2003 brochure on Vaccine Safety Datalink [LONG] Case-control

[Guest guest]

Read this 2003 brochure about the Vaccine Safety Datalink. This annual report is

sent to health insurers that supply the VSD with data on possible vaccine

injuries.

On page 7, paragraph 1, a casual reader might assume that consumer reports of

adverse reaction to vaccines are not taken seriously.

http://www.ahip.org/content/fileviewer.aspx?docid=307 & linkid=3146

Has anyone seen the Thimerosal case-control study mentioned?

- Hokkanen

____________________________________

1

THE VACCINE SAFETY DATALINK

(VSD) PROJECT

Annual Report for 2003

2

With questions/comments or to request additional copies of this report, please

contact:

Barbara Lardy

America's Health Insurance Plans . 601 Pennsylvania Avenue, NW, Suite 500 .

Washington, DC . 20004

202-778-3229 or blardy@...

© America's Health Insurance Plans, 2004

Vision/Mission

The vision of the Vaccine Safety Datalink (VSD) project is to provide a powerful

and cost-effective resource for the ongoing evaluation of vaccine safety. The

mission of the VSD project is to carefully monitor vaccine safety through

planned vaccine safety studies and timely investigations of hypotheses.

" Sound immunization policies and recommendations affecting the health of our

nation depend upon the consistent monitoring of vaccines and ongoing assessment

of immunization benefits and risks. The Vaccine Safety Datalink project is one

of our most important tools to ensure the safety and efficacy of vaccines. "

Centers for Disease Control and Prevention

3

44

5

Letter from America's Health Insurance Plans

............................................. 7

Letter from Centers for Disease Control and Prevention/

National Immunization Program ................................................ 9

Introduction .......................................... 11

VSD Priority Studies ........................................... 12

Hepatitis B

? Autoimmune Thyroid Disease (ATD) Study

? Risk of Alopecia Following Hepatitis B Vaccination (Case/Control)

? Risk of Alopecia Following Hepatitis B Vaccination (Cohort)

Influenza

? Influenza Vaccine and Bell's Palsy

? Pediatric Flu Study, Part II

MMR

? Idiopathic Thrombocytopenia Purpura (ITP) and MMR Vaccination

Vaccine Non-Specific

? Thimerosal Follow-Up Study

? Thimerosal / Autism Case-Control Study

? Rapid Cycle Analysis

? Sex-Based Analysis

VSD Sites ............................................ 29

Publications from 2001, 2002, 2003 ....................................... 38

Table of Contents

66

7

Vaccines are important allies in the effort to prevent illness and control the

spread of many diseases. Yet, each year there are reports that highlight

possible side effects or other adverse events related to vaccines. Such reports

can lead to unwarranted public concern about the risks of vaccines and lead to

potential avoidance of vaccinations. Such public actions can have a deleterious

effect on the health of the nation. It is critical to the health of our nation

to have a scientific system for collecting vaccine safety information from a

large population. The Vaccine Safety Datalink (VSD) project, with the ultimate

goal of protecting the public's health through the ongoing monitoring of vaccine

safety, provides just such a system.

America's Health Insurance Plans (AHIP), providing health benefits to over 200

million Americans, is proud to be a part of the CDC's VSD project. For more than

20 years-predating the VSD project-researchers in health plans have been

involved in vaccine safety and efficacy studies. Since the inception of the VSD

project, researchers affiliated with eight health plans have worked

collaboratively with CDC researchers to continue studying vaccine safety. Health

plans and insurers have long championed the use of preventive services,

especially vaccines, to improve health and prevent disease. AHIP member plans

consider vaccination to be an essential component for ensuring a healthy nation

and have been innovators in the design of immunization programs to increase

rates and timeliness of immunization among infants, children, adolescents and

adults. This annual report highlights the continuing contributions being made to

vaccine safety by health plans serving as VSD participating sites.

M. Ignagni

President and CEO, America's Health Insurance Plans (AHIP)

7

88

9

Vaccines are among the most successful and cost-effective public health tools

for preventing disease and death in the modern era. The National Immunization

Program (NIP) is devoted to undertaking and promoting a wide range of scientific

activities to support immunization and prevent disease worldwide. However, no

vaccine is 100% safe. When the majority of the population has been vaccinated

and the disease risk becomes rare, both real and perceived vaccine side effects

increase, which result in heightened public concern about the safety of

vaccines. A loss of public confidence in vaccines could result in decreased

vaccination levels, followed by epidemics of disease. A timely, credible and

effective immunization safety monitoring system to determine which illnesses are

caused by vaccines, and which are not, must exist to maintain public confidence

in immunizations and prevent the return of disease epidemics. Within NIP's

Immunization Safety Branch (ISB), we are engaged in many programs and activities

to monitor the safety of vaccines. The Vaccine Adverse Event Reporting System

(VAERS), in collaboration with the Food and Drug Administration, serves as an

early warning system to detect problems that may be related to vaccines. The

Clinical Immunization Safety Assessment (CISA) Network provides in-depth,

standardized clinical evaluations for individuals with unusual or severe vaccine

adverse events that might be reported to VAERS. The Brighton Collaboration is a

global collaboration which was established to standardize case definitions for

study of vaccines, thereby creating a common " vocabulary " for vaccine safety

research. Further vaccine safety research for causal relationships is conducted

within ISB through the Vaccine Safety Datalink (VSD) Project, a large-linked

database containing comprehensive medical and immunization histories of over 7.5

million people. The VSD enables population-based vaccine safety research studies

to compare the incidence of health problems between vaccinated and unvaccinated

people. In addition, the VSD established a data sharing process to allow

external researchers access to datasets created through the VSD. Research

conducted by the Vaccine Acceptance Risk Perceptions (VARP) group determines how

best to disseminate information on the benefits and risks of vaccinations, and

the Vaccine Development (VAXDEV) activity works to develop safer vaccines and

delivery methods, especially needle-free jet injectors for mass immunization

campaigns. I am proud of the accomplishments we have made to monitor the safety

of vaccines as documented in this report, conducted by CDC and in collaboration

with the various external partners like America's Health Insurance Plans (AHIP).

I hope you will join me in supporting the research projects conducted through

our vaccine safety programs and activities.

I thank you for your contributions and your support in the past year, and

welcome the opportunity to continue our collaboration in the coming year.

Sincerely,

L. Cochi, MD, MPH

Captain, United States Public Health Service

Acting Director, National Immunization Program

9

10

VSD Staff

America's Health Insurance Plans (AHIP) Staff:

Barbara Lardy, MPH, Vice President, Medical Affairs, Project Director

Carmella Bocchino, RN, MBA, Sr. Vice President, Medical Affairs, Management

Liaison

Fahey, MA. Deputy Director, VSD/CISA

Daphnis, MPH, Program Manager, VSD

Viggiano, Operations Manager, VSD/CISA

Sharron , Research Associate/Contract Administrator, VSD/CISA

Rick Ramsay, Sr. Associate Counsel & Compliance Officer

Centers for Disease Control and Prevention,

National Immunization Program, Immunization Safety Branch Staff:

Chen, MD, MA , Chief

Broom , Deputy Chief

DeStefano, MD, MPH , Medical Epidemiologist

Shay, MD, MPH, Medical Epidemiologist

Margarette Kolczak, PhD, Epidemiologist

, PhD, Epidemiologist

Baggs, PhD, Epidemiologist

nne Gee, MPH, Epidemiologist

Jufu Chen, PhD, Epidemiologist

Weintraub, MPH, Epidemiologist

Charissa Densen, Program Analyst

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Introduction

Source: Offit, and Bell, Louis, Vaccines: What You Should Know

(Third Edition); (page 3); Wiley & Sons, Inc. 2003.

