05 santoli hepatitis b 508

VFC Resolution Update:  Hepatitis B Vaccine
December 4, 2025National Center for Immunization & Respiratory Diseases

•Red font in the presentation is used to indicate changes to the resolution in
comparison to the currently approved version.Note
•The purpose of this resolution is to update the Recommended Vaccination
Schedule and Intervals section to reflect updated ACIP recommendations
about the use of Hepatitis B vaccine.  Purpose of the Resolution
•  All children and adolescents birth through 18 years of age.  Eligible Groups
The tables below list the acceptable vaccination schedules for children and
adolescents, birth through 18 years of age.
Table 1. InfantsRecommended Vaccination Schedule and Intervals (1)
Single antigen vaccine1Single -antigen1and combination
vaccine2,3,4
Birth
weight Maternal
HBsAg status Dose Age Dose Age
≥2000 g Positive 1 B irth (≤12 hrs)11 B irth (≤12 hrs )1
2 1-2 months12 2 months
3 6 months 3 4 months
4 6 months
Unknown 1 B irth (≤12 hrs)1 1 B irth (≤12 hrs)1
2 1-2 months12 2 months
3 6 months 3 4 months
4 6 months
Negative51 2 months 1 2 months
2 3-4 months 2 4 months
3 6 -18 months 3 6 months
The tables below list the acceptable vaccination schedules for children and
adolescents, birth through 18 years of age.
Table 1. InfantsRecommended Vaccination Schedule and Intervals (2)
Single antigen vaccine1Single -antigen1and combination
vaccine2,3,4
Birth
weight Maternal
HBsAg
status Dose Age Dose Age
<2000 g Positive 1 Birth (≤12 hrs)1 1 B irth (≤12 hrs)1
2 1 month1 2 2 months
3 2-3 months 3 4 months
4 6 months 4 6 months
Unknown 1 B irth (≤12 hrs)1 1 B irth (≤12 hrs)1
2 1 month1 2 2 months
3 2-3 months 3 4 months
4 6 months 4 6 months
Negative51 2 months 1 2 months
2 3-4 months 2 4 months
3 6 -18 months 3 6 months
Table Notes:
1. Only a single antigen hepatitis B vaccine (ENGERIX -B or RECOMBIVAX HB) can be given at <6 weeks of age.
2. Pediarix [DTaP -IPV-HepB] is licensed for children 6 weeks through 6 years of age. For adequate immune response, the
last dose of hepatitis B vaccine should be given >24 weeks of age and therefore this combination vaccine should not be
administered as a complete primary series on an accelerated schedule at 4- week intervals for prevention of pertussis.
3. Vaxelis [DTaP -IPV-Hib-HepB ] is licensed for children 6 weeks through 4 years of age.  For adequate immune response,
the last dose of hepatitis B vaccine should be given >24 weeks of age and therefore this combination vaccine should
not be administered as a complete primary series on an accelerated schedule at 4- week intervals for prevention of
pertussis.
4. Use of brand names is not meant to preclude the use of other comparable US licensed vaccines.
5. Infants born to HBsAg -negative mothers may receive a dose of hepatitis B vaccine before two months of age  under
individual-based decision -making (also referred to as shared clinical decision -making), including consideration of risks
such as a household member who is HBsAg positive or when there is frequent contact with persons who have
emigrated from areas where Hepatitis B is common.  Infants vaccinated before two months of age under individual-
based decision -making may receive up to four doses of hepatitis B vaccine (1 dose of single antigen vaccine followed
by 3 doses of combination vaccine). Recommended Vaccination Schedule and Intervals (3)
Table 2. Children and AdolescentsRecommended Vaccination Schedule and Intervals (5)
Age Schedule1,6
Children
(1 through 10 years)0, 1, and 6 months2
0, 2, and 4 months2
0, 1, 2, and 12 months2,4
Adolescents (11 through 18 years)0, 1, and 6 months
2
0, 1, and 4 months2
0, 2, and 4 months2
0, 12, and 24 months2
0 and 4 -6 months3
0, 1, 2, and 12 months2,4
0, 7 days, 21 -30 days, 12 months5
Table Notes:
1.Children and adolescents not vaccinated at birth may be vaccinated according to any of the
schedules indicated, except as noted. Selection of a schedule should consider the need to optimize
compliance with vaccination.
2.Pediatric/adolescent formulation.
3.A two -dose schedule of Recombivax -HB Adult Formulation is (10 micrograms) is licensed for
adolescents aged 11 through 15 years.  When scheduled to receive the second dose, adolescents
aged > 15 years should be switched to a three -dose series, with doses 2 and 3 consisting of the
pediatric formulation administered on an appropriate schedule.
4.A four -dose schedule of Engerix B is licensed for all age groups.
5.Twinrix can be administered to persons 18 years of age before travel or any other potential
exposure on an accelerated schedule at 0, 7, and 21 -30 days, followed by a dose at 12 months.
6.Use of brand names is not meant to preclude the use of other comparable US licensed vaccines.  Recommended Vaccination Schedule and Intervals (6)
Interrupted schedules and minimum dosing intervals
•When the HepB vaccine schedule is interrupted, the vaccine series does not need to be restarted.  If
the series is interrupted after the first dose, the second dose should be administered as soon as
possible, and the second and third doses should be separated by an interval of at least eight weeks.
If only the third dose has been delayed, it should be administered as soon as possible.
•The final dose of vaccine must be administered at least eight weeks after the second dose and should
follow the first dose by at least 16 weeks; the minimum interval between the first and second doses
is four weeks. Inadequate doses of hepatitis B vaccine or doses received after a shorter -than
recommended dosing interval should be re -administered, using the correct dosage or schedule.
•Vaccine doses administered ≤4 days before the minimum interval or age are considered valid.  Because of the unique accelerated schedule for Twinrix , the four -day guideline does not apply to the
first three doses of this vaccine when administered on a 0 day, 7 day, 21 -30 day, and 12 month
schedule.
•In infants, administration of the final dose is not recommended before age 24 weeks (164 days). Recommended Vaccination Schedule and Intervals (7)
Revaccination
Revaccination (i.e., booster dose, challenge dose, or revaccination with a complete series) is not
generally recommended for persons with a normal immune status who were vaccinated as infants,
children, or adolescents. Revaccination when anti -HBs is <10 mIU/mL is recommended for the following:
-Infants born to HBsAg -positive mothers .  HBsAg -negative infants with anti -HBs <10 mIU/mL
should be re -vaccinated with a single dose of HepB vaccine and receive post vaccination serologic
testing 1 -2 months later.  Infants whose anti -HBs remains <10 mIU/mL following single dose
revaccination should receive two additional doses of HepB vaccine, followed by PVST 1 -2 months
after the final dose.
•Based on clinical circumstances or family preference, HBsAg -negative infants with anti -HBs
<10 mIU/mL may instead be revaccinated with a second, complete 3 -dose series, followed
by post vaccination serologic testing (PVST) performed 1 -2 months after the final dose of
vaccine.
-Hemodialysis patients .  For hemodialysis patients, the need for booster doses should be assessed
by annual anti -HBs testing.  A booster dose should be administered when anti -HBs levels decline to
<10 mIU/mL.Recommended Vaccination Schedule and Intervals (8)
Revaccination
-Other immunocompromised persons .  For other immunocompromised persons (e.g., HIV -infected
persons, hematopoietic stem -cell transplant recipients, and persons receiving chemotherapy), the
need for booster doses has not been determined.  When anti -HBs levels decline to <10 mIU/mL,
annual anti -HBs testing and booster doses should be considered for persons with an ongoing risk
for exposure.
-Persons with postvaccination serologic testing results that do not demonstrate protection . This
includes children and adolescents through age 18 years who are chronic hemodialysis patients,
HIV-infected, otherwise immunocompromised (e.g., hematopoietic stem -cell transplant recipients
or persons receiving chemotherapy), or sex partners of HBsAg -positive persons. Persons in these
groups found to have anti -HBs concentrations of <10 mIU/mL after the primary vaccine series
should be revaccinated.  Recommended Vaccination Schedule and Intervals (9)
Recommended dosage
Refer to package inserts available at:  Vaccines Licensed for Use in the United
States | FDA
Contraindications and Precautions
Contraindications can be found in the package inserts available at: Vaccines
Licensed for Use in the United States | FDADosage, Contraindications, Precautions
•[If an ACIP recommendation or notice regarding hepatitis B vaccination
immunization is published within 6 months following this resolution, the
relevant language above (except in the eligible groups sections) will be
replaced with the language in the recommendation and incorporated by
reference to the publication URL.]Statement Regarding Update Based on Published Documents

Summary: VFC Resolution Update:  Hepatitis B Vaccine December 4, 2025National Center for Immunization & Respiratory Diseases  •Red font in the presentation is used to indicate changes to the resolution in  comparison to the currently approved version.Note •The purpose of this resolution is to update the Recommended Vaccination  Schedule and Intervals section to reflect updated ACIP recommendations  about the use of Hepatitis B vaccine.  Purpose of the Resolution •  All children and adolescents birth…


