# Interagency Vaccine Group (IAVG)

# Meeting on the Development of CDC's

# Immunization Safety Office (ISO)

# Research Agenda 

# August 3, 2007, Washington D.C.

**Meeting Summary**

  -----------------------------------------------------------------------
  Disclaimer: The ideas and recommendations of this report reflect those
  of federal scientists. This report does not represent Centers for
  Disease Control and Prevention (CDC) or Department of Health and Human
  Services policy, nor does it necessarily reflect which ideas will be
  incorporated into CDC's final Immunization Safety Office Research
  Agenda.

  -----------------------------------------------------------------------

***Background***

The Centers for Disease Control and Prevention's (CDC) Immunization
Safety Office (ISO) is developing a comprehensive, scientifically robust
research agenda with extensive input in a transparent manner. ISO is
working with the National Vaccine Program Office (NVPO) and National
Vaccine Advisory Committee (NVAC) to respond to a recommendation from
the 2005 Institute of Medicine (IOM) report: "Vaccine Safety Research,
Data Access, and Public Trust." IOM recommended that a subcommittee of
NVAC advise CDC on the Vaccine Safety Datalink (VSD) Project research
agenda. Because carrying out high-quality research requires integration
across the ISO research and surveillance components, the scope will
include the full ISO research agenda, including the VSD Project.

In this context, ISO collaborated with NVPO to obtain input from Federal
scientists to inform development of the ISO draft research agenda before
the NVAC scientific review. ISO solicited input from Federal scientists
representing relevant Department of Health and Human Services (HHS) and
Department of Defense (DoD) agencies and programs during an Interagency
Vaccine Group (IAVG) meeting, convened by NPVO in Washington, D.C. on
August 3, 2007. HHS meeting participants included representatives from
the NVPO, FDA, NIH, HRSA, and CDC. All participants received briefing
materials, including the charge, before the meeting. A summary of the
meeting is provided below. Additional information from the meeting's
brainstorming sessions is available in Appendix A.

***In Attendance:***

COL Randall G. Anderson

Robert Ball, M.D., M.P.H.

Kenneth Bart, M.D., M.P.H.

Brigid Batten, M.P.H.

CDR Karen R. Broder

Carmen M. Collazo, Ph.D.

George Curlin, M.D.

COL Renata J.M. Engler

Geoffrey Evans, M.D.

LT Kent Forde

Paul M. Gargiullo, Ph.D.

Bruce Gellin, M.D., M.P.H.

Marion Gruber, Ph.D.

LTC Wayne Hachey

Florence Houn, M.D.

CDR John Iskander

Rosemary Johann-Liang, M.D.

Laura Leidel, M.S.N., M.P.H.

Bill G. Kapogiannis, M.D.

Feng-Ying (Kimi) C. Lin, M.D.

Alison Mawle, Ph.D.

Karen Midthun, M.D.

Jennifer Reid, M.D.

Dan Salmon, Ph.D.

CAPT Ben Schwartz

LCDR Angela Shen (by phone)

Barbara Slade, M.D., M.S. (by phone)

Dixie Snider, M.D., M.P.H.

(Rear Admiral, retired) (Chair)

***Welcome---John Iskander***

CDR John Iskander welcomed the participants and thanked them for their
attendance. He spoke briefly of the events leading to the present
meeting.

In 1986, Congress asked the Institute of Medicine (IOM) to assess the
causal relationship between vaccines and purported adverse events. The
IOM found that, in two-thirds of the cases investigated, there was
inadequate scientific evidence to determine that relationship. The IOM
gave the following reasons for the limitations in knowledge at that
time:

-   An inadequate understanding of the biologic mechanisms underlying
    adverse events;

-   Inconsistent information from case reports and case series;

-   Inadequate size and followup of many population-based epidemiologic
    studies; and

-   Limitations of existing surveillance systems.

To address these problems, the CDC created the the Vaccine Adverse Event
Reporting System (VAERS), in collaboration with the Food and Drug
Administration (FDA), the Vaccine Safety Datalink (VSD) Project, and the
Clinical Immunization Safety Assessment (CISA) Network.