Immunization is one of the greatest public health success stories of all time.

Every year, many serious childhood diseases are prevented by using vaccines

routinely recommended for newborns, infants and children. Since the introduction

of these vaccines, reported cases of vaccinepreventable childhood diseases have

decreased dramatically in the United States and millions of lives have been

saved. As a result, most Americans today have only vague memories of diseases

such as polio, rubella, measles, diphtheria, meningitis and pertussis. Without

vaccines, the diseases we are now protected from could return to cause serious

illness or even death in many infants and children.

Before Vaccines, Parents in the United States Could Expect that Every Year:

? Polio would paralyze about 15,000 children.

? Rubella ( " German measles " ) would cause birth defects

and mental retardation in as many as 20,000 newborns;

? Measles would infect about 4 million children, killing

3,000.

? Diphtheria would be one of the most common causes of death in school-aged

children.

? A bacterium called Hib would cause meningitis in 15,000 children, leaving many

with permanent brain damage.

? Pertussis ( " whooping cough " ) would kill 8,000 children.

Although vaccines are widely considered to be important and safe allies in the

effort to prevent many serious diseases, vaccines are not completely without

risk of side effects or other adverse outcomes. At several points in time during

the past decade, the public has expressed concern about possible side effects of

vaccines and questioned the safety of specific Source: Adapted from The

Children's Hospital of Philadelphia's Vaccine Education Center at

www.chop.edu/consumers/jsp/division/generic.jsp?id=75730

vaccines. Most recently, there has been public concern over the use of

thimerosal (a mercury-containing preservative) in vaccines, reports of severe

side effects associated with the smallpox vaccine, and studies suggesting a link

between the measles-mumps-rubella (MMR) vaccine and autism. In most instances,

concerns about the risks of specific vaccines can be addressed and reduced by

providing empirically-based information that allows the public to see that the

benefits of a specific vaccine outweigh its risks. However, such information is

dependent on a systematic approach for continually monitoring and assessing the

safety of specific vaccines in a variety of populations.

Do the Benefits Outweigh the Risks? The Case of Hepatitis B Vaccine

Each year in the United States about 5,000 people die soon after contracting

hepatitis B virus. In addition, every year about 10,000 people become

chronically infected with hepatitis B virus, putting them at high risk for

developing cirrhosis and liver cancer. In fact, with the exception of influenza

virus, hepatitis B virus causes more severe disease and death in the United

States than any other vaccinepreventable disease.

On the other hand, severe side effects associated with hepatitis B vaccine are

extremely rare. One of every 600,000 doses of the hepatitis B vaccine will cause

a severe allergic reaction called anaphylaxis. Anaphylaxis usually occurs within

15 minutes of receiving the vaccine and is treatable. To date, no one has died

from this reaction. Because hepatitis B virus is a common cause of severe

disease and death in the United States, and the hepatitis B vaccine does not

cause permanent damage or death, the benefits of the hepatitis B vaccine clearly

outweigh its risks.

12

The Vaccine Safety Datalink (VSD) Project

The Vaccine Safety Datalink (VSD) was established in 1990 as a crucial part of

the federal government's systematic effort to monitor the safety of vaccines

commonly used in the United States and to reassure public confidence in

vaccines. Through the VSD project, researchers from the private and public

sectors work together on studies designed to monitor the safety of vaccines

administered to infants, children, adolescents and adults. Based at one of eight

participating sites or the Centers for Disease Control and Prevention (CDC), the

VSD researchers conduct studies that provide vital information about the short

and long-term effects of specific vaccines on various populations. Collectively,

the data from the VSD studies are based on active surveillance of approximately

seven million people (2.5% of the total U.S. population).

Although all VSD studies are designed to answer critical questions about vaccine

safety, each year a select number of studies is given a special " priority "

designation that indicates their vital importance to the nation's health. VSD

priority studies focus on vaccine safety, are generally based on data collected

from multiple sites, and are allocated highest priority in the event that time

or financial resources become limited. In this report, we highlight ten priority

studies. The CDC's National Immunization Program (NIP) is charged with the

responsibility of providing leadership, expertise and ongoing education about

the development and delivery of an effective immunization delivery program for

the United States. As part of its mission, NIP's Immunization Safety Branch

supports epidemiologic research to evaluate the safety, immunogenicity and

efficacy of vaccines recommended for routine human use after licensure by the

U.S. Food and Drug Administration (FDA). NIP provides leadership for the

planning, coordination and conduct of immunization activities across the nation.

Such activities include the provision of consultation, training, statistical,

promotional, educational and technical services to assist health departments and

other entities to implement effective immunization programs.

The CDC/NIP Immunization

Safety Branch

The Immunization Safety Branch of the CDC's National Immunization Program is

charged with enhancing the nation's capacity to monitor and evaluate vaccine

safety.

Projects underway within the CDC/NIP Immunization Safety

Branch include:

? Vaccine Safety Datalink (VSD) Project. To collaborate with researchers in the

private sector for the purpose of conducting studies that monitor the safety of

vaccines commonly used in the United States.

? Clinical Immunization Safety Assessment (CISA) Network.

To improve scientific understanding of vaccine safety issues at the patient

level and develop protocols to assist healthcare providers to better manage

situations in which adverse vaccine events occur.

? Vaccine Adverse Event Reporting System (VAERS). To monitor reports of

post-vaccination adverse events from health professionals, vaccine

manufacturers, and the general public for the purpose of identifying new or rare

vaccine side effects, increases in the occurrence of known side effects, and

patient risk factors for specific adverse events.

? Brighton Collaboration. The Brighton Collaboration is an international

voluntary collaboration to facilitate the development, evaluation, and

dissemination of high quality information about the safety of human vaccines and

to develop globally accepted and implemented standardized case definitions of

Adverse Events Following Immunization (AEFIs).

? The Vaccine Acceptance Research Program (VARP). The Vaccine Acceptance

Research Program was conceived to better understand the way in which individuals

interpret risks and make decisions about vaccination. The primary goal of this

program is to develop and evaluate interventions that help individuals make

informed decisions about vaccinations and help people understand the potential

increased risk of disease if a significant number of people refuse to be

vaccinated because of the current low disease prevalence.

? The Vaccine Development (VAXDEV). Unit promotes safer vaccine administration

methods such as needle-free injection technology, through contract R & D for

high-speed jet injectors, clinical studies, and an information database,

website, and news service. VAXDEV also monitors new vaccines and technologies in

development, and promotes guidelines for improved vaccine labeling and packaging

to minimize medical errors, improve recordkeeping, and enhance surveillance of

vaccination adverse events.

Participating VSD Sites

? Centers for Disease Control and Prevention

National Immunization Program

Immunization Safety Branch

Atlanta, Georgia

? Group Health ative

Center for Health Studies

Seattle, Washington

? Harvard Pilgrim Health Care, Harvard

Medical School and Harvard Vanguard

Department of Ambulatory Care

and Prevention

Boston, Massachusetts

? HealthPartners Research Foundation

Minneapolis, Minnesota

? Kaiser Permanente Colorado

Clinical Research Unit

Denver, Colorado

? Kaiser Permanente Northwest

Center for Health Research

Portland, Oregon

? Marshfield Clinic Research Foundation

Marshfield, Wisconsin

? Northern California Kaiser Permanente

Kaiser Permanente Vaccine Study Center

Oakland, California

? UCLA Center for Vaccine Research /

Southern California Kaiser Permanente

Health Care Plan

Los Angeles, California

13

America's Health Insurance Plan (AHIP) (formerly known as the

American Association of Health Plans) was selected by CDC to provide

overall management and coordination for the VSD project. As part of

its role in the VSD project, AHIP's responsibilities include:

? Maintain the strategic direction of the VSD projects;

? Monitor and review the quality of work associated with VSD

projects and studies;

? Verify that all fiduciary responsibilities and budget specifications are

met; and

? Assure timely completion of all work and efforts associated with

the scope of the VSD project.

