**DRAFT**

**Centers for Disease Control and Prevention's**

**Immunization Safety Office Scientific Agenda:**

**Background Document**

"To raise new questions, new possibilities, to regard old problems from
a new angle, requires creative imagination and marks real advance in
science"

Albert Einstein

**Immunization Safety Office**

**Office of the Chief Science Officer**

**Centers for Disease Control and Prevention**[^1]

**[Report Table of Contents: Draft ISO Scientific Agenda Background
Document]{.underline}**

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| TOPIC                                                          | P   |
|                                                                | age |
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| TITLE                                                          | 1   |
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| TABLE OF CONTENTS                                              | 2   |
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| EXECUTIVE SUMMARY                                              | 3   |
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| BACKGROUND                                                     | 4   |
|                                                                | -   |
|                                                                | -12 |
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| Importance of Vaccine Safety Science                           | 4   |
|                                                                | --6 |
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| Immunization Safety Office (ISO), CDC                          | 6-  |
|                                                                | -12 |
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| RATIONALE FOR DEVELOPING AN IMMUNIZATION SAFETY OFFICE         | 12  |
| SCIENTFIC AGENDA                                               | -15 |
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| OBJECTIVE, SCOPE AND INTENDED USE OF THE ISO SCIENTIFIC AGENDA | 15- |
|                                                                | -16 |
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| APPROACH                                                       | 16  |
|                                                                | -18 |
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| General Process of ISO Scientific Agenda Development and       | 16- |
| National Vaccine                                               | -17 |
|                                                                |     |
| Advisory Committee (NVAC) Scientific Review                    |     |
+----------------------------------------------------------------+-----+
| CDC Development of the Draft ISO Scientific Agenda: Input      | 17- |
| Venues                                                         | -18 |
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| FUTURE ACTIVITIES                                              | 19  |
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| REFERENCES                                                     | 20- |
|                                                                | -22 |
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| ACKNOWLEDGEMENTS                                               | 23  |
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| APPENDICES                                                     | 24- |
|                                                                | -29 |
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| Appendix A: ISO Scientific Agenda Writing and Reviewing Group  | 24  |
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| Appendix B: Institute of Medicine Immunization Safety Review   | 25- |
| Summary                                                        | -27 |
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| Appendix C: Summary Table of External Input Meetings on the    | 28  |
| ISO Research Agenda                                            |     |
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| Appendix D: List of Abbreviations                              | 29  |
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**EXECUTIVE SUMMARY**

Ensuring that vaccines are as safe as possible is a public health
priority and national expectations for vaccine safety are high. Within
the Department of Health and Human Services, the Center's for Disease
Control and Prevention's (CDC) Immunization Safety Office (ISO) leads
most of the agency's risk assessment research and surveillance
activities for vaccines used in a civilian population. Four research and
surveillance components work together to carry out the ISO mission of
assessing the safety of vaccines used in children, adolescents, and
adults: the Vaccine Adverse Event Reporting System (VAERS), the Vaccine
Safety Datalink (VSD) Project, the Clinical Immunization Safety
Assessment (CISA) Network, and the Brighton Collaboration. VAERS is
jointly operated by CDC and the Food and Drug Administration (FDA). Each
of the four ISO teams has mechanisms in place to develop and prioritize
its scientific activities; however no comprehensive ISO Agenda exists.

In response to a 2005 Institute of Medicine (IOM) recommendation and to
guide ISO\'s scientific direction, ISO is developing a 5-year ISO
Scientific Agenda. During 2007--2008, ISO obtained input from expert
scientists through three planned meetings (with external expert
scientists, federal scientists, and vaccine manufacturers'
representatives) and other venues. The National Vaccine Advisory
Committee (NVAC), Vaccine Safety Working Group will advise on the
content and priorities of the ISO Scientific Agenda. NVAC and NVPO will
lead the NVAC scientific review. CDC will finalize the Agenda and
respond to NVAC feedback. The Agenda (under development) makes
recommendations for the next 5 years in three scientific areas: vaccine
safety research, selected surveillance, and selected clinical guidance
activities. The Agenda covers topics that are part of ISO's mission, are
in ISO's realm to lead, and could be implemented during the next 5 years
with infrastructure generally accessible to CDC. It is not a
comprehensive ISO strategic plan and does not address all issues related
to vaccine safety science, such as risk perception research. The chief
users of the Agenda will be ISO staff and their day-to-day research and
surveillance partners. The Agenda will be useful to all ISO teams as
they set priorities for projects in a coordinated manner. It will also
serve as a platform to discuss collaborative vaccine safety science
activities among ISO and other internal and external partners. Looking
forward 5 years after CDC implements this Agenda, we would expect to
find that it contributed to advancing the field of vaccine safety
science and enhancing public health.

**BACKGROUND**

**[Importance of Vaccine Safety Science]{.underline}**

Widespread use of vaccines has greatly reduced the incidence of
vaccine-preventable diseases since the pre-vaccine era (Roush et al.,
JAMA 2007). As the rate of vaccine-preventable diseases has declined,
interest in the real and perceived risks associated with vaccines has
increased. Before the Food and Drug Administration (FDA) licenses a
vaccine in the United States it must undergo stringent testing for
safety. However, no vaccine is completely safe and adverse events
following immunization (AEFI),[^2] which may or may not be caused by
vaccination, occur in populations receiving vaccines. Ensuring that
vaccines are as safe as possible is a public health priority and
national expectations for vaccine safety are high. Currently a federal
vaccine safety infrastructure is in place to monitor vaccine safety,
largely stimulated by the passage of the National Childhood Vaccine
Injury Act (NCVIA) in 1986
(<http://www.cdc.gov/od/science/iso/general_info/overview.htm>). In
parallel with improvements in vaccine safety infrastructure, the
prominence of vaccine safety as a scientific field has also increased
nationally and internationally. NCVIA required health professionals and
vaccine manufacturers to report to the U.S. Department of Health and
Human Services (HHS) specific adverse events that occur after the
administration of routinely recommended vaccines, listed in the in the
Vaccine Injury Table
(<http://www.hrsa.gov/vaccinecompensation/table.htm>). Following NCVIA,
the Vaccine Adverse Event Reporting System (VAERS) was established on
November 1, 1990 to accept spontaneous reports of suspected vaccine
adverse events (VAEs)^2^ after administration of any vaccine licensed in
the United States
(<http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5201a1.htm>). NCVIA also
established a committee from the Institute of Medicine (IOM) to review
the existing literature on VAEs. During the 1990s, this group concluded
that there are limitations in our knowledge of the risks associated with
vaccines. Of the 76 adverse events it reviewed for a causal
relationship, 50 (66%) had no or inadequate research to form a
conclusion (Chen RT et al., Pediatrics 1997). During the 2000s the IOM
convened a new Immunization Safety Review (ISR) committee to examine
eight specific vaccine safety hypotheses
(<http://www.iom.edu/?ID=4705>). Similar to the earlier reports, the ISR
found that the evidence was inconclusive to accept or reject many of the
hypothesized associations; of the 30 conclusions from the report, 18
(60%) found that the evidence "is inadequate to accept or reject a
causal relationship" or that there was "no evidence bearing on
causality" (Appendix B). IOM recommended improving vaccine safety
infrastructure to address gaps in vaccine safety knowledge and in
response CDC created the Vaccine Safety Datalink (VSD) Project, the
Clinical Immunization Safety Assessment (CISA) Network, and the Brighton
Collaboration described below, to address vaccine safety questions (IOM,
1991 and IOM 2004).