CDR Iskander addressed the reasons for the remaining gaps in our
knowledge of vaccine safety. These include the rarity of serious adverse
events, the difficulty of conducting high-quality scientific studies,
the relative infancy of vaccine safety as a science, and the large
number of licensed vaccines and of alleged vaccine-related adverse
events.

Though, in 2005, ISO's mission refocused on vaccine risk assessment, CDR
Iskander noted that the ISO remains in engagement with broader science
and policy initiatives concerned with vaccine safety.

***ISO Program Overview, Research Agenda Development Process, and
Meeting Organization---Karen Broder***

CDR Karen Broder said that the ISO works with US and international
partners to develop and support research to identify adverse events
after vaccination and to assess their causality and risk factors, to
communicate the results of research, and to establish scientific
methodology and standardize case definitions for vaccine adverse events.

Key ISO research and surveillance components include

-   VAERS, a passive surveillance system that identifies vaccine safety
    signals of possible concern and allows the formation of hypotheses;

-   The Brighton Collaboration, offering standardized case definitions
    to provide a common vocabulary for vaccine research and
    surveillance;

-   The VSD, a collaboration between the Centers for Disease Control and
    Prevention (CDC) and eight managed care organizations (MCOs) with
    comprehensive medical and immunization histories of 5.5 million
    people per year; VSD is a resource for testing hypotheses and
    conducting surveillance; and

-   CISA, a collaboration of the CDC with six academic centers to study
    the pathophysiology of adverse events, identify risk factors, and
    offer evidence-based guidance for clinicians.

> In 2005, the IOM recommended that a subcommittee of NVAC advise CDC on
> the Vaccine Safety Datalink (VSD) Project research agenda. In
> response, ISO is developing a comprehensive research agenda with
> extensive internal and external input. The research agenda development
> is currently structured as a three-phase process: CDC develops a draft
> agenda; the National Vaccine Advisory Committee (NVAC) facilitates a
> scientific review of the draft; and CDC finalizes the agenda, taking
> the NVAC feedback into account.
>
> A meeting of external scientific consultants was held in May of 2007.
> CDR Broder discussed the composition of the body of consultants, the
> charge to the group, the framework of that meeting, and the areas of
> research they suggested.
>
> CDR Broder then described the charge to the participants of the
> present meeting. Participants were asked to identify:

-   Vaccine safety topics that are, or will be, important for public
    health and could be studied by the ISO;

-   Vaccine safety research priorities; and

-   Areas for research collaboration between the ISO and other Federal
    programs.

***The VSD Project---Paul Gargiullo***

Dr. Gargiullo began by outlining the historical background of the
project, noting that the VSD was established in 1990 to monitor
immunization safety and address the gaps in scientific knowledge about
rare and serious events following immunization. The VSD incorporates
demographic data such as age and gender, vaccination records, and
diagnoses in the form of ICD9 codes and offers the ability to review
medical charts. Dr. Gargiullo said that, in practice, the codes are used
to cast a wide net, while the charts furnish specificity. VSD data
support cohort, case control, case series, and sequential monitoring
studies. Limited access minimizes the risk of loss of confidentiality.

The VSD Project MCO sites are:

-   Group Health Cooperative of Puget Sound, Seattle, WA, US

-   Kaiser Permanente Northwest, Portland, OR, US

-   Kaiser Permanente Medical Care Program of Northern California,
    Oakland, CA

-   Southern California Kaiser Permanente Health Care Program, Los
    Angeles, CA

-   HealthPartners Research Foundation, Minneapolis, MN

-   Marshfield Clinic Research Foundation, Marshfield, WI

-   Kaiser Permanente Colorado, Denver, CO

-   Harvard Pilgrim Health Care, Boston, MA

More than 85 articles using VSD data have been published in
peer-reviewed journals; more than 75 studies are now in progress.
Current studies are looking at the safety of newly licensed vaccines,
evaluating the safety implications of new recommendations for existing
vaccines, examining clinical disorders following immunization, and
assessing vaccine safety in special populations.