02 johnson coverage implications

Centers for Medicare & Medicaid Services
Overview of Vaccine Coverage
December 2025
1
Medicaid and CHIP
•Coverage of vaccines is anchored to ACIP recommendations, and the
adult/pediatric vaccine schedules, which is based on those recommendations.
•State Medicaid and Children’s Health Insurance Programs (CHIP) are required to
cover all vaccines recommended by CDC/ACIP that are included on the
adult/pediatric immunization schedules without cost sharing for most
beneficiaries, including children and adults.*
•Recommendations included on the pediatric/adult immunization schedules that
refer to shared clinical decision making, also known as individual -based decision
making, are mandatorily covered in both Medicaid and CHIP .
•The Vaccines For Children (VFC) program is a vaccine distribution program
overseen by CDC that provides federally purchased vaccines to children through
age 18 who are either enrolled in Medicaid, uninsured, underinsured, or
American Indian/Alaska Native. Each state runs a VFC program according to CDC
guidelines, typically through the state health department, and makes state
coverage decisions.
* Mandatory Medicaid vaccination coverage varies between adults and children, see the coverage chart on slide 4 for more info rmation.
2
Medicaid and CHIP (continued)
•States have flexibility to determine Medicaid/CHIP coverage beyond mandatory
coverage anchored to the ACIP/CDC recommendations and the pediatric and adult
immunization schedules. Therefore, any recommendation that is not on the pediatric
vaccine schedule or any recommendation that narrows the criteria will lead to variable
coverage across state Medicaid & CHIP programs.
•In Medicaid, through Early and Periodic Screening, Diagnostic, and Treatment (EPSDT)
requirements, coverage for individuals up to age 21 could include additional
vaccinations beyond what is included on the vaccine schedule based on the state’s
medical necessity criteria. In CHIP , states have the flexibility to choose to cover vaccines
beyond what is included in the immunization schedule.
•If states opt to provide expanded vaccine coverage, they will receive federal match for
the full scope of coverage. States may not need approval from CMS to provide coverage
beyond the ACIP recommendation as that level of detail is not required in the Medicaid
& CHIP state plans.
3
Medicaid and CHIP (continued)
4Population Is coverage of vaccines and their administration mandatory?
Adult Medicaid Full Coverage/Full
Benefit Enrollees YES, for all categories of ACIP recommendations .
Adults Enrolled in Alternative
Benefit Plans (typically adults
enrolled in the Medicaid expansion)YES, for all routine ACIP recommendations (those on the adult/pediatric immunization
schedule) .  States that align ABP coverage with state plan coverage will need to cover all
ACIP recommended vaccinations per the IRA coverage requirements.
Child Medicaid Full Coverage/Full
Benefit Enrollees Aged 18 and
Younger YES, for all vaccines on the CDC/ACIP pediatric schedule and those vaccinations determined
to be medically necessary as established by the state. Therefore, any recommendation that
is not on the pediatric vaccine schedule or any recommendation that narrows the criteria
will lead to variable coverage across state Medicaid & CHIP programs.
Child Medicaid Full Coverage/Full
Benefit Enrollees Aged 19 and OlderYES, for all categories of ACIP recommendations.
CHIP Enrollees YES, for all categories of ACIP recommendations .
Private / Employer Sponsored Plans
•Non -grandfathered employer -sponsored plans and non -grandfathered group and
individual health insurance coverage are required to cover all ACIP -recommended
vaccines for routine use without cost sharing.
oThis includes recommended vaccines on the pediatric vaccine schedule.
•With respect to employer -sponsored and individual health insurance coverage (as
opposed to self -insured employer -sponsored plans governed by ERISA), states may
impose benefit mandates, including vaccination mandates, that are more expansive
than Federal requirements.
•Plans and issuers are required to continue to cover the vaccine in a manner
consistent with the current recommendation for the duration of a plan or policy year
before the applicable plan or policy year of the new recommendation, unless doing so
would pose a significant safety concern.
5

Summary: Centers for Medicare & Medicaid Services Overview of Vaccine Coverage December 2025 1 Medicaid and CHIP •Coverage of vaccines is anchored to ACIP recommendations, and the  adult/pediatric vaccine schedules, which is based on those recommendations.  •State Medicaid and Children’s Health Insurance Programs (CHIP) are required to  cover all vaccines recommended by CDC/ACIP that are included on the  adult/pediatric immunization schedules without cost sharing for most  beneficiaries, including…


01 siri child imz schedule 508

Development of the U.S. Childhood Vaccine Schedule
Aaron SiriACIP Meeting, December 5, 2025With A Focus on Suggested Improvements
DisclosuresManaging Partner of Siri & Glimstad LLP with 100+ professionals who handle civil rights, exemptions, immigration, employment, and injury claims related to vaccination. Author of Vaccines, Amen: The Religion of Vaccines.
2

Growth of U.S. Childhood Vaccine Schedule
Growth of U.S. Vaccine Schedule
4Source:https://www.cdc.gov/vaccines/hcp/imz-schedules/resources.html
1983 U.S. Vaccine Schedule

Growth of U.S. Vaccine Schedule2025 U.S. Vaccine Schedule
5
Source: https://www.cdc.gov/vaccines/hcp/imz-schedules/downloads/child/0-18yrs-child-combined-schedule.pdf