During the next five years, the importance of vaccine safety as a
scientific field is likely to continue to increase for several reasons.
Advances in vaccine research and development are leading to an
increasing number of licensed vaccines in the United States. In October
2007, 59 vaccines were licensed
(<http://www.fda.gov/cber/vaccine/licvacc.htm>) and several are
currently under review by the FDA or in phase 3 clinical trials
(<http://clinicaltrials.gov/> and
<http://aapredbook.aappublications.org/news/vaccstatus.shtml>). With a
greater number of licensed vaccines available, the US immunization
schedule is becoming more complex. For example, in 1998, seven vaccines
were routinely recommended for children and adolescents
(<http://www.cdc.gov/mmwr/preview/mmwrhtml/00053300.htm>). By contrast,
in 2008, 13 vaccines were routinely recommended for this age group.
Vaccines are also being used more frequently in new populations, such as
adolescents or older adults. These populations may have higher
background rates of certain clinical conditions than children who have
historically been the main focus of the US immunization program, leading
to more frequent coincidental VAEs.
(<http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5701a8.htm?s_cid=mm5701a8_e>).

In addition, new technologies are being used. For example, in 2003, the
first US intranasal vaccine (live, attenuated influenza vaccine
\[FluMist^®^\]) was licensed. Vaccines containing novel adjuvants such
as agonists of toll-like receptors are likely to be licensed in the near
future.

Concerns about national preparedness for an influenza pandemic or
bioterrorism event may necessitate emergency use of vaccines that have
undergone limited pre-licensure testing
(<http://www.cdc.gov/eid/content/13/7/1046.htm>). Consistent with the
past experience, public perception about vaccine safety will also
continue to drive the need to provide evidence regarding vaccine risks.
Unlike efficacy, vaccine safety requires different scientific methods,
and cannot be assessed directly. Communicating accurate information
about vaccine risk to the public is challenging. Finally, the Department
of Health and Human Services 2007-2012 strategic plan has identified
"personalized health care" as a strategic priority. Since individual
host factors, including genetic factors, may influence the risk for
VAEs, vaccine safety research in this area would be relevant to
achieving this HHS goal.

**[Immunization Safety Office, Centers for Disease Control and
Prevention]{.underline}**

[ISO Organization]{.underline}

Within the Department of Health and Human Services, the Centers for
Disease Control and Prevention (CDC) is one of five agencies and
programs involved in vaccine safety research, surveillance or
programmatic activities; the others are the National Vaccine Program
Office (NVPO), Food and Drug Administration (FDA), National Institutes
of Health (NIH), and the Health Services and Resources Administration
(HRSA), primary through its National Vaccine Injury Compensation Program
(VICP). The Department of Defense (DoD) also conducts vaccine safety
activities. At CDC, the Immunization Safety Office (ISO) leads most of
the agency's vaccine safety research and surveillance activities for
vaccines used in the civilian population. CDC's Immunization Safety
Office (ISO) serves as a national and international resource for vaccine
safety science and has played a major role in advancing the field during
the past two decades. Since 2005, the Immunization Safety Office (ISO)
has been a part of CDC's Office of the Chief Science Officer (OCSO),
Office of the Director (<http://www.cdc.gov/od/science/aboutus/>) and
its mission is distinct from other immunization programs within the
agency (see below). Most other CDC immunization activities are located
in the Coordinating Center for Infectious Diseases
(<http://www.cdc.gov/about/organization/ccid.htm>). Several CDC programs
outside of ISO also conduct vaccine safety activities; a prominent
example is the Vaccine Safety Analytic Unit (VAU). The VAU is
collaboration between CDC and DoD and its research focuses on anthrax
vaccine safety; the VAU has developed its own research agenda (Payne,
Pharmacoepidemiology and Drug Safety, 2006). ISO collaborates on an
ongoing basis with other vaccine programs at CDC, other federal agencies
and programs, and outside the federal government.

Four federal advisory committees advise HHS on issues related to vaccine
safety: the National Vaccine Advisory Committee (NVAC), the Vaccines and
Related Products Advisory Committee (VRPBAC), the Advisory Committee on
Immunization Practices (ACIP), and the Advisory Commission on Childhood
Vaccines (ACCV). Of these, ISO formally participates in three: ACIP,
NVAC, and ACCV. The reader is referred to the websites for more
information about these committees; a brief review of the CDC's ACIP is
described below (<http://www.hhs.gov/nvpo/nvac/index.html>,
<http://www.fda.gov/cber/advisory/vrbp/vrbpmain.htm>,
<http://www.cdc.gov/vaccines/pubs/ACIP-list.htm>,
<http://www.hrsa.gov/vaccinecompensation/accv.htm>).

ACIP advises the Secretary, HHS, the Assistant Secretary for Health, and
the Director, CDC on recommendations for vaccine use after licensure.
ISO has substantial representation on ACIP workgroups and the ACIP
Steering Committee.[^3] Working Groups routinely consider safety
evidence when developing immunization policies. ACIP updates its
recommendations routinely and along with professional societies these
recommendations set a standard of care for healthcare providers
nationwide
(<http://www.cdc.gov/vaccines/recs/schedules/child-schedule.htm> and
<http://www.cdc.gov/vaccines/recs/schedules/adult-schedule.htm>).

[ISO Mission]{.underline}

ISO's mission is to assess the safety of vaccines received by children,
adolescents, and adults.[^4] ISO seeks to accomplish its mission by
working closely with partners nationally and internationally to develop,
provide and support high quality activities in three areas. The first is
research and surveillance in the vaccine safety field to identify VAEs
and assess causality and risk factors. The second is communication of
the office's work in a clear and transparent manner that allows partners
to incorporate vaccine safety findings into public health policy
decisions and for the public to be well informed about vaccine risks and
benefits. Third, ISO strives to develop and advance scientific
methodology and standardized case definitions for VAEs. ISO values
scientific excellence, integrity, transparency, informed
decision-making, trust and respect.

[ISO Infrastructure for Vaccine Safety Research and
Surveillance]{.underline}

ISO has four principle research and surveillance components that conduct
vaccine safety science activities. These include the Vaccine Adverse
Event Reporting System (VAERS), the Vaccine Safety Datalink (VSD)
Project, the Clinical Immunization Safety Assessment (CISA) Network, and
the Brighton Collaboration. We describe a brief summary of each
component below; more information is also available at
<http://www.cdc.gov/od/science/iso/about_iso.htm>. In addition to the
activities above, ISO includes the Vaccine Technology Development
(VAXDEV) activity[^5] and communication and policy activities that are
not reviewed in this document.