Dr. Gargiullo noted that the possibility of continuous monitoring of
newly licensed vaccines has stimulated the development of new
statistical methods. He discussed self-control case series methodology
in which the probability of an adverse event during a defined risk
period (following vaccination) is compared with the probability during
control periods for the same person. He also noted that different
statistical methods may be combined to fit epidemiological needs.

Dr. Gargiullo discussed the origin of VSD research ideas and the process
of initiating and performing VSD studies. He noted that the number of
researchers wanting access to VSD data make prioritization a critical
issue.

Dr. Gargiullo also addressed current challenges facing the project.
These include the need to expand the number of MCOs providing adult
data, the trade-off between timeliness and quality of vaccine safety
studies, public perception of data-sharing issues, and a need to be open
to the possibility of adverse events that have yet to be considered.

***CISA Network---John Iskander***

The CISA Network has been in existence for approximately 5 years. Its
goals are

-   To study the pathophysiology of adverse events following
    immunization;

-   To identify risk factors associated with the development of adverse
    events following immunization; and

-   To develop evidence-based guidance for use by clinicians.

The CISA Network sites are

-   Boston Medical Center;

-   Columbia University Medical Center;

-   Johns Hopkins University;

-   Northern California Kaiser Permanente;

-   Stanford University Medical Center; and

-   Vanderbilt University Medical Center.

Accomplishments of the CISA Network include

-   The establishment of a registry and repository for the enrollment of
    persons experiencing an adverse event following immunization and for
    the collection and storage of specimens;

-   The development of an algorithm for the management of
    hypersensitivity reactions immediately following vaccination; and

-   Contribution to the characterization and monitoring of adverse
    events following smallpox vaccination of civilian healthcare
    workers.

Priorities of research studies are determined by the CISA team leader
and ISO director after input from CISA team members and principal
investigators at the network sites and are based not only on CISA's own
goals, outlined above, but on VAERS and VSD signals and on the severity
or high incidence of particular adverse events. Research proposals must
be scientifically sound and logistically and financially feasible.

CDR Iskander outlined the process for initiating a CISA research
project, from initial discussion of the concept, through presentation to
CISA investigators and the establishment of working groups, to
institutional review board approvals and Health Insurance Portability
and Accountability Act (HIPAA) data use agreements. He spoke, also, of
the challenges facing CISA, which include the rarity and geographic
dispersion of cases, the costliness of clinical and DNA studies, and the
maintenance of HIPAA requirements for data privacy.

CDR Iskander closed his remarks with examples of CISA projects.

**Discussion**

CDR Iskander opened the floor to questions on the presentations on the
VSD and CISA.

In response to a question about how CISA interfaces with other agencies
in research, CDR Iskander said that the focus is on the feasibility of
the proposed study, including the feasibility of enrollment, the
availability of the required expertise, and an appropriateness of fit
between the research needs and the agency resources.

Dr. Gargiullo was asked how many of the 85 papers published using VSD
data required chart review. He replied that most do and added, because
the question implied a concern regarding the time a study could take,
that it is rare that a VSD study is complete within a few years.

This led to a discussion of research priorities. A participant voiced
the concern that suggestions from the present meeting would not be in
the research queue for years and asked for a commitment to shift
priorities if the discussion raises issues of immediate concern. CDR
Iskander replied that that was the intent of the meeting.

A participant expressed admiration of the case series method that Dr.
Gargiullo had discussed and asked whether there was ever the temptation
to redo earlier studies with more recently developed statistical tools.
CDR Broder acknowledged that there could be such a desire, for several
reasons, although for any previous study to be revived, it would need to
be viable in terms of current research needs.

Dr. Gargiullo was asked whether the backlog of VSD research projects was
due to limited resources. He responded that the major difficulty was
that there were not enough researchers at the MCOs.