Hepatitis B: An Overview

Hepatitis B is a virus that infects the liver. Each year in the United States,

approximately 300,000 people become infected with hepatitis B. Among people

who contract hepatitis B, about 5,000 die soon after they are infected and

another 10,000 develop long-term hepatitis that puts them at risk for cirrhosis

and cancer of the liver. A vaccine for hepatitis B was first licensed for use in

the United States in 1982. Since that time, millions of adults, infants, and

children have received the hepatitis B vaccine. Side effects are rare. About

three percent of children develop pain and tenderness where the shot was given

and one percent develop low-grade fevers. An extremely rare side effect of

hepatitis B vaccine is anaphylaxis, which is treatable and estimated to occur

only once in every 600,000 doses.

Vaccination and Risk of Autoimmune Thyroid Disorder: Is Hepatitis B Vaccine

Associated with Graves' Disease or Hashimoto's Thyroiditis?

ISSUE

Recent concerns have been raised about a possible association between hepatitis

B vaccine

and occurrences of autoimmune thyroid diseases (ATD), such as Graves' disease

and Hashimoto's thyroiditis. The concerns are based in part on case reports.

Information from such reports is insufficient to infer a causal link between

hepatitis B vaccine and ATD because reported cases may simply represent

coincidental timing between vaccination and the onset of ATD. Thus far, only a

single case-control study, published as an abstract in Pharmacoepidemiology and

Drug Safety, has addressed this question. Given the sparse data currently

available, and the potential implications of public concern regarding these

early reports of a possible association between hepatitis B vaccine and ATD,

confirmatory studies are needed.

Hepatitis B

14

VSD RESPONSE

A group of VSD researchers has begun a collaborative study to evaluate the

association between receipt of hepatitis B vaccine and risk of ATD, specifically

Graves' disease orHashimoto's thyroiditis. As part of the study, researchers

will simultaneously conduct two case-control studies among the adult populations

of three HMOs participating in the VSD project (Group Health ative, Kaiser

Permanente Northwest, and Northern California Kaiser Permanente). At each

participating site, automated data sources will be used to identify persons with

Graves' disease or Hashimoto's thyroiditis (cases) and persons with no history

of thyroid disease (controls). Data will be confirmed by chart review, and

persons identified as eligible cases and controls will be contacted by telephone

to obtain additional information about vaccinations, identify relevant

covariates (i.e., family and personal history of select autoimmune conditions),

and estimate date of symptom onset among persons with ATD.

The specific objectives of this VSD priority study are to:

? Evaluate the association between having ever received a hepatitis B vaccine

and risk of Graves' disease or Hashimoto's thyroiditis;

? Assess the association between receipt of hepatitis B vaccine within intervals

of

<1 year, 1-5 years, and >5 years of the index date and risk of Graves' disease

or Hashimoto's thyroiditis;

? Evaluate the association between other adult vaccines and the risk of Graves'

disease or Hashimoto's thyroiditis;

? Assess the association between receipt of other adult vaccines within

intervals of

<1 year, 1-5 years, and >5 years of the index date and risk of Graves' disease

or

Hashimoto's thyroiditis.

The results from this VSD priority study will provide the data necessary to

determine whether receipt of hepatitis B vaccine is associated with an increased

risk of autoimmune thyroid disease. The study will also fill a gap in the study

of autoimmune disorders currently ongoing or recently completed through the VSD

project.

" By collecting complete information about hepatitis B vaccination history from a

well-defined study population, this study will confirm or refute concerns raised

by case reports. "

Kari Bohlke, ScD, Principal Investigator, Group Health ative

VSD Priority Study

Research Team:

KARI BOHLKE, ScD

Principal Investigator

Group Health ative

LISA JACKSON, MD, MPH

Group Health ative

WILLIAM THOMPSON, PhD

Centers for Disease Control

and Prevention

DAVID SHAY, MD, MPH

Centers for Disease Control

and Prevention

JOHN MULLOOLY, PhD

Kaiser Permanente Northwest

STEVEN B. BLACK, MD

Northern California

Kaiser Permanente

15

Alopecia Following Hepatitis B Vaccine in Adults and Adolescents: Is Hepatitis B

Vaccine Associated with an Increased Risk of Alopecia?

ISSUE

Recent reports submitted to VAERS suggest that alopecia areata (hair loss) may

rarely occur in persons who have received hepatitis B vaccine. While the

mechanisms responsible for alopecia following vaccination are not certain, the

condition could be immune-mediated.

Therefore, CDC continues to conduct research to examine the effects vaccines may

have on the immune system in general and alopecia in particular.

VSD RESPONSE

At Group Health ative (GHC), VSD researchers have been working on a

matched case-control study to assess the association between receipt of

hepatitis B vaccine and the risk of alopecia in adults and adolescents. Chart

reviews were used to validate outcome and exposure status for cases and exposure

status for controls. In the first phase of the study, cases were drawn from

those identified for an earlier retrospective matched case-control analysis that

GHC conducted using automated data and controls were matched to cases 5:1 by

age, sex, and length of enrollment in GHC prior to the index date. Analyses from

the first phase were based on 206 cases and 610 controls, and there was

inadequate power to detect an association between alopecia and vaccination (if

one exists). Since some associations between alopecia and vaccination have been

suggested, the VSD Adult Studies Work Group approved GHC's proposal to expand

the analysis to include at least two additional years of data. This second phase

of the study is currently underway.

The specific objective of this VSD priority study is to:

? Evaluate the association between receipt of hepatitis B vaccine and risk of

alopecia.

The results from this VSD priority study will increase our knowledge about

vaccine side

effects and contribute to a greater understanding of the impact vaccines may

have on the

immune system.

Hepatitis B

VSD Priority Study

Research Team:

LISA JACKSON, MD, MPH

Principal Investigator

Group Health ative

BARBARA CARSTE, MPH

Group Health ative

16

17

Risk of Alopecia Following Hepatitis B Vaccination:

A Preliminary Cohort Analysis of 15-59 Year Olds

ISSUE

Recent studies suggest that alopecia areata (hair loss) may rarely occur in

persons who have received hepatitis B vaccine. While the mechanisms responsible

for alopecia followingvaccination are not certain, the condition could be

immune-mediated. Therefore, CDCcontinues to conduct research to examine the

effects vaccines may have on the immune system in general and alopecia in

particular.

VSD RESPONSE

Researchers at Northern California Kaiser Permanente (NCKP) are conducting a

cohort study to assess the risk of alopecia following hepatitis B vaccination

among persons aged 15 to 59 years. The study has involved a cohort of persons

continuously enrolled in NCKP from 1/1/95 to 12/31/99. Automated data on clinic

visits were collected for the cohort and persons with visits for hair loss prior

to their follow-up start date were excluded. Vaccine data were collected from an

automated immunization database, and the relative risk for alopecia by type of

vaccine exposure (i.e., hepatitus B, tetanus/diptheria, influenza) was

estimated. Although a statistically significant association was seen for

alopecia in persons exposed to hepatitis B vaccine, similar results were seen in

comparisons between persons exposed vs. unexposed to Td. These same results were

not found in persons exposed to flu vaccine. The similarities in alopecia rates

in the HepB and Td vaccine exposed groups suggest the possibility of

unidentified confounders, possibly related to utilization patterns. Further

analyses will be necessary to identify potential confounders. The relatively

high incidence of alopecia diagnoses seen in the NCKP automated clinic data

compared to published incidence rates for alopecia as well as results of earlier

chart review studies suggest a possible lack of specificity in the automated

data for alopecia. Chart reviews will be necessary to verify rates of alopecia

in exposed vs. unexposed groups.