**Vaccine Adverse Event Report System (VAERS)**

The Vaccine Adverse Event Reporting System (VAERS) is a national passive
surveillance program that collects information about adverse events that
occur after the administration of US licensed vaccines. The primary
function of VAERS is to detect early warning signals or generate
hypothesis about possible new VAEs or the frequency of known VAEs
(Varricchio F et al. Pediatric Infect Dis J, 2004). NCVIA mandated that
all health care providers report certain adverse events that occur
following vaccination. As a result, in 1990 CDC and FDA jointly
established VAERS. Specific objectives are VAERS are: 1) to detect new,
unusual, or rare VAEs, 2) monitor increases in known VAEs; 3) determine
potential patient risk factors for particular VAEs, 4) identify vaccine
lots with increased numbers or types of reported VAEs, and 5) assess the
safety of newly licensed and/or recommended vaccines
(<http://www.cdc.gov/mmwr/PDF/ss/ss5201.pdf>). VAERS demonstrated its
public health importance when the system detected a signal for
intussusception after RotaShield^®^ rotavirus vaccine in 1999; later
epidemiologic studies confirmed an increased risk and these data
contributed to the product's removal from the US market (Varricchio PIDJ
2004).[^6] VAERS is subject to underreporting and other previously
described limitations (Varricchio PIDJ 2004).

CDC and FDA VAERS teams establish priorities through routine interagency
scientific planning calls. FDA vaccine licensure, CDC's ACIP vaccine
recommendations, and public health emergencies largely drive VAERS
priorities. VAERS is ISO's front-line system for detecting VAEs and
commonly conducts investigations for potential vaccine safety concerns.
For example, in 2007, VAERS conducted a rapid review of reports after
Merck voluntarily recalled 1.2 million doses of *Haemophilus influenza*
type b (Hib) conjugate vaccine, because *Bacillus cereus* was isolated
from the manufacturing equipment (no contamination of the vaccine was
found). This initial review and subsequent VAERS analysis provided
additional reassurance that no cases of *Bacillus cereus* infections
occurred in persons who had received the recalled Hib vaccine
(<http://www.cdc.gov/vaccines/recs/recalls/hib-recall-faqs-12-12-07.htm>).

**Vaccine Safety Datalink (VSD) Project**

CDC established the Vaccine Safety Datalink (VSD) Project in 1990 to
improve the evaluation of vaccine safety through the use of
epidemiologic studies and surveillance
(<http://www.cdc.gov/OD/science/iso/research_activties/vsdp.htm> and
Chen Pediatrics 1997). The VSD Project is a collaboration among CDC's
Immunization Safety Office and eight large managed care organizations
(MCOs).[^7] The goals of the VSD Project are to conduct population-based
research and surveillance on immunization safety questions; evaluate
immunization safety hypotheses that arise from the medical literature,
passive surveillance systems, adjustments to immunization schedules, and
introduction of new vaccines; and to guide national immunization policy
decisions.

The VSD Project use administrative data sources and provides
comprehensive medical and immunization histories for more than 5.5
million people annually. The data are derived from participating MCOs
that contain more than 9 million members. Of the eight sites, six cover
persons of all ages and two cover children and adolescents aged \<18
years. Each participating site gathers data on vaccination (e.g.,
vaccine type, date of vaccination, concurrent vaccinations), medical
outcomes (e.g., outpatient visits, inpatient visits, urgent care
visits), birth data, and census data.

The VSD Project allows for planned immunization safety research studies
and surveillance. In addition, the VSD Project contributes to public
health response and conducts timely investigations of hypotheses that
arise from review of medical literature and IOM, reports to VAERS,
changes in immunization schedules, or the introduction of new vaccines.
The VSD Project has established five strategic priorities: 1) to
evaluate the safety of newly licensed vaccines, 2) to evaluate the
safety of new vaccine recommendations for existing vaccines, 3) to
evaluate clinical disorders following immunization, 4) to assess vaccine
safety in special high-risk populations, and 5) to develop and evaluate
methodologies for vaccine safety assessment. Studies are prioritized on
the basis of the public health importance of the topic, alignment with
the VSD Project strategic priorities, and availability of resources. The
VSD Project disseminates study results through presentations to the ACIP
and professional meetings, publication in CDC's Morbidity and Mortality
Weekly Report (MMWR) and peer reviewed journals.

The VSD Project has proven to be a highly effective tool for evaluating
immunization safety and providing critical guidance for vaccination
policy. Since its inception, the VSD Project has published more than 85
articles in peer reviewed journals. The VSD Project has addressed
important vaccine safety questions including landmark studies on the
effect of early thimerosal exposure and neuropsychological outcomes at 7
to 10 years (Thompson et al, NEJM 2007) and the risk of seizures after
receipt of whole-cell pertussis or measles, mumps, and rubella (MMR)
vaccine (Barlow et al., NEJM 2001). Additional studies include examining
the risk of anaphylaxis after vaccination, the safety of trivalent
influenza vaccine among children, as well childhood vaccination and the
risk of type 1 diabetes
(<http://www.cdc.gov/od/science/iso/vsd/vsd_publications.htm>)*.* In
addition, the VSD Project has developed dynamic data files and applied
sequential analysis to allow for near real-time surveillance of VAEs
through its "rapid cycle analysis (RCA)" project (Lieu, Med Care 2007).

**Clinical Immunization Safety Assessment (CISA) Network**

CDC established the Clinical Immunization Safety Assessment (CISA)
Network in 2001 to conduct clinical vaccine safety research
(<http://www.cdc.gov/OD/science/iso/research_activties/cisa.htm> and
<http://www.cdc.gov/od/science/iso/cisa/cisa_publications.htm>). The
CISA Network's goals are: 1) to develop research protocols for clinical
evaluation, diagnosis, and management of adverse events following
immunization (AEFI); 2) to improve the understanding of AEFI at the
individual level, including determination of possible genetic and other
risk factors for predisposed individuals and high-risk subpopulations;
3) to develop evidence based guidelines for vaccination of individuals
at risk of serious adverse events following immunization; and 4) to
serve as a resource for clinical vaccine safety inquiries. The network
consists of the six academic sites.[^8] CISA also collaborates with the
Vaccine Health Centers (VHC) Network of the DoD
(<http://www.vhcinfo.org/>). CISA is well suited to study postlicensure
vaccine safety in special populations due to its access to both the
special populations and the specialists who care for them.

The CISA Network uses a registry for clinical consultations to conduct
its research. It also has created standardized protocols to evaluate
specific AEFI. CISA provides a national service function by advising
clinicians on how to evaluate, diagnosis, and manage patients who
experience AEFI; information from these consultations helps generate
hypotheses that may lead to further research. These data also will be
used to improve the scientific understanding of adverse events and lead
to new or improved protocols and guidelines for health care
professionals to use to evaluate and manage patients who experience
AEFI. CISA selects and prioritizes research topics through discussion
among ISO scientific staff and CISA investigators. In determining the
priority of a research study, the Network assesses the project's
scientific merit, relevance to CISA's mission, and feasibility.

Key achievements of the CISA network include establishing the first
national registry and a biologic specimen repository for persons
experiencing VAEs. Patients with rare and serious AEFI can be referred
to CISA for inclusion in the CISA Vaccine Consult Registry and
Repository so that these persons may be enrolled in future vaccine
safety studies. In January 2008, CISA hosted the first interdisciplinary
US workshop on understanding the genetic basis of vaccine safety that
was funded by the National Vaccine Program Office. A summary of the
meeting is in progress and will guide future scientific activities in
the emerging field of vaccine safety genomics.