***Brainstorming Session 1: Infant and Child***

For each of the brainstorming sessions, CDR Broder provided background
information in the form of the concerns raised, and suggestions made, at
a previous meeting of ISO external consultants. She also reviewed US
immunization recommendations for civilians for each life stage. She
reminded the participants that they should

-   Identify the important gaps in our current knowledge;

-   Indicate why these areas were important; and

-   Suggest possible approaches to address the areas identified.

> She noted that the focus would be on the first two of the three tasks
> but that insights as to possible approaches would be welcome. The
> ideas, she said, could be either thematic or specific.
>
> Following each brainstorming session, participants were asked to fill
> in a form asking for the five most important research topics; this
> information is summarized in Appendix A.
>
> Dr. Dixie Snider served as moderator for the brainstorming sessions.
>
> The following were suggested as areas for research or issues of
> concern. Responses are listed in the order in which the suggestions
> were made.

-   Mumps/measles/rubella vaccine (MMR) and
    thrombocytopenia---mechanisms

-   Mumps/measles/rubella/varicella vaccine (MMRV) versus MMR and
    Varivax given separately

-   Reimmunization protocols (challenge/rechallenge)

> -- Systematic guidelines for medical exemption following an adverse
> event, including identifying false contraindications

-   Causality assessment, particularly in complex clinical cases

    -   Improved data in VAERS to support this

    -   Rechallenge reproducibility (worsening of AE)

-   Sudden unexpected death following infant vaccination (up to 18 mo.)

> -- Record individual level, birth dose
>
> -- Epidemiological studies, mortality rates

-   How high a priority should thimerosal/autism studies be?

> -- Raises questions of communication among physicians, patients, and
> researchers
>
> -- Focus on other neurological conditions than autism
>
> -- Use the self-control case series statistical method to screen for
>
> neurological visits/neurodevelopmental disabilities within specified
> time
>
> periods after vaccination

-   Focus on special populations (e.g., low birth weight)

-   Focus on other issues involving autism and vaccines but not
    thimerosal

-   Adjuvants, combination vaccines- other potential etiology for autism
    caused by vaccines that do not contain thimerosal

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-   Risk perception research (e.g., level of public concern regarding
    multiple vaccinations)

***Brainstorming Session 2: Adolescent (ages 11 to 18)***

The following were suggested as areas for research or issues of concern:

-   Human papillomavirus (HPV) vaccine use in immunocompromised
    adolescents

    -   May apply to other vaccines (e.g., second dose of varicella
        vaccine)

-   Immunocompromised hosts

    -   Effects of vaccination on disease ( viral load, CD4 counts, etc)

    -   Local and systemic unanticipated AEs

    -   Replacement serotypes

    -   How does immunodeficiency or immunoreactivity affect vaccine
        dose

-   General issue of special populations in adolescence

> -- It may be possible to use existing networks (e.g., for HIV clinical
> care or research)

-   Seek out adolescent minority groups for study

-   Establish baseline rates of neuropsychiatric, rheumatic, and
    autoimmune disease

-   Need for improved risk-benefit calculations

-   There is a need to look for rare adverse events (especially for
    vaccines, like quadrivalent meningococcal conjugate (Menactra^®^),
    that are preventing rare diseases)

-   Studies to rule out spurious associations of vaccines with normal
    adolescent phenomena (e.g., acne, onset of menses)

-   Safety of concomitant vaccines (e.g., quadrivalent meningococcal
    conjugate, tetanus-diphtheria-pertussis (Tdap), and HPV vaccines
    together or separately)

-   Changes in disease incidence, by gender, in adolescence

-   Establish baseline side-effect profiles of specific vaccine
    components (e.g., novel adjuvant for bivalent HPV)

-   Improved communication regarding expected side effects of vaccines

***Brainstorming Session 3: Adulthood and Pregnancy***

The following were suggested as areas for research or issues of concern:

-   Relevant safety information from passive immunization (e.g.,
    intravenous immunoglobulin, Rh-immune globulin)

