ACIP EtR Users Guide October 1 2020

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A
CIP Evidence to Recommendation User’s Guide

October 1 , 2020
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  Contents
Introduction .................................................................................................................................................. 3
How to Use This Guide  .................................................................................................................................. 3
The EtR Framework  ................................................................................................................................... 4
Organization of this Guide  ........................................................................................................................ 5
Overarching Framework Completion Guidance  ....................................................................................... 5
Specific Criteria  ............................................................................................................................................. 6
Domain 1: The Problem  ............................................................................................................................ 6
Criterion: Public Health Priority  ............................................................................................................ 6
Domain 2: Benefits & Harms of the Options  ............................................................................................ 6
Criterion 1: Magnitude of desirable anticipated effects  ....................................................................... 6
Criterion 2: Magnitude of undesirable anticipated effects  .................................................................. 7
Criterion 3: Balance of desirable versus undesirable anticipated effects  ............................................ 8
Criterion 4: Certainty of evidence for outcomes  .................................................................................. 8
Domain 3: Values and Preferences  ........................................................................................................... 9
Criterion 1: Target population perception of value  .............................................................................. 9
Criterion 2: Uncertainty around target population perception of value  .............................................. 9
Domain 4: Acceptability  .......................................................................................................................... 10
Criterion:  Acceptability to key stakeholders  ....................................................................................... 10
Domain 5: Resource Use  ......................................................................................................................... 10
Criterion: Resource allocation  ............................................................................................................ 10
Domain 6: Equity  ..................................................................................................................................... 11
Criterion: Healt h equity  ...................................................................................................................... 11
Domain 7: Feasibility  ................................ ............................................................................................... 12
Criterion: Implementation feasibility  .................................................................................................. 12
Conclusions and Additional Considerations ............................................................................................ 12
Summary of the ACIP’s deliberations and final recommendations  ........................................................ 13
Additional Resources  .................................................................................................................................. 13
Appendix 1: ACIP Evidence to Recommendations Framework  .................................................................. 14
Appendix 2 When to Prepare GRADE Evidence Profile Algorithm  ............................................................. 21
Appendix 3 Implementation Considerations Checklist  ............................................................................... 22

3
 Introduction
In 2010, the Advisory Committee on Immunization Practice ( ACIP ) formally adopted the Grading of
Recommendations Assessment, Development and Evaluation (GRADE) approach for assessing the
evidence and developing evidence -based recommendations. Since then, an assessment of the certainty
of available evidence  using GRADE ha s been an integral part of ACIP recommendation development . In
addition to assessing the certainty of evidence, guideline panel s consider other domains when making a
recommendation (e.g., the balance of benefits and harms, patient’s values and preferences, etc.). This
document presents the information that must be considered when making a recommendation.  Previous
documents/publica tions provide information on assessing the certainty of the evidence (Ahmed 2011 ).

D
uring the process of recommendation formulation, panels consider a range of factors in addition to the
certainty in the evidence.  Elucidation of these factors and the j udgments behind them facilitates
transparency, consistency, and communication of recommendations to healthcare providers, partner
organizations, and the public  (Alonso -Cuello 2017a & b) .  To structure the discussion of these additional
factors and to make the judgments transparent, an evidence to decision -making  (EtD) framework is
used.

The EtD structures decision -making by:
• Inform ing panel members’ judgments about the pros and cons of each intervention under
consideration;
• Ensuring the important factors that determine a decision (criteria) are considered;
• Provid ing a concise summary of the best available evidence to inform judgements about each
criterion;
• Helping structure discussion and identify reasons for disagreements when they occur; and
• Making the b asis for decisions transparent to guideline users or those affected by a policy
decision.

The ACIP has continued to follow and build upon the methodological advances in the GRADE approach
and, as a result, has developed a modified Evidence to Recommendation (EtR) framework tailored to the needs of ACIP (Appendix 1). The purpose of EtR framework is to help panels making recommendations
move from evidence to decisions, and to provide transparency around the impact of additional factors on deliberations when considering a recommendation .

How to Use This Guide
The following supplementary information is intended to guide ACIP work groups while they complete
the EtR framework , as they address specific policy questions and develop  policy options for ACIP ’s
consideration .

ACIP’s EtR frameworks are prepared by ACIP work groups for presentation to ACIP.  As such, the EtR
frameworks represent the information reviewed and considered by the ACIP w ork group in developing
policy options for ACIP’s consideration.  The ACIP’s final recommendation and any additional considerations of ACIP during its deliberations  are captured  in a separate table titled ‘Final deliberation
and decision by ACIP’ at the bottom of the EtR framework  (Appendix 1) .

4
 The ACIP’s EtR frameworks and accompanying GRADE evidence profiles are posted on the ACIP website
(https://www.cdc.gov/vaccines/acip/recs/index.html ), and are referenced with links in  the MMWR
Policy Note  or Recommendations and Reports  document s, upon publication  in MMWR .

The EtR Framework
The EtR  frameworks are designed to include key background information, criteria  for making a decision,
and conclusions .

The background section of the EtR is intended to provide details of the policy question that is the topic
of the framework.  In the EtR framew ork table, this section is opened by a statement of the policy
question and the PICO (Population, Intervention, Comparator, Outcome), followed by a brief summary of information needed to understand the question and why a recommendation is needed.  Specific
items that should be addressed include whether the recommendation would be for “off -label” use (i.e.,
an indication not specified in the FDA approved label) or a preferential recommendation.

The second part of the framework is composed of rows delineating the factors or criteria  considered
during recommendation development, which are grouped into “domains.”  These questions are
intended to frame the discussions and guide literature searches and collection of relevant data.

T
he following columns are included for each criterion:
• Judgments  that the work group  members must make in relation to each criterion are summarized in
the first column of the framework as checkboxes.  In most cases, it is anticipated that the framework
will be  developed with  judgments  for each criterion  suggested by the work group and subject
matter experts (SMEs) who have prepared the framework.  The judgments should be a result of the work group reaching a consensus; however, minority opinions expressed during the discussion
should be  captured in the “additional considerations” section (see below).

• Evidence  to inform each of those judgments is presented in the  second  column of the table.
Evidence refers to facts  used to inform the work group’s  judgments that are derived from studies
that used systematic and explicit methods.1  If published evidence is available, a paragraph or
bulleted list summarizing the important considerations is sufficient, with mention of the most
critical references or links to more detailed summaries of the evidence such as the GRADE evidence
profile1. If no peer -reviewed body of evidence is available, this should be simply stated and any
additional information used to inform the judgment indicated.  The intent is to be  transparent about
the information that was used to make the judgment, not to imply the need for the development of
evidence when it is not available.
• Additional information that informs or justifies each judgment may be provided in the final, right -
hand c olumn of the table.  Additional information can include other data, assumptions, and logic
used to make a judgment.  Work groups  may make different judgments for one or more subgroups
(such as patients who are older or who have more severe disease) in relation to some or all of the criteria.   When relevant, they may also report additional details, such as dissenting views of work
group  members or the results of voting on judgments where there was disagreement.
   Minority
opinions voiced during discussions should be presented to increase transparency around the
deliberation process.  In addition, interpretations of the evidence may be presented here.

1 If using GRADEpro Guideline Development Tool software ( https://gradepro.org/ ), a GRADE evidence profile can
be automatically inserted into the EtR framework.
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 Organization of this Guide
This document provides additional information for each domain and criterion, including the criterion
question as presented in the EtR framework, related questions that expand on the issues to consider for each criterion (adapted from the GRADE Handbook ), and completion guidance.  A Discussion section is
also included to provide further information and clarification on issues specific to each criterion/question.  This additional information is intended to assist work groups and the ACIP in providing the relevant information to populate the framework.

Overarching Framework Completion Guid ance
Despite availability of a framework, individuals and groups will need to continue to make judgments at several points, especially when data are minimal or absent.  One purpose of the framework is to make
those judgments explicit.  Therefore, when evid ence is not available, this should be stated and a
summary of the discussion included.  It is also anticipated that there will be differences of opinion within
the work group, and the framework should be used to reflect these differences, particularly with  regard
to the final recommendation.  Since one goal of the framework is to enhance transparency and communication of deliberations, significant differences of opinion or discussion points should be captured within each domain when relevant.
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 Specific Criteria
Domain 1: The Problem
Criterion: Public Health Priority
Criterion question: Is the problem of public health importance?
Related questions:
• Are the consequences of the problem serious (i.e. severe or important in terms of the potential
benefits or savings)?
• Is the problem urgent?
• Are a large number of people affected by the problem?
• Is the problem related to emerging diseases, antimicrobial resistance, or epidemic potential?
• Are there disadvantaged groups or populations disproportionately/differentially affected by this problem?

C
ompletion Guidance: Provide a short summary of the background and significant elements of the
problem, including a description of epidemiology, clinical features , and sequelae of the
disease/condition in terms of public health consequences.  This may be excerpted or summary information from presentations to the full ACIP.  Specific items to consider may include:

• F
requency of the disease/condition (e.g., incidence,  prevalence, secular trends)
• Severity of the disease/condition (e.g., mortality, morbidity)
• Social impact of the disease/condition (e.g., hospitalization rate, sickness absenteeism, effects on high -risk groups and vulnerable  populations, clinical features,  perception of importance, and
the existence of other  preventive measures)

A
ny additional considerations regarding the public health priority may also be included.

Domain 2: Benefits & Harms of the Options
Criterion 1: Magnitude of desirable anticipated effects
Criterion question: How substantial are the desirable anticipated effects?
Related question:
• How substantial is the anticipated effect for each main outcome for which there is a desirable effect?

C
ompletion Guidance:  Across  the critical outcomes (as specified in the PICO question and elaborated in
the evidence profiles), evaluate the magnitude of the anticipated effect.  The anticipated direct and indirect ( e.g.,  herd immunity) benefits of vaccination or other interventions,  should then be listed in the
framework in terms of specified outcomes with a description of how substantial the effects are.  For effectiveness or efficacy, specific items that may be considered are immunogenicity, strain coverage, capacity to reduce the disease incidence, capacity to disrupt carriage, duration of protection, and/or serotype replacements.

T
he range of effectiveness/efficacy estimates should be included here, but specific information
regarding the confidence in point estimates should be pr esented in the certainty of evidence section
(Criterion 4) below as part of the GRADE evidence profile.  Describe any differences in
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 effectiveness/efficacy estimates for special populations (e.g., immunocompromised, specific age groups,
etc.) and disadvantaged groups or settings  (i.e. baseline risk) .  Work groups should also consider the
uncertainties (if any) related to benefit with regard to durability of effectiveness, and effect on serious health outcomes (e.g., death and hospitalization), which are not  often measured pre -licensure because
such studies would require a sample size too large to be feasible.  The numbers of illnesses, hospitalizations and deaths that can be averted by use of the vaccine may be presented here but is not required.