**The Brighton Collaboration**

The Brighton Collaboration is an international voluntary collaboration,
administered by CDC. It develops globally accepted and standardized case
definitions for AEFI for use in surveillance and research. It also
establishes guidelines for collecting, analyzing, and presenting vaccine
safety data. The Brighton Collaboration's goal is to enable
comparability of vaccine safety data across different surveillance
systems and studies within different geographical populations. The
collaboration began in 2000 as a joint effort of the CDC and University
Children's Hospital, Basel with the formation of a steering committee
and working groups. These working groups are composed of international
volunteers with expertise in vaccine safety, patient care,
pharmaceuticals, regulatory affairs, public health, and vaccine
delivery. The Brighton Collaboration prioritizes AEFIs based on
severity, frequency of reporting, enhanced public interest, and emerging
scientific needs. As of November 2007, Brighton had completed a total of
24 case definitions; these include definitions on anaphylaxis,
intussusception, unexplained sudden death in the first and second years
of life, and thrombocytopenia
(<http://www.brightoncollaboration.org/internet/en/index.html> and Kohl,
Gidudu Vaccine 2007). In addition, several case definitions are under
development including one for Guillain-Barré Syndrome (GBS).

**RATIONALE FOR DEVELOPING AN**

**IMMUNIZATION SAFETY OFFICE SCIENTFIC AGENDA**

Each of the four ISO research and surveillance components has mechanisms
in place to develop and prioritize its scientific activities with its
federal and academic partners; however, no formal office wide scientific
agenda setting process or comprehensive ISO Scientific Agenda exists.
ISO recognizes that carrying out effective research, surveillance, and
clinical guidance will benefit from establishing common scientific
priorities. Developing the ISO Scientific Agenda will promote the twin
principles of scientific excellence and public trust through
transparency. In 2006, CDC initiated a process of developing an ISO
Scientific Agenda.[^9] The rationale for developing this ISO Scientific
Agenda includes the following factors: 1) part of CDC and ISO missions,
2) responsive to a 2005 IOM recommendation and 3) opportunity to
contribute to vaccine safety science and patient safety initiatives.
Below, we highlight how the ISO Agenda will contribute to each of these
areas.

[Part of CDC and ISO Missions]{.underline}

The mission of CDC is "to promote health and quality of life by
preventing and controlling disease, injury, and disability."
(<http://www.cdc.gov/about/organization/mission.htm>). By assessing risk
of vaccination and communicating its findings in a clear and transparent
manner ISO enhances vaccine safety and contributes to the Agency's
mission. To guide scientific agenda development and promote
collaboration across the agency and other partners to meet public health
objectives, CDC has developed *"*Advancing the Nation's Health: A Guide
for Public Health Research Needs, 2006-2015
(<http://www.cdc.gov/od/science/PHResearch/cdcra/AdvancingTheNationsHealth.pdf>)."
This Research Guide encourages programs to develop more specific
scientific and research agendas. It also identifies broad thematic areas
that may inform other CDC agendas. For example, the Research Guide
includes a thematic area on vaccine safety. In addition, CDC is one of
the lead federal agencies for the Healthy People 2010 initiative,
(<http://www.healthypeople.gov/About/>). The Health People goals are "to
increase quality and years of life" and "eliminate health disparities."
Improving ISO vaccine safety activities would help fulfill these
goals.[^10]

In alignment with broader agency goals and its mission, in October 2006,
ISO conducted an internal Peer Review of its program with seven senior
CDC scientists from outside ISO. The individual reviewers made
suggestions in three main areas
(<http://www.cdc.gov/vaccines/recs/ACIP/downloads/mtg-slides-jun07/11-izsafetyoffice-broder.pdf>).
First they noted that ISO should strive for transparency, clearly
identifiable research priorities, scientific credibility, enhancement of
existing collaborations, and identification of new partnerships. Second
they suggested that ISO should ensure it can perform core public health
functions under both routine and emergency situations. Third, they
suggested that development of the ISO research agenda should include
input from stakeholders in immunization safety and an external review
(e.g., through the National Vaccine Advisory Committee \[NVAC\]).

[Responsive to an Institute of Medicine Recommendation from the 2005
"Vaccine Safety, Data Access, and Public Trust" Report]{.underline}

During the late 1990s, the pubic and Congress raised concerns about the
accessibility of the VSD Project data to independent researchers. In
2002, the VSD Project established a data sharing program that is
administered by the National Center for Health Statistics, CDC
(<http://www.cdc.gov/OD/science/iso/research_activties/vsdatasharing.htm>).
At the request of CDC, the IOM convened a committee[^11] to review and
make recommendations about aspects of the VSD Project's data sharing
program. The committee made 28 recommendations in four main areas: 1)
independent review of the VSD Project activities, 2) the applicability
of the Shelby Amendment and Information Quality Act (legislation that
promotes public access to federal information) to the VSD Project data,
3) the VSD Project data sharing program, and 4) the release of
preliminary findings based on the VSD Project data. In its section on
independent review of the VSD Project activities, the IOM made the
following recommendation (recommendation 5.1): "The committee recommends
that a subcommittee on the National Vaccine Advisory Committee that
includes representatives of a wide variety of stakeholders review and
provide advice to NIP \[National Immunization Program\][^12] on the VSD
Project plan annually. The subcommittee charged with this role could be
the existing Subcommittee on Safety and Communications[^13] or a
subcommittee created specifically for the purpose." The report further
described that the group "should represent a broad cross-section of
stakeholders and be charged with thinking strategically about the VSD
Project research priorities. The group should meet publicly and allow
interested persons to observe the process and provide input through
established mechanisms." CDC concurred with this recommendation (CDC,
unpublished document).[^14]

[Opportunity to Contribute to Vaccine Safety Science in Organizations
outside ISO and Other Patient Safety Initiatives]{.underline}

ISO provides ongoing technical vaccine safety support to other programs
and agencies and develops methodology that is relevant to the broader
field of pharmocepidemiology.[^15] In light of the these roles, it is
likely that an ISO Scientific Agenda would enhance vaccine safety and
patient safety initiatives outside of the office, even if the scope were
directed to cover ISO-specific activities. W Within CDC, an ISO
Scientific Agenda might be particularly useful to the CDC Patient Safety
Workgroup (WG).  Launched in August 2007, this WG is comprised of
subject matter experts from 14 divisions across ten national centers at
CDC.  These experts specialize in the science, program and policy
aspects of patient safety issues, including healthcare-associated
infections and medical and biological product safety (i.e., drugs,
vaccines, devices, blood, organs, and tissues); and the statistical and
methodological aspects of patient safety surveillance and research.  The
Patient Safety WG's mission is to provide a \"central,\" cross-cutting
forum for CDC experts to discuss and make recommendations about patient
safety issues for the agency; define CDC\'s role in the broader context
of patient safety; and identify ways to coordinate more efficiently and
effectively with key patient safety partners, including FDA. 

**OBJECTIVE, SCOPE AND INTENDED USE OF THE ISO SCIENTIFIC AGENDA**

The objective of ISO's Scientific Agenda is to recommend priority
vaccine safety science activities for the next five years.
Recommendations for CDC's ISO Scientific Agenda (under development),
cover three vaccine safety areas: research studies, selected
surveillance activities, and selected clinical guidance activities. The
scope of the ISO Agenda recommendations is broader than the 2005 IOM
recommendation to develop and set priorities for the VSD Project
research agenda.