Growth of U.S. Vaccine Schedule1983 v. 2025 U.S. Childhood Vaccine Schedule
6Reflects: stand-alone routine vaccines given at earliest recommended age; and 3-dose RV, 4-dose Hib, and 2-dose HPV series. Sources: https://www.cdc.gov/vaccines/hcp/imz-schedules/resources.html; https://www.cdc.gov/vaccines/hcp/imz-schedules/child-adolescent-age.html; https://www.cdc.gov/vaccines-pregnancy/hcp/vaccination-guidelines/index.html   Routine Vaccines: In Utero to 18 Years
Vaccines given<12 months of ageVaccines given > 12 months of age19832025DTP (2 Months)OPV (2 Months)DTP (4 Months)OPV (4 Months)DTP (6 Months)MMR (15 Months)DTP (18 Months)OPV (18 Months)DTP (4 Years)OPV (4 Years)Td (14 Years)IPV (6 Months)Hep B (6 Months)Flu (6 Months)Flu (7 Months)Hib (12 Months)PCV (12 Months)Hep A (12 Months)VAR (12 Months)MMR (12 Months)DTaP (15 Months)Hep A (18 Months)Flu (2 Years)Flu (3 YearsDTaP (4 Years)IPV (4 Years)Flu (4 Years)MMR (4 Years)VAR (4 Years)Flu (5 Years)Flu (6 Years)Flu (7 Years)Flu (8 Years)Flu (9 Years)Flu (10 Years)Tdap (11 Years)HPV (11 Years)Flu (11 Years)HPV (11 Years)MenACWY (11 Years)Flu (12 Years)Flu (13 Years)Flu (14 Years)Flu (15 Years)MenACWY (16 Years)Flu (16 Years)Flu (17 Years)Flu (18 Years)TdaP (In Utero)Flu (In Utero)RSV (In Utero or Birth)Hep B (Birth)Hep B (1 Month)RV (2 Months)DTap (2 Months)Hib (2 Months)PCV15 (2 Months)IPV (2 Months)RV (4 Months)DTap (4 Months)Hib (4 Months)IPV (4 Months)PCV15 (4 Months)RV (6 Months)DTap (6 Months)Hib (6 Months)PCV15 (6 Months)
Growth of U.S. Vaccine Schedule1983 v. 2025 U.S. Childhood Vaccine Schedule
7Routine + Shared Decision-Making Vaccines (Covid-19 and MenB)
Reflects: stand-alone routine vaccines given at earliest recommended age; and 3-dose RV, 4-dose Hib, 2-dose HPV, and 3-dose Covid-19 series. Sources: https://www.cdc.gov/vaccines/hcp/imz-schedules/resources.html; https://www.cdc.gov/vaccines/hcp/imz-schedules/child-adolescent-age.html; https://www.cdc.gov/vaccines-pregnancy/hcp/vaccination-guidelines/index.html   Vaccines given<12 months of ageVaccines given > 12 months of age19832025DTP (2 Months)OPV (2 Months)DTP (4 Months)OPV (4 Months)DTP (6 Months)MMR (15 Months)DTP (18 Months)OPV (18 Months)DTP (4 Years)OPV (4 Years)Td (14 Years)Covid-19 (11 Years)Flu (12 Years)Covid-19 (12 Years)Flu (13 Years)Covid-19 (13 Years)Flu (14 Years)Covid-19 (14 Years)Flu (15 Years)Covid-19 (15 Years)MenB (16 Years pt.1)MenACWY (16 Years)Flu (16 Years)MenB (16 Years pt.2)Covid-19 (16 Years)Flu (17 Years)Covid-19 (17 Years)Flu (18 Years)Covid-19 (18 Years)TdaP (In Utero)Flu (In Utero)RSV (In Utero or Birth)Hep B (Birth)Hep B (1 Month)RV (2 Months)DTap (2 Months)Hib (2 Months)PCV15 (2 Months)IPV (2 Months)RV (4 Months)DTap (4 Months)Hib (4 Months)IPV (4 Months)PCV15 (4 Months)RV (6 Months)DTap (6 Months)Hib (6 Months)PCV15 (6 Months)IPV (6 Months)Hep B (6 Months)Flu (6 Months)Covid-19 (6 Months)Flu (7 Months)Covid-19 (7 Months)Covid-19 (9 Months)Hib (12 Months)PCV (12 Months)Hep A (12 Months)VAR (12 Months)MMR (12 Months)DTaP (15 Months)Hep A (18 Months)Flu (2 Years)Covid-19 (2 Years)Flu (3 YearsCovid-19 (3 Years)DTaP (4 Years)IPV (4 Years)Flu (4 Years)MMR (4 Years)VAR (4 Years)Covid-19 (4Years)Flu (5 Years)Covid-19 (5 Years)Flu (6 Years)Covid-19 (6 Years)Flu (7 Years)Covid-19 (7 Years)Flu (8 Years)Covid-19 (8 Years)Flu (9 Years)Covid-19 (9Years)Flu (10 Years)Covid-19 (10 Years)Tdap (11 Years)HPV (11 Years)Flu (11 Years)HPV (11 Years)MenACWY (11 Years)
Growth of U.S. Vaccine Schedule
1983 v. 2025 U.S. Vaccine Schedules
8Routine Vaccines: In Utero To 12 Months
Reflects stand-alone routine vaccines given at earliest recommended age; and 3-dose RV and 4-dose Hib series. Sources:https://www.cdc.gov/vaccines/hcp/imz-schedules/resources.html; https://www.cdc.gov/vaccines/hcp/imz-schedules/child-adolescent-age.html; https://www.cdc.gov/vaccines-pregnancy/hcp/vaccination-guidelines/index.html
Growth of U.S. Vaccine Schedule2025 U.S. Vaccine Schedule
9All data reflects rates at approximately 2 years of age except for Tdap, HPV, and MenACWY which reflect the rate for ages 13 to 17.  Sources: https://web.archive.org/web/20190618125412https:/www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/e/coverage-levels.pdf; 1983 IIV uptake is an estimate; https://www.cdc.gov/mmwr/volumes/73/wr/mm7338a3.htm; https://www.cdc.gov/mmwr/volumes/70/wr/mm7035a1.htm?s_cid=mm7035a1_wRoutine Vaccine Coverage: United States 1983 v. 20201983202066%65%57%3%0%0%0%0%0%0%0%0%MMRDTPOPVIIVHepBHibPCVRVVARHepATdapHPV0%MenACWY3+ Doses1+ Doses3+ Doses94%92%93%63%93%94%
DTaPMMRIPVIIVHepBHibPCVRVVARHepATdapHPVMenACWY1+ Doses3+ Doses3+ Doses2+ Doses3+ Doses2+ Doses93%3+ Doses77%2+ Doses91%1+ Doses88%1+ Doses90%1+ Doses75%1+ Doses89%1+ Doses
Pre-Licensure Safety: U.S. Childhood Vaccine Schedule
Pre-Licensure Safety of the U.S. Vaccine ScheduleImportance of Clinical Trials
11* Stand-alone vaccines for children, excluding influenza; IPOL date is an estimate; DTP date uncertain. Source of data: see accompanying memorandum.Vaccine*Year Licensed for ChildrenYear ACIP Recommended for Routine Use in Children [Earlier Non-Routine Use]Days Between Licensure & RecommendationDTP (various)M-M-R-II (Merck)MenomuneRecombivax HB (Merck)Engerix-B (GSK)PedvaxHIB (Merck)Ipol (Sanofi)ActHIB (Sanofi)Varivax (Merck)Havrix (GSK)Vaqta (Merck)Infanrix (GSK)Prevnar 7*19781981198619891989199019931995199519961997200019661978199119911990 199719931996 2006 200619972000*49 days 1948 days 816 days133 days 2580 days24 days294 days 4104 days 3703 days73 days-1 days[1985][1987][1990][1994][1996][1996][1264][331][192][1691][674][273]Vaccine*Year Licensed for ChildrenYear ACIP Recommended for Routine Use in Children [Earlier Non-Routine Use]Days Between Licensure & RecommendationDaptacel (Sanofi)Boostrix (GSK)Adacel (Sanofi)Menactra (Sanofi)Gardasil (Merck)Hiberix (GSK)Prevnar 13 (Pfizer)Menveo (GSK)Gardasil-9MenQuadfi (Sanofi)Vaxneuvance (Merck)Priorix (GSK)Prevnar 20 (Pfizer)2002200520052005200620092010201020142020202220222023200220052005200520062009201020102015202020222022202352 days24 days20 days27 days21 days30 days0 days19 days78 days62 days5 days17 days56 daysCurrent routine vaccine recommended for children.Previously recommended for children and used as control to license currently recommended vaccine.
Pre-Licensure Safety of the U.S. Vaccine ScheduleQuality of Trials Crucial
12Source:  * https://www.fda.gov/media/130326/download  † https://jamanetwork.com/journals/jamapediatrics/fullarticle/2714387 ControlSafety Review PeriodPowerA placebo (defined by FDA as “inert substances”*) or another vaccine for same indication that was properly trialed prior to licensure.To “provide complete safety data across all critical periods of growth and development,” as compared to trials for adults, “data on drug efficacy and safety in children may require an additional 6 years.” JAMA Pediatrics, author affiliations Office of Pediatric Therapeutics, FDA, and Duke Clinical Research Institute.†Enough participants to assess if benefits outweigh risks.Critical to avoid bias.Randomized and Blinded
Pre-Licensure Safety of the U.S. Vaccine ScheduleDrug Trials
13Trials Relied Upon to License Pfizer’s Top 4 Most Profitable Drugs*
* As of 2019. Sources: https://moneyinc.com/the-five-highest-selling-pfizer-drugs-of-all-time/; https://www.fda.gov/drugs/development-approval-process-drugs/drug-approvals-and-databases  Eliquis 7.4 Years PlaceboLipitor4.9 YearsPlaceboLyrica2 YearsPlaceboDRUG SAFETY REVIEW CONTROL Enbrel 6.6 Years Placebo
Pre-Licensure Safety of the U.S. Vaccine ScheduleChildhood Vaccine Trials
“[W]idespread vaccine hesitancy observed during the Covid-19 pandemic suggests that the public is no longer satisfied with the traditional safety goal of simply detecting and quantifying the associated risks after a vaccine has been authorized for use.”“Postauthorization studies are needed to fully characterize the safety profile of a new vaccine, since prelicensure clinical trials have limited sample sizes, follow-up durations, and population heterogeneity.”14
Source: https://www.nejm.org/doi/full/10.1056/NEJMp2402379
Pre-Licensure Safety of the U.S. Vaccine ScheduleControls Routine Vaccines: Birth to 6 Months
15Lists stand-alone routine vaccines. Some DTP trials use other DTP vaccines as a control but none licensed based on placebo-controlled trial. See supporting memorandum for sources.Vaccine TypeVaccineControlPlacebo?Hep BEngerix-B (GSK)No controlRecombivax HB (Merck)No controlDTaPInfanrix (GSK)DTP No controlDaptacel (Sanofi)DTP No controlHibActHIB (Sanofi)Hep B    No controlHiberix (GSK)ActHIB     Hep B        No ControlPedvaxHIB (Merck)Lyophilized PedvaxHIB            Injection of lactose, aluminum adjuvant, and thimerosalPCVVaxneuvance (Merck)Prevnar 13            Prevnar 7   Investigational vaccinePrevnar 20 (Pfizer)Prevnar 13            Prevnar 7   Investigational vaccineIPVIpol (Sanofi)No controlIIVVariousNo placebo control – see memorandumNONONONONONONONONONONO
Pre-Licensure Safety of the U.S. Vaccine ScheduleControls Routine Vaccines: 7+ Months of Age
16Lists stand-alone routine vaccines. See supporting memorandum for sources.Vaccine TypeVaccineControlPlacebo?MMRM-M-R-II (Merck)No controlPriorix (GSK)M-M-R-II            No controlVaricellaxVarivax (Merck)Injection of 45mg of neomycin per ml (465 subjects)Havrix (GSK)Engerix-B            No controlHep AVaqta (Merck)Injection of AAHS and thimerosalBoostrix (GSK)Decavac        No controlAdacel (Sanofi)Decavac        No controlTdapGardisil-9 (Merck)Gardasil or Placebo+Gardasil (3 doses) (306 subjects)HPVMenveo (GSK)Menactra            Menomune             No controlMenACWYMenQuadfi (Sanofi)Menveo            Menactra             Menomune or Menactra            No controlNONONONONONONONONONOInjection of AAHS or Gardasil carriersolution (yeast protein...) (320 subjects)
Pre-Licensure Safety of the U.S. Vaccine ScheduleSafety DurationsSafety in childhood trials is typically reviewed for 6 months or less after injection—often only days or weeks.
17Stand-alone routine infant vaccines. See supporting memorandum for sources.Vaccine TypeVaccineSolicited ReactionsUnsolicited ReactionsHep BRecombivax HB (Merck)5 daysEngerix-B (GSK)4 daysHibActHIB (Sanofi)3 daysPedvaxHIB (Merck)3 daysDTaPHiberix (GSK)4 daysInfanrix (GSK)8 daysDaptacel (Sanofi)14 daysIPVIPOL (Sanofi)3 daysVaxneuvance (Merck)14 daysPrevnar 20 (Pfizer)7 daysDuration of Safety Review After Injection
PCV5 days4 days30 days3 days31 days30 days6 months3 days6 months6 months
Pre-Licensure Safety of the U.S. Vaccine ScheduleStatistical PowerInsufficient number of children in trials to assess if benefits outweigh risks.
18See supporting memorandum for discussion and sources.
Example: First vaccine on the schedule, Hep B
Pre-Licensure Safety of the U.S. Vaccine ScheduleExample: Hep B Vaccines
19
Sources: https://www.fda.gov/vaccines-blood-biologics/vaccines/recombivax-hb; https://www.fda.gov/vaccines-blood-biologics/vaccines/engerix-b

Pre-Licensure Safety of the U.S. Vaccine ScheduleExample: Hep B Vaccines
20Source: https://www.cdc.gov/mmwr/preview/mmwrhtml/00033405.htm
295281229438142528292Cited Articles Involving Children Receiving Recombivax, Engerix-B, or Other Recombinant DNA VaccinePMIDSafety Monitoring After InjectionNumber of ChildrenFunding7 days5 days3 days122794,250Merck conducted and fundedIMerck conducted and fundedGSK funded
Pre-Licensure Safety of the U.S. Vaccine ScheduleExample: Hep B Vaccines
21Source: https://www.cdc.gov/acip/downloads/slides-2025-09-18-19/02-langer-hep-b-508.pdf; https://www.nationalacademies.org/read/13164/chapter/2#2
ACIP Presentation:September 18, 2025Institute of Medicine FindingsAdverse Event – Hep B VaccineAnaphylaxisEncephalitisEncephalopathySeizuresAcute Disseminated EncephalomyelitisTransverse MyelitisOptic NeuritisNeuromyelitis OpticaMultiple Sclerosis OnsetMultiple Sclerosis RelapseFirst Demyelinating EventGuillain-Barre SyndromeCIDPSupportsInadequateInadequateInadequateInadequateInadequateInadequateInadequateInadequateInadequateInadequateInadequateInadequateBrachial NeuritisErythema NodosumSystemic Lupus ErythematosusVasculitisPolyarteritis NodosaPsoriatic ArthritisReactive ArthritisInadequateRheumatoid ArthiritisJuvenile Idiopathic ArthiritisType 1 DiabetesFibromyalgiaInadequateInadequateInadequateInadequateInadequateInadequateInadequateInadequateInadequateInadequateInadequateInadequateAdverse Event – Hep B VaccineThe Evidence on Causation:Supports, Rejects, or InadequateThe Evidence on Causation:Supports, Rejects, or Inadequate
Pre-Licensure Safety of the U.S. Vaccine ScheduleExample: PCV VaccinesFirst Licensed PCV Vaccine: PCV-7Licensed: February 17, 2000Control: “Investigational meningococcal group C conjugate vaccine”Safety review: 30 days (emergency room), 60 days (hospitalizations), longer (select conditions)
22Source: https://stacks.cdc.gov/view/cdc/76558; https://jamanetwork.com/journals/jama/fullarticle/199581
“Prior to licensure … the control group in the main study received another experimental vaccine, rather than a placebo. If both vaccines provoked similar adverse effects, little or no difference between the 2 groups might have been evident.” Also noting the “limited sample sizes of trials.”
__________________________________________________________________________________________ACIP Added to Schedule: February 16, 2000
Pre-Licensure Safety of the U.S. Vaccine ScheduleExample: PCV VaccinesSecond Licensed PCV Vaccine: PCV-13
23Source: https://www.fda.gov/media/107657/download; https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5911a1.htm; https://www.fda.gov/safety/reporting-serious-problems-fda/what-serious-adverse-event
•Death•Life-threatening•Hospitalization•Disability or Permanent Damage•Congenital Anomaly/Birth Defect•Required Intervention to Prevent Permanent Impairment•Require Medical or Surgical Intervention to Prevent an Outcome Above
Licensed: February 24, 2010ACIP Added to Schedule: February 24, 2010
Pre-Licensure Safety of the U.S. Vaccine ScheduleExample: PCV VaccinesThird Licensed PCV Vaccine: PCV-15Licensed: June 17, 2022ACIP Added to Schedule: June 22, 2022
24Source: https://www.fda.gov/media/150819/download