-   Establish a single national registry for vaccine exposures in
    pregnancy

-   Better ways to study intended/unintended vaccine exposures during
    pregnancy

-   Chronic fatigue syndrome as an adverse event (e.g., anthrax vaccine,
    new adjuvanted influenza vaccines)

-   Safety of reimmunization using pneumococcal polysaccharide vaccine

-   Ways to study previously unstudied vaccine combinations

-   "Disability" as an outcome following vaccination

> -- Quantify level of disability- include in registry

-   Issues of immunosenescence for zoster vaccine

    -   As immunity wanes, potentially increased incidence and increased
        severity of wild type disease: how does vaccine impact?

-   Are current systems adequate to study off-label use? (e.g., Tdap,
    zoster vaccines)

    -   If vaccines are expensive, are they given to people outside of
        recommendations

    -   Unintentional/Intentional Off label use

-   Rare adverse events (e.g., vasculitis) following influenza vaccine

-   Travel vaccines---off-label use

-   Travel clinics---potential setting for research

-   Dose response to adjuvants

-   Framework needed to study multiple near-concurrent vaccination

-   "Hyperimmunization" within the Department of Defense

-   ACIP adult guidelines extrapolated from children recommendations?

    -   Guidelines based on civilian population that does not receive as
        many vaccines

-   Gender and race considerations, generally

-   Myopericarditis as an outcome following vaccines other than smallpox
    vaccine

-   Other cardiac adverse events

-   Age-specific considerations within the adult age range

    -   Study design considerations

***Brainstorming Session 4: Vaccine Adjuvants and New Vaccine
Technologies***

The following were suggested as areas for research or issues of concern:

-   Subpopulation affects

-   Gender effects

-   Dose response

-   Better definition of baseline reactivity

-   More emphasis on nonclinical studies

-   Difficulty of ascribing causality to specific components of vaccines

-   Better characterization and communication of vaccine components
    (e.g., by the FDA and by the manufacturer), including changes made
    in vaccine composition, over time, by the manufacturer

-   Much research in this area will need to be led and/or conducted by
    agencies and programs outside CDC

-   "Class effect" as a postlicensure surveillance strategy

-   Need to look across age groups

> -- Broad age categories an oversimplification

-   Immune response functions in complex ways (e.g., autoimmune
    functions may be affected by age, race, and gender

-   Younger age groups may have more reactive immune systems, while
    older persons' immune systems may be less reactive?

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-   Need to define the adverse events of most interest

-   Formal risk assessments needed for each vaccine component

-   Vectors---"class effects" (e.g., poxvirus for human immunodeficiency
    virus vaccines)

-   How to list vaccine components (e.g., in package insert) in order to
    be detailed but easy to understand?

-   It is possible that 2 vaccines being licensed may never be given
    together until both are licensed, so no information about potential
    adverse events from the combination may be available before
    licensure

***Discussion and Input from Federal Scientists: Synthesis,
Prioritization, and Potential Collaboration***

Dr. Snider moderated the discussion. The following points were raised:

-   Strive for balance between "external" (i.e., what the public
    perceives as important) and "internal" safety issues as a focus for
    research

-   Real-time active surveillance systems (e.g., for pandemic influenza)

-   Linkage among existing registries/immunization information systems
    to enhance real-time surveillance

-   Establish a national registry and repository to aid in tracking
    long-latency exposures (e.g., simian virus 40)

> -- Need for multisite clinical linkages

-   Overcome barriers to research (e.g., remote enrollment)

-   Pandemic influenza integrated into research agenda

> -- Identify new projects to be taken on by other agencies

CDR Broder thanked the participants. She said that the next step would
be to incorporate the suggestions from today's meeting and the previous
meeting of external consultants into the draft research agenda for
NVAC's review. It will be important for the research undertaken to
provide meaningful information that will enhance public health.

***Closing Remarks---Bruce Gellin***

In his closing remarks, Dr. Gellin stressed the need for readiness
across all Department of Health and Human Services agencies when the
research agenda is finalized in 2008.