The ISO Scientific Agenda recommendations will include activities that
are aligned with ISO's mission, are in ISO's realm to lead, and could be
implemented during the next 5 years using infrastructure generally
accessible to CDC. However, the ISO Scientific Agenda is not a
comprehensive ISO strategic plan and does not address all issues related
to vaccine safety science. Specifically, it does not cover vaccine
safety science initiatives that are not clearly already in ISO's purview
to lead under its current mission (e.g., risk perception activities);
therapeutic vaccines or vaccines not expected to be licensed within 5
years. Recommendations also do not include routine service, formal
surveillance evaluation (MMWR,
<http://www.cdc.gov/mmwR/preview/mmwrhtml/rr5013a1.htm>), programmatic,
or communication activities. They also do not address issues related to
specifics of ISO collaboration with federal and non-federal partners.

The chief users of the ISO Scientific Agenda will be ISO staff and their
day-to-day research and surveillance partners, including the VSD
Project, VAERS, CISA, the Brighton Collaboration, and CDC vaccine
subject matter expert investigators and scientists,. The Agenda
recommendations will be useful to all ISO teams as they establish and
set priorities for projects in a coordinated manner. The Agenda will
help ISO to fill knowledge gaps in vaccine safety science and advance
ISO's future capacity to carry out research, surveillance, and clinical
guidance activities. It will also serve as a platform to discuss
collaborative vaccine safety science projects among ISO and internal and
external partners. A secondary purpose of this Agenda is to provide
vaccine and patient safety scientists, outside ISO, with information
that may be useful to other federal or non-governmental research or
scientific agendas. Looking forward 5 years after CDC implements this
Agenda; we would expect to find that it contributed to advancing the
field of vaccine safety science and enhancing public health.

**APPROACH**

**[General Process of ISO Scientific Agenda Development and National
Vaccine Advisory Committee (NVAC) Scientific Review]{.underline}**

[Scientific Development]{.underline}

During 2006−2008, CDC, the National Vaccine Program Office (NVPO), and
the NVAC Subcommittee on Vaccine Safety
(<http://www.hhs.gov/nvpo/nvac/subcomm.html>) established and
implemented a general process for developing the ISO Scientific Agenda.
The parties agreed that ISO Scientific Agenda development will involve
three phases and that CDC, NVPO and NVAC will collaborate closely on
both development and review. In the first phase, CDC will develop a
Draft ISO Scientific Agenda and provide it to the NVAC. In the second
phase, NVAC will review the Draft ISO Scientific Agenda and provide
input on the draft to CDC. In the third phase, ISO and CDC will consider
the NVAC advice and finalize the ISO Scientific Agenda. It is important
to note that CDC will lead Phases 1 and 3; final decisions about the
Scientific Agenda content and priorities would be those of ISO and CDC.
NVAC and NVPO will lead the NVAC scientific review. NVPO and NVAC formed
a Vaccine Working Group on Vaccine Safety, including members and invited
consultants with different expertise and backgrounds. CDC provided the
following charge to NVPO for the NVAC scientific review and it was
accepted. The NVAC reviewers will undertake and coordinate a scientific
review of the Draft ISO Scientific Agenda and advise on: 1) content of
ISO draft Scientific Agenda (e.g., are the topics on the agenda
appropriate? Should other topics be included?); 2) prioritization of
scientific topics, and 3) possible scientific barriers to implementing
the Scientific Agenda and suggestions for addressing them.

[Public Involvement]{.underline}

Trust and transparency about vaccine safety are values that CDC, NVPO
and NVAC share, and involving the public in the ISO Scientific Agenda
process is also responsive to the IOM recommendation from 2005 (see
section on ISO mission and "Vaccine Safety Research, Data Access, and
Public Trust). ISO is committed to receiving input from the public and
carefully considering this input before CDC finalizes the Scientific
Agenda.  In June 2007, participants attending the joint NVAC
Subcommittee on Vaccine Safety and Subcommittee on Public Communication,
Consultation, and Participation meeting discussed the topic
([http://www.hhs.gov/nvpo/nvac/documents/2007june/Pavia.ppt](https://atlanta.securemail.hhs.gov/exchweb/bin/redir.asp?URL=http://www.hhs.gov/nvpo/nvac/documents/2007june/Pavia.ppt)). 

The public has had an opportunity to learn about the Agenda plans
through public presentations to NVAC and ACIP
([http://www.hhs.gov/nvpo/nvac/documents/2007june/Pavia.ppt](https://atlanta.securemail.hhs.gov/exchweb/bin/redir.asp?URL=http://www.hhs.gov/nvpo/nvac/documents/2007june/Pavia.ppt)
and
[http://www.cdc.gov/vaccines/recs/ACIP/downloads/mtg-slides-jun07/11-izsafetyoffice-broder.pdf](https://atlanta.securemail.hhs.gov/exchweb/bin/redir.asp?URL=http://www.cdc.gov/vaccines/recs/ACIP/downloads/mtg-slides-jun07/11-izsafetyoffice-broder.pdf)). 
All in-person meetings among the NVAC scientific reviewers for the ISO
Scientific Agenda and full NVAC will be open to the public.  In
addition, the NVAC Vaccine Safety Working Group which will conduct the
review of the ISO Scientific Agenda includes two public representatives
who have personal experience with vaccine and vaccine safety issues
(personal communication, Dan Salmon on 1/18/2008). Following the NVAC
Working Group review, ISO will solicit comments on the draft ISO
Scientific Agenda, through mechanisms such as the *Federal Register*
(<http://www.gpoaccess.gov/fr/index.html>) and CDC website. 

The remainder of this document focuses on the CDC development of the
Draft ISO Scientific Agenda (phase 1).  Information about the proposed
approach for the NVAC scientific review will be described in a companion
draft document on Agenda recommendations. The approach that CDC will use
to finalize the Agenda after the NVAC review (phase 3) will be described
in the Final ISO Scientific Agenda. 

**[CDC Development of the Draft ISO Scientific Agenda: Input
Venues]{.underline}**

[External Input Meetings on the ISO Research Agenda]{.underline}

CDC recognized that obtaining external input before the NVAC scientific
review would enhance the quality of the Agenda and help inform the NVAC
scientific review. During May 2007 through November 2007 CDC and NVPO
convened three meetings to obtain input from the following groups:
external expert scientists, vaccine safety representatives from HHS and
Department of Defense agencies and programs, and US vaccine
manufacturers' representatives.[^16] Before each meeting ISO prepared
briefing materials including lists of research studies underway or
planned and background presentations that were shared with participants.
The charge to individual participants in each meeting was also similar.
In each meeting participants were asked to: 1) identify emerging vaccine
safety questions and gaps in knowledge that will be important for public
health and could by studied by ISO, 2) advise on prioritization of the
topics and 3) propose some potential approaches to study the topics.
During each meeting one or more note takers summarized the key events
and suggestions. We also asked non-ISO participants to complete feedback
worksheets for ISO staff to review. We drafted separate reports from
each meeting describing the approaches used and key suggestions from the
participating scientists.[^17] Brief summaries about the organization of
the three meetings are provided in Appendix C. In addition to these
planned meetings, we reviewed additional external input from existing
sources (e.g. a review of ACIP statements).