In
 addition, information may be included in the “additional considerations” section to highlight where
evidence may be lacking (e.g., subgroups where additional data are needed to assess the benefits).

Discussion

A
dditional considerations here can include quality of life, acute and chronic pain, and functional status,
among those who receive the vaccine and those who do not, including those who suffer the condition that could be prevented or ameliorated by vaccination.  Work groups are encouraged to perform  a
number needed to vaccinate (NNV) analysis.  If a number needed to vaccinate (NNV) analysis is performed, any important uncertainty or assumptions should be included. There are no defined thresholds for an “acceptable” NNV .

G
uidance surrounding the use  of immunogenicity data as a surrogate for efficacy or effectiveness can be
found in the GRADE Handbook  (Schünemann 2013 ).  It is important to use the same language around
judgments (e.g., “ minimal,” “small,” “moderate,” “large”) as included in the framewo rk.  The framework
requires that the work  group check one box  and rationale should be provided for the judgment selected
by the work group.  However , any differences in opinions on the judgement selected should be reflected
in the additional Information se ction to ensure transparency.

Criterion 2: Magnitude of undesirable anticipated effects
Criterion question: How substantial are the undesirable anticipated effects?
Related question:
• How substantial is the anticipated effect for each main outcome for which there is an undesirable effect (taking into account the severity or importance of the adverse effects and the number of people affected)?

C
ompletion Guidance: For each of the critical outcomes (as specified in the PICO question and
elaborated in the evidence profiles), evaluate the magnitude of the undesirable anticipated effect.  List
the anticipated harms of vaccination, in terms of chosen outcomes and describe how substantial those
effects are.  Specific items to consider may include reactogenicity, adverse events, and interactions with other vaccines.  Describe any differences in harms for disadvantaged groups or settings.  As above, information may be included in the Additional Information section to highlight where evidence may be lacking.

D
iscussi on

W
hen answering this question, work groups should consider the size and strength of the pre -licensure
safety database to sufficiently examine safety outcomes of interest.  Groups can also discuss safety
experience with vaccines from the same product cla ss, and any uncertainties related to the safety of the
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 product based on limitations of study design, limitations of size of safety database for rare outcomes,
and duration of follow up.  Work groups should consider “risk of harm” (e.g., unknown long -term  effects
of new adjuvants,  having only clinical trial data vs . long -term real- world  experience).

Just
 as for the benefits section, it is important to use the same language around judgments (e.g.,
“minimal,” “small,” “moderate,” “large”) as included in the framework.  Only one box should be
checked, but differences in opinions should be reflected in the Additional Information section to ensure
transparency.

Similar t
o the previous criterion, work groups should consider the existing safety information for both
the product under consideration, as well as similar products (e.g., vaccines in the same class).   Any
uncertainties related to safety should be clearly articulate d and discussed.

Criterion 3: Balance of desirable versus undesirable anticipated effects
Criterion question: Do the desirable effects outweigh the undesirable effects?
Related question:
• What is the balance between the desirable effects relative to the undesirable effects?

Co
mpletion Guidance: The work group should describe the deliberations on this topic, ensuring that any
minority opinions are included.  If specific subgroups have a different benefit to harm balance than the general population, describe  those considerations here (especially if those groups are not included in
the recommendation on the basis of this altered balance).

Di
scussion

Wh
en the comparator is “no vaccination,” this section is focused on comparing the balance of risks and
benefit s of the same  vaccine.  Comparison of the adverse events profile of this vaccine to other
vaccine(s) available to prevent the same  disease  can be addressed in the implementation section (e.g.,
communication with providers and patients to ensure recipients are counseled about severity of adverse events) or in the ‘Additional Considerations ’ section.  Since  it may be difficult to compare benefits and
risks, as measures are inherently different, judgment must be exercised.

Criterion 4: Certainty of evidence for outcomes
Criterion question: What is the overall certainty  of this evidence  for the critical outcomes?
Related question:
• What is the overall certainty of this evidence of effects, across all of the outcomes that are critical to making a decision?

Co
mpletion Guidance: For most situations, the overall certainty of the evidence is the lowest certainty of
the critical outcomes. See the ACIP GRADE Handbook regarding the process of making detailed judgments about the quality of evidence or certainty in e stimates of effects and preparation of evidence
profiles. The GRADE evidence profiles and associated documents should be referenced here.  If there is uncertainty about whether to prepare evidence profiles, please follow the “When to GRADE” algorithm (Appe ndix 2) and consult the ACIP Secretariat.  If evidence profiles are not prepared, a rationale and
summary of any alternative methods should be provided.

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 Discussion

I
t is expected that the overall certainty of the evidence will be informed by the  GRADE e vidence profiles
used to inform Criteria 2 and 3 (benefits and harms) . If evidence profiles are not prepared, a rationale
and summary of any alternative methods should be provided.

Domain 3: Values  and Preferences
Criterion 1: Target population perception of value
Criterion question: Does the target population feel that the desirable effects are large relative to
undesirable effects?
Related questions:
• How does the target population (i.e., those affected or potentially affected by the disease) v iew
the balance of desirable effects versus undesirable effects?
• Would patients and caregivers feel that the benefits outweigh the harms and burden?
• Does the population appreciate and value the vaccination?

C
ompletion Guidance: Provide information regarding the perspectives and perceptions of potential
recipients about the disease and the vaccine.  Describe the source of target population values and
preferences for critical outcomes (e.g., targeted research, questionnaires).  Discussion and evidence regarding the possible value to the population due to herd immunity may also be included, where applicable.

D
iscussion

W
ork groups  may want to consider the following topics:
• How much less people value outcomes that occur in the future versus  outcomes that occur now
• Potential recipient attitudes to undesirable effects (i.e. how risk averse they are)
• Risk perception – whether some segment of the population is inclined to view itself as not at risk
for the disease

I
f the evidence is limited, wo rk group  deliberations can be used.  If evaluation of values is desirable and
there is sufficient time to conduct research, there are existing survey mechanisms that may be used when funding and space are available.  Work groups interested in this should c onsult with the ACIP
Secretariat.

Criterion 2: Uncertainty around target population perception of value
Criterion question: Is there important uncertainty about , or variability in , how much people value the
main outcomes?
Related questions:
• How much do individuals value each of the outcomes in relation to the other outcomes (i.e. ,
what is the relative importance of the outcomes)?
•  Is there evidence to support those value judgements, or is there evidence that the variability in
those values is  large enough to lead to different decisions?

C
ompletion Guidance: It is not anticipated that there will be a need to routinely gather evidence if none
is currently available; rather, any paucity of information should be indicated here.  However, if the
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 variability is estimated to be so significant that this factor alone could lead to a different decision, this
should be indicated and consideration given to obtaining additional evidence. The more likely it is that differences in values would lead to different decisions, the less likely it is that there  will be a consensus
that an option is a priority from both an individual and public health perspective and the more
important it is to obtain evidence of the values of those potentially affected by the disease.

Domain 4: Acceptability
Criterion: Acceptability to key stakeholders
Criterion question: Is the option acceptable to key stakeholders?
Related question:
• Are there key stakeholders that would not accept the distribution of benefits, harms , and costs?
• Are there key stakeholders that would not accept the costs or undesirable effects in the short
term for the desirable effects (benefits) in the future?

C
ompletion Guidance: This will often represent the opinion of the work group .  Input  from ACIP
members  may also be obtained through commentary and discussion at meetings and incorporated into
the final framework.  Stakeholders may include professional societies, liaison organizations, providers, pharmaceutical companies, advocacy groups, and the general public.  Acceptability may vary across
stakeh older groups and any such variability, and the rationale  for it , should  be captured here.  Similar to
other domains, the work group consensus opinion on whether it would be acceptable to the majority of stakeholders will be the basis for the final judgment ; there is not a specified “threshold” to determine
the answer.

D
iscussion

W
ork groups should carefully consider and define which specific stakeholders ( e.g., providers in
healthcare settings, providers in community settings, providers in public health s ettings, healthcare
delivery systems, and the  public) are considered in their discussions.  Critical stakeholders for each
circumstance may differ and therefore there is no pre -specified list of stakeholders that should always
be considered, rather work gr oups should determine those groups that are relevant for their given
situation.  Liaison members on work groups can often provide perspective for their organizations that may be useful in deliberations.

D
omain 5: Resource Use
Criterion: Resource allocation
Criterion question: Is the option a reasonable and efficient allocation of resources?
Related questions:
• What is the cost -effectiveness of the vaccination?
• How does the cost -effectiveness of the vaccination vary in any sensitivity analyses?
• How does the cost -effectiveness change in response to changes in context, assumptions, model
structure, across different studies, etc.?

C
ompletion Guidance: The objective of this section is to describe the available evidence from cost-
effectiveness analyses (CEAs)  as well as any major factors that could affect the cost -effectiveness profile
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 of the vaccine. Identify the cost- effectiveness results, including the base- case and a sensitivity range,
from any available cost -effectiveness studies.  When possible, indicate  which assumptions cause the
greatest change in results by examining the sensitivity analyses of a study.   If there are two or more
studies, identify any major differences between the studies.   Identify any other important factors that
may affect the cost -effectiveness profile of the vaccination.  For example, issues identified in other
domains of the EtR framework regarding the overall certainty of the evidence for critical outcomes may
also be important factors that affect vaccination cost -effectiveness.

D
iscussion

W
ork groups should assemble economic evidence on the study question and the intervention strategies
being evaluated.   It may be helpful for the health economic evidence to be assembled in consultation
with the ACIP Economics Lead and/or the NC IRD Lead Economist.  The evidence collected can include
analyses conducted by independent researchers, the vaccine industry and CDC economists.  The work group lead and the ACIP Secretariat will determine if an internal CDC CEA should be conducted.  This w ill
generally be needed for new vaccines and new recommendations with major programmatic economic impact.

T
he findings from the health economic analyses should be reviewed and presented in accordance with
ACIP guidance on economic studies (https://www.cdc.gov/vaccines/acip/committee/guidance/economic -studies.html
).  The work group
should consider the quality of the CEAs as described by the Second Panel on Cost -Effect iveness in Health
and Medicine.  4  This may include review of the model design and inputs to determine if the estimates
are reasonable in terms of disease transmission, intervention effects, vaccine costs, implementation costs, disease outcome costs, and c ommunity vs. patient preferences.  It may be important to
understand and articulate whether there is variability in local epidemiology, infrastructure, or costs that influence impact of the intervention.