**APPENDIX A: Summary of Brainstorming Session Worksheets**

[**Overview:**]{.underline}

At the completion of each brainstorming session, participants were asked
to complete worksheets listing the top 5 vaccine safety research topics
in rank order. For each topic, participants were also asked to note the
reason for importance and identify potential approaches to study it. An
ISO medical officer reviewed the worksheets and summarized the feedback
by key research themes.

**[Findings:]{.underline}**

**Forms Returned**:

Fifteen individuals completed forms for at least one of the four
sessions. At least one scientist from each of the following agencies
completed a form for each session: NVPO, NIH, FDA, CDC (outside ISO),
DoD, and HRSA. Staff from ISO, CDC did not complete forms.

**Suggested Research Topics Identified by ≥1 Rater:**

Superscripts are used to show if at least one rater ranked the topic as
a first (1) or second (2) priority level. Other levels of priority are
not shown.

[Session 1: Infants and Children]{.underline}

-   Vaccine:

    -   Newly licensed vaccines

    -   MMR and thrombocytopenia (including genetic risk factors and
        prevention strategies)^1^

    -   Rotavirus and intussusception, including genetics^2^

    -   MMRV (different than individual MMR and varicella vaccines)

    -   Combination vaccines^2^

    -   Pediatric bioterrorism vaccines

    -   Pediatric pandemic vaccines (especially with novel adjuvants)^2^

-   Vaccination practices:

    -   Multiple vaccines at same visit, including risk for
        neurodevelopmental disorder (also nearly concurrent
        vaccination)^1,2^

    -   Analysis of medical exemptions for vaccination

    -   Off label use of vaccines^1^

    -   Clinical guidelines for medical exemptions, outcomes
        rechallenges^1^

    -   Clinical guidelines for adverse event causality assessment^2^

-   Adjuvants and non-antigen components of vaccines

    -   Cumulative exposure to proteins (e.g., diphtheria, aluminum)

    -   Thimerosal and neurodevelopmental disorders, including those
        other than autism^1^

    -   Novel adjuvants: need long-term follow-up^1^

-   Host:

    -   Premature, low birth weight^2^

    -   Presence of genetic and metabolic conditions

    -   Immunocompromising conditions (nephrotic syndrome, HIV)

    -   Genetic risk factors[^1]

    -   Race

-   Reported adverse event following immunization (AEFI)

    -   Serious adverse events for newly licensed vaccines^1^

    -   Life threatening disorders, including allergic

    -   Allergic disease (e.g., wheeze after LAIV)^2^

    -   Unexpected death in infancy/ deaths^2^

    -   Encephalopathy, including acute disseminated encephalomyelitis
        (ADEM)

    -   Medically attended events after vaccination (case series
        method)^1^

    -   Chronic disease onset long after vaccination

    -   Autism and other neurodevelopmental disorders (including other
        than thimerosal-containing vaccines and MMR; assess causes)^1^

-   Risk perception

    -   Risk perception and communication (particular around autism)

    -   Perception of causality of neural disease in infants through 3
        years^2^

    -   Reasons for delay in immunization^2^

[Session 1: Infants and Children (continued)]{.underline}

-   Other related to vaccine safety research

    -   Collect control samples for specimens collected via CISA^1^

    -   Background rates for childhood medical events (\< 5 years)

    -   Is immunization compliance associated with wellness?^2^

-   Other not related to vaccine safety research

    -   Surveillance for serotype replacement for pneumoccocal disease

    -   Vaccine effectiveness in low birth weight populations

[Session 2: Adolescents (non-pregnant) Aged 11-18 Years]{.underline}

-   Vaccines

    -   Newly licensed vaccines^1^

    -   HPV, especially new vaccine with novel adjuvant; suggest broad
        look for adverse events; assess risk in persons with chronic
        conditions, including HIV (noted HPV also licensed for girls
        aged 9 and 10 years)^1,2^