[Ongoing Input from ISO Day-to-Day Partners]{.underline}

While reaching out to external groups for novel ideas, ISO has also
worked closely with its day-to-day partners to obtain input on the ISO
Scientific Agenda. These partners include CISA and VSD investigators,
the FDA VAERS team, and non-CDC colleagues in the Brighton
Collaboration. All have discussed the Agenda and will continue to have
opportunities to provide input. In January 2008, OCSO convened an ISO
Writing and Reviewing Group to enhance the quality of the ISO Scientific
Agenda and optimize collaboration among its teams and leadership
(Appendix A).

In addition to these partners, ISO scientists interact routinely with
CDC immunization experts outside ISO by collaborating on scientific
projects and participating in appropriate ACIP Working Groups. To ensure
that CDC immunization experts and ACIP have appropriate involvement with
the ISO Scientific Agenda, ISO staff are working closely with CDC's
National Center for Immunization and Respiratory Diseases (NCIRD) and
ACIP leadership. In June 2007, ISO presented an update on the status of
the ISO Scientific Agenda to ACIP and discussed agenda development
during a CDC "Vaccine Interest Group" meeting. This topic also has been
discussed on monthly NCIRD calls with professional partner
organizations.

**FUTURE ACTIVITIES**

The NVAC Vaccine Safety Working Group will convene for its first meeting
on April 11, 2008 in Washington DC. During this meeting the Working
Group will review and advise on the content and priorities of the draft
ISO Scientific Agenda. The ISO Internal Writing and Reviewing team is
currently developing draft Agenda recommendations for this review. ISO
will provide these draft Agenda recommendations in a companion document
before the meeting. In addition, during the meeting, the NVAC Working
Group will have the opportunity to consider various approaches to
prioritizing the ISO Agenda.

**REFERENCES**

[Printed material]{.underline}

Chen RT et al.  Vaccine Safety Datalink Project: A new tool for
improving vaccine safety monitoring in the United States. *Pediatrics*.
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[Websites]{.underline}

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2008.

IOM. Immunization Safety Review, available at
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IOM. Vaccine Safety Research, Data Access, and Public Trust. 2005,
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Vaccines and Related Biological Products Advisory Committee (VRBPAC),
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<http://www.cdc.gov/vaccines/pubs/ACIP-list.htm>, accessed on January
15, 2008.

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15, 2008.

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<http://www.cdc.gov/about/organization/ccid.htm>, accessed on January
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Draft Guidance on Prioritization of Pandemic Influenza Vaccine: Who
Should Get Vaccinations First?, available at
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on January 22, 2008.

**AKNOWLEDGEMENTS**

We acknowledge the contributions of the individuals from following
groups; OCSO leadership, ISO staff and research and surveillance
partners, participants in the CDC and NVPO input meetings, and NVPO and
NVAC colleagues, particularly Drs. Dan Salmon, Andrew Pavia, Tanja
Popovic and Jimmy Stephens. We recognize the contributions of Dr. Robert
Davis, who directed the Immunization Safety Office from 2006--2007 and
Dr. Frank DeStephano who was Acting ISO Director from 2004--2006. We
acknowledge Dr. Robert Chen who directed CDC's Vaccine Safety activities
for 16 years; his pioneering scientific leadership helped advance the
field of vaccine safety science nationally and internationally.

**APPENDICES**

**[Appendix A: ISO Scientific Agenda Writing and Reviewing
Group]{.underline}**

Karen R. Broder, MD,

Commander, USPHS (lead)

Senior Medical Advisor

Immunization Safety Office (ISO),

Office of the Chief Science Officer (OCSO), CDC

James Donahue, DVM, PhD,

Project Scientist

Vaccine Safety Datalink (VSD) Project\
Marshfield Clinic Research Foundation\
Marshfield, WI 

Kathryn Edwards, MD\
Principal Investigator

Clinical Immunization Safety Assessment (CISA) Network\
Vanderbilt University\
Nashville, TN

Julianne Gee, MPH

Senior Epidemiologist and Project Officer

Vaccine Safety Datalink (VSD) Project

ISO, OCSO, CDC

Jane Gidudu, MD, MPH

Team Leader

The Brighton Collaboration

ISO, OCSO, CDC

Beth Hibbs, RN

Nurse Consultant,

Vaccine Adverse Event Reporting System

ISO, OCSO, CDC

John K. Iskander, MD, MPH,

Commander, USPHS

Acting Director

ISO, OCSO, CDC

Nancy Levine, PhD

Senior Policy Analyst

ISO, OCSO, CDC

Chesley Richards, MD

Deputy Director

Division of Healthcare Quality Promotion

National Center for Preparedness, Detection, and Control of Infectious
Diseases (NCPDCID), CDC

Elizabeth Skillen, PhD, MS

Health Scientist

ISO, OCSO, CDC (on detail)

Barbara Slade, MD, MS

Team Leader, CISA Network

ISO, OCSO, CDC

Dixie E. Snider, Jr, MD, MPH, Rear Admiral, USPHS (retired)

Senior Consultant

OCSO, CDC

Melinda Wharton, MD, MPH

Captain, USPHS (*Ex Officio* member)

Deputy Director

National Center for Immunization and Respiratory Diseases (NCIRD), CDC

**[Appendix B: Institute of Medicine Immunization Safety Review
Summary]{.underline}\***

+-----------------+-------------------+--------------+-----------------+
| Institute of    |                   |              |                 |
| Medicine        |                   |              |                 |
| Immunization    |                   |              |                 |
| Safety Reviews, |                   |              |                 |
| 2001--2004      |                   |              |                 |
+=================+===================+==============+=================+
| **IOM           | **Outcome**       | **Vaccine**  | **Conclusion**  |
| Immunization    |                   |              |                 |
| Safety Review** |                   |              |                 |
+-----------------+-------------------+--------------+-----------------+
| Thimer          | N                 | Childhood    | **Evidence is   |
| osal-Containing | eurodevelopmental | vaccines     | inadequate to   |
| Vaccines and    | disorders (e.g.   | with         | accept or       |
| Neu             | autism, ADHD, and | Thimerosal   | reject a causal |
| rodevelopmental | speech language   |              | relationship    |
| Disorders       | delay).           |              | (also see 2004  |
| (2001)          |                   |              | review)**       |
+-----------------+-------------------+--------------+-----------------+
| Measle          | Autistic Spectrum | MMR Vaccine  | Evidence favors |
| s-Mumps-Rubella | Disorder (ASD)    |              | rejection of a  |
| Vaccine and     |                   |              | causal          |
| Autism (2001)   |                   |              | relationship    |
+-----------------+-------------------+--------------+-----------------+
| Hepatitis B     | Multiple          | Hepatitis B  | Evidence favors |
| Vaccine and     | sclerosis --      | Vaccine      | rejection of a  |
| Demyelinating   | incident          |              | causal          |
| Neurological    |                   |              | relationship    |
| Disorders       |                   |              |                 |
| (2002)          |                   |              |                 |
+-----------------+-------------------+--------------+-----------------+
|                 | Multiple          |              | Evidence favors |
|                 | sclerosis --      |              | rejection of a  |
|                 | relapse           |              | causal          |
|                 |                   |              | relationship    |
+-----------------+-------------------+--------------+-----------------+
|                 | Central Nervous   |              | **Evidence is   |
|                 | System            |              | inadequate to   |
|                 | Demyelinating^3^  |              | accept or       |
|                 | Disorder -- first |              | reject a causal |
|                 | episode           |              | relationship**  |
+-----------------+-------------------+--------------+-----------------+
|                 | Acute             |              | **Evidence is   |
|                 | disseminated      |              | inadequate to   |
|                 | encephalomyelitis |              | accept or       |
|                 | (ADEM)            |              | reject a causal |
|                 |                   |              | relationship**  |
+-----------------+-------------------+--------------+-----------------+
|                 | Optic neuritis    |              | **Evidence is   |
|                 |                   |              | inadequate to   |
|                 |                   |              | accept or       |
|                 |                   |              | reject a causal |
|                 |                   |              | relationship**  |
+-----------------+-------------------+--------------+-----------------+
|                 | Transverse        |              | **Evidence is   |
|                 | myelitis          |              | inadequate to   |
|                 |                   |              | accept or       |
|                 |                   |              | reject a causal |
|                 |                   |              | relationship**  |
+-----------------+-------------------+--------------+-----------------+
|                 | Guillain-Barré    |              | **Evidence is   |
|                 | Syndrome (GBS)    |              | inadequate to   |
|                 |                   |              | accept or       |
|                 |                   |              | reject a causal |
|                 |                   |              | relationship**  |
+-----------------+-------------------+--------------+-----------------+
|                 | Brachial neuritis |              | **Evidence is   |
|                 |                   |              | inadequate to   |
|                 |                   |              | accept or       |
|                 |                   |              | reject a causal |
|                 |                   |              | relationship**  |
+-----------------+-------------------+--------------+-----------------+
| Multiple        | Heterologous      | Multiple     | Evidence favors |
| Immunizations   | infections        | Vaccinations | rejection of a  |
| and Immune      |                   |              | causal          |
| Dysfunction     |                   |              | relationship    |
| (2002)          |                   |              |                 |
+-----------------+-------------------+--------------+-----------------+
|                 | Type 1 diabetes   |              | Evidence favors |
|                 |                   |              | rejection of a  |
|                 |                   |              | causal          |
|                 |                   |              | relationship    |
+-----------------+-------------------+--------------+-----------------+
|                 | Increased risk of |              | **Evidence is   |
|                 | allergic disease, |              | inadequate to   |
|                 | particularly      |              | accept or       |
|                 | asthma            |              | reject a causal |
|                 |                   |              | relationship**  |
+-----------------+-------------------+--------------+-----------------+
| SV40            | Cancer            | Oral polio   | **Evidence is   |
| Contamination   |                   | vaccine      | inadequate to   |
| of Polio        |                   | (OPV)        | accept or       |
| Vaccine and     |                   |              | reject a causal |
| Cancer (2002)   |                   |              | relationship**  |
+-----------------+-------------------+--------------+-----------------+
| Vaccinations    | Sudden infant     | Diptheria    | Evidence favors |
| and Sudden      | death syndrome    | and tetanus  |                 |
| Unexpected      | (SIDS)            | toxoids and  | rejection of a  |
| Death in        |                   | whole cell   | causal          |
| Infancy (2003)  |                   | pertussis    | relationship    |
|                 |                   | vaccine      |                 |
|                 |                   | (DTwP)       |                 |
+-----------------+-------------------+--------------+-----------------+
|                 |                   | Diphtheria   | **Evidence is   |
|                 |                   | and tetanus  | inadequate to   |
|                 |                   | toxoids and  | accept or       |
|                 |                   | acellular    | reject a**      |
|                 |                   | pertussis    |                 |
|                 |                   | vaccine      | **causal        |
|                 |                   | (DTaP)       | relationship**  |
+-----------------+-------------------+--------------+-----------------+
|                 |                   | Haemophilus  | **Evidence is   |
|                 |                   | Influenza    | inadequate to   |
|                 |                   | (Hib),       | accept or       |
|                 |                   | Hepatitis B  | reject causal   |
|                 |                   | (HepB), Oral | relationships** |
|                 |                   | Polio        |                 |
|                 |                   | Vaccine      |                 |
|                 |                   | (OPV),       |                 |
|                 |                   | Inactivated  |                 |
|                 |                   | Polio        |                 |
|                 |                   | Vaccine      |                 |
|                 |                   | (IPV)        |                 |
+-----------------+-------------------+--------------+-----------------+
|                 |                   | Multiple     | Evidence favors |
|                 |                   | simultaneous | rejection of a  |
|                 |                   | vaccinations | causal          |
|                 |                   |              | relationship    |
+-----------------+-------------------+--------------+-----------------+
|                 | Sudden unexpected | Multiple     | **Evidence is   |
|                 | death in infancy, | simultaneous | inadequate to   |
|                 | other than SIDS   | vaccinations | accept or       |
|                 |                   |              | reject a causal |
|                 |                   |              | relationship**  |
+-----------------+-------------------+--------------+-----------------+
|                 | Anaphylaxis in    | DTwP         | Evidence favors |
|                 | infants           |              | acceptance of a |
|                 |                   |              | causal          |
|                 |                   |              | relationship    |
+-----------------+-------------------+--------------+-----------------+
|                 | Neonatal death    | Hepatitis B  | **Evidence is   |
|                 |                   | vaccine      | inadequate to   |
|                 |                   |              | accept or       |
|                 |                   |              | reject a causal |
|                 |                   |              | relationship**  |
+-----------------+-------------------+--------------+-----------------+
| Influenza       | GBS               | 1976 Swine   | Evidence favors |
| Vaccines and    |                   | Influenza    | acceptance of a |
| Neurological    |                   | Vaccine      | causal          |
| Complications   |                   |              |                 |
| (2004)          |                   |              | relationship    |
+-----------------+-------------------+--------------+-----------------+
|                 |                   | Influenza    | **Evidence is   |
|                 |                   | vaccine      | inadequate to   |
|                 |                   | administered | accept or       |
|                 |                   | after 1976   | reject a causal |
|                 |                   |              | relationship**  |
+-----------------+-------------------+--------------+-----------------+
|                 | Multiple          | Influenza    | Evidence favors |
|                 | sclerosis --      | vaccine      |                 |
|                 | relapse           | administered | rejection of a  |
|                 |                   | after 1976   | causal          |
|                 |                   |              | relationship    |
+-----------------+-------------------+--------------+-----------------+
|                 | Multiple          |              | **Evidence is   |
|                 | sclerosis --      |              | inadequate**    |
|                 | incident          |              |                 |
|                 |                   |              | **to accept or  |
|                 |                   |              | reject a causal |
|                 |                   |              | relationship**  |
+-----------------+-------------------+--------------+-----------------+
|                 | Optic neuritis    |              | **Evidence is   |
|                 |                   |              | inadequate to   |
|                 |                   |              | accept or       |
|                 |                   |              | reject a causal |
|                 |                   |              | relationship**  |
+-----------------+-------------------+--------------+-----------------+
|                 | Other             |              | **Evidence is   |
|                 | Demyelinating     |              | inadequate to   |
|                 | Neurological      |              | accept or       |
|                 | Conditions        |              | reject a causal |
|                 |                   |              | relationship**  |
+-----------------+-------------------+--------------+-----------------+
|                 | Demyelinating     |              | **No evidence   |
|                 | neurological      |              | bearing on a    |
|                 | disorders in      |              | causal          |
|                 | children aged     |              | relationship**  |
|                 | 6-23 months       |              |                 |
+-----------------+-------------------+--------------+-----------------+
| Vaccines and    | Autism            | Thimerosal-  | Evidence favors |
| Autism (2004)   |                   | containing   | rejection of a  |
|                 |                   | vaccines     | causal          |
|                 |                   |              | relationship    |
+-----------------+-------------------+--------------+-----------------+
|                 |                   | MMR vaccine  | Evidence favors |
|                 |                   |              | rejection of a  |
|                 |                   |              | causal          |
|                 |                   |              | relationship    |
+-----------------+-------------------+--------------+-----------------+

\* Source: National Vaccine Program Office, provided by Dan Salmon and
information available at <http://www.iom.edu/?ID=4705>, accessed on
March 21, 2008.