Domain 6: Equity
Criterion: Health equity
Criterion  question: What would be the impact on health equity?
Related questions:
• Are there any groups or settings that might be disadvantaged in relation to the problem or options that are considered?
• Are there plausible reasons for anticipating differences in the relative effectiveness of the option for disadvantaged groups or settings?
• Are there different baseline conditions across groups or settings that affect the absolute effectiveness of the option or the importance of the problem for disadvantaged groups or settings?
• Are there important considerations that should be made when implementing the intervention (option) in order to ensure that inequities are reduced, if possible, and that they are not increased?

C
ompletion Guidance: Clinical and p ublic health guidelines  need to explicitly consider health equity
(Welch et al, 2017). Health inequities are differences in health considered unfair or unjust and could
have been avoided . This domain facilitates transparent and explicit consideration of t he impact of the
intervention when compared with the alternative option on the target population, specifically to identify if any persons would be disadvantaged as a result of the intervention. The identification of factors that
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 may lead to health inequiti es may lead to modified recommendations that apply to the target
population or separate recommendations tailored to disadvantaged groups. Work groups may conduct a
high -level search to identify any publications reporting on issues of health equity or inequity on the topic
under consideration. Relevant publications may be qualitative  or quantitative. If no evidence is
identified, then the work group should provide additional considerations addressing the related questions to the best of their ability.

Doma in 7: Feasibility
Criterion: Implementation feasibility
Criterion question: Is the option feasible to implement?
Related questions:
• Is the intervention sustainable?
• Are there important barriers that are likely to limit the feasibility of implementing the intervention or require consideration when implementing it?
• Is access to the vaccine an important concern?
• Would the vaccine recommendation have any impact on health equity?
• Are there important considerations when implementing the intervention in order to ensure that inequities are reduced, if possible, and that they are not increased?

Co
mpletion Guidance: The Implementation Checklist tool (Appendix 3) summarizes potential barriers to
implementation and can be used to guide these discussions.  Impact on health equity is a component that factors into several areas of the tool, but any outstanding concerns can be explicitly described.  Information regarding barriers that would be difficult to overcome should be provided.  Implementation
issue s are not expected to drive the recommendation, but it is possible that implementation
considerations may change the type of recommendation, influence the wording of the recommendation
or only inform the guidance that accompanies the recommendation.  If th ere are specific factors that
influence the ultimate decision regarding the recommendation or its wording, the rationale would be important to include here.  As with other areas of the framework, if data are lacking this should be stated.  Factors that may  impact guidance accompanying the recommendation may be briefly listed
here, with additional information included in the “Additional Considerations” section of the framework.

Conclusions and Additional Considerations
Finally, the conclusions  that the work group  reaches and any additional considerations that the work
group  would like to present regarding the policy question or recommendation are presented in the last
four rows of the EtR framework (Appendix 1).

The t
ype of recommendation and actual text o f the recommendation are based on the judgments made
for all of the criteria and relate directly to the summary “Balance of Consequences” judgement presented in the first row of the conclusions section.  The specific wording of each of the three recommenda tion types will stand alone.  The three recommendation options include: ACIP recommend s
the intervention; ACIP  recommend s the intervention  for individuals based on shared clinical decision -
making; and, ACIP does not recommend the intervention ( Even though the Intervention may be used
within FDA licensed indications) .

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 The final row of the EtR framework table provides space to emphasize any additional considerations that
are pertinent to the recommendation, including suggestions for overcoming implementation  barriers,
proposed monitoring and evaluation needs, and/or areas requiring additional research to inform future decisions.

Summary of  the ACIP ’s deliberation s and final recommendations
A summary of the ACIP discussions regarding the work group recommendations and the final wording
approved  should be included in  the table ‘Final deliberation and decision by the ACIP .’  This should
include a brief description of the rationale supporting any ACIP modification of, or disagreement with,
the work group recommendation. This section will be completed by the ACIP work group lead and the ACIP work group chair collaboratively.
Additional Resources
1. Alonso -Coello P, Schünemann HJ, Moberg J, Brignardello -Petersen R, Akl EA, Davoli M, Treweek
S, Mustafa RA, Rada G, Rosenbaum S, Morelli A. GRADE Evidence to Decision (EtD) frameworks:
a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. bmj. 2016 Jun 28;353:i2016.
2. Alonso -Coello P, Oxman AD, Moberg J,  Brignardello -Petersen R, Akl EA, Davoli M, Treweek S,
Mustafa RA, Vandvik PO, Meerpohl J, Guyatt GH. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. bmj. 2016 Jun 30;353:i2089.
3. Ahmed, F., Temte, J.L., Campos -Outcalt, D., Schünemann, H.J. and ACIP Evidence Based
Recommendations Work Group (EBRWG, 2011. Methods for developing evidence-based recommendations by the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC).  Vaccine , 29(49), pp.9171 -9176.
4. Schünemann H, Brożek J, Guyatt G, Oxman A. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The  GRADE Working Group, 2013.
Available from guidelinedevelopment.org/handbook. 2013.
5. Welch, V. A., Akl, E. A., Guyatt, G., Pottie, K., Eslava -Schmalbach, J., Ansari, M. T., ... &
Hultcrantz, M. (2017). GRADE equity guidelines 1: considering health equity in  GRADE guideline
development: introduction and rationale.  Journal of clinical epidemiology , 90, 59-67.
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 Appendix 1: ACIP Evidence to Recommendations Framework

Question: Overarching policy question to be answered by the guideline panel (ACIP)  using the Evidence to Recommendations (EtR) frame work.
The quest ion shou ld be precise and ident ify the specific interv ention, compar ison, and outcome, as w ell as the tar get popul ation and t he setting
(specific s ubpopul ations) in PICO format.
Popula tion: Target popul ation  for vaccine (e.g., a ge range, se x, immune sta tus, pregnancy )
Intervention: Vaccination (if appl icable, dosag e and sc hedul e)
Compa rison(s): No Vaccination/S tandard  of care/An existing vaccine/O ther prevention option
Outcome : Outcome(s) associated with vaccination  (e.g., prevention outcomes or adverse effects)

 Background: The addressed PICO question should be described in detail, and important background information for understanding the questio n
and why a recommendation or decision is needed should be briefly provided.  If a recommendation is preferential or represents off-label use,
this should be indicated.
Include sample language: Additional background information supporting the ACIP recommendations on the use of xxx vaccine can be found in
the relevant publication of the recommendation referenced on the ACIP website .
WORK GROUP  JUDGMENTS  EVIDENCE  ADDITIONAL INFORMATION  PROBLEMIs the problem of public health importance?

  ○
○ ○
○

○
○ No
P
robably no
Probably yes
Yes
Varies
Don't know  Provide available  scientific evidence on
burden of  disease, preferably within the
target population for the
recommendation.
I
f no published evidence is available,
provide expert judgment on the  public
health priority  considerations.  Identify any additional public health
priority  considerations, including
consideration of disparities.

15 WORK GROUP JUDGMENTS  EVIDENCE  ADDITIONAL INFORMATION  BENEFITS & HARMS  How substantial are the desirable
anticipated effects?
○
○
○
○
○
○
○
○○
○
○
○
○
○ ○
○
○ ○ Minimal
Small
Moderate
Large
Varies
Don't know  Describe the magnitude of the  beneficial
effects of vaccination  on individual
(vaccine  effectiveness, duration of
protection) and population  (herd
immunity) levels.   Take into consideration:
Is the baseline benefit similar across
subgroups (by age, sex,  pregnancy or
lactation s tatus, occupation [ i.e., healthcare
workers], immune s tatus, r ace, S ES, and
other gr oups)?
Are there indirect ef fects that should b e
considered ( e.g.,  herd i mmunity)?
How substantial are the undesirable
anticipated effects?
 Minimal
 S
mall
 Moderate
 Large
 Varies
 Don't know  Are there undesirable effects of the
vaccine, either on the individual (e.g.,
adverse events following immunization) or population (e .g., age -shift of disease,
serotype replacement) levels?  Take into consideration:
Is the baseline risk for harm similar across subgroups (see above)?
S
hould there be separate recommendations
for subgroups based on harms?
Do the desirable effects outweigh the
undesirable effects?
Favors interventionl
F
avors comparison
Favors both
Favors neither
Varies
Don't know  Describe the balance of benefits of the
vaccine with possible harms (individual and population level).
16

 ○
○
○
○
○○○
○
○
○
○
○
○
○
○
○
 WORK GROUP JUDGMENTS  EVIDENCE  ADDITIONAL INFORMATION
What is the overall certainty of this
evidence for the critical outcomes ?
Effectiveness of the intervention
 No  studies found
 4 (very low)
 3 (low)
 2 (moderate)
 1 (high)
Safety of the intervention
 No studies found
 4 (very low)
 3 (low)
 2 (moderate)
 1 (high)  Please refer to GRADE evidence profiles  for
detailed assessment of the certainty of the
evidence. For more information, please see the
 ACIP Handbook for Developing Evidence -
Based Recommendations.   If GRADE was n ot used to evaluate the
certainty of evidence, please provide
justification and the method and outcome of any other tools used to evaluate the body of evidence relevant to the critical outcomes.  VALUES  Does the target population feel that the
desirable effects are large relative to undesirable effects?
 No
 P
robably no
 Probably yes
 Yes
 Varies
 Don't know  Provide any available evidence on target
population values & preferences related to vaccination and comparative health benefits
and risks. Describe the source of these
estimates.  Are values and preferences for relevant
outcomes measured?  Are the benefits, harms and costs of vaccination valued
differently by different subgroups?

If the target group doesn’t value the intervention, or attributes little value to the
harms and benefits, consider whether potential education measures are needed.

17
  WORK GROUP JUDGMENTS  EVIDENCE  ADDITIONAL INFORMATION
Is there important uncertainty about or
variability in how much people value the
main outcomes?