Pre-Licensure Safety of the U.S. Vaccine ScheduleExample: PCV Vaccines Recap
25Days in each box reflects period between licensure & ACIP addition to scheduleInvestigationalVaccinePrevnar 7-1 DAYSPrevnar 130 DAYSVaxneuvance5 DAYSPrevnar 2056 DAYS
Pre-Licensure Safety of the U.S. Vaccine ScheduleFinal Example: DTaP Vaccines2014 SAGE Systematic Review“The majority of studies indicated a deleterious effect of DTP on mortality.”26Source: https://terrance.who.int/mediacentre/data/sage/SAGE_Docs_Ppt_Apr2014/9_session_non-specific_vaccine_effects/Apr2014_session9_epidemiologic_review.pdfDays in each box reflects period between licensure & ACIP addition to scheduleDTPInfanrixDaptacel73 DAYS52 DAYS
Pre-Licensure Safety of the U.S. Vaccine ScheduleFinal Example: DTaP Vaccines
27Source: https://pubmed.ncbi.nlm.nih.gov/28188123/. See memorandum for discussion and additional sources.

Pre-Licensure Safety of the U.S. Vaccine ScheduleNon-Routine VaccinesExample: Dengue VaccineClinical Trial:•Safety Review: 6 Years for severe dengue•Control: Placebo•Size: 30,000+Findings:•Age <6: increased risk of severe harm and death from the vaccine•Age >6 and never had dengue: increased risk of severe harm and death from the vaccine28Source: https://www.fda.gov/media/125481/download; https://www.fda.gov/media/124379/download
Pre-Licensure Safety of the U.S. Vaccine ScheduleDrug Trials v. Vaccine Trials
29Trials Relied Upon to License Pfizer’s Top 4 Most Profitable Drugs*
* As of 2019. Sources: https://moneyinc.com/the-five-highest-selling-pfizer-drugs-of-all-time/; https://www.fda.gov/vaccines-blood-biologics/vaccines/vaccines-licensed-use-united-statesEliquis 7.4 Years PlaceboLipitor4.9 YearsPlaceboLyrica2 YearsPlaceboDRUG SAFETY REVIEW CONTROL Enbrel 6.6 Years Placebo
Pre-Licensure Safety of the U.S. Vaccine ScheduleImpact of Immunity on Market Forces
30
See supporting memorandum
Pre-Licensure Safety of the U.S. Vaccine ScheduleEthics Of Relying On Improperly Controlled Trials
31Source: https://pmc.ncbi.nlm.nih.gov/articles/PMC1113953/“In some trials placebos were omitted on ethical grounds. This is illogical because studies destined to produce unreliable results should themselves be considered unethical.”British Medical JournalAuthor affiliations: University of Oxford, Oxford Radcliffe Hospital, Radcliffe Infirmary, and Geneva University Hospital
Pre-Licensure Safety of the U.S. Vaccine ScheduleRevisit ACIP Recommendations
32Robust clinical trial data should support the safety of each recommendation.
Post-Licensure Safety: U.S. Childhood Vaccine Schedule
Post-Licensure Safety of the U.S. Vaccine Schedule1991 IOM report: Adverse Effects of Pertussis and Rubella Vaccines
Source: https://www.nationalacademies.org/publications/181534Vaccine TypePertussis1. Acute encephalopathy  2. Shock and “unusual  shock-like state”  3. Anaphylaxis 4. Protracted, inconsolable  crying1. Autism  2. Aseptic meningitis 3. Chronic neurologic damage 4. Erythema multiforme or  other rash 5. Guillain-Barre syndrome 6. Hemolytic anemia 7. Juvenile diabetes 8. Learning disabilities and  attention-deficit disorder 9. Peripheral mononeuropathy 10. Thrombocytopenia 11. Radiculoneuritis and  other neuropathies 12. Thrombocytopenic purpuraRubella5. Chronic arthritis 6. Acute arthritis1. Infantile spasms 2. Hypsarrythmia 3. Reye syndrome; 4. Sudden infant death syndromeThe EvidenceFavors Rejectinga Causal RelationshipFavors Accepting or Convincingly Supports a Causal RelationshipIs Inadequate to Accept or Rejecta Causal Relationship
Post-Licensure Safety of the U.S. Vaccine Schedule1994 IOM report: Adverse Events Associated with Childhood Vaccines
Source: https://www.nationalacademies.org/publications/213835“The lack of adequate data regarding many of the adverse events under study was of major concern to the committee.Presentations at public meetings indicated that many parents and physicians share this concern.”DT/Td/TMeaslesMumpsOPV/IPV Hepatitis B H. influenzaetype (Hib) Vaccine Type1. Encephalopathy  2. Infantile spasms (DT only) 3. Death from SIDS (DT only)The EvidenceFavors Rejectinga Causal RelationshipFavors Accepting or Convincingly Supports a Causal RelationshipIs Inadequate to Accept or Rejecta Causal Relationship1. Guillain-Barre syndrome 2. Brachial neuritis 3. Anaphylaxis4. Anaphylaxis 5. Thrombocytopenia (MMR) 6. Anaphylaxis (MMR)7. Death from measles  vaccine-strain viral infection1. Residual seizure disorder than infantile spasms 2. Demyelinating diseases of the central nervous system 3. Mononeuropathy4. Arthritis5. Erythema maltiforme6. Encephalopathy 7. Subacute sclerosing panencephalitis   central nervous system 8. Residual seizure9. Sensorineural deafness (MMR) 10. Optic neuritis11. Transverse-myelitis12. Guillain-Barre syndrome 13. Thrombocytopenia14. Insulin-dependent diabetes mellitus15. Neuropathy16. Residual seizure disorder 17. Encephalopathy 18. Aseptic meningitis  19. Sensorineural deafness (MMR) 20. Insulin-dependent diabetes mellitus21. Sterility22. Thrombocytopenia23. Anaphylaxis24. Encephalopathy25. Subacute sclerosing panencephalitis26. Residual seizure 27. Sensorineural deafness (MMR)  28. Optic neuritis29. Transverse-myelitis30. Guillain-Barre syndrome31. Thrombocytopenia32. Insulin-dependent diabetes mellitus8. Guillain-Barre syndrome  (OPV)  9. Poliomyelitis in recipient or  contact (OPV)  10. Death from polio 11. Anaphylaxis33. Guillain-Barre syndrome34. Demyelinating diseases of the central nervous system35. Arthritis36. Death from SIDS12. Early-onset H. influenzae b  disease in children age 18  months or older who receive  their first Hib immunization  with unconjugated PRP  vaccine37. Guillain-Barre syndrome38. Transverse myelitis39. Thrombocytopenia40. Anaphylaxis41. Death from SIDS4. Early onset H. influenzae  disease (conjugate vaccines)
Post-Licensure Safety of the U.S. Vaccine Schedule2012 IOM report: Adverse Effects of Vaccines: Evidence and Causality
Source: https://www.nationalacademies.org/projects/PHPH-H-08-17-A/publication/13164 362624232312 108  8Hep BDTaP/Tdap/TD/TdInfluenzaMMRHPVVaricellaHep AMeningococcal01220 0 0011251501Vaccine TypeThe EvidenceFavors Rejectinga Causal RelationshipFavors Accepting or Convincingly Supports a Causal RelationshipIs Inadequate to Accept or Rejecta Causal Relationship
Total516134
Post-Licensure Safety of the U.S. Vaccine ScheduleCombined Results of the IOM Reports
Source: https://www.nationalacademies.org/publications/1815; https://www.nationalacademies.org/publications/2138; https://www.nationalacademies.org/projects/PHPH-H-08-17-A/publication/13164 374339302312109855MMRDTaP/Tdap/TD/TdHep BInfluenzaHPVVaricellaHep AMeningococcalHibOPV/IPV28020 0 001011822150113Vaccine TypeThe EvidenceFavors Rejectinga Causal RelationshipFavors Accepting or Convincingly Supports a Causal RelationshipIs Inadequate to Accept or Rejecta Causal Relationship
Total1334183
Post-Licensure Safety of the U.S. Vaccine SchedulePost-Licensure Vaccine Safety Funding Insufficient
“It is critical to examine adverse events following immunization (AEFIs) that have not been detected in clinical trials, to ascertain whether they are causally or coincidentally related to vaccination.”“Although the ACIP acknowledges the need, there are currently no resources earmarked for postauthorization safety studies beyond annual appropriations, which must be approved by Congress each year.” “[T]he budget for vaccine-safety monitoring at the CDC (which is responsible for the majority of U.S. federal efforts) has remained stagnant … at about $20 million per year” which is an “inadequate level of funding.”Source: https://www.nejm.org/doi/full/10.1056/NEJMp2402379  38
Post-Licensure Safety of the U.S. Vaccine ScheduleInjury Claimed To Have Been Most Thoroughly Studied
Source: https://www.congress.gov/99/statute/STATUTE-100/STATUTE-100-Pg3743.pdf
39
Post-Licensure Safety of the U.S. Vaccine Schedule
Source: https://doi.org/10.17226/1815Injury Claimed To Have Been Most Thoroughly Studied
40
Post-Licensure Safety of the U.S. Vaccine Schedule
Source: https://doi.org/10.17226/13164
Injury Claimed To Have Been Most Thoroughly Studied
41
Post-Licensure Safety of the U.S. Vaccine Schedule
See accompanying memorandum for source and discussion.
Injury Claimed To Have Been Most Thoroughly Studied
42
Post-Licensure Safety of the U.S. Vaccine ScheduleInjury claimed to have been most thoroughly studied
Source: https://ecf.nysd.uscourts.gov/doc1/127126484251
18 involving thimerosal and/or MMR1  involving antigen (not vaccine) exposure1 involving MMR, thimerosal, and DTaP43
Post-Licensure Safety of the U.S. Vaccine ScheduleInjury claimed to have been most thoroughly studied
44
Source: https://www.cdc.gov/vaccine-safety/about/autism.html
Post-Licensure Safety of the U.S. Vaccine ScheduleAdverse Reactions Manufacturers Have a Basis to Believe Are Causally RelatedFederal Law: 21 C.F.R. §201.57Package inserts for vaccines should include “only those adverse events for which there is some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event.”
Source: https://www.fda.gov/media/72139/download FDA: Guidance for Industry: Adverse Reaction Section for Labeling for Drugs and Biological Products – Content and Format: “For purposes of prescription drug labeling and this guidance, an adverse reaction … does not include all adverse events observed during use of a drug, only those for which there is some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event.” 45
Post-Licensure Safety of the U.S. Vaccine ScheduleImportance of Unexposed GroupCDC Manual for the Surveillance of Vaccine-Preventable Diseases“Because … there is a lack of an unvaccinated group for comparison in VAERS…, reports to VAERS are useful for generating hypotheses, but studies with vaccinated and unvaccinated subjects are necessary to confirm any hypotheses.”* * *Studies finding safety concerns that lack an unexposed group are often discarded. Example: DTaP and autism study. Sources: https://www.cdc.gov/surv-manual/php/table-of-contents/chapter-21-vaers.html46
Post-Licensure Safety of the U.S. Vaccine Schedule2013 IOM Vaccine Schedule Safety Review“[N]o study … compared the differences in health outcomes … between entirely unimmunized populations of children and fully immunized children. Experts who addressed the committee pointed not to a body of evidence that had been overlooked but rather to the fact that existing research has not been designed to test the entire immunization schedule. …[Also,] studies designed to examine the long-term effects of the cumulative number of vaccines or other aspects of the immunization schedule have not been conducted.”The IOM committee explained “there is no evidence that the schedule is not safe.”Source: https://www.ncbi.nlm.nih.gov/books/NBK206948/  The Childhood Immunization Schedule and Safety
47
Post-Licensure Safety of the U.S. Vaccine ScheduleUnvaccinated Children in the U.S.
* National Immunization Survey-Child estimates 1.2% of 2-year-olds in the U.S. are unvaccinated. Based on exemption rate data for school age children, at least 1% appear to remain unvaccinated.https://www.cdc.gov/mmwr/volumes/73/wr/pdfs/mm7341a3-H.pdf; https://www.cdc.gov/schoolvaxview/data/index.html 48Age(s)Unvaccinated(no vaccines) est.2 Years of Age2-17 Years of Age45,300658,000
Post-Licensure Safety of the U.S. Vaccine ScheduleCDC Surveillance Systems
See supporting memorandum for sources and discussion. * https://www.cdc.gov/vaccine-safety/media/pdfs/white-paper-safety-508.pdf   49“The current safety surveillance systems such as the VSD … already have extensive systems in place to assess short-term outcomes … [despite the fact] the childhood immunization schedule is essentially a long-term exposure, occurring over 18 to 24 months, [and hence] long-term adverse events may be more biologically plausible than short-term events.” – CDC*CDCStudy Vaccinated v. UnvaccinatedPopulationsVSDNoteVAERSV-SafeCISANONONONOEstimated to include >20,000 unvaccinated children. Deidentified data not shared with public.CDC has refused to automate capture and submission of VAERS reports.Automated but fails to list reactions of interest.Not useful for assessing safety at a population level.
Post-Licensure Safety of the U.S. Vaccine ScheduleStudies With Unvaccinated GroupsData comparing vaccinated and unvaccinated children show a consistent pattern of vaccinated children having multiple times the rate of various chronic health issues. Sampling:
50Study LinkAuthor AffiliationsFindingshttps://pmc.ncbi.nlm.nih.gov/articles/PMC7268563/ Simpson University (CA) and Institute of Medical and Scientific Inquiry (NM)Vaccination before 1year of age was associated with increased odds of developmental delays (OR=2.18, 95% CI 1.47–3.24), asthma (OR=4.49, 95% CI 2.04–9.88) and ear infections (OR=2.13, 95% CI 1.63–2.78).https://doi.org/10.1080/02772240701806501State University of New York at Stony BrookThe odds of receiving early intervention or special education services were 8.63 times as great (OR=8.63, 95% CI 3.24–22.98) for vaccinated boys as for unvaccinated boys after adjustment for confounders.https://pubmed.ncbi.nlm.nih.gov/21058170/ State University of New York at Stony BrookMale neonates vaccinated with the hepatitis B vaccine had a 3 times risk (OR=3.002, 95% CI 1.109-8.126) for parental report of autism diagnosis compared to boys not vaccinated as neonates during that same time period.https://www.oatext.com/pdf/JTS-3-187.pdf Jackson State University (MS)Vaccination associated with neurodevelopmental disorders (NDD) in children born at term (OR 2.7, 95% CI: 1.2, 6.0). Vaccination and preterm birth had 5.4 times risk (95% CI: 2.5, 11.9) compared to vaccinated but non-preterm children, and 14.5 times risk (95% CI: 5.4, 38.7) compared to neither preterm nor vaccinated. https://www.oatext.com/pdf/JTS-3-186.pdf Jackson State University (MS)Vaccinated children compared to unvaccinated more likely to be been diagnosed with: allergic rhinitis (10.4% vs. 0.4%, p <0.001), other allergies (22.2% vs. 6.9%, p <0.001), eczema/ atopic dermatitis (9.5% vs. 3.6%, p = 0.035), a learning disability (5.7% vs. 1.2%, p = 0.003), ADHD (4.7% vs. 1.0%, p =0.013), ASD (4.7% vs. 1.0%, p = 0.013), any neurodevelopmental disorder (10.5% vs. 3.1%, p<0.001) and any chronic illness (44.0% vs. 25.0%, p <0.001). https://pubmed.ncbi.nlm.nih.gov/15805992/ Vanderbilt University (TN)In multiple regression analyses there were significant ( P < .0005) and dose-dependent negative relationships between vaccination refusal and self-reported asthma or hay fever only in children with no family history of the condition and, for asthma, in children with no exposure to antibiotics during infancy.
Post-Licensure Safety of the U.S. Vaccine ScheduleExamples of Generally Unreliable Studies•Comparing vaccinated children with vaccinated children•Using risk windows post-vaccination
51
Post-Licensure Safety of the U.S. Vaccine ScheduleRise in Chronic DiseasesMost of the disease contributing to the increase are related to some form of immune system deregulation, including asthma, allergies, ADHD, etc., as discussed in the accompanying memorandum. Many are also disclosed in Section 6.2 of one or more vaccine package inserts.Source: https://pubmed.ncbi.nlm.nih.gov/3944229/ (https://perma.cc/NGA9-93KW) (“According to data from the National Health Interview Survey (NHIS) [1979-1981] over two million children under 17 years (3.8%) are afflicted by chronic conditions that cause some limitation of activity.”); https://pmc.ncbi.nlm.nih.gov/articles/PMC1646496/ (https://perma.cc/KN4A-94TV) (“Data from the National Health Interview Survey indicate that the prevalence of activity-limiting chronic conditions among children under age 17 years doubled between 1960 and 1981, from 1.8 to 3.8 per cent.”); https://pubmed.ncbi.nlm.nih.gov/9551003/ (https://perma.cc/JTZ5-JBNK) (Among “children younger than 18 years who were included in the 1992-1994 National Health Interview Survey … [a] significant proportion of children, estimated at 6.5% of all US children, experienced some degree of disability.”); https://www.cdc.gov/chronic-disease/about/index.html (https://perma.cc/N4GT-38L2) (“Chronic diseases are defined broadly as conditions that last 1 year or more and require ongoing medical attention or limit activities of daily living or both.”).52Year(s)Percent of Childrenwith a Chronic DiseaseEarly 1980sPresent<10%>40%Year(s)Percent of Children with a Chronic Disease
Post-Licensure Safety of the U.S. Vaccine ScheduleAluminum Adjuvants
Source: https://pubmed.ncbi.nlm.nih.gov/33887692/. See memorandum for additional sources.
Finding: Six vaccines (Pentacel, Havrix, Adacel, Pedvax, Prevnar 13, Vaqta) contained a statistically significant greater quantity and four vaccines (Infanrix, Kinrix, Pediarix, and Synflorix) contained a statistically significant lower quantity of aluminum adjuvant than listed on the product’s label.53
Post-Licensure Safety of the U.S. Vaccine SchedulePost-Licensure Safety•When robust clinical trial data is not possible to obtain, robust post-licensure safety data should support recommendations.•Condition recommendations on sponsors providing any requested follow-up safety data.•Revisit recommendations regularly.
54
Efficacy in Preventing Transmission: U.S. Childhood Vaccine Schedule
Efficacy of the U.S. Vaccine ScheduleTransmission
56Some live-attenuated vaccines, such as Varivax for varicella, generally prevent transmission of the target pathogen in most recipients for an extended duration post-vaccination.
Source: see accompanying memorandum. Live-Attenuated Vaccines
Efficacy of the U.S. Vaccine ScheduleTransmission
57“IPV does not prevent intestinal infection and therefore does not prevent poliovirus transmission”Source: https://www.cdc.gov/mmwr/volumes/71/wr/mm7133e2.htm Polio

Efficacy of the U.S. Vaccine ScheduleTransmission
58Source: https://www.cdc.gov/orr/polioviruscontainment/diseaseandvirus.htmPolio

Efficacy of the U.S. Vaccine ScheduleTransmission
59Source: https://pubmed.ncbi.nlm.nih.gov/24277828/ Pertussis

Efficacy of the U.S. Vaccine ScheduleTransmission
60Source: https://pubmed.ncbi.nlm.nih.gov/31333640/ Pertussis“Natural infection [with pertussis] evokes both mucosal and systemic immune responses, while aPVs [acellular pertussis vaccines] include only a systemic immune response. … Mucosal immunity is essential to prevent colonization and transmission of B. pertussis organism. Consequently, preventive measures such as aPVs that do not induce a valid mucosal response can prevent disease but cannot avoid infection and transmission. … aPV pertussis vaccines do not prevent colonization. Consequently, they do not reduce the circulation of B. pertussis and do not exert any herd immunity effect.”