**[Appendix C: Summary Table of External Input Meetings on the ISO
Scientific Agenda]{.underline}**[^18]

+-----------------+-----------------+-----------------+-----------------+
| **Input Group** | **Sponsor**     | **Meeting       | **Meeting       |
|                 |                 | Description**   | Date**          |
+-----------------+-----------------+-----------------+-----------------+
| Immunization    | CDC             | CDC individual  | May 10-11,      |
| Safety Office   |                 | simultaneous    | 2007, Atlanta,  |
| External        |                 | consultation    | GA              |
| Scientific      |                 | with seven      |                 |
| Consultancy     |                 | individual      |                 |
|                 |                 | expert          |                 |
|                 |                 | scientists and  |                 |
|                 |                 | liaisons        |                 |
|                 |                 | representing    |                 |
|                 |                 | the fields of   |                 |
|                 |                 | pediatric       |                 |
|                 |                 | infectious      |                 |
|                 |                 | diseases, adult |                 |
|                 |                 | infectious      |                 |
|                 |                 | diseases,       |                 |
|                 |                 | obstetrics and  |                 |
|                 |                 | gynecology,     |                 |
|                 |                 | immunology,     |                 |
|                 |                 | genomics, and   |                 |
|                 |                 | epidemiology    |                 |
+-----------------+-----------------+-----------------+-----------------+
| US Department   | NVPO            | National        | August 3, 2007, |
| of Health and   |                 | Vaccine Program | Washington DC   |
| Human Services  |                 | Office (NVPO)   |                 |
| and US          |                 | Interagency     |                 |
| Department of   |                 | Vaccine Group   |                 |
| Defense         |                 | (IAVG) meeting  |                 |
| agencies and    |                 | with 21 Federal |                 |
| programs        |                 | scientists with |                 |
|                 |                 | expertise in    |                 |
|                 |                 | vaccines        |                 |
+-----------------+-----------------+-----------------+-----------------+
| Non-federal     | NVPO            | NVPO-sponsored  | November 16,    |
| partners        |                 | meeting with    | 2007,           |
|                 |                 | vaccine         |                 |
|                 |                 | manufacturer    | Washington DC   |
|                 |                 | representatives |                 |
|                 |                 | from six US     |                 |
|                 |                 | vaccine         |                 |
|                 |                 | manufacturers   |                 |
+-----------------+-----------------+-----------------+-----------------+

**[Appendix D: List of Abbreviations]{.underline}**

  -------------- --------------------------------------------------------
  ACIP           Advisory Committee on Immunization Practices

  AEFI           adverse events following immunization

  BLA            Biologics License Application

  CDC            Centers for Disease Control and Prevention

  CISA           Clinical Immunization Safety Assessment

  FDA            Food and Drug Administration

  GBS            Guillain-Barré Syndrome

  Hib            *Haemophilus influenza* type b

  IOM            Institute of Medicine

  ISO            Immunization Safety Office

  NIH            National Institutes of Health

  NVAC           National Vaccine Advisory Committee

  NVPO           National Vaccine Program Office

  OCSO           Office of the Chief Science Officer

  VAE            vaccine adverse event

  VAERS          Vaccine Adverse Event Reporting System

  VHC            Vaccine Health Center

  VSD            Vaccine Safety Datalink

  USPHS          United States Public Health Service
  -------------- --------------------------------------------------------

[^1]: This draft background document was prepared for the National
    Vaccine Advisory Committee (NVAC), Vaccine Safety Working Group.
    Address comments on this draft to Karen R. Broder, MD, Immunization
    Safety Office (ISO), CDC, Phone: 404-639-8538 Fax: 404-639-8616
    Email:Kbroder@cdc.gov. See Appendix A for a list of persons on the
    ISO Scientific Agenda Writing and Reviewing Group.

[^2]: The terms adverse event following immunization (AEFI) and vaccine
    adverse event (VAE) and are used interchangeably throughout this
    document and do not imply that an event was caused by a vaccine.

[^3]: As of March 21, 2008, ISO staff serve on 10 ACIP Working Groups
    and the Acting Director ISO serves on the steering committee.

[^4]: As of March 21, 2008, the ISO mission is provisional and does not
    represent CDC or HHS policy; the mission will be finalized after the
    ISO Scientific Agenda is complete.

[^5]: The VAXDEV activity is under a separate CDC review to determine
    its optimal organizational placement at CDC; it is not included in
    the ISO Scientific Agenda.

[^6]: A different rotavirus vaccine, Rotateq^®^, is currently licensed
    and recommended for use in the United States.

[^7]: The MCOs are: Group Health Cooperative of Puget Sound, Seattle,
    WA; Kaiser Permanente Northwest, Portland, OR; 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; and Harvard Pilgrim Healthcare, Boston, MA.

[^8]: The sites are: Northern California Kaiser, Stanford University,
    CA; Vanderbilt University, TN; Boston University Medical Center, MA;
    Columbia-New York Presbyterian Hospital, NY; and Johns Hopkins
    University, MD

[^9]: ISO adopted the term Scientific Agenda in December 2007.
    Previously the term "Research Agenda" was used.

[^10]: Of the 467 objectives stated in the Healthy People 2010 guidance,
    two are specific to vaccine safety.

[^11]: The committee was distinct from the committees that conducted
    earlier IOM reviews of vaccine safety.

[^12]: In 2006, the National Immunization Program (NIP) was reorganized
    into other parts of CDC. Before 2005, most vaccine safety activities
    were in NIP.

[^13]: As of January 16, 2008, the NVAC Subcommittee on Safety and
    Communication are two separate subcommittees.

[^14]: CDC response to the 2005 IOM report is available by request from
    the corresponding author.

[^15]: Pharmocoepidemiology is defined as by the International Society
    of Pharmacoepidemiology as the study of the utilization and effects
    of drugs in large numbers of people and as the application of
    epidemiological methods to pharmacological issues
    (<http://www.pharmacoepi.org/aboutpe.cfm>).

[^16]: The meetings were as follows: CDC Individual Simultaneous
    Consultation on CDC's Immunization Safety Office Research Agenda
    (5/2007), NVPO Interagency Vaccine Group (IAVG) Meeting on CDC's ISO
    Research Agenda (8/2007), and NVPO Individual Simultaneous
    Consultation with US Vaccine Manufacturers' Representatives on CDC's
    ISO Research Agenda (11/2007)

[^17]: The unpublished reports from the external input meetings about
    the ISO Research Agenda are available by request from the
    corresponding author.

[^18]: Separate reports for each meeting are available from the
    corresponding author.