○
○
○
○
○

○
○
○ ○

○
○

○
○
○
○

○
○Important uncertainty or variability
Probably important uncertainty or variability
Probabl not important uncertainty or variability
No important uncertainty or variability
No known undesireable outcomes  Please provide available data used to
determine the relative importance that the target population attributes to the desirable and the undesirable outcomes related to the intervention as well as the comparison.  Describe the source of variability, if any.
 Are there methods for determining values satisfactory for this recommendation?
 If not, systematic assessment of values and preferences of target group may be
considered.  ACCEPTABILITY  Is the intervention acceptable to key
stakeholders?
No
P
robably no
Probably yes
Yes
Varies
Don't know  Provide assessment of whether intervention
would be acceptable to stakeholders
(ethically, programmatically, financially, etc.)   RESOURCE USE  Is the intervention a reasonable and
efficient allocation of resources?
 No
 P
robably no
 Probably yes
 Yes
 Varies
 Don't know
 Provide summary of cost -effectiveness
analyses (CEAs) of the vaccine in the target population. Include base case results and a sensitivity range. Include any other notable findings, for example, specific policy -
relevant scenario s.  Overall findings: Summarize the findings
from available CEAs, including major differences in baseline assumptions.
 Uncertainty: Does the analysis capture the full range of uncertainty? For example, are
the findings from the uncertainty of
evidence ana lysis, identified earlier in this
document (the EtR Framework), appropriately represented in the methods of the CEAs?

Multiple assessments: Are there multiple CEAs? If so, what are the major differences
in methods and results?

18

 WORK GROUP JUDGMENTS  EVIDENCE  ADDITIONAL INFORMATION  EQUITY  What would be the impact on health
equity?

 ○
○
○
○
○
○
○

○
○
○
○
 ○
○
  Reduced
 Pr
obably reduced
 Probably no impact
 Probably increased
 Increased
 Varies
 Don't know  Summarize the  findings from a review of the
literature  addressing issues of health
inequities or groups who may be disadvantaged.  Consider from the evidence or guideline
panel:
• Are there any groups or settings that might be disadvantaged in relation to the problem or o ptions that are
considered?
• Are there plausible reasons for anticipating differences in the relative effectiveness of the option for disadvantaged groups or settings?
• Are there different baseline conditions across groups or settings that affect the absolut e effectiveness of the option or
the importance of the problem for disadvantaged groups or settings?
• Are there important considerations
that should be made when implementing the intervention
(option) in order to ensure that
inequities are reduced, if possible,
and that they are not increased?  FEASIBILITY  Is the intervention feasible to implement?
No
Pro
bably no
Probably yes
Yes
Varies
Don't know  Are there any barriers to implementation?
 Please refer to the Implementation
Considerations checklist.
19
 Balance of
consequences  Undesirable
consequences
clearly outweigh
desirable
consequences
in most settings  Undesirable
consequences
probably outweigh
desirable
consequences
in most settings  The balance
between
desirable and
undesirable
consequences
is closely balanced
or uncertain
 Desirable
consequences
probably outweigh
undesirable
consequences
in most settings  Desirable
consequences
clearly outweigh
undesirable
consequences
in most s ettings  There is
insufficient
evidence to
determine the
balance of
consequences
 ○ ○ ○ ○ ○ ○
Is there sufficient information to move forward with a recommendation?
Yes   ○                                              No   ○

○ ○ ○ Policy options for
ACIP consideration  ACIP does not recommend the
i
ntervention*
*Intervention may be used within
FDA licensed indications
 ACIP recommends the intervention
for individuals based on shared
clinical decision -making
ACIP recommends the intervention

Draft
recommendation
(text)  Please provide the draft recommendations proposed to ACIP.

Additional
considerations
(optional)  Please outline any significant additional considerations (e.g., aspects related to implementation, monitoring and
evaluation, research priorities, etc.).

Fina
l deliberation and decision by the ACIP

20

 Final ACIP
recommendation

○ ○ ACIP does not recommend the
intervention *
*Intervention m ay be used within FDA
licensed indications  ACIP recommends the intervention for
in
dividuals based on shared clinical
decision -making
○ ACIP recommends the intervention

Additional ACIP
considerations
 Wording as accepted in the guide
21
 Appendix 2 When to Prepare GRADE Evidence Profile  Algorithm

22
 Appendix 3 Implementation Considerations Checklist

Summary: 1            A CIP Evidence to Recommendation User’s Guide    October 1 , 2020 2    Contents   Introduction .................................................................................................................................................. 3   How to Use This Guide  .................................................................................................................................. 3   The EtR Framework …


01 Pebsworth hepatitis b 508

Hepatitis B Virus Vaccine
Birth Dose
Vicky Pebsworth, PhD, RN
Advisory Committee on Immunization Practice
Childhood/Adolescent Schedule Workgroup
December 4, 2025
1
Presentation Overview
•Introduction and Policy Context
•Burden of Disease
•Efficacy
•Safety
•Conclusions
2
Introduction to Policy Context
Policy Request
•Assess the current recommended schedule, including the use
of a universal birth dose of Hepatitis B Virus (HBV) vaccine in children whose mothers test negative for HBsAg at delivery
•Why Are We Here Today?
Feedback from stakeholders
Misalignment of existing recommendations in most developed
countries
Prolonged time since last comprehensive review as per ACIP’s charter
3
•Rising transmission of acute hepatitis from 1960s to the mid -1980s due
to blood -borne exposures in high- risk groups
•Introduction of plasma -based vaccine in 1981,  high -risk groups targeted
•Concerns over vaccine safety, technology changes, reduced liability
•Evolution of ACIP birth recommendations during the 1980s
•Dissatisfaction with targeting strategy, ambitious new strategy proposed
•Leap to universal birth dose made in 1991How Did We Get to Where We Are Now?
Rapid Rise of Reported Acute U.S. Cases of Hepatitis B
 - 5,000 10,000 15,000 20,000 25,000 30,000
1965 1970 1975 1980 1985 1990Source: CDC National Center for HIV, Viral Hepatitis, STD, and Tuberculosis Prevention, Viral Hepatitis Division, Epidemiology and Survei llance Branch
•New Vaccine Licensed in 1981
•Safety Concerns Related to Donor Source Material in Plasma -Derived
Vaccine
•Availability of New Recombinant Technology Platform and Hepatitis B
Antigen- based Product Manufactured in Yeast
•Approval of the National Childhood Vaccine Injury Act in 1986
•Policymaker Support Factors That Affected Policy Shifts
“If vaccinations were given universally at birth to infants in
populations that have a high rate of perinatal HBV transmission,and with childhood immunizations to infants in other parts ofthe world, a worldwide cohort of persons with protection fromthis long -term infection would be established. ”
“In the United States, selective immunization of groups at risk ofinfection has not been effective in lowering the overall incidence
of disease. ”Worldwide Elimination of Hepatitis B Transmissions:
We Have the Way, We Need the Will
Evolution of ACIP Recommendations:
Infant Target Groups, Treatments/Vaccines
ACIP
meetingTarget group Infant treatment Vaccine type Recommendation change logic
6/25/1982 Infants  born to
HBsAg+ mothersFirst infant PEP
•HBIG at birth
•Vaccine at 3 monthsHeptavax  licensed
11/16/81 Recommended for high- risk groupsNew vaccine licensed.
Numerous risk groups targeted
Infant treatment timing unclear
6/1/1984 Infants  born to HBsAg+ mothersRefined infant PEP•HBIG within 12 hours of birth
•Vaccine with 7 daysHeptavax 1983 Lancet study tested 3 different dosing schedules w/HBIG & vaccine. Schedule B
was the rec’n
6/7/1985 Infants  born to
HBsAg+ mothersConcurrent PEP dosing•HBIG and vaccine <12 hoursHeptavax 1984 Lancet study finds no interference with
HBIG and vaccine.
1985 JAMA study doses concurrently
6/19/1987 Infants  born to
HBsAg+ mothersConcurrent PEP dosing•HBIG and vaccine <12 hoursRecombivax -HB licensed
and recommended
Heptavax  New vaccine licensed
Concerns over plasma vaccine citedConcurrent dosing schedule kept
11/22/1991 Universal infant vaccinationVaccination before hospital discharge, no later than 2 months, added to childhood scheduleRecombivax -HB
Engerix -BConcerns w/failure of targeted policy
Safety in infant/child trials cited
12/23/2005 Universal infant
vaccinationVaccination within 12- 24 hrs of birth Recombivax -HB
Engerix -BProvide a “safety net” for medical errors
Eliminate “flexible”/”inconsistent” practices
Motivations to Ask The Question?
What Are We Trying to Accomplish Today?
•Address Stakeholder/Parent Dissatisfaction
•Report on the required periodic review conducted by the Workgroup
•Consider policies that:
•are better aligned with other countries similar to ours
•Are based on evidence and target the needs of high -risk persons and
populations
•Explicitly consider the principles of public health and vaccination ethics
9
The Importance of Stakeholders
•Terms of Reference – IOM Stakeholder
Concerns
2002 - Multiple Immunizations and Immune Dysfunction
2013 - The Childhood Immunization Schedule and Safety: Stakeholder
Concerns, Scientific Evidence, and Future Studies
•Stakeholder Surveys
Oregon Survey of Hepatitis B Vaccine Refusal in Newborns, 2014
KFF/Washington Post Survey of Parents, 2025
Stakeholder Feedback
Oregon Survey
2014
•5% Refused HBV birth dose
•8% wanted to wait
•6% were undecided.
Why?
•78.1% baby was too young
•70.4 % vaccine safety concerns
•43.8% baby was at low risk of
infectionKFF/Washington Post Survey
2025
•13% skipped/delayed HBV
•16% skipped/delayed vaccines
---67% side effects concerns
---53% vaccine safety doubts
---51% vaccines not necessary
---42% not wanting multiple shots
---35% safety testing lacking
---26% CDC recommends too
many vaccines
---41% want to space out shots
---58% little/no confidence in
federal agencies
11
U.S. Birth Dose Policy is an Outlier Among
Low -prevalence Nations
12

•Markman, Putting Public Health Ethics Into Practice
•Expected health benefits for the target population
•Potential harms and burdens for all stakeholders
•Impact on autonomy
•Impact on equity
•Expected efficiency
•Ethics of Vaccination
•Preserve Health
•Means -end Proportionality
•Discretion
•Parsimony
-Marckmann G, Schmidt H, Sofaer N, Strech D. Putting public health ethics into practice: a systematic framework. Front Public Hea lth. 2015
Feb 6;3:23. doi: 10.3389/fpubh.2015.00023. PMID: 25705615; PMCID: PMC4319377.Public Health and Vaccination Ethics
Policy Context Summary (1)
•Causes of hepatitis B increases in 1970s-80s diminished
with targeted measures
•Universal birth dose set out to eliminate worldwide transmission
•Other countries with similar incidence and prevalence of Hepatitis B use a selective vaccination practice, and not a universal birth dose
•Some parent stakeholder groups would like greater flexibility and the ability to decide what is best for their child.
14
Policy Context Summary (2)
•Stakeholder dissatisfaction has been documented for 25 years, is
of societal significance, and creates challenges for immunization policymaking.
•The belief that universal vaccination can eradicate Hepatitis B was endorsed by leaders and shaped public policy.
•In response, between 1983 and 1991, ACIP recommendations shifted from an approach that only targeted high- risk infants to
one that targets all infants.
•The context included the emergence of advanced vaccine technologies and fewer liability concerns.
15