Efficacy of the U.S. Vaccine ScheduleTransmission
61Source: https://pubmed.ncbi.nlm.nih.gov/29180031/Pertussis
“That vaccination does not prevent B. pertussis infection in humans, nor the circulation of the organism in human populations in any important manner, comes from the observation that the inter-epidemic intervals have not changed in a major way since the implementation of mass vaccination.”

Efficacy of the U.S. Vaccine ScheduleTransmission
62Source: https://pubmed.ncbi.nlm.nih.gov/31333640/ Pertussis“FDA’s licensure standards for vaccines do not require demonstration of the prevention of infection or transmission. … [T]he pertussis vaccines that FDA has licensed are for prevention of pertussis disease not infection with B. pertussis.” FDA is also not “convinced that there is a any widespread misconception about this.”

Efficacy of the U.S. Vaccine ScheduleTransmission
63Source: https://www.cdc.gov/acip/vaccine-recommendations/shared-clinical-decision-making.html“Unlike routine, catch-up, and risk-based recommendations … ACIP makes shared clinical decision-making recommendations when individuals may benefit from vaccination, but broad vaccination of people in that group is unlikely to have population-level impacts.”

Efficacy in Preventing Mortality:U.S. Childhood Vaccine Schedule
Efficacy of the U.S. Vaccine ScheduleBenefits
65Vaccines are intended to prevent symptoms if the vaccinee is infected with the target pathogen, thereby potentially preventing disease and mortality.
Efficacy of the U.S. Vaccine ScheduleClaimed Benefits
66Source: https://www.cdc.gov/mmwr/volumes/73/wr/mm7331a2.htm“Among children born during 1994–2023, routine childhood vaccinations will have prevented approximately 508 million cases of illness, 32 million hospitalizations, and 1,129,000 deaths”

Efficacy of the U.S. Vaccine ScheduleClaimed Benefits: Mortality
67Source: https://www.cdc.gov/mmwr/preview/mmwrhtml/su6004a2.htm-Ignores all confounders, explaining “factors other than immunization (e.g., hygiene…) might have contributed to lower disease risks in recent decades, and reductions resulting from these contributions have not been incorporated into the model”-No confidence intervals-Data is unreliable-Clearance process versus peer-review

Efficacy of the U.S. Vaccine ScheduleClaimed Benefits: Mortality
68
U.S. Public Health Service Report
2023 MMWR Report: Claims 25,000 diphtheria deaths prevented each year between 1994 and 2023, totaling 750,000 of the 1.1 million lives.CDC Mortality Data: 634 diphtheria deaths in 1948
Source: https://stacks.cdc.gov/view/cdc/6200; https://www.cdc.gov/nchs/data/vsus/VSUS_1948_2.pdf
Efficacy of the U.S. Vaccine ScheduleClaimed Benefits: Mortality
69Source: https://web.archive.org/web/20190615081539/https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/e/reported-cases.pdf MMWR Report: Claims 3,003 Hepatitis B deaths prevented each year between 1994 and 2023 (totaling 90,100 of the 1.1 million lives).CDC Pink Book: There were 294 deaths from Hepatitis B in 1980, the year before the first Hep B vaccine was introduced in 1981.
Efficacy of the U.S. Vaccine ScheduleClaimed Benefits: Mortality
70Source: https://stacks.cdc.gov/view/cdc/6200; https://web.archive.org/web/20190615081539/https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/e/reported-cases.pdf
2023 MMWR Report: claims 2,833 measles deaths prevented each year between 1994 and 2023 (totaling 85,000 of the 1.1 million lives)CDC Mortality Data: 407 measles deaths in 1962 after an over 98% decline in mortality between 1900 and 1962U.S. Public Health Service Report
Efficacy of the U.S. Vaccine ScheduleClaimed Benefit: Mortality
71Studies on non-specific effects on mortality in children: live v. non-live vaccines and developed v. developing countries
Efficacy of the U.S. Vaccine ScheduleClaimed Benefit: Mortality
72Source: https://pubmed.ncbi.nlm.nih.gov/26122188/
!!
!!

Efficacy of the U.S. Vaccine Schedule
73Pneumococcal deaths are during childhood. Mortality data for: diphtheria, pertussis, and tetanus (https://www.cdc.gov/nchs/data/vsus/VSUS_1948_2.pdf, p.440, https://perma.cc/N2PN-5UPU);polio, measles, mumps, rubella, hepatitis B, hepatitis A, and varicella (https://web.archive.org/web/20190615081539/https:// www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/e/reported-cases.pdf,https://per-ma.cc/7GPK-32AC); Hib (There was an ineffective vaccine introduced in 1985 and withdrawn. After a Hib vaccine considered effective for infants was first licensedinlate 1990, the CDC in 1991 for the first time recommended a Hib vaccine for infants, and by 1992 vaccine uptake was only 28%. There were 17 deaths in 1991 from Hib, so to be conservative, this death number was doubled to 34 for the chart. See discussion regarding Hib vaccine in this chapter for sup-porting citations.); pneumococcal (“Before routine use of pneumococcal conjugate vaccine in 2000, the burden of pneumococcal disease among children younger than age 5 years was … 200 deaths from invasive pneumococcal disease.” Hence, this CDC estimate was used even though it appears inflated based on other data. https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-17-pneumococcal-disease.html, https://perma.cc/6YQT-F4CA);and rotavirus and meningococcal (CDC listing, “Deaths per year in the United States prior to recommended vaccines,” for these diseases on slide 7: https://web.archive.org/web/20240518044830/https:// www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-05-19/01- COVID-Daley-508.pdf, https://perma.cc/VV9F-C77B).Claimed Benefit: MortalityDisease Year VaccineLicensedDiphtheria 634 Pertussis 1949 (DTP) 1,146 Tetanus 506 Polio 1955 1,368 Measles 1963 408 Mumps 1967 43 Rubella 1969 24 Hepatitis B 1981 294 Hib 1990 34 Hepatitis A 1995 97 Varicella 1995 124 Pneumococcal 2000 200 Meningococcal 2005 8 Rotavirus 2006 20 Number of Deaths in YearPrior to Licensure
Informed Consent & Considerations
Informed ConsentInformed Consent“Unlike routine, catch-up, and risk-based recommendations, … shared clinical decision-making recommendations are individually based and informed by a decision process between the health care provider and the patient or parent/guardian.”
75Source: https://www.cdc.gov/acip/vaccine-recommendations/shared-clinical-decision-making.html

Informed ConsentItems to Consider-Revisit prior recommendations made without robust data. -Require robust trial and, when possible, post-licensure safety data.-Liaison members should respect right of informed consent.
76

Summary: Development of the U.S. Childhood Vaccine Schedule Aaron SiriACIP Meeting, December 5, 2025With A Focus on Suggested Improvements DisclosuresManaging Partner of Siri & Glimstad LLP with 100+ professionals who handle civil rights, exemptions, immigration, employment, and injury claims related to vaccination. Author of Vaccines, Amen: The Religion of Vaccines. 2  Growth of U.S. Childhood Vaccine Schedule Growth of U.S. Vaccine Schedule…


04 Dengue Kaul 508

Summary of two economic
models for dengue vaccine
TAK-003 use in Puerto Rico
Advisory Committee on Immunization Practices

June 22, 2023
The models summarized are currently undergoing the CDC economic review following the ACIP
Guidance for Health Economics Studies, so results should be considered as preliminary.RajReni Kaul, PhD
CDC/NCIRD/ISD
The findings and conclusions in this presentation are those of the author(s) and do not
necessarily represent the views of the Centers for Disease Control and Prevention.
Acknowledgements
•This presentation summarizes work conducted by two modeling
teams
•Notre Dame team contracted by CDC (ND/CDC Model)
•Guido España , Manar Alkuzweny , Alex Perkins
•Takeda team (Takeda Model)
•J. Shen, R. Hanley, I. Zerda , et al.
•CDC and ACIP contributors and reviewers
•Dengue ACIP workgroup
•Economists at CDC and colleagues (NCIRD/ISD)
Conflicts of Interest Statements
•RajReni Kaul: None.
•Notre Dame team:
•Dr. Guido España and Dr. Alex Perkins have previously received research
funding from GlaxoSmithKline to support unrelated research on dengue
vaccine development.
•Dr. Alex Perkins currently receives research funding and consulting fees
from Emergent Biosciences to support unrelated research on
chikungunya vaccine development.
•Takeda team:
•Takeda is the developer and manufacturer of the TAK -003 vaccine.
•Directly employed by Takeda or consultants employed by Putnam PHMR and
contracted by Takeda
Terminology
Abbreviation Full term/Meaning
ND/CDC Notre Dame/CDC model
VE Vaccine efficacy
DENV (e.g., DENV -3) Dengue virus (e.g., serotype 3 dengue virus)
PICO Policy question articulated as Population, Intervention, Comparison, Outcomes
Case Medically -attended case
Hosp Hospitalization
Additional hospitalizations Hospitalization induced by vaccine -enhanced disease
NNV Number needed to vaccinate to avert an outcome (e.g., NNV hospitalization)
QALY Quality -adjusted life -years
All values rounded to 3 significant figures.
Outline
•Recap of PICO questions
•Overview of models
•Comparison of results
•Exploring differences in assumptions
•QALY values used, vaccine efficacy
•Summary of Takeda model results
•Base case
•Scenario analysis
•Model comparison summary and limitations
•Application to PICO questions
PICO Questions
•Should two doses of TAK -003 be administered routinely to seropositive
persons aged 4 –16 years living in dengue -endemic areas?
•Should two doses of TAK -003 be administered routinely to seronegative
persons aged 4 –16 years living in dengue -endemic areas?
•Should two doses of TAK -003 be administered routinely to seropositive
persons aged 17 –60years living in dengue -endemic areas?
•Should two doses of TAK -003 be administered routinely to seronegative
persons aged 17 –60years living in dengue -endemic areas?
General Model Design
Assumption/Model Characteristic Notre Dame/CDC Takeda
Model type Stochastic individual -based model Deterministic compartmental model
Prevaccination screening Included Not included
Vaccine implementation Age range, varying coverage rate over
timeSingle age, a catch -up routine in year
1possible, varying coverage rate over
first four years then constant
thereafter
Serotype specific VE point
estimatePoint estimate estimated using multi -
level Bayesian modelPoint estimate estimated using
traditional methods from clinical trial*
Serotype specific VE ranges Each simulation used VE inputs
sampled from the confidence interval
around the point estimateNo range, only point estimate used
Geographic area San Juan municipality (N=280,000) Puerto Rico (N= 3,256,028 )
DENV caused deaths Not included in QALYs Included in QALYs
Assumption/Model Characteristic Notre Dame/CDC Takeda
Model type Stochastic individual -based model Deterministic compartmental model
Prevaccination screening Included Not included
Vaccine implementation Age range, varying coverage rate over
timeSingle age, a catch -up routine in year
1possible, varying coverage rate over
first four years then constant thereafter
Serotype specific VE point
estimatePoint estimate estimated using multi -
level Bayesian modelPoint estimate estimated using
traditional methods from clinical trial*
Serotype specific VE ranges Each simulation used VE inputs
sampled from the confidence interval
around the point estimateNo range, only point estimate used
* When the clinical trial estimate was negative or confidence interval included negative values, a VE model input of zero was assumed.Geographic area San Juan municipality (N=280,000) Puerto Rico (N= 3,256,028 )
DENV caused deaths Not included in QALYs Included in QALYsGeneral Model Design
Assumption/Model Characteristic Notre Dame/CDC Takeda
Model type Stochastic individual -based model Deterministic compartmental model
Prevaccination screening Included Not included
Vaccine implementation Age range, varying coverage rate over
timeSingle age, a catch -up routine in year
1possible, varying coverage rate over
first four years then constant thereafter
Serotype specific VE point
estimatePoint estimate estimated using multi -
level Bayesian modelPoint estimate estimated using
traditional methods from clinical trial*
Serotype specific VE ranges Each simulation used VE inputs
sampled from the confidence interval
around the point estimateNo range, only point estimate used
Geographic area San Juan municipality (N=280,000) Puerto Rico (N= 3,256,028 )General Model Design
* When the clinical trial estimate was negative or confidence interval included negative values, a VE model input of zero was assumed.DENV caused deaths Not included in QALYs Included in QALYs
General Model Design
Assumption/Model Characteristic Notre Dame/CDC Takeda
Model type Stochastic individual -based model Deterministic compartmental model
Prevaccination screening Included Not included
Vaccine implementation Age range, varying coverage rate over
timeSingle age, a catch -up routine in year
1possible, varying coverage rate over
first four years then constant thereafter
Serotype specific VE point
estimatePoint estimate estimated using multi -
level Bayesian modelPoint estimate estimated using
traditional methods from clinical trial*
Serotype specific VE ranges Each simulation used VE inputs
sampled from the confidence interval
around the point estimateNo range, only point estimate used
Geographic area San Juan municipality (N=280,000) Puerto Rico (N= 3,256,028 )
DENV caused deaths Not included in QALYs Included in QALYs
* When the clinical trial estimate was negative or confidence interval included negative values, a VE model input of zero was assumed.
Economic Model Preliminary Results by PICO
Age 4-16 years
ModelScenario conditionsNumber
vaccinatedNet number averted with vaccination §
$/QALY
(ICER)§ Geographic
Area† AgePrevaccination
screening Cases Hospitalizations Deaths
ND/CDCSan Juan
Municipality4-16 Yes 11,700 485 (1.2%) 182 (2.6%) 1 (2.9%) 182,000 *
ND/CDCSan Juan
Municipality4-16 No 30,300 1,070 (2.5%) 192 (2.8%) 1 (2.9%) 255,000 *
Takeda Puerto Rico8,
catch -
up 9 -16 No 157,000 46,700 (12%) 9,150 (14 %) 5 (13%) Cost -
saving
†Modeled population size is 280,000 for the San Juan Municipality (ND/CDC model) and 3,256,028 for all of Puerto Rico (Takeda model).
§When compared to no vaccination
*Death is not incorporated into QALYs gained in the ND/CDC model base case assumptions. If QALY gains from averted deaths wer e
included, then the ICERs would change from $182,000 to $65,000 per QALY for the scenario with prevaccination screening and would
change from $255,000 to $137,000 per QALY for the scenario without prevaccination screening.
Economic Model Preliminary Results by PICO
Age 4-16 years
ModelScenario conditionsNumber
vaccinatedNet number averted with vaccination §
$/QALY
(ICER)§ Geographic
Area† AgePrevaccination
screening Cases Hospitalizations Deaths
ND/CDCSan Juan
Municipality4-16 Yes 11,700 485 (1.2%) 182 (2.6%) 1 (2.9%) 182,000 *
ND/CDCSan Juan
Municipality4-16 No 30,300 1,070 (2.5%) 192 (2.8%) 1 (2.9%) 255,000 *
Takeda Puerto Rico8,
catch -
up 9 -16 No 157,000 46,700 (12%) 9,150 (14 %) 5 (13%) Cost -
saving
†Modeled population size is 280,000 for the San Juan Municipality (ND/CDC model) and 3,256,028 for all of Puerto Rico (Takeda model).
§When compared to no vaccination
*Death is not incorporated into QALYs gained in the ND/CDC model base case assumptions. If QALY gains from averted deaths wer e
included, then the ICERs would change from $182,000 to $65,000 per QALY for the scenario with prevaccination screening, and would
change from $255,000 to $137,000 per QALY for the scenario without prevaccination screening.
ModelScenario conditionsNumber
vaccinatedNet number averted with vaccination§
$/QALY
(ICER)§ Geographic
Area† AgePrevaccination
screening Cases Hospitalizations Deaths
ND/CDCSan Juan
Municipality17-60 Yes 105,000 2,710 (6%) 724 (10%) 5(11%) 397,000 *
ND/CDCSan Juan
Municipality17-60 No 121,000 3,360 (8%) 928 (13%) 4(14%) 315,000 *
Takeda Puerto Rico17,
catch -
up 18 -
60No 449,000 67,000 (17%) 13,100 (21%) 8 (21%)Cost -
saving
†Modeled population size is 280,000 for the San Juan Municipality (ND/CDC model) and 3,256,028 for all of Puerto Rico (Takeda model).
§When compared to no vaccination
*Death is not incorporated into QALYs gained in the ND/CDC model base case assumptions. If QALY gains from averted deaths
were included, then the ICERs would change from $397,000 to $188,000 per QALY for the scenario with prevaccination screening,
and would change from $315,000 to $153,000 per QALY for the scenario without prevaccination screening.Economic Model Preliminary Results by PICO
Age 17-60 years
ModelScenario conditionsNumber
vaccinatedNet number averted with vaccination§
$/QALY
(ICER)§ Geographic
Area† AgePrevaccination
screening Cases Hospitalizations Deaths
ND/CDCSan Juan
Municipality17-60 Yes 105,000 2,710 (6%) 724 (10%) 5(11%) 397,000 *
ND/CDCSan Juan
Municipality17-60 No 121,000 3,360 (8%) 928 (13%) 4(14%) 315,000 *
Takeda Puerto Rico17,
catch -
up 18 -
60No 449,000 67,000 (17%) 13,100 (21%) 8 (21%)Cost -
saving
†Modeled population size is 280,000 for the San Juan Municipality (ND/CDC model) and 3,256,028 for all of Puerto Rico (Takeda model).
§When compared to no vaccination
*Death is not incorporated into QALYs gained in the ND/CDC model base case assumptions. If QALY gains from averted deaths
were included, then the ICERs would change from $397,000 to $188,000 per QALY for the scenario with prevaccination screening,
and would change from $315,000 to $153,000 per QALY for the scenario without prevaccination screening.Economic Model Preliminary Results by PICO
Age 17-60 years
Exploring Difference
Model Inputs : QALY loss from dengue episodes
Disease OutcomeQuality -adjusted
days lost
ND/CDC Takeda
Non -hospitalized dengue 11.2§5.5
Hospitalized dengue 12.8§6.8
Persistent dengue after non -hospitalized or
hospitalized caseNA 4.9*
Dengue caused deaths NAAge-
dependent
§QALY lost for dengue episodes includes persistent dengue in 34% of all cases.
* Model assumes 34% of dengue episodes aged 30 or older develop persistent symptoms.
Disease OutcomeQuality -adjusted
days lost
ND/CDC Takeda
Non -hospitalized dengue 11.2§6.1†
Hospitalized dengue 12.8§7.2†
Persistent dengue after non -hospitalized or
hospitalized caseNA -
Dengue caused deaths NAAge-
dependentExploring Difference
Model Inputs : QALY loss from dengue episodes
When persistent
dengue QALY loss is
combined with
acute phase QALY
loss
§QALY lost for dengue episodes includes persistent dengue in 34% of all cases.
† Calculated as if 34% of cases ages 30 or older develop persistent symptoms.
Exploring Difference
Model Inputs : Vaccine Efficacy
68.1%
(27.2, 86.2)
Takeda 75.8% 98.5% 0%# 0%§ 75.8% 98.5% 71.4% 100%-4
Non -
hospitalized
Symptomatic
caseND/CDC*29.7%
(6.7, 48.5)96.3%
(87.1, 100)30.0%
(7.8, 49.4)-1.1%
(-73.5,64.4)63.1%
(52.7, 82.2)85.2%
(75.6, 94.4)42.5%
(26.4, 55.8)60.2%Vaccine efficacy inputs by serostatus and by dengue serotype
Seronegative at vaccination Seropositive at vaccination
DENV -1 DENV -2 DENV -3 DENV -4 DENV -1 DENV -2 DENV -3 DENV
(19.8, 89.6)
Takeda† 30.8 % 69.8 % 0%#0%#46.7 % 69.8 % 42.6 % 61.2 %
Hospitalized
caseND/CDC*84.6%
(54.5, 98.7)99.0% Model
(95.6, 100)-30.3%
(-91.6, 25.6)39.2%
(-20.4, 81.0)54.1%
(13.3, 82.2)99.5%
(97.8, 100)70.2%
(45.6, 90.4)Disease
Outcome
29.7%
(6.7, 48.5)96.3%
(87.1, 100)30.0%
(7.8, 49.4)-1.1%
(-73.5,64.4)63.1%
(52.7, 82.2)85.2%
(75.6, 94.4)42.5%
(26.4, 55.8)60.2%
(19.8, 89.6)
Takeda† 30.8 % 69.8 % 0%#0%#46.7 % 69.8 % 42.6 % 61.2 %
Hospitalized
caseND/CDC*84.6%
(54.5, 98.7)99.0%
(95.6, 100)-30.3%
(-91.6, 25.6)39.2%
(-20.4, 81.0)54.1%
(13.3, 82.2)99.5%
(97.8, 100)70.2%
(45.6, 90.4)68.1%
(27.2, 86.2)
Takeda 75.8% 98.5% 0%# 0%§ 75.8% 98.5% 71.4% 100%Exploring Difference
Model Inputs : Vaccine Efficacy
* Point estimate with 95% confidence interval
† Non -hospitalized case
§Due to lack of data* Point estimate with 95% confidence interval
† Average VE over 5 years post -vaccination. Includes vaccine waning.
§Due to lack of data
#Value used because pivotal clinical trial estimate or confidence interval included negative valuesDisease
OutcomeModelVaccine efficacy inputs by serostatus and by dengue serotype
Seronegative at vaccination Seropositive at vaccination
DENV -1 DENV -2 DENV -3 DENV -4 DENV -1 DENV -2 DENV -3 DENV -4
Non -
hospitalized
Symptomatic
caseND/CDC*
Disease
OutcomeModelVaccine efficacy inputs by serostatus and by dengue serotype
Seronegative at vaccination Seropositive at vaccination
DENV -1 DENV -2 DENV -3 DENV -4 DENV -1 DENV -2 DENV -3 DENV -4
Non -
hospitalized
Symptomatic
caseND/CDC*29.7%
(6.7, 48.5)96.3%
(87.1, 100)30.0%
(7.8, 49.4)-1.1%
(-73.5,64.4)63.1%
(52.7, 82.2)85.2%
(75.6, 94.4)42.5%
(26.4, 55.8)60.2%
(19.8, 89.6)
Takeda† 30.8 % 69.8 % 0%#0%#46.7 % 69.8 % 42.6 % 61.2 %
Hospitalized
caseND/CDC*84.6%
(54.5, 98.7)99.0%
(95.6, 100)-30.3%
(-91.6, 25.6)39.2%
(-20.4, 81.0)54.1%
(13.3, 82.2)99.5%
(97.8, 100)70.2%
(45.6, 90.4)68.1%
(27.2, 86.2)
Takeda 75.8% 98.5% 0%# 0%§ 75.8% 98.5% 71.4% 100%
* Point estimate with 95% confidence interval
† Average VE over 5 years post -vaccination. Includes vaccine waning.
§Due to lack of data
#Value used because pivotal clinical trial estimate or confidence interval included negative valuesExploring Difference
Model Inputs : Vaccine Efficacy
Disease
OutcomeModelVaccine efficacy inputs by serostatus and by dengue serotype
Seronegative at vaccination Seropositive at vaccination
DENV -1 DENV -2 DENV -3 DENV -4 DENV -1 DENV -2 DENV -3 DENV -4
Non -
hospitalized
symptomatic
caseND/CDC*29.7%
(6.7, 48.5)96.3%
(87.1, 100)30.0%
(7.8, 49.4)-1.1%
(-73.5,64.4)63.1%
(52.7, 82.2)85.2%
(75.6, 94.4)42.5%
(26.4, 55.8)60.2%
(19.8, 89.6)
Takeda† 30.8 % 69.8 % 0%#0%#46.7 % 69.8 % 42.6 % 61.2 %
Hospitalized
caseND/CDC*84.6%
(54.5, 98.7)99.0%
(95.6, 100)-30.3%
(-91.6, 25.6)39.2%
(-20.4, 81.0)54.1%
(13.3, 82.2)99.5%
(97.8, 100)70.2%
(45.6, 90.4)68.1%
(27.2, 86.2)
Takeda 75.8% 98.5% 0%# 0%§ 75.8% 98.5% 71.4% 100%Exploring Difference
Model Inputs : Vaccine Efficacy
* Point estimate with 95% confidence interval
† Average VE over 5 years post -vaccination. Includes vaccine waning.
§Due to lack of data
#Value used because pivotal clinical trial estimate or confidence interval included negative values
Disease
OutcomeModelVaccine efficacy inputs by serostatus and by dengue serotype
Seronegative at vaccination Seropositive at vaccination
DENV -1 DENV -2 DENV -3 DENV -4 DENV -1 DENV -2 DENV -3 DENV -4
Non -
hospitalized
symptomatic
caseND/CDC*29.7%
(6.7, 48.5)96.3%
(87.1, 100)30.0%
(7.8, 49.4)-1.1%
(-73.5,64.4)63.1%
(52.7, 82.2)85.2%
(75.6, 94.4)42.5%
(26.4, 55.8)60.2%
(19.8, 89.6)
Takeda† 30.8 % 69.8 % 0%#0%#46.7 % 69.8 % 42.6 % 61.2 %
Hospitalized
caseND/CDC*84.6%
(54.5, 98.7)99.0%
(95.6, 100)-30.3%
(-91.6, 25.6)39.2%
(-20.4, 81.0)54.1%
(13.3, 82.2)99.5%
(97.8, 100)70.2%
(45.6, 90.4)68.1%
(27.2, 86.2)
Takeda 75.8% 98.5% 0%# 0%§ 75.8% 98.5% 71.4% 100%Exploring Difference
Model Inputs : Vaccine Efficacy
* Point estimate with 95% confidence interval
† Average VE over 5 years post -vaccination. Includes vaccine waning.
§Due to lack of data
#Value used because pivotal clinical trial estimate or confidence interval included negative values
Exploring Difference
Impact of vaccine efficacy inputs on outcome
•What if the ND/CDC model uses the Takeda VE inputs in the scenario
where 4 –16-year -olds are vaccinated without screening?
•Takeda’s VE inputs did not substantially impact the results of the ND/CDC
model.
VE
inputsNumber
vaccinatedNet number averted with vaccination Vaccination enhanced
disease NNV
hosp.QALYs
gained*$/QALY
(ICER)*
Cases Hosp. DeathsAdditional
casesAdditional
hosp.
ND/CDC† 30,300 1,070
(651 -1,470) 192
(112 -300)1
(0.5 -1.5)45
(35-52)32
(29-37)158
(101 -270)35 255,000
Takeda† 30,300 1,030
(699 -1,300) 287
(197 -425)1
(0.9 -2.1)NA NA 105
(71-153)34 262,000
*QALY loss due to dengue caused death is not incorporated into ICER calculation.
†Range of model results due to stochasticity
Outline
•Recap of PICO questions
•Overview of models
•Comparison of results
•Exploring differences in assumptions
•QALY values used, vaccine efficacy
•Summary of Takeda model results
•Base case
•Scenario analysis
•Model comparison summary and limitations
•Application to PICO questions
Takeda Base Case Preliminary Results
Routine vaccination at age 8
Base case conditions
•Entire population of Puerto Rico
•20-year time horizon
•Routine vaccination at age 8
•Vaccination rate increases from
0% at year 0 to 60% at year 4.
•Using slightly different QALY loss
than previously presented*Base Case
Number vaccinated 449,000
Averted cases 123,000 (15%)
Averted hospitalizations 25,000 (20%)
Averted deaths 15 (20%)
NNV hospitalization 17.6
QALY sgained 2,070
$/QALY Cost -saving
$/hospitalization Cost -saving
*Values reported in supplemental slides
Scenario Analysis
Takeda Model: Routine vaccination at age 8
*Used a fixed vaccine coverage parameter of 21.5% to approximate vaccination
coverage that increases from 0% to 43% over 10 years.Scenario
Number
vaccinatedNumber averted with vaccination
NNV
hospQALYs
gainedICER
($/QALY)Time
(years)TAK-003
routine
ageTAK-003
catchup
ageTAK-003
coverage*Cases Hosp Deaths
10 8 None 22% 87,000 24,000 (6%) 4,510 (7%) 3 (8%) 19.3 402Cost -
saving
10 8 9-16 22% 157,000 47,000 (12%) 9,150 (14%) 5 (13%) 17.1 838Cost -
saving
Overall Cost -effectiveness
Preliminary results
Incremental Cost (in thousands)
QALYs gained
Overall Cost-effectiveness
Preliminary results