VSD Priority Study

Research Team:

STEVEN B. BLACK, MD

Principal Investigator

Northern California

Kaiser Permanente

HENRY SHINEFIELD, MD

Northern California

Kaiser Permanente

" This study is a good example of the pairing of the VAERS and the VSD for

evaluations of vaccine safety. In this case, VAERS reports suggested a possible

link between hepatitis B vaccine, or other vaccines, and alopecia areata in

children and adults. As a follow-up to this signal, a controlled epidemiologic

study was initiated in the VSD. "

, MD, MPH, Principal Investigator, Group Health ative

18

Influenza: An Overview

Commonly known as the flu, influenza is a virus that infects the respiratory

system. Every year in the United States, about 115,000 people are hospitalized

and about 20,000 people die from severe pneumonia caused by influenza. Most of

the deaths caused by influenza occur in people 65 or older. However, young

children are more likely than adults to be hospitalized with infections caused

by influenza. An influenza vaccine is given to people who are at high risk for

developing severe influenza. Recently, CDC advised that all children between 6

months and 23 months of age should also receive the influenza vaccine. Known

side effects from influenza vaccine are extremely rare. The influenza vaccine

causes fever, muscle aches and fatigue in less than one percent of people given

the vaccine.

Influenza Vaccine and Bell's Palsy:

Does Influenza Vaccine Increase the Risk of Bell's Palsy?

ISSUE

Bell's palsy is a common neurological disorder that accounts for up to 75% of

all peripheral facial palsies. Although the etiology of Bell's palsy is not

clear, one of the theories put forward involves an autoimmune etiology.

Following the introduction of a newly licensed intranasal influenza vaccine in

Switzerland in October 2000, 46 cases of Bell's palsy were noted among people

who received the vaccine. The situation warranted a thorough investigation to

determine whether there is any association between influenza vaccine and Bell's

palsy.

Influenza

VSD Priority Study

Research Team:

WEIGONG ZHOU, MD, PhD

Principal Investigator

Centers for Disease Control

and Prevention

LISA JACKSON, MD, MPH

Group Health ative

STEVEN B. BLACK, MD

Northern California

Kaiser Permanente

FEIFEI WEI, PhD

HealthPartners

Research Foundation

JAMES DONAHUE, DVM, PhD

Marshfield Clinic

Research Foundation

ALLISON NALEWAY, PhD

Kaiser Permanente Northwest

19

VSD RESPONSE

A group of VSD researchers are currently conducting a case-control study to

investigate the possible association between use of the intranasal influenza

vaccine and Bell's palsy. As part of the study, researchers will identify people

with Bell's palsy who are members of HMOs participating in the VSD project. At

each participating site, medical records of persons with Bell's palsy will be

reviewed to assess exposure to influenza vaccine, hepatitis B vaccine, Td

vaccine, and other vaccines. Data will be analyzed to calculate relative risk of

Bell's palsy following vaccination and the incidence of Bell's palsy will be

assessed in vaccinated and unvaccinated populations.

The specific objectives of this VSD priority study are to:

? Investigate whether or not receipt of influenza vaccine increases the risk for

Bell's palsy;

? Assess the extent to which receipt of other vaccines are risk factors for

Bell's palsy.

The results from this VSD priority study will contribute to the ongoing

investigation of the association between influenza vaccine and Bell's palsy. The

study will also contribute to our understanding of the interaction between

autoimmune disorders and vaccines. " This study will investigate any association

between influenza vaccine and Bell's palsy to ensure the safety of the general

public. "

, MD, MPH, Group Health ative

20

Safety of the Trivalent Inactivated Influenza Vaccine Among

Children Ages 6-23 Months: A Population-Based Study,

1993-2003

ISSUE

During the influenza season of 2002/2003, CDC encouraged the vaccination of

healthy children aged 6 to 23 months for the first time ever. The decision to

encourage vaccination of children against influenza was largely based on the

increased risk for hospitalization due to influenza that was seen among children

in this age group. The decision was also based on new evidence that universal

vaccination of school children may prevent influenza in the population of adults

over 65 years of age through " herd immunity. " In October 2003, the Advisory

Committee on Immunization Practices (ACIP) voted to formally recommend

vaccination against influenza for all healthy children ages 6-23 months. In

deciding on this recommendation, national policy groups based their decision

partly on existing data on the safety of the Trivalent Influenza Vaccine (TIV)

in young children. However, they have also requested ongoing surveillance for

possible rare adverse events due to this vaccine.

VSD RESPONSE

VSD researchers are currently working on a study that will provide the data

needed to accurately assess the safety of the Trivalent Influenza Vaccine (TIV).

Researchers will study a large cohort of young children who received the

Trivalent Influenza Vaccine (TIV) over a period of 10 years (1993 - 2003) for

evidence of any increased risk of adverse events requiring medical attention

following vaccination. The study will include all children aged 6 to 23 months

of age who received at least one TIV vaccination between 1993 and 2003, and who

were continuously enrolled in the Vaccine Safety Datalink participating site at

least 42 days prior to and 70 days following vaccination. Approximately 25,000

children are expected to be included in the study. All inpatient, outpatient,

and emergency department visits will be used to identify patterns of medically

attended events (MAEs) occurring within three " risk windows " following influenza

vaccination (i.e., 0-2 days, 1-14 days, 15-42 days).

Influenza

VSD Priority Study

Research Team:

SIMON HAMBIDGE, MD, PhD

Principal Investigator

Kaiser Permanente Colorado

JASON GLANZ, MS

Kaiser Permanente Colorado

STAN XU, PhD

Kaiser Permanente Colorado

ERIC FRANCE, MD, MSPH

Kaiser Permanente Colorado

LISA JACKSON, MD, MPH

Group Health ative

STEVEN B. BLACK, MD

Northern California

Kaiser Permanente

JOHN MULLOOLY, PhD

Kaiser Permanente Northwest

TRACY LIEU, MD, MPH

Harvard Pilgrim Health Care

MIKE GOODMAN, PhD

Health Partners

Research Foundation

KEN ZANGWILL, MD

UCLA Center for Vaccine Research /

Southern California Kaiser Permanente

Health Care Plan

JAMES DONAHUE, DVM, PhD

Marshfield Clinic

Research Foundation

DAVID SHAY, MD, MPH

Centers for Disease Control

and Prevention

21

The specific objectives of this VSD priority study are to:

? Investigate whether or not receipt of the Trivalent Influenza Vaccine (TIV) in

young children increases the risk for medically attended events (MAEs) in the

postvaccination period;

? Classify MAEs following TIV as either immediate (day 0 to 2), acute (day 1 to

14), or delayed (day 15 to 42);

? Assess the risk of MAEs after the second seasonal influenza vaccination, and

in the subset of children who are at high risk for complications from influenza

infection.

The preliminary results from this VSD priority study will be presented to the

ACIP in February and June of 2004. Final study results are likely to have a

strong influence on future vaccine policies and ACIP recommendations.

" The influenza vaccine will prevent an enormous amount of illness and suffering

in infants and young children. All studies to date show the vaccine to be safe

and effective in this population. Our study aims to further examine the safety

of the influenza vaccine in very young children by looking for rare events that

might occur after vaccination. "

Simon J. Hambidge, MD, PhD, Co-Investigator, Kaiser Permanente Colorado

Measles-Mumps-Rubella: An Overview

MEASLES

Measles is a very contagious disease caused by a virus that usually begins with

a cough, runny nose, fever, and " pink eye. " A rash then appears on the face,

spreads to the rest of the body, and lasts for about five days. Many children

develop severe dehydration from the infection. About five percent of children

infected with the measles virus develop pneumonia. In older children, measles

can cause encephalitis, which can lead to brain damage. Although only about one

out of every thousand children infected with measles develops encephalitis,

permanent brain damage will occur in about 25 percent of those children.