    -   MCV4, especially risk for Guillain-Barre syndrome (GBS)^1^

    -   Tdap

    -   Varicella

    -   Travel vaccines, including use with regular vaccines

    -   Combination vaccine

-   Vaccination practices

    -   Simultaneous vaccination^1,2^

    -   Vaccination of persons immune (problems with incomplete
        immunization history)

    -   Clinical guidelines for medical exemptions, outcomes
        rechallenges

    -   Clinical guidelines for adverse event causality assessment

-   Non-antigen components

    -   Diphtheria toxoid (multiple doses), including risk for GBS^1^

    -   Adjuvants, especially new adjuvant in HPV (BLA)

-   Host:

    -   Gender

    -   Immunocompromised, particular for live viral vaccines

    -   Chronic conditions (including HIV and immunocompromised --
        especially live vaccines)

    -   Genetic risk factors

    -   Sports (effect of strenuous exercise on AEFI)

[Session 2: Adolescents (non-pregnant) Aged 11-18 Years]{.underline}

-   Reported adverse event following immunization (AEFI)

    -   Establish baseline rates for adverse events that could be
        perceived as AEFI^1^

    -   GBS and other demyelinating diseases (especially with MCV4,
        influenza vaccine or hepatitis vaccine)^2^

    -   Autoimmune diseases

    -   Baseline rates for adolescent health conditions, including
        gynecologic, acne, psychiatric, especially with HPV^2^

    -   Sexual initiation, especially with HPV^1^

    -   Risk perception and communications

    -   Overall communication for safety

-   Other not related to vaccine safety research

    -   HPV serotype replacement

    -   Improve methods for risk benefit assessment, especially for
        vaccines preventing rare diseases

    -   Consent issues for adolescents

[Session 3: Adults Aged ≥19 Years and Pregnant Women]{.underline}

-   Vaccines

    -   Newly licensed vaccines^1^

    -   Live vaccine safety in older persons

    -   Multiple pneumococcal polysaccharide vaccines; how many doses is
        it safety to receive as an older adult?^2^

    -   Zoster vaccine, including immunosenescence^1^

    -   Influenza vaccine and association with neurologic and rare AEFI,
        other than GBS (e.g., vasculitis)

    -   Travel and deployment vaccines (e.g., anthrax, smallpox), in
        conjunction with regular vaccines and medications (suggested use
        of DoD cohort)^2^

    -   Influenza vaccine in pregnant women^1^

    -   Tdap vaccine in pregnant women^1^

-   Vaccination practices

    -   Simultaneous and near-simultaneous vaccination

    -   Off label use of vaccines (e.g., Zoster, Tdap, HPV)^1^

    -   Clinical guidelines for medical exemptions, outcomes
        rechallenges^2^

    -   Clinical guidelines for adverse event causality assessment^1^

[Session 3: Adults Aged ≥19 Years and Pregnant Women
(continued)]{.underline}

-   Non-antigen components

    -   Total adjuvant content received with multiple vaccines; dose
        response

    -   Aluminum (exposure from multiple vaccines; component of smallpox
        and Anthrax vaccines)

    -   Adjuvants - pre-licensure trials need 3 arms to assess safety in
        adjuvant-only recipients^1^

    -   Adjuvants in multiple vaccines and combination vaccines (e.g.,
        role of adjuvants and autism)^2^

    -   Adjuvant risk in different populations (e.g, across age, race
        and gender groups; autoimmunity in older persons)

    -   Adjuvants in pandemic and pre-pandemic vaccines

    -   Effects of cumulative levels of components in vaccines^2^

    -   Thimerosal and risk for AEFIs in pregnant women^1^

-   Host:

    -   Gender differences for AEFIs, including serious adverse events

    -   Interactions with other medications, particularly in older
        adults^1^

    -   Chronic conditions^1^

    -   Older age, immunosenescence^1,2^

    -   Ethnicity

    -   Genetic risk factors

    -   Pregnancy (suggestions for single maternal registry, pregnancy
        outcome database)^1,2^