Summary: Hepatitis B Virus Vaccine Birth Dose Vicky Pebsworth, PhD, RN Advisory Committee on Immunization Practice Childhood/Adolescent Schedule Workgroup December 4, 2025 1 Presentation Overview •Introduction and Policy Context •Burden of Disease •Efficacy •Safety •Conclusions 2 Introduction to Policy Context Policy Request  •Assess the current recommended schedule, including the use  of a universal birth dose of Hepatitis B Virus (HBV) vaccine in children whose mothers test negative for HBsAg at…


02 nevison Hepatitis B 508

Burden of disease
•Morbidity trends
-What has the universal birth dose accomplished compared to more targeted measures?
•Vertical (perinatal mother- to-child) transmission
-Targeted vaccination of at -risk infants vs. the universal birth dose?
•Horizontal transmission in childhood
-  What evidence exists and has the risk to most American children been overstated?
Surveillance data: Acute hepatitis B cases are the longest and
most consistently reported metric of morbidity
MMWR 1991,
“… selective vaccinationof persons with identified risk factors … has notlowered the incidencehepatitis B.”
Data from the National Notifiable Diseases Surveillance System
•Increased blood screening for HBsAg
•Sharp declines in post transfusion hepatitis (PTH)
•Cleaner practices in dialysis
•Widespread adoption of safer sexual practices
•Needle exchange
•Screening and case management for HBsAg+ mothers
Universal birth dose contribution to acute case decline is likely very small.Sources of decline in acute hepatitis B cases
Chronic case data raise new questions
NNDSS began collecting new chronic case data in 2003
NNDSS =  National Notifiable
Diseases Surveillance System

Increasing new chronic cases of hepatitis B
in older adults after 2020
Upticks after 2020
also seen in adults30-39, 40- 49, and
50-59 years old.
Data from National Notifiable
Diseases Surveillance System

Infant morbidity
Data from the National Notifiable Diseases Surveillance SystemCDC model of
perinatal infections:
Year     # of Cases
2015 :   952 (Ko et al. 2016)
2023:   601  (CDC staff)36              7
•Acute cases have declined sharply from peak in 1985 for multiple reasons.
•New chronic cases have been increasing among older adults after 2020.
•Perinatal cases are down to 36 and 7 in 2015 and 2023, respectively, but
    CDC model predicts many more cases.Summary of hepatitis B morbidity trends
Modeling perinatal infections
Estimate begins by tabulating how many mothers are HBsAg+,
i.e., chronic carriers of hepatitis B virus
Majority of HBsAg+ mothers in US are foreign -born
Koneru et al., 2019, Table 2 excerpts; estimated for 2015
Maternal country
of birthTotal Births HBsAg+ prevalence
(%)Estimated births to
HBsAg+ women
Total 3,978,500 20,678  (15,625 -30,640)
US-born total 3,070,700 0.17 (0.07 -0.39) 8,296  (4,031 -17,100)
Non-US-born
Total 857,105 11,981  (11,395 -12,762)
Africa 64,228 3.42 (3.27 -3.96) 2,197 (2,100 -2,543)
Asia
East Asia 66,384 8.73 (8.52 -8.93) 5,795  (5656 -5928)
Southeast Asia 62,044 3.92 (3.76 -4.08) 2,432  (2,333 -2531)
Modeling perinatal cases
based on Ko et al., 2016 model
Births to HBsAg+
women
~ 18,000
Suscep tib le
I nfantsMothe r
HBe Ag +M other HBe Ag -F = 70% 1-F = 30%
T ransmission rate K+ = 90%T ransmission rate K- =  5-20%Perinatal
I nfections
Chronic rate L = 90%Chronically
infected infantsChang et al., 2007;
Ko et al., 2016Mothe r
HBe Ag -
PEPUpdated input from C DC
 in response to A C I P query .
PEP (post exposure prophylaxis)
PEP includes hepatitis B vaccine and HBIG at birth
HBsAg+ mothers
screened 88%
I nfants with
timely PEP at
birth  98.5%I nfants with no
PEP at birth
1.5%I nfants with no
PEP at birth
20.5%
M other HBe Ag -
Suscep tib le
infants 9%HB sA g+ mothers
unscreened  12%
8% failed
 PEPI nfants with
timely  PEP at
birth  79.5%
8% failed PEP
601 chronically infected infants in 2023 but NNDSS reports only 7 !
Updated inputs from
C DC  in response to ACIP q u e r y.
Suscep tib le
infants 27%
Perinatal (mother -to-child) transmission summary
•Risk is isolated to ~0.5% of pregnancies, mainly immigrants from high endemicity
countries.
       - Add hep B to immigrant medical examination.
•Improve screening measures in prenatal care and delivery.  PEP is effective in
preventing transmission!
•CDC’s Ko et al. model may overestimate perinatal cases.
      -U.S.  infants are not all equally at risk - many mothers intentionally decline birth dose.
      - Other inputs (screening rate, PEP failure rate) may be too pessimistic.
•Little published evidence documenting horizontal transmission.
•A single modeling study, Armstrong et al. [2001], raised
concerns that all young children in the U.S. are at significant
risk for horizontal transmission of hepatitis B .
•The model estimated ~ 16,000 cases/yr in children age 0- 9
years old in the pre -vaccine era due to horizontal transmission,
half in Asian immigrants, half in the general U.S. population.Modeling horizontal transmission in childhood
Armstrong G, Mast E, Wojczynski  M, Margolis H. 2001. Childhood Hepatitis B Virus Infections in the
United States Before  Hepatitis B Immunization, Pediatrics 108(5), 1123 -1128.
Armstrong 2001 modeled HepB  horizontal transmission based on
seropositivity v. age in NHANES and among Asian immigrants

Independent calculation of Armstrong linear fits
Without the assumed
perinatal infection (Po),
seropositivity is significantly correlated
with age only for the
Southeast Asian model.
NHANES seropositivity
v. age correlation is
statistically
insignificant with a
natural intercept of
0.22% (perinatal).

Comparison of 2 SE Asian Groups
Characteristic Louisiana (Vietnamese) Wisconsin (Hmong)
All, families, US -born children N =1403, 227, 679 N=1183, 161 ,429
HBV markers used, past or present
infectionAnti -HBc Anti -HBc or HBsAg+
HBV markers used, chronic HBsAg+, anti -HBsIgM - HBsAg+
US born, % any HBV (% chronic) 16%, (4%) 14% (6%)
Asian -born, % any HBV (% chronic) 59% (11%)*      (inferred) 72% (19%)**
% of children with HBsAg+ moms 9%  (60/656) 16% (69/429)
Reference Mahoney et al., 1995 Hurie  et al., 1992
* Nguyen and Trevison . 2020. Vietnam a country in transition: BMJ doi:10.1.1136/bmjnph -2020- 000069
    does not list hepatitis B among the leading causes of death in Vietnam .
** In the Asian -born Hmong, 86% -97% of those aged 15 to >40 years had HBV blood markers.
Horizontal transmission in childhood?
•Horizontal transmission is rare among most U.S. children …
•Although it can occur in some high- risk immigrant families
•Armstrong et al.’s 16,000 cases/year are not supported by NNDSS data

                           ~ 400 acute cases/year
   pre -UBD
NNDSS =  National NotifiableDiseases Surveillance System
The Informed Consent Action Network (ICAN) asked the CDC
for “documentation sufficient to reflect any case(s) of
transmission of Hepatitis B in an elementary, middle, or
high school setting. ”
The CDC responded, “A search of our records failed to
reveal any documents pertaining to your request. ”Horizontal transmission in childhood – final note
https://icandecide.org/article/cdc -concedes -it-lacks -any-proof- of-hepatitis -b-being -transmitted -in-a-
school -setting/
Summary of burden of disease
Mixed trends in hepatitis B morbidity 34 years after the Universal
Birth Dose
- Acute cases have declined sharply for multiple reasons.
- New chronic cases are increasing since 2020 in adults over 30.
- Reported perinatal cases are in the single to low double digits thanks to
P E P.