The measles vaccine was first administered in the United States in 1963 and

hundreds of millions of doses have been administered since that time. Due to the

measles vaccine, measles infections are now uncommon in the United States. Yet,

in the late 1980's and early 1990's, an outbreak of measles swept across the

United States. More than 11,000 children were hospitalized and 120 died from

measles during that outbreak. The outbreak of the 1980's and 1990's served as a

reminder of the devastating effect that measles can have on children and

communities.

MUMPS

Mumps is a virus that typically infects children and causes a painful swelling

of the salivary or parotid glands (located just below the ears). Mumps can also

infect the brain (encephalitis) and lining of the brain (meningitis). In

addition, mumps can infect an unborn child during the first trimester of

pregnancy and cause fetal death. Before the mumps vaccine, the mumps virus was

the most common cause of viral meningitis and deafness. Since the mumps vaccine,

only about 500 cases of mumps virus are reported in the United States each year

(down from 200,000 cases prior to the vaccine). The mumps vaccine is not known

to cause any serious reactions and is therefore considered a very safe

vaccine.

RUBELLA

Rubella, like measles and mumps, is a virus that typically infects children.

Rubella, also known as German

measles, begins with fever, swollen glands, and a light rash on the face.

Although usually harmless, the rubella virus

occasionally causes encephalitis and can cause a decrease in platelets. The

rubella virus is most harmful in pregnant women.

Up to 85% of infants whose mothers are infected with rubella in the first

trimester of pregnancy will have blindness, deafness,

heart defects, or mental retardation.

Between 1964 and 1965 there were about 12 million cases of rubella in the United

States, resulting in birth defects in about 20,000

children. Since the rubella vaccine has been available in the United States, the

number of birth defects due to rubella has decreased

to about five per year. There are no known serious side effects from the rubella

vaccine.

Measles-Mumps-Rubella

22

23

Idiopathic Thrombocytopenia Purpura (ITP) and MMR

Vaccination: Is there an Increased Risk of ITP Following

MMR Vaccination?

ISSUE

Idiopathic thrombocytopenia purpura (ITP) is an acquired disease that is caused

by the destruction or impaired production of platelets. In children who are

otherwise healthy, the acute onset of thrombocytopenia is commonly characterized

as ITP. Over the last several years, there has been growing concern that the

live virus measles-mumps-rubella (MMR) vaccination is associated with an

increased incidence of idiopathic thrombocytopenia purpura

(ITP). Two studies published in 2001 and in 2003 demonstrated a significant risk

of ITP following the receipt of MMR vaccination. These studies, however, were

based on only 28 and 23 cases, respectively.

VSD RESPONSE

To better quantify the relationship between MMR vaccination and ITP, VSD

researchers are currently investigating the association in a large cohort of

children. Researchers will use inpatient, outpatient and laboratory data to

identify children with a diagnosis of ITP during a specified period of time.

Medical charts will then be reviewed to verify cases of ITP and collect

information on vaccination history. Analyses will be performed to assess the

risk of ITP following MMR vaccination.

The specific objectives of this VSD priority study are to:

? Evaluate the risk of ITP following recent MMR vaccination in children between

the ages of 1 to 2, 4 to 6, and 11 to 13 years of age;

? Identify periods of greatest risk for ITP within a six-week window after MMR

vaccination;

? Explore the level of increased risk of ITP following the second dose of MMR;

? Assess the risk of recurrence of ITP following MMR vaccination.

The results of this VSD priority study will provide the most accurate assessment

of the association between MMR vaccination and ITP. Thus, the study will have a

significant impact on MMR vaccine recommendations, policies, and clinical

practice.

" We believe this study will prove to be the most definitive investigation to

examine the relationship between MMR vaccination and the onset of ITP to date " .

K. France, MD, MSPH, Principal Investigator, Kaiser Permanente Colorado

VSD Priority Study

Research Team:

ERIC FRANCE, MD, MSPH

Principal Investigator

Kaiser Permanente Colorado

JASON GLANZ, MS

Kaiser Permanente Colorado

SIMON HAMBIDGE, MD, PhD

Kaiser Permanente Colorado

KRISTI YAMASAKI, PharmD

Kaiser Permanente Colorado

MARSHA RAEBEL, PharmD

Kaiser Permanente Colorado

LISA JACKSON, MD, MPH

Group Health ative

STEVEN B. BLACK, MD

Northern California Kaiser Permanente

JOHN MULLOOLY, PhD

Kaiser Permanente Northwest

KEN ZANGWILL, MD

UCLA Center for Vaccine Research /

Southern California Kaiser Permanente

Health Care Plan

S. MICHAEL MARCY, MD

Southern California Kaiser Permanente

TRACY LIEU, MD, MPH

Harvard Pilgrim Health Care

JAMES DONAHUE, DVM, PhD

Marshfield Clinic Research Foundation

MIKE GOODMAN, PhD

HealthPartners Research Foundation

DAVID SHAY, MD, MPH

Centers for Disease Control

and Prevention

24

Vaccine Non-Specific Studies

Four of the VSD priority studies are non-vaccine specific in that the research

questions pertain to multiple vaccines or the overall process of evaluating

vaccine safety. Two of these studies are designed to assess the effect of

thimerosal on child health and development.

Thimerosal, a mercury-containing preservative, has been the focus of intense

scrutiny by the U.S. Congress and the news media following its removal from all

routinely recommended childhood vaccines in 2001. Prior to that time, thimerosal

was added to multidose vials of vaccines such as diphtheria-tetanus-acellular

pertussis (DtaP), hepatitis B, and Haemophilus influenzae type B (Hib) to

prevent bacterial or fungal contamination. There continues to be concern that

thimerosal contained in vaccines administered prior to 2001 might have harmed

children.

The remaining two vaccine non-specific priority studies are aimed at improving

the overall process associated with evaluating vaccine safety. One is a

feasibility study to assess the extent to which VSD data can be used to provide

real-time data and evidence to the CDC and other organizations (e.g., the FDA)

about the presence and rate of adverse events following vaccination. The other

study is concerned with evaluating sex-based differences in reporting of adverse

effects associated with administration of vaccines.

Infant Environmental Exposures and Neurodevelopmental

Outcomes: A Thimerosal Follow-up Study

ISSUE

In 2001, the Immunization Safety Review Committee of the Institute of Medicine

(IOM) concluded that although a relationship between thimerosal-containing

vaccines and neurodevelopmental disorders was biologically plausible, the

evidence was insufficient to either accept or reject a causal relationship. The

IOM report recommended follow-up studies of children who had participated in

randomized trials of acellular pertussis trials to further investigate the

possible relationship between the amount of thimerosal received in different

trial study arms and subsequent neurodevelopmental disorders.

Vaccine Non-Specific Studies

VSD Priority Study

Research Team:

IMMUNIZATION SAFETY BRANCH

CENTERS FOR DISEASE CONTROL

AND PREVENTION

JOHN DUNN, MD, MPH

Group Health ative

LISA JACKSON, MD, MPH

Group Health ative

STEVEN B. BLACK, MD

Northern California

Kaiser Permanente

S. MICHAEL MARCY, MD

Southern California

Kaiser Permanente

TRACY LIEU, MD, MPH

Harvard Pilgrim Health Care

ABT ASSOCIATES, INC.