    -   Increased fetal inflammatory mediators affecting neonatal
        outcome such as low birth weight

-   Reported adverse event following immunization (AEFI)

    -   Establish baseline rates for adverse events that could be
        perceived as AEFI, adjusting for gender, race and age

    -   Demyelinating diseases^1^

    -   Chronic diseases, with onset in older adults^2^

    -   Chronic fatigue syndrome^2^

    -   Common AEFIs with ranges of severity, including syncope,
        injection site reactions and more severe events

    -   Disability outcomes

    -   Autoimmune diseases (e.g., multiple sclerosis, hepatitis)

    -   AEFIs in pregnant women (VSD case series)

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-   Other related to vaccine safety research

    -   Live vaccine transmission studies

    -   Break adult age-group into sub-groups

    -   Therapeutic vaccine safety, including cancer vaccines

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-   Other not related to vaccine safety research

    -   Vaccine immunogenicity studies in the elderly^2^

    -   Affect of demographic factors (e.g., ethnicity) on vaccine
        effectiveness

    -   Vaccine effectiveness studies in pregnant women

    -   Elective termination of pregnancy practices after vaccine

[Session 4: Vaccine Adjuvants, Other Non-antigen Vaccine Components and
New Vaccine Technologies]{.underline}

Related topics were also identified during the life-stage sessions,
described above.

-   Identify non-antigen components in each vaccine and assess safety
    profile of these components; consider other biological and
    environmental exposures (suggestion that ISO is not the lead) ^1^

-   Association of adjuvants and AEFI (and effectiveness); look at
    effect of single and multiple adjuvants administered once or
    multiple times^1^

-   Cytokine responses to new adjuvants; cell-based safety ^1^

-   Identify potential adverse events in phase 3 trials for which number
    of subject was too small to fully assess risk; ensure information is
    communicated to ISO^1^

-   Long-term risk of repeated exposure to adjuvant vaccines in older
    persons, particularly for autoimmune diseases^2^

-   Assess if vaccines with same ingredients are associated with similar
    AEFI^2^

-   Exposure to aluminum in multiple vaccines

-   Cumulative exposures to proteins (e.g., diphtheria toxoid, CRM,
    tetanus toxoid)

-   Surveillance for adjuvant safety (suggest large surveillance
    evaluation)

    -   Across product classes and age-groups

    -   Long-term AEFIs, including cancer (suggest collaboration with
        NCI SEER)

-   Identify specific AEFI of interest for new adjuvant vaccines, by
    age, gender and race; assess background rates

-   Evaluate for cardiotoxicity with novel pox virus vector vaccines

-   Pre-exisiting immunity with recombinant viral vectors and
    reactogenicity (e.g., adenovirus 5)

-   Investigate AEFI (and effectiveness) in sub-populations of older
    persons to determine if additional or fewer doses are needed.

Appendix B: Abbreviations

  -------------- ---------------------------------------------------------
  Abbreviation   Definition

  ADEM           acute disseminated encephalomyelitis

  AEFI           adverse event following immunization

  BLA            biologics license application

  CDC            Centers for Disease Control and Prevention

  CISA           Clinical Immunization Safety Assessment Network

  DoD            Department of Defense

  FDA            Food and Drug Administration

  GBS            Guillain-Barre syndrome

  HPV            human papillomavirus vaccine

  HRSA           Health Resources and Services Administration

  ISO            Immunization Safety Office

  LAIV           live, attenuated influenza vaccine

  MCV4           meningococcal conjugate vaccine

  MMR            measles, mumps and rubella vaccine

  MMRV           measles, mumps, rubella and varicella vaccine (combined)

  NCI            National Cancer Institute

  NIH            National Institutes of Health

  NVPO           National Vaccine Program Office

  SEER           Surveillance, Epidemiology, and End Results

  Tdap           tetanus toxoid, reduced diphtheria toxoid, and acellular
                 pertussis vaccine

  VSD            Vaccine Safety Datalink
  -------------- ---------------------------------------------------------

[^1]: