun-FebICER ($/QALY)ICER: RSVpreF vs. Natural History
37
 $- $50,000 $100,000 $150,000 $200,000 $250,000 $300,000 $350,000
$0 $50 $100 $150 $200 $250 $300ICER
Total Cost of RSVpreFScenario: Upper Respiratory
Tract Infection Effect
38RSVpreF is assumed to have 37.9% efficacy for upper respiratory tract infections based on overall respiratory tract
efficacy from phase 3 trial ( Kampmann , 2023)
ICER= incremental cost effectiveness ratio; QALY= Quality adjusted life year$153,674/QALY
39Methods: RSVpreF efficacy
“flat efficacy” scenario
OverallCosts ($)QALYs
lostICER ($/QALY)
Natural History 418,556 4.73
RSVpreF 486,812 4.38 191,749
Slightly lower costs with
RSVpreF , slightly fewer
QALYs lost, slightly lower
ICER0%20%40%60%80%100%
0 3 6 9 12Efficacy
Month
Against medically-attended RSV-associated LRTI
Against hospitalization
ICER: Incremental cost -effectiveness ratio
LRTI= Lower respiratory tract infection
Limitations
•Model Structure
–No risk groups
–No dynamic transmission. No impact of the vaccine
on transmission and indirect effects
•Uncertain inputs
–RSVpreF cost
–QALYs lost
–Upper respiratory tract infections
–Prematurity
40
Summary
•RSVpreF may improve RSV outcomes, but will
also increase costs
•RSVpreF has the potential to be cost -effective
•Results sensitive to:
–Rate of prematurity
–Cost per dose (Cost -Saving –350,000 $/QALY)
–Efficacy (~150,000 -350,000 $/QALY)
–QALYs lost (~50,000 -480,000 $/QALY)
•Hospitalization, Outpatient, ED
•Child, Parent
–Month of Administration (~120,000 –215,000 $/QALY)
41QALY: Quality -Adjusted Life -Year
Thank You
•Please send comments to:
•dwhutton@umich.edu
42
Appendix
43
Methods: Epidemiological model
SeasonalityIncidence
•Outpatient
•ED
•Hospitalizations
Nirsevimab
Waning
ProtectionHealth Effects
• Outpatient
• ED
• Hospitalizations
• Deaths
Economic Effects
• Intervention
• Disease
• Societal
• QALYs
• ICERInterventionsEpidemiology
Timing
Cost Burden/
•Outpatient
•ED
•HospitalizationsHealth Economics
Health Burden/
•Outpatient
•ED
•Hospitalizations
44
Methods: Inputs
•Incidence
–Raw reported incidence may be
underreported because of imperfect PCR
sensitivity, so we consider an additional
scenario in sensitivity analysis:
•based on CDC Unpublished re -analysis of raw
data from Zhang et al study which found
decreased RSV PCR sensitivity in light of paired
serology testing (adjustment factor: 87.6%).
45
Health -Related Quality -of-Life
•Sources
–Glaser (2022)
•Estimate based on comparison of utility losses between premature
children who had RSV vs. premature children without RSV and their
caregivers
•Used as base case for hospitalization for children and their caregivers
–Regnier (2013)
•Estimate QALY losses for hospitalization, ED visits, and outpatient visits
for children with pertussis
•Use relative QALYs between hospitalization, ED, and outpatient to
estimate base losses for ED and outpatient in base case
–JIVE RSV Utilities Survey (2021)
•Estimates QALY losses for hospitalization and outpatient visits for child
and caregiver
•Estimates may be impacted by COVID -related concerns about
respiratory viruses
•Inform upper bound of range
46
47 Timing of those who received vaccination during pregnancy
RSVpreF is assumed to start earlier at week 24 (vs. week 27)00.020.040.060.080.10.120.140.160.18
13579111315171921232527293133353739Fraction Vaccinated (given
receipt of vaccine)
Gestational Age
Reported Tdap Modeled RSVpreF vaccination timingMethods: Provision of RSVpreF
480.0%5.0%10.0%15.0%20.0%25.0%30.0%35.0%40.0%45.0%
0 10 20 30 40 50
Gestational Age (Week)
Source: NCHS from 2019 and 2021Methods: Birth Timing
Validation
231
66
8225
65
13
050100150200250
Outpatient Clinic
VisitsED Visits HospitalizationsRates of Medically -Attended
RSV (per 1000 births)
Rainisch et al, Vaccine, 2020 JIVE model
49
Methods: Maternal Adverse
Event Health Effects
Variable Value Range Source
Adult Quality -Adjusted Life -
Years lost due to adverse events
Injection Site Reaction 0 Assumed
Serious Adverse Event 0.141 0.092 -0.199 Prosser, 2006
50
Results: Cost -Effectiveness
51
Base costs of RSVpreF : $200/doseCohort:1,000 births, assuming 50% uptake in RSVpreF group $410,000 $420,000 $430,000 $440,000 $450,000 $460,000 $470,000 $480,000 $490,000 $500,000
 (4.80)  (4.70)  (4.60)  (4.50)  (4.40)  (4.30)Costs
QALYs (lost) from RSV
Natural History RSVPreF
Results: RSVpreF Administration
June -February
52OverallCosts ($) QALYsICER
($/QALY)
Vs. NH
Natural
History 418,556 4.73
RSVpreF 454,928 4.43 119,398

Summary: Economics of Pfizer maternal  RSVpreF vaccine David W. Hutton, PhD, MS Associate Professor, Health Management and Policy, School of Public Health Associate Professor of Global Public Health, School of Public Health Associate Professor, Industrial and Operations Engineering, College of Engineering University of MichiganPresentation to the ACIP  June 22, 2023  Research team University of Michigan •David Hutton, PhD •Lisa Prosser, PhD •Angela Rose, MPH •Kerra Mercon , MSCDC •Jefferson Jones, MD,…