25

VSD RESPONSE

VSD researchers are currently collaborating on a retrospective cohort study that

will provide additional data needed to assess the relationship between

thimerosal and neurodevelopmental disorders. As part of this VSD priority study,

researchers will administer a neuropsychological test to a cohort of children

aged 7 to 10 years whose vaccinations in the first year of life could have

contained thimerosal. Outcomes will include speech and language skills, fine

motor coordination, motor tics, academic and intellectual functioning, and ADHD

symptomology.

Results will be stratified by level of thimerosal exposure.

The specific objectives of this VSD priority study are to:

? Investigate the possible relationship between the amount of thimerosal

received in different trial study arms and subsequent neurodevelopmental

disorders;

? Compare the neuropsychological performance of children exposed to different

quantities of thimerosal from vaccines administered during the first year of

life. The results of this VSD priority study are likely to have important policy

implications.

26

Thimerosal and Autism: A Case Control Study

to Investigate the Relationship Between Exposure

to Thimerosal and Onset of Autism

ISSUE

Over the past decade, autism prevalence rates have been rising. Although there

is no evidence that any vaccine or vaccine additive increases the risk of

developing autism, there has been considerable concern among parents and others

regarding vaccines and autism. In 2001, the Institute of Medicine (IOM)

established an independent expert committee to review the possible link between

the MMR vaccine and autism. The committee concluded that the vast

majority of cases of autism cannot be caused by MMR vaccine and therefore MMR

vaccine cannot be used to explain the increasing trend in autism diagnoses.

VSD RESPONSE

Due to public concerns, VSD researchers have begun a case-control study to

rigorously examine the association between thimerosal and autism. As part of the

study, researchers will use automated data and registries to identify children

with autism (cases) and without autism (controls). In-person examinations,

telephone interviews, medical chart reviews, and immunization tracking systems

will be used to collect information on vaccine history and other possible

covariates.

The specific objectives of this VSD priority study are to:

? Determine whether exposure to thimerosal in infancy or in-utero is related to

development of autism;

? Evaluate whether exposure to thimerosal in infancy is related to development

of the subclass of autism predominantly associated with regression.

This IOM-recommended VSD study will be the first rigorous, epidemiological study

conducted on the issue of thimerosal and autism. Data from this VSD priority

study should provide the best available scientific information on whether or not

there is a possible causal association between exposure to thimerosal and

development of autism.

Vaccine Non-Specific Studies

" The hypothesis that thimerosal exposure may be related to the development of

autism has created considerable concern among parents, particularly the parents

of autistic children. The VSD study of thimerosal and autism will provide

critically needed objective scientific information to address these concerns and

guide public policy. "

Croen, PhD, Northern California Kaiser Permanente

VSD Priority Study

Research Team:

IMMUNIZATION SAFETY BRANCH

CENTERS FOR DISEASE CONTROL

AND PREVENTION

LISA CROEN, PhD

Northern California

Kaiser Permanente

S. MICHAEL MARCY, MD

Southern California

Kaiser Permanente

TRACY LIEU, MD, MPH

Harvard Pilgrim Health Care

ABT ASSOCIATES, INC.

27

Sex-Based Differences in Reporting of

Potential Vaccine-Associated Adverse Events

ISSUE

Sex-based differences are well documented in many biologic systems, including

immunology. In 2001, the Institute of Medicine (IOM) recommended that research

analyses, including those concerned with vaccine safety, consider potential

differences between men and women. Some of this interest was generated by

anthrax vaccine trials in which females experienced a greater incidence of

adverse events following vaccination. Sex-based differences in vaccine-related

adverse events have also been noted in studies of measles, acellular pertussis,

DTaP, and influenza vaccines. In these studies, women usually experience greater

reactogenicity than men. Much of these data, however, are either uncontrolled,

include small sample sizes, and/or do not evaluatea large spectrum of possible

adverse outcomes. In addition, most large phase II and III studies do not report

adverse events by sex. The VSD project provides a useful infrastructure to

evaluate sex-specific vaccine safety in all age groups, using population-based

data.

VSD RESPONSE

In response to the IOM recommendation, VSD researchers have been collaborating

on a study to examine potential inequality in the sex distribution of local

and/or systemic adverse events following vaccination. In this VSD priority

study, researchers are using inpatient and outpatient data from health plans to

conduct sex-specific analyses as follows: 1) for all routineand individual

vaccines, by age and time interval post-vaccination; and 2) evaluation

withadjustment for outcomes that are known to have a predilection for one or the

other sex. Preliminary results from this large study indicate that there may be

sex-based differences in the incidence of adverse events related to vaccination.

In general, females appear to be at higher risk than men and are more likely to

be identified with one of several systemic conditions after vaccination

including syncope, hematologic abnormalities, asthma and autoimmune conditions.

Further work to clarify incidence rates, adjustment for various confounders

includingage and HMO, timing of the event after vaccination, and certainty of

diagnosis is ongoing. This priority VSD study will provide insight into the

extent to which there are sex-baseddifferences in the reporting of

vaccine-related adverse events. We hope these data will assist the IOM in

raising awareness in the scientific community of the potential for sex-based

differences in adverse events following vaccination. This topic is not currently

emphasized in preclinical and post-licensure trials of new vaccines.

VSD Priority Study

Research Team:

KEN ZANGWILL, MD

Principal Investigator

UCLA Center for Vaccine Research /

Southern California

Kaiser Permanente Health Plan

MARTIN LEE, PHD

Biostatistician

UCLA Center for Vaccine Research /

Southern California

Kaiser Permanente Health Plan

S. MICHAEL MARCY, MD

Co-Investigator

UCLA Center for Vaccine Research /

Southern California

Kaiser Permanente Health Plan

JOEL WARD, MD

Co-Investigator

UCLA Center for Vaccine Research /

Southern California

Kaiser Permanente Health Plan

" A fuller understanding of potential differences between men and women regarding

adverse responses to vaccination should

lead to greater reporting and investigation of this issue in large pre and

post-licensure trials of new vaccines. "

Ken Zangwill, MD, Principal Investigator, UCLA Center for Vaccine Research /

Southern California Kaiser Permanente

28

Rapid Cycle Analysis of Vaccine Safety Data: Can VSD

Data Be Used to Simulate a Rapid Cycle Analysis?

ISSUE

Recent events in the United States highlight the importance of setting up

omputerized reporting systems to detect adverse events in real time. The primary

goal of such an adverse events reporting system would be to minimize lag time

between the onset of vaccine adverse events and the proper evaluation,

management and treatment of individuals experiencing such events. A secondary

goal of such a system would be to provide real-time data to the Centers for

Disease Control and Prevention (CDC) regarding rates of adverse events following

vaccination, along with an assessment of the severity of the events. The need

for such a system was highlighted when the newly licensed rotavirus vaccine was

found to be associated with an increased risk of intussusception following

vaccination.

VSD RESPONSE

VSD researchers have been collaborating on a study to assess the feasibility of

using VSD data to develop computerized reporting systems that can detect adverse

vaccine-related events in real time. As part of the study, researchers

restructured the existing VSD cycle datasets into a format that would simulate

how data would appear if received on a weekly basis in a rapid cycle analysis

project. By doing so, researchers were able to evaluate the feasibility of the

VSD to deal with three major challenges facing rapid cycle data analysis:

outcome definition, rapid and routine creation of analytic datasets based on

automated data, and statistical analysis of signal detection.

The specific objectives of this VSD priority study were to:

? Simulate a rapid cycle analysis framework within the VSD dataset;

? Evaluate VSD data " as if " analysis had been carried out on a weekly basis;

? Assess capability to find known or presumed signals for adverse events.