Incremental Cost (in thousands)
QALYs gained
4-16
w/prevaccination
screening17-60 w/o
prevaccination
screeningR8
Catch-up 9- 16R17
Catch-up 18- 60
Limitations
•Parameter Uncertainty
•Large confidence interval (>100%) for DENV -3 and DENV -4 VE estimates for
those seronegative at vaccination.
•Given vaccine’s range in serotype specific efficacy, actual outcome will
be heavily influenced by the dominant circulating serotype.
•In the ND/CDC model, deaths were not part of the QALY calculation.
•Using Takeda’s model, we cannot assess benefits and risks of pre -
vaccination screening strategies vs strategies without pre -vaccination
screening.The models summarized are currently undergoing the CDC economic review following the ACIP
Guidance for Health Economics Studies, so results should be considered as preliminary.
Only seropositives
(prescreening)All individuals
(no prescreening)
4–16 years
Children/AdolescentsAnswered by ND/CDC ModelAnswered by ND/CDC Model
& Takeda Model
17–60 years
AdultsAnswered by ND/CDC ModelAnswered by ND/CDC Model
& Takeda ModelModels answering the PICO Questions
Acknowledgements
•This presentation summarized work conducted by two modeling
teams
•Notre Dame team contracted by CDC (ND/CDC Model)
•Guido España , Manar Alkuzweny , Alex Perkins
•Takeda team (Takeda Model)
•J. Shen, R. Hanley, I. Zerda *, Z.  Janusz *, E. Kharitonova*, A. Rosas, A. Garcia, M. Curtis,
M. Lu, C. Ruff, V. Tricou , M. Sharma, R. Kastner, E. Lloyd, G. Perez, S. Biswal, T. Tsai, I.
Willits*
•Name with (*) are employed by Putnam PHMR and contracted by Takeda. All others are
directly employed by Takeda.
•CDC and ACIP contributors and reviewers
•Dengue ACIP workgroup
•Economists at CDC and colleagues (NCIRD/ISD)
The findings and conclusions in this presentation are those of the author(s) and do not
necessarily represent the views of the Centers for Disease Control and Prevention.

Summary: Summary of two economic models for dengue vaccine TAK-003 use in Puerto Rico Advisory Committee on Immunization Practices    June 22, 2023  The models summarized are currently undergoing the CDC economic review following the ACIP  Guidance for Health Economics Studies, so results should be considered as preliminary.RajReni Kaul, PhD CDC/NCIRD/ISD The findings and conclusions in this presentation are those of the author(s) and do not  necessarily represent the views of the Centers for Disease…