Models yield larger estimates than surveillance data  -   cross
checks useful
          - Ko et al. model may overstate perinatal chronic cases.
          - Horizontal transmission among young children is rare and was strongly
 overstated by the Armstrong et al. model.
Efficacy and Waning Immunity
Many studies show reduced antibody levels over time following hepatitis B
vaccination, especially when vaccination begins in infancy or early childhood.
Age (years) at the time
of:Anti-HBs ( mIU/ml )
Before booster doseAnti-HBs ( mIU/ml)
After booster dose*
Booster Primary series GMC % with ≥ 10 (N >10/Ntotal)GMC % with ≥ 10 (N >10/Ntotal)
< 40 < 5 6.8 32% (19/59) 98.2 83% (25/30)
35 to 39 5 to 9 24.9 61% (30/49) 134.2 94% (16/17)
40 to 49 10 to 19 22.8 64% (58/90) 275.7 89% (17/19)
≥ 50 ≥ 20 8.5 40% (18/45) 179.4 89% (17/19)Native Alaskans vaccinated for hepatitis B between
ages 5 -19 years had highest titers 30 years later
Bruce et al. 2016. Protection and  antib od y levels after Hep atitis B vaccine: Results of a 30 -year follow -up study and response t o a
booster dose, JID 214: 16- 22. (Tables 1,3)* B ooster dose was given to 85 people with titers < 10 m IU/ml as well as an
additional N=36 people who were not boosted in the 22 -year follow -up.
By age 16 -19 years, most US children vaccinated as infants had low
antibodies, but most responded well to a booster dose
Middleman et al. 2014. Duration of protection after infant Hep atitis B vaccination series, Ped iatrics 133(6) .Gr o u p  1 : Fir s t
 vaccine ≤ 7 days Gr o u p  2 : Fir s t vaccine ≥ 4 weeks Group 1, % Group 2, % Total, % P value
1st dose
≤7 d ays1st dose
≥ 4 weeks
Baseline
seroprotection16.7 % 33.9 % 24.1 % < 0.0001
Postchallenge
dose seroprotection90.4 % 93.9 % 91.9 % 0.2T able 2 L evels of Seroprotection  (anti -HBs Tite r ≥ 10 IU/m L) b y Group
Waning immunity also seen among teenagers vaccinated as
infants in NHANES data
Cohorts most likely
vaccinated as infants
Data compiled by CDCHepatitis Division
•Anti -HBs titers wane the most rapidly in children who begin
their primary series as infants, especially as newborns.
•While most vaccinees respond well to a booster dose, some
of those vaccinated as infants may lack protection when they
enter their years of highest risk for acquiring hepatitis B.Waning immunity summary and concluding thoughts
References
Armstrong G, Mast E, Wojczynski  M, Margolis H. 2001. Childhood Hepatitis B Virus Infections in the United States
Before Hepatitis B Immunization, Pediatrics 108(5), 1123 -1128
Bruce et al. 2016.  Protection and antibody levels after Hepatitis B vaccine:  Results of a 30 -year follow -up study and
response to a booster dose, The Journal of Infections Diseases, 214(1 July) 16 -22
Chang, M -H. 2007. Hepatitis B virus infection.  Seminars in Fetal & Neonatal Medicine (2007) 12, 160e167.
Hurie  MB, Mast EE, Davis JP. Horizontal transmission of hepatitis B virus infection to United States -born children of
Hmong refugees. Pediatrics . 1992;89:269– 273
Klevens  RM, Liu S, Roberts H, Jiles RB, Holmberg SD.  2014. Estimating acute viral hepatitis infections from nationally
reported cases.  Am J Public Health, 104(3): 482 -487
Koneru, A. 2019. Estimating Annual Births to Hepatitis B Surface Antigen –Positive Women in the United States by
Using Data on Maternal Country of Birth Public Health Reports 134(3)
Ko SC et al. Estimated Annual Perinatal Hepatitis B Virus Infections in the United States, 2000 -2009. J Pediatric Infect
Dis Soc. 2016 Jun;5(2):114- 21
Mahoney FJ, Lawrence M, Scott C, et al. Continuing risk for hepatitis B virus transmission among Southeast Asian
infants in Louisiana. Pediatrics . 1995;96:1113– 1116
McQuillan GM, Townsend TR, Fields HA, et al. Seroepidemiology  of hepatitis B virus infection in the United States.
1976 to 1980. Am J Med.  1989:87:5S –10S
McQuillan GM, Coleman PJ, Kruszon -Moran D, et al. Prevalence of hepatitis B virus infection in the United States: the
National Health and Nutrition Examination Surveys, 1976 through 1994. Am J Public Health. 1999; 89:14– 18
Middleman et al. 2014. Duration of protection after infant Hepatitis B vaccination series, Pediatrics 133(6)
MMWR 1991. CDC/ACIP, Hepatitis B Virus: A Comprehensive Strategy for Eliminating Transmission in the United
States Through Universal Childhood Vaccination: Recommendations of the Immunization Practices Advisory Committee (ACIP), MMWR, November 22, 1991 / 40(RR -13);1- 19,
https://www.cdc.gov/mmwr/preview/mmwrhtml/00033405.htm
Ott et al. The risk of perinatal hepatitis B virus transmission: hepatitis B e antigen ( HBeAg ) prevalence estimates for all
world regions BMC Infectious Diseases 2012, 12:131 http:// www.biomedcentral.com /1471 -2334/12/131
Smith E.A. et al., 2012. The national Perinatal Hepatitis B Prevention Program 1994 -2008. Pediatrics 129(4).
doi:10.1542/peds.2011- 2866
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.
Closing Slide / Disclaimer

Summary: Burden of disease •Morbidity trends  -What has the universal birth dose accomplished compared to more targeted measures? •Vertical (perinatal mother- to-child) transmission -Targeted vaccination of at -risk infants vs. the universal birth dose? •Horizontal transmission in childhood -  What evidence exists and has the risk to most American children been overstated? Surveillance data: Acute hepatitis B cases are the longest and  most consistently reported metric of morbidity MMWR 1991, “……


03 blaxill Hepatitis B 508

Safety Review of Hepatitis B Birth Dose Vaccination
CDC Advisory Committee on Immunization Practices meeting
Mark F. Blaxill, MBA
December 4, 2025Office of the Director

Safety of the hepatitis B vaccine
•Clinical trials
•Post -licensure safety studies
•IOM and VICP on vaccine -related injuries
•Animal models
•There were no randomized placebo -controlled trials in infants; cited trials used
short follow up periods of 7 days or less and discounted safety concerns
•CDC/ISO’s “rapid systematic review” of post -licensure safety studies reveals
concerns but evidence of chronic, late -onset effects was not presented
•IOM Safety of Vaccine reports have highlighted the absence of evidence to
assess potential adverse effects in over 30 endpoints
•VICP has processed large numbers of HBV related claims, compensating many
•Mechanisms of injury, especially immune activation, reported in animal models Overview of Hepatitis B Vaccine (HBV) Safety:
Safety evidence is limited and often concerning
Clinical trials on infants/children cited for birth dose of
Recombivax HB or Engerix -B in 1991 ACIP recommendation
Trial
publicationVaccine Control
groupSample size and
compositionSafety follow up
periodSafety findings
Zajac et al,
1986Recombivax HB None 79 children, ages 1 -12 years5 days after each dose18% “systemic” complaints:
“fatigue, weakness,
diarrhoea or irritability. ”
Stevens et al,
1987Re co m b iva x HB Plasma vaccine122 infants
39 plasma/83 recombinantAsia n -Am e rica n
HBs Ag + / HBe Ag + mothers7 days after each dose1 death in recombinant group due to “ inoperable congenital malformation”
A ndre et al,  1989En g e rix -B None 1187 neonates Up to 3 days after each dose96% “had no reaction to the
vaccine. ”
2.5% mild/moderate fever
“Symptoms of encephalitis…
“Encephalitis can be dangerous in infants. Watch for fever , lethargy ( weakness or drowsiness), poor feeding,
vomiting, body stiffness, unexplained/unusual irritability or crying”
Source: Encephalitis | National Institute of Neurological Disorders and Stroke“Systemic” clinical complaints in children reported in Zajac et al (1986)

ISO’s “rapid systematic review” of hepatitis B post -licensure safety data
(ISO, 9/18/25) included 20 studies— presented findings from 9 of 20
Categories Unvaccinated or no vaccine as control Vaccine(s) as control
Birth dose defined as <24 hours
Linder et al, 1999
Lewis et al, 2001 (VSD)
Morgan et al, 2025Bassily et al, 1995
Yerushalmi et al, 1997
Birth dose defined as 0 -8 days
Eriksen et al, 2004 (VSD) Greenberg et al, 2002Lopez et al, 2002
Wood et al, 2018
Birth dose defined as <30 days
Gallagher & Goodman, 2010 (NHIS, ASD)Geier et al, 2015 (VSD, Tics)Geier et al, 2016 (VSD, Dev Delay)
Geier et al, 2017 (VSD, Emot Disturb)
Geier et al, 2018 (VSD, prem puberty)Verstraeten et al, 2003 (VSD)
VAERS studies (3)
-Niu et al, 1996
-Niu et al, 1999 (death)
-Haber et al, 2018Sapru et al, 2007
Geier et al, 2013 (ASD)
ISO’s “rapid systematic review” of hepatitis B post -licensure safety data
(ISO, 9/18/25) included 20 studies— presented findings from 9 of 20
Categories Unvaccinated or no vaccine as control Vaccine(s) as control
Birth dose defined as <24 hours
Linder et al, 1999
Lewis et al, 2001 (VSD)
Morgan et al, 2025Bassily et al, 1995
Yerushalmi et al, 1997
Birth dose defined as 0 -8 days
Eriksen et al, 2004 (VSD) Greenberg et al, 2002Lopez et al, 2002
Wood et al, 2018
Birth dose defined as <30 days
Gallagher & Goodman, 2010 (NHIS, ASD)Geier et al, 2015 (VSD, Tics)Geier et al, 2016 (VSD, Dev Delay)
Geier et al, 2017 (VSD, Emot Disturb)
Geier et al, 2018 (VSD, prem puberty)Verstraeten et al, 2003 (VSD)
VAERS studies (3)
-Niu et al, 1996
-Niu et al, 1999 (death)
-Haber et al, 2018Sapru et al, 2007
Geier et al, 2013 (ASD)
Early post -licensure study described unexplained fever
in neonates in the year after HBV introduction in Israel
OR= 2.16“In conclusion, we found that an
increased incidence of unexplained
neonatal fever, which resulted in
evaluation for sepsis, administration of
intravenous antibiotics, and prolonged
hospital stay, may be associated with
vaccination against hepatitis B on the
first day of life. “
Post -licensure safety studies with unvaccinated group and
negative/protective findings show healthy vaccinee effect (HVE)
Study Condition(s)
examinedFinding HVE effects in sample
selection
Included in 9/2025 ACIP safety review
1. Lewis et al, 2001 ( VSD) Fever, sepsis, allergies, seizures
Testing frequencyNo differences0.73 OR for testsExclusions of preterm, LBWUnexplained testing frequency
2. Ericksen et al, 2004 ( VSD)Death Lower death rate
in exposedUnvaccinated sample mean birth wgt <44% of vaccinated
3. Morgan et al 2025
(Australia)Bronchopulmonary dysplasia in preterm0.83 RR “it is not known how clinician perception of the stability of the newborn affects the decision to vaccinate or not”
Eriksen et al, 2004 (VSD)
HVE effect: unvaccinated vs. vaccinated neonates
•<44% of median birth weight
•11 weeks lower median gestational age
•Only 5% of 1993- 98 cohort deaths were in
vaccinated infants, 72 of 1363