Early results from this study indicate that it is feasible to use VSD data to

conduct rapid cycle analysis of routinely collected vaccine data. The VSD data

could provide the basis for a population-based, non-biased surveillance system

for vaccine safety.

" This study demonstrates that it is feasible to develop systems for rapid and

routine assessment of new vaccine safety. Such systems can provide valuable

population based estimates of vaccine adverse event rates in a more timely

manner than is currently available. "

, MD, MPH, Principal Investigator, Northern California Kaiser

Permanente

VSD Priority Study

Research Team:

ROBERT DAVIS, MD, MPH

Principal Investigator

Northern California

Kaiser Permanente

JIM NORDIN, MD

HealthPartners

Research Foundation

MICHAEL GOODMAN, PhD

HealthPartners

Research Foundation

RICHARD PLATT, MD, MSc

Harvard Pilgrim Health Care

DAVID SHAY, MD, MPH

Centers for Disease Control

and Prevention

NED LEWIS, MPH

Northern California

Kaiser Permanente

DEBRA P. RITZWOLLER, PhD

Kaiser Permanente Colorado

MARGARETTE KOLCZAK, PhD

Centers for Disease Control

and Prevention

Vaccine Non-Specific Studies

29

VSD Sites

CENTERS FOR DISEASE CONTROL AND PREVENTION

National Immunization Program

Immunization Safety Branch

Atlanta, GA

Branch Chief: Chen, MD

Site Description

The Immunization Safety Branch (ISB) is the funding organization for the Vaccine

Safety Datalink (VSD) and the Clinical Immunization Safety Assessment (CISA)

centers. The ISB provides scientific leadership and fully collaborates in all

aspects of VSD and CISA activities. ISB scientists serve as principal or

co-investigators on several VSD and CISA research studies. The ISB has the

largest group of scientists worldwide to assess and minimize (whenever possible)

the risks associated with immunization programs in the United States (and

elsewhere upon request). Besides conducting epidemiologic activities related to

surveillance and evaluation of the safety of routine vaccinations, ISB also

develops new surveillance methodologies (e.g., data mining, syndromic

surveillance), assists policy makers in rational vaccine use, and identifies

optimal ways to communicate vaccine risks and benefits. Most recently, ISB has

begun conducting surveillance for the safety of vaccinations used to protect

against bioterrorism agents such as anthrax and smallpox.

Areas of VSD Research Activity

ISB scientists are involved in a wide array of immunization safety studies,

including high-profile issues like intussusception afterrotavirus vaccination

and risks associated with thimerosal in vaccines. Other recent studies have

included the occurrence of a newly identified oculorespiratory syndrome after

influenza vaccine, identification of risk factors for serious reactions to the

yellow fever vaccine, safety of acellular pertussis vaccines in managed care

organizations, safety and effectiveness of influenza vaccine in asthmatic

children, and whether hepatitis B vaccination is associated with multiple

sclerosis.

Possibilities for new projects include: 1) assessing trends in prevalence of

neurodevelopmental disabilities and risk factors in managed care populations; 2)

assessing opportunities for using twins in vaccine safety studies; 3)

investigating safety of new pediatric

combination vaccines; 4) assessing safety of live intranasal influenza vaccines;

5) case control studies of risk factors for smallpox vaccine adverse events; 6)

assessment of extensive limb swelling after DTaP vaccine boosters.

For Further Information Please Contact:

T. (Bob) Chen, MD

Immunization Safety Branch

National Immunization Program

Centers for Disease Control and Prevention

Phone: 404-639-8256

Email: bchen@...

30

GROUP HEALTH COOPERATIVE

Center for Health Studies

Seattle, Washington

Principal Investigator: A. , MD, MPH

Site Description

Group Health ative has been a VSD site since the project's inception in

1990 and Group Health investigators have played an active role in the design,

conduct, analysis, interpretation, and reporting of VSD research. Sources of

data for VSD studies at Group Health include administrative databases, chart

abstraction, and patient interview. Group Health has long standing

administrative

databases recording information on immunizations, diagnoses assigned to

outpatient and inpatient medical encounters, pharmacy prescriptions, and

laboratory results. These databases record data for Group Health's population of

400,000 people over periods ranging from 12 to 30 years, depending on the data

source, and provide millions of cumulative person-years of information for

research purposes. Group Health's VSD team includes epidemiologists,

biostatisticians, project managers, programmers, and research assistants. The

Group Health VSD study team is part of Group Health's Center for Health Studies,

an internationally recognized academically focused research organization that

conducts primarily government funded clinical, epidemiologic, and health

services research.

The Center includes 21 MD and PhD investigators, over 200 staff members, and

receives approximately $20 million in annual grant

funding.

Areas of Research Activity

Group Health VSD researchers have led and participated in multiple VSD studies

of vaccine safety and effectiveness. Recent VSD studies conducted at Group

Health include a multi-site descriptive study of the risk of anaphylaxis in

children and adolescentsfollowing vaccination, a multi-site case-control study

of the risk of autoimmune thyroid disease following hepatitis B vaccination,an

inception cohort study of the association between influenza vaccination and risk

of recurrent cardiovascular events in adults, a comparison of DT rates of use

and reasons for use during DTP and DTaP eras, and a cohort study of the

effectiveness of pneumococcal polysaccharide vaccine in the elderly.

For Further Information Please Contact:

, MD, MPH

GHC Center for Health Studies

1730 Minor Avenue, Suite 1600

Seattle, WA 98101

Phone: 206- 442-5216

Email: jackson.l@...

VSD Sites

31

HARVARD PILGRIM HEALTH CARE, HARVARD MEDICAL SCHOOL AND HARVARD VANGUARD

Department of Ambulatory Care and Prevention

Boston, Massachusetts

Principal Investigators: Lieu, MD, MPH, and Platt, MD, MS

Site Description

The Harvard VSD site is located in the Department of Ambulatory Care and

Prevention, a unique partnership between Harvard

Pilgrim Health Care, Harvard Medical School and Harvard Vanguard. The core study

population for the VSD Project at Harvard

is patients of Harvard Vanguard Medical Associates, a multi-specialty physician

group with 14 centers in the greater Boston area.

The site has a fully computerized medical record that has been used with the

core study population since 1969, ensuring maximally accurate vaccine

administration data and access to full-text outpatient medical records. The

VSD's association with Harvard offers special opportunities to collaborate with

colleagues in the Department of Epidemiologyat the Harvard School of Public

Health and adds to the geographic diversity to the VSD population. The Harvard

site also contributes methodologic and technologic innovation through the

expertise of its investigators in time-series analysis, health economics, and

bioterrorism surveillance methods. The site also has close ties to Children's

Hospital Boston, one of the nation's premier institutions in pediatric research

and teaching.

Areas of VSD Research Activity

Each year, the Harvard VSD Team initiates several studies that focus on a broad

range of topics related to vaccine safety. Recently completed studies include a

smallpox study that identified vaccine safety as a key factor in hospital

workers' projected decisions about acceptance or rejection of smallpox

vaccination, and an influenza study that determined the incidence of outpatient

visits associated with influenza among young children in the Harvard VSD cohort.

Ongoing VSD studies include a Pneumococcal vaccination study evaluating the

impact of the introduction of pneumococcal conjugate vaccine on immunization

up-to-date status, a study of the association between thimerosal exposure from

vaccines and neurodevelopmental outcomes in children, and an evaluation of the

impact of shifts in practice for multiple immunizations on the risk of fever.

For Further Information Please Contact:

Lieu, MD, MPH

Department of Ambulatory Care and Prevention

Harvard Pilgrim Health Care, Harvard Medical School and Harvard Vanguard

133 Brookline Ave., 6th floor

Boston, MA 02215

Phone: 617-509-9949

Email: tracy_lieu@...