Study design
(1) identified all neonatal deaths in NCK and SCK from 1993 -98
(2) determined cases that had been vaccinated with HBV
(3) selected 2– 4 matched HBV -unvaccinated controls for each HBV -vaccinated neonatal death
Matching based on “days of life” category (0 -1, 2- 5 and 6 -28), birth year, sex and HMO
(4) determined pre -existing illness and the causes of death
(5) Categorized deaths as “expected” or “unexpected” in a blinded review
(6) assessed the clinical plausibility that HBV contributed to death
(7) assessed SIDS rates, searched for unvaccinated SIDS cases beyond matched sample
(8) Compared maternal and perinatal factors in both groupsEriksen et al, 2004: death assessment method
Eriksen et al, 2004: Death assessment in matched samples
Primary cause of death Vaccinated Unvaccinated
Total deaths 72 196
“Expected” 50 (69%) 128 (65%)
“Unexpected” 22 (31%) 68 (35%)
SIDS 8 0
Sepsis after birth 7 4
Necrotizing enterocolitis (NEC) 3 29
Insufficient information 2
CNS hemorrhage 1 15
Laryngeal edema 1
Pulmonary/other hemorrhage 0 5
Other - 15
ISO’s “rapid systematic review” of hepatitis B post -licensure safety data
(ISO, 9/18/25) included 20 studies— presented findings from 9 of 20
Categories Unvaccinated or no vaccine as control Vaccine(s) as control
Birth dose defined as <24 hours
Linder et al, 1999
Lewis et al, 2001 (VSD)
Morgan et al, 2025Bassily  et al, 1995
Yerushalmi et al, 1997
Birth dose defined as 0 -8 days
Eriksen et al, 2004 (VSD) Greenberg et al, 2002Lopez et al, 2002
Wood et al, 2018
Birth dose defined as <30 days
Gallagher & Goodman, 2010 (NHIS, ASD)Geier et al, 2015 (VSD, Tics)Geier et al, 2016 (VSD, Dev Delay)
Geier et al, 2017 (VSD, Emot  Disturb)
Geier et al, 2018 (VSD, prem puberty)Verstraeten  et al, 2003 (VSD)
VAERS studies (3)
-Niu et al, 1996
-Niu et al, 1999 (death)
-Haber et al, 2018Sapru et al, 2007
Geier et al, 2013 (ASD)
Additional studies with unvaccinated comparisons listed—but
not presented —in 9/2025 ACIP safety review presentation
Study Condition(s) examined Finding Comments
1. Verstraeten  et al, 2003 Neurodevelopmental disorders (VSD) No significant associations Hg/HBV exposure within 1st month
2. Gallagher & Goodman, 2010 Autism (NHIS) 3.002 OR in males Vaccinated w/in 1st month
3. Geier et al, 2015 Tics (VSD) 1.59 OR total
•1.65 OR in malesHg/HBV exposure within 1st month
4. Geier et al, 2016 Developmental delay (VSD) 1.22 RR Hg/HBV exposure within 1st month
5. Geier et al, 2017 Emotional disturbance (VSD) 1.34 OR
•1.36 OR in malesHg/HBV exposure within 1st month
6. Geier et al 2018 Premature puberty (VSD) 1.80 OR
•1.87 OR in femalesHg/HBV exposure within 1st month
7. Niu et al, 1996 VAERS reports: 1/1991 -5/1995
“neonates” <1 month and
“infants” < 1 year“No unexpected adverse
events in neonates and
infants”Neonates:13 of 24 SAEs were fever, 4 seizures3 of 6 deaths were SIDS
8. Niu et al, 1999 VAERS reports: 1/1991 -10/1998 No “clear increase in neonatal deaths”18 death reports within 1st month12 SIDS cases, 3 initially SIDS
9. Haber et al 2017 VAERS reports, inc. infants: 2005 -15 No “new or unexpected safety concerns”27 deaths, 64 SAEs  in 1
st month,
197 SIDS cases
4 VSD studies with consistent methodologies found increased risk of injury
for chronic, late -onset conditions from HBV in 1st month
0.511.52
Tics
               Developm
delayEmotional
disturbancePremature
pubertyT M F
T M F T M FT M FOdds
RatioLegend
T= total
M= maleF= female
IOM studies of causal relationships with HBV (1)
Condition 1994 2002 2012
Death
Death following anaphylaxis Y
SIDS
All other causes
Arthritis
Acute Arthropathy
Chronic Arthropathy
Psoriatic, onset or exacerbation
Reactive, onset or exacerbation
Rheumatoid, onset or exacerbation
Juvenile Idiopathic, onset or exacerbation
Anaphylaxis Y Y
Brachial Neuritis
Erythema Nodosum
Systemic Lupus Erythematosus, Onset or ExacerbationVasculitis, onset or exacerbationPolyarteritis Nodusa , onset or exacerbation
Diabetes, Type 1
FibromyalgiaEvidence is:
insufficient to accept
or reject ,
establishes (Y), or
favors rejection of (N)causality
IOM studies of causal relationships with HBV (2)
Condition 1994 2002 2012
Encephalitis
Encephalopathy
Seizures
Guillain -Barre Syndrome
Encephalomyelitis, Acute Disseminated
Demyelinating Disorder, Central Nervous System,  1st episode
Demyelinating Event, first episode, ADULTS
Demyelinating Event, first episode, CHILDREN
Optic Neuritis
Multiple Sclerosis
Multiple sclerosis, incident/onset,  ADULTS N
Multiple sclerosis, incident/onset,  CHILDREN
Multiple sclerosis relapse,  ADULTS N
Multiple sclerosis relapse,  CHILDREN
Transverse Myelitis Neuromyelitis OpticaChronic Inflammatory Disseminated PolyneuropathyEvidence is:
insufficient to accept
or reject ,
establishes (Y), or
favors rejection of (N)causality
Vaccine Injury Compensation Program (VICP)
Adult compensation claims for hepatitis B vaccine total $92 million
Multiple sclerosis, transverse myelitis, GBS, encephalitis,
alopecia,  fibromyalgia,  thrombocytopenia,  hypotension,  arthritis,  uveitis,  and optic neuritis are outcomes both compensated by V I C P and listed in the Re co m b iva x  HB
and/or En g e rix -B  package inserts.
Vaccine Injury Compensation Program (VICP)
Children’s compensation claims for hepatitis B vaccine
$18 million in  payments for hepatitis B vaccine alone.
VICP has p aid an additional $80 million for claims due to hepatitis B  in combination with other vaccines.
Children’s claims for hepatitis B vaccine are more
commonly denied than compensated by VICP
Animal models of hepatitis vaccine birth dose
Study Model Selected findings
Immune Brain Behavioral
Studies finding altered development
Yang et al, 2016 mice Th2 bias ↓ hippocampal neurogenesis ↑ anxiety ↓locomotor activity
Wang et al, 2018 mice ↑ IL-4 levels ↑ neuroinflammation ↓ spatial learning & memory
Zhou et al, 2024 mice CD8+ infiltrate CNS ↓ hippocampal neurogenesis ↑ anxiety
Li et al, 2015 rats Th2 shift ↓ synaptic plasticity --
Hewitson et al 2010a macaques -- -- Delayed neonatal reflexes
Hewitson et al 2010b macaques -- Altered amygdala maturation --
Studies finding no changes
Curtis et al 2015 macaques -- -- No consistent evidence of deficits
Gadad  et al 2015 macaques -- No evidence of neuropathology No evidence of aberrant behavior
Immune activation after infant birth dose in rodent models
leads to neurodevelopmental and behavioral impairments
Study Immune findings Immune ->
brainBrain findings Brain ->
behaviorBehavioral
findings
Li et al, 2015
(rats)• Anti -HBs response; Th2 bias at 8
wks
• ↑ TNF-α, ↑IL-6, ↓ IFN-γ, ↓BDNF, ↓
IGF-1•  Serum &  hippocampal
cytokines track together• IFN -γ/IL-4 ratio tracks with
hi ppocampal  B DN F  &  I G F -1I mpai red DG  L T P
• ↓ dendritic spine density,
↓ stubby spi nes
• ↓ synaptophysin, PSD -95,
NR2 A, NR2 B-- --
Y ang et al
2016 (mice)•  H i ppocampus ( 6 wks ): ↓ IFN-γ, ↓
BDNF, ↓ IGF-1; ↑ TNF-α, ↑IL-1β, ↑
IL-6
•  Serum T h2 bias ( ↓ IFN-γ/IL-4)
• HEL+ a lu m  reproduces
phenotype;  alum alone does not• IFN -γ/IL-4 correlates with
hi ppocampal  B DN F /I G F -1
&  neurogenesis markers• ↓ Brd U +, ↓ Brd U +/DCX +, ↓
Brd U +/NeuN+
• Impaired CA1 L TP at 8
wks•  E arly neurogenesis &
cytokine changes precede
behavior• OFT: ↓ distance, ↓ rearing,
↓ center time
• EPM: ↓ open- arm  activity
• MWM: im paired learning &  memory ( normal  swi m speed)• Deficits only at 8 wks
W ang et al,
2018 (mice)•  Sustained ↑ IL-4 in serum &
hippocampus
•  Delayed neuroinflammation ( ↑
TNF-α, IL-1β, IL-6)
• Se ru m  IL -4 correlates with
hi ppocampal  I L -4• Neonatal IL-4 reproduces
HBV outcome
• HBV & IL -4 ↑BBB
perm eability t o  IL -4
• ↓IL-4 R in  hippocampus•  Delayed hi ppocampal
neuroinflammation• Ea rly IL -4 surge → later
neuroinflammation →
behavior deficitsDelayed spatial cognition
Zhou et al,
2024 (mice)•  HB V  induces effector memory
CD8+ T -cells
• CD8+ T cells: ↑ CXCR6; ↓ Arid 5a ,
Mc1r, Flt3, etc.
• ↑ effector -memory C D4+ and
CD8+ T cells• ↑ TNF-α+ / IFN-γ+ CD8+ cells•  C D8+ T  cells enter C NS
via CXCL16/ CXCR6 axis•  A doptive transfer of HB V -
T cells → ↓ neurogenesis• ↓ K i67+ and ↓  DCX+ cells
in DG
• CXCL16 from  glia recruits CD8+ cells• CD8 infiltration →
anxiety -like behavior• OFT: ↓ center time, ↓
exploration
• EPM: ↓ open- arm  activity
• ↑ anxiety -like behavior
The safety of the universal birth dose (UBD) was not studied, pre -licensure,
in randomized, placebo -controlled, extended follow -up trials.
Post -licensure studies have in some cases been confounded by the healthy
vaccinee affect; others have found evidence of chronic, late onset adverse
effects.
IOM Safety of Vaccine reports have highlighted the absence of evidence to
assess potential adverse effects in over 30 endpoints
Animal models provide evidence for risk of immunological activation and
neurobehavioral impairment. Conclusions

Summary: Safety Review of Hepatitis B Birth Dose Vaccination CDC Advisory Committee on Immunization Practices meeting  Mark F. Blaxill, MBA December 4, 2025Office of the Director  Safety of the hepatitis B vaccine •Clinical trials •Post -licensure safety studies •IOM and VICP on vaccine -related injuries •Animal models •There were no randomized placebo -controlled trials in infants; cited trials used  short follow up periods of 7 days or less and discounted safety concerns •CDC/ISO’s “rapid systematic…


04 pebsworth hepatitis b 508

Summary of Information
Childhood/Adolescent Schedule Workgroup
Hepatitis B Virus Vaccine Birth Dose
December 4, 2025
Overview
•Childhood/Adolescent Schedule Workgroup
•Workgroup Process
•Workgroup Findings
•Proposed Voting Language
1
Workgroup Members
ACIP members
Kirk Milhoan, MD, PhD
Martin Kulldorff , PhD
Evelyn Griffin, MDVicky Pebsworth, PhD, RN
Outside Experts
Brian Morse, MD, PhD, Christine Stabell Benn, MD
Ex-officio
Tracy Beth Hoeg, MD, PhD
2
Policy Request
Assess the use of a universal birth dose of
Hepatitis B vaccine in children whose mothers are
HBsAg- negative.
(Which necessarily involves more than the birth dose.)
Terms of Reference Document
“Review the efficacy and safety of the
immunization schedule for children and
adolescents, identify efficacy and safety
problems, and address stakeholder concerns. ”
3
Motivation and Public Health Importance
•Feedback from stakeholders
•Misalignment with existing recommendations in
most developed countries
•Prolonged time since last comprehensive review as per ACIP’s charter
4
Workgroup Process
•September 18 -19, 2025, ACIP Meeting
•Request to CDC for Additional Information to Address
ACIP Questions
16 questions: descriptive safety and  data
•Workgroup Meetings
Between 10/17/25 and 11/24/25, the workgroup met 7 times
•Workgroup Process - Presentations, Discussions, and
Straw Polls
12 presentations by CDC staff, workgroup members, and invited ad
hoc experts that covered clinical ethics, non- specific vaccination
effects, aluminum adjuvant exposures, clinical practice challenges and solutions, and the Alaska Hepatitis B vaccine trials.
5
Workgroup Findings:
Areas of Full/Nearly Full Agreement (1)
•Hepatitis B virus can be
transmitted vertically and
horizontally  to infants, is a
serious disease, and can be prevented by vaccination with the HBV vaccine
•There is uncertainty  about
true rates of incidence,
prevalence and horizontal
transmission rates•There is uncertainty  about
whether all three
recommended doses are
needed to acquire protection
•There are gaps in evidence
and limitations related to evidence of safety (per
GRADE quality of safety
evidence is poor)
6
Workgroup Findings:
Areas of Full/Nearly Full Agreement (2)
•Infants born to mothers who
test positive for HBsAg should
continue to be vaccinated with HBV vaccine and receive hepatitis B immunoglobulin
soon after birth
•Any gaps in screening pregnant
women for HBsAg should be eliminated so that all infants
receive appropriate care •Re- screening  of pregnant
mothers upon admission for
delivery should be considered
so that there are no mothers
whose HBsAg is “unknown ”
which should be regarded as a serious quality of care problem, if not a medical error, and a
“never event”
•Infants born to mothers who
test negative for HBsAg have
extremely low risk of horizontal infection during childhood and particularly in first months of life
and therefore, do not need to be
routinely vaccinated with the HBV vaccine at birth
7
Workgroup Findings:
Central Themes Related to Hepatitis B Preventive Care
Improving Quality and Appropriateness of Hepatitis B
Preventive Care
•screen all pregnant mothers (no unknowns), appropriately treat
all newborns
Minimizing AEFI in Vulnerable Newborns
•avoid unnecessary early life exposures
Fostering Individual -based Decision -making and Respect for
Parental Autonomy
•permit clinical flexibility and individual risk assessments
Improving Safety Monitoring and Research
•close evidence gaps
Modifying US Policy, Consider other Countries
•return to a targeted and successful strategy more in line with other
developed countries with low endemicity
8
Evaluation of Voting Language Categories
•Universal Vaccination Option
•No Recommendation Option
•Individual -based Decision -making Option
 (preferred first choice for Workgroup members.)
9
Rationale for Preferring an Individual- based
Decision -making Option (1)
•The overwhelming majority of infants born to mothers who test
negative for hepatitis B surface antigen are not at high risk of being infected with the hepatitis B virus, especially in the first few months of life.
•The 1991 recommendation was made in error.
•Vaccine safety risks are not well understood and were never assessed appropriately.
•An individualized, risk -based approach is needed, with
recommendations tailored to risk/benefit profiles and preferences and involve informed consent.
10
Rationale for Preferring an Individual- based
Decision -making Option (2)
•It has the potential to allow the parent to choose a point in time
closer to the onset of risky behaviors sometimes encountered in
adolescence, and, for those who prefer to wait, the “catch -up”
schedule could be used by those who delay until age 11.
•It also provides options for avoiding vaccinating in early infancy and
adolescence when there are biological windows of vulnerability.
•Creates an opportunity to use serology testing to determine whether additional doses of vaccine are needed for protection.
•Could end disputes between parents of newborns, hospital staff and others who do not agree about administration of a birth dose,
consent, and cease to be the “gateway to vaccine hesitancy. ”
11
Rationale for Preferring an Individual- based
Decision -making Option (3)
•Provides for a return of decision -making to parents in
collaboration with the health care provider who wants to be
able to recommend a flexible schedule and the ability to tailor
care to individual needs, risks and preferences.
•Benefits of using two months for starting HBV vaccine series
•the additional two months of maturation, as it relates to the
blood -brain barrier, liver, and kidney function, is desirable.
•is in line with the policy of other comparable countries
•would permit the use of combination vaccines and limit the number of injections, as well as access to lower -aluminum-
containing products
.
12
Rationale for NOT Preferring an Individual-
based Decision -making Option
•Concerns about rare exposures to the hepatitis B virus that could cause an infection and a chronic infection

•Concerns about acceptability to the medical and public health communities and others, media backlash, unfair treatment by medical boards
•The system that’s in place that will be difficult to change
•It will take too much time to counsel patients about risks and benefits, and access to educational materials isn’t obvious
•Concerns about liability, payments, additional paperwork
•The safety concern may be more theoretical than real
13
Implementation Considerations
•PEP in births to HBsAg+ mothers:
Strengthen maternal screening programs
Immigrant medical examination screening
•Delaying the timing of the first dose will allow choice of using
different vaccines, monovalent and polyvalent
14Birth dose 2/4/6 month 4 years 8 years 12 years
Target groups HBsAg+ only All or high risk HHs All All All
Vaccine type Monovalent/poly
valent mixPolyvalent Monovalent series Monovalent Monovalent
Implementation Considerations
•Even under the existing universal dose policy not all babies are
vaccinated at birth with no detectable increase in incidence of HBV infections
•Data from the 2016 -2021 Centers for Medicare & Medicaid
Services (CMS) Transformed Medicaid Statistical Information System (T -MSIS)1
Comments:
•T-MSIS Analytic Files are research- optimized collection data submitted as part of state -
level Medicaid submission.
•Includes enrollment data, demographics, and service utilization.2
•Hepatitis B antigen tests identified using Current Procedural Terminology [CPT] codes
1https://www.medicaid.gov/medicaid/data -systems/macbis/transformed -medicaid -
statistical -information- system -t-msis/index.html
2https://www.medicaid.gov/medicaid/data -systems/macbis/transformed -medicaid -
statistical -information- system -t-msis/t -msis -analytic -files
15
CMS Medicaid
•Pregnancies:
•At least one ICD -10 diagnosis code ('O80' , 'O81' , 'O82' , 'O83' , 'O84' ,
'Z370' , 'Z372' , 'Z375’) in inpatient or other service files
•Live Born Pregnancies:
•At least one ICD -10 Diagnosis code ('O80' , 'O81' , 'O82' , 'O83' , 'O84' ,
'Z370' , 'Z372' , 'Z375’)
•Death not recorded during first hospitalization
16
Table 1: Receipt of HBV Vaccine Among Infants
CMS Medicaid Births, 2016 -2020
T otal B irth%  To t a l
Birt h s
T otal B irths 7,284,953 100%
Infants Receiving First HBV Dose by 2 yrs
  (0-730 days)6,573,976 90%
Infants R eceiving HB V  B irth Dose   (0-30 days)5,076,855 70%
17
Age of First HBV Vaccination
within first 730 Days
A ge of First HBV  V accinationTo t a l
V accinatedTo t a l
V accinated
%
Birth Dose Received During Birth Hospitalization 4,966,112 76%
1 - 30 days 110,743 2%
31 - 180 days 1,289,749 20%
181 - 365 days 145,947 2%
365 - 730 days 61,425 1%
Infants Receiving First Dose by 2 yrs (0 -730 days) 6,573,976 100%
18
•Markman, Putting Public Health Ethics Into Practice
•Expected health benefits for the target population
•Potential harms and burdens for all stakeholders
•Impact on autonomy
•Impact on equity
•Expected efficiency
•Ethics of Vaccination
•Preserve Health
•Means -end Proportionality
•Discretion
•Parsimony
-Marckmann G, Schmidt H, Sofaer N, Strech D. Putting public health ethics into practice: a systematic framework. Front Public Hea lth. 2015
Feb 6;3:23. doi: 10.3389/fpubh.2015.00023. PMID: 25705615; PMCID: PMC4319377.Public Health and Vaccination Ethics
ACIP Childhood/Adolescent Immunization Schedule Workgroup
Vote Language, 12/3/25
VOTE 1
•ACIP recommends a birth dose of Hepatitis B virus (HBV) vaccine and
Hepatitis B Immunoglobulin for infants born to women who test HBsAg -
positive. ACIP recommends individual -based decision -making, in
consultation with a health care provider, for parents deciding whether to give the HBV vaccine birth dose to infants born to women who are HBsAg -
negative or whose HBsAg status is unknown. Parents should consult with health care providers and decide when or if their child will begin the HBV vaccine series.
1 Parents and health care providers should consider vaccine
benefits, vaccine risks, and infection risks. For those not receiving the HBV birth dose, it is suggested that the initial dose is administered no earlier than 2 months of age. Y/N
VOTE 2
•When evaluating the need for subsequent HBV vaccine dose in children, parents should consult with health care providers to determine if a post -
vaccination anti -HBs serology testing should be offered prior to subsequent
HBV vaccine dose administration. Serology results should determine whether the established protective anti -HBs titer threshold of ≥10 mIU /mL
has been achieved. The cost of this testing should be covered by insurance. Y/N
1 Parents and health care providers should also consider whether there are risks, for example, such as a household
member is HBsAg -positive or when there is frequent contact with persons who have emigrated from areas where
Hepatitis B is common.
20

Summary: Summary of Information Childhood/Adolescent Schedule Workgroup Hepatitis B Virus Vaccine Birth Dose  December 4, 2025 Overview •Childhood/Adolescent Schedule Workgroup  •Workgroup Process •Workgroup Findings •Proposed Voting Language 1 Workgroup Members ACIP members  Kirk Milhoan, MD, PhD  Martin Kulldorff , PhD Evelyn Griffin, MDVicky Pebsworth, PhD, RN  Outside Experts Brian Morse, MD, PhD, Christine Stabell Benn, MD Ex-officio Tracy Beth Hoeg, MD, PhD 2 Policy Request Assess the use of a…