32

VSD Sites

HEALTHPARTNERS RESEARCH FOUNDATION

Minneapolis, Minnesota

Principal Investigator: J. Goodman, PhD

Site Description

HealthPartners Research Foundation (HPRF) is a nonprofit research center that

conducts public domain research as an independent part of the HealthPartners

family of companies. HPRF joined the VSD project in March of 2001 and serves as

a pediatric-only site that focuses on all areas of vaccine safety in children.

HealthPartners is a mixed-model HMO with a large network of owned and contracted

clinics, medical and dental centers. The VSD population is drawn from the two

largest HealthPartners clinics serving more than 600,000 enrollees.

HealthPartners serves a diverse population of urban, suburban, and rural

residents, including low socioeconomic populations in the Minneapolis-St.

metropolitan area. HPRF has a wealth of experience using administrative

databases in vaccine-related, pharmacoepidemiology, pharmacoeconomic, and other

large link database studies. HealthPartners' computerized information services

system provides a fully integrated structure that captures inpatient and

outpatient claims and encounters, electronic physician notes, and laboratory,

pharmacy, emergency room, and urgent care data that can be accessed by the HPRF

VSD staff. HPRF investigators also have access to electronic physician notes

containing information not present in any other administrative data system.

HealthPartners implemented an Epicare electronicmedical record in the 2003 and

has had an immunization registry since 1997.

Areas of VSD Research Activity

HPRF's multi-specialty VSD team consists of bio-statisticians, pediatricians, an

economist, an epidemiologist, programmers, support staff and contracts with

well-known vaccine researchers. The HPRF VSD team initiates and participates in

several studies that focus on a wide range of vaccine safety topics. Some of our

recent studies include a study of rotavirus vaccine and intussusception, an

examination of the health consequences that result from exemption from

immunization, an assessment of the safety of Yellow Fever vaccine in children

and adults, and a feasibility study to enable real time surveillance using

automated data to rapidly detect vaccine adverse events.

For Further Information Please Contact:

J. Goodman, PhD

HealthPartners Research Foundation

8100 34th Avenue South, MS 23302G

Minneapolis, MN 55440-1524

Phone: 952-967-5039

Email: michael.j.goodman@...

33

KAISER PERMANENTE COLORADO

Clinical Research Unit

Denver, Colorado

Principal Investigator: France, MD, MSPH

Site Description

Kaiser Permanente Colorado (KPC) has been a Vaccine Safety Datalink (VSD) site

since 2000. The KPC site includes multi-disciplinary

expertise in pediatrics, biostatistics, epidemiology, pharmacoepidemiology,

prevention, and health economics. The VSD research

team is located within the Clinical Research Unit of KPC, which has a high level

of active grant support in a broad range of health

services research areas, and clinical trials research. The KPC Clinical Research

Unit is also involved with a wide range of pediatric

studies including phase 3 and 4 trials, and prospective randomized studies of

vaccine safety.

Areas of VSD Research Activity

KPC's areas of research interest include the impact of new vaccines or changing

vaccine recommendations on vaccine coverage or vaccine policy, methodology

research, and epidemiologic assessments. The KPC site first became involved with

the VSD following Dr. France's work with the group that helped to delineate the

relationship between vaccination against rotavirus and intussusception in young

children. Current research studies at the KPC site include assessing the safety

of the trivalent inactivated influenza vaccine among the pediatric

population, evaluating the possible association of idiopathic thrombocytopenic

purpura with the measles, mumps, and rubella vaccination, the possible benefit

of influenza vaccination in pregnancy on infant outcomes, and comparing four

study designs used to examine the association between vaccination and acute

adverse events. KPC is also interested in methodology research to develop

analytic methods to minimize or assess bias in observational epidemiologic

studies. Work includes comparing conditional models to longitudinal models used

in vaccine safety studies, and evaluating the validity and stability of four

types of study designs used to examine the association between vaccination and

acute adverse events. Future plans include using HLA typing from cord bloods to

look at adverse events and investigating the concept of the " healthy vaccinee

effect " .

For Further Information Please Contact:

France, MD, MSPH

Kaiser Permanente Colorado

Clinical Research Unit

2550 S. Road

Aurora, CO 80014

Phone: (303) 636-3151

Email: eric.k.france@...

34

KAISER PERMANENTE NORTHWEST

Center for Health Research

Portland, Oregon

Principal Investigator: Mullooly, PhD

Site Description

Kaiser Permanente Northwest (KPNW) has been a Vaccine Safety Datalink (VSD) site

since the research program's inception in

1990, and conducts a wide range of pediatric and adult immunization studies. The

multi-discipline VSD investigative team includes

biostatistics, epidemiology, pediatrics and internal medicine,

allergy/immunology, pharmaco-epidemiology, and health economics.

The VSD research group exists within the larger Center for Health Research that

is noted for epidemiologic and health services

research in many areas.

Areas of VSD Research Activity

Areas of research activity include risk assessment of adverse events following

vaccination, data quality assessment of automated immunization and diagnosis

databases, statistical adjustments for misclassification, vaccine coverage and

compliance, vaccine effectiveness, impacts of vaccination programs, medical care

costs of infectious diseases, cost-effectiveness of vaccination programs,

household transmission of infectious diseases, and infectious disease

transmission modeling. Current studies of adverse events following vaccination

include wheezing in premature infants following hepatitis B vaccination,

childhood asthma and atopy, and local and systemic adverse events following

pediatric flu vaccination. Kaiser Permanente Northwest also leads the VSD data

quality work group. Data quality studies include those related to assessing the

completeness and accuracy of automated vaccination and vaccination exemption

records, temperatures, fever codes, and inpatient and outpatient pneumonia

codes.

For Further Information Please Contact:

Mullooly, PhD

Kaiser Permanente Center for Health Research

3800 N. Interstate

Portland, OR 97227

Phone: 503-335-6768

Email: john.mullooly@...

VSD Sites

35

MARSHFIELD CLINIC RESEARCH FOUNDATION

Vaccine Safety Datalink Site

Marshfield, Wisconsin

Principal Investigator: Belongia, MD

Site Description

Marshfield Clinic is the largest private group medical practice in Wisconsin and

one of the largest in the United States. Although the primary service area

includes northern, central, and western Wisconsin, and the Upper Peninsula of

Michigan, patients from every county in Wisconsin, every state in the nation,

and 24 foreign countries were seen within the Clinic system last fiscal year.

The Marshfield Clinic and the Marshfield Clinic Research Foundation, the

nonprofit research division of the Marshfield Clinic, have participated in the

VSD project since March 2001. Strengths of the Marshfield Clinic for vaccine

safety research include access to a stable rural population, an electronic

medical record with a sophisticated diagnosis coding system (with mapping to ICD

codes), a real-time electronic immunization registry used by public and private

providers, and an epidemiology research group with experience in vaccine safety

research and infectious disease epidemiology. Areas of VSD Research Activity

Current studies of adverse events following vaccination that are directed by

investigators at the Marshfield Clinic include two investigations related to the

small pox vaccination program. For one study, the main objectives are to

determine the prevalence of diagnosed atopic dermatitis and eczema in a defined

population, estimate the proportion of people who would be at increased risk of

developing eczema vaccinatum if they or their household contacts were

vaccinated, and determine if adults are able to accurately recall past diagnoses

of atopic dermatitis for themselves, their children, or other members of their

households. A second smallpox study will determine the sensitivity of a

self-administered screening instrument to identify health care workers who

should not receive smallpox vaccine, using the medical record as the gold

standard. MCRF is also leading a study to determine if immune-mediated hemolytic

anemia (IMHA) in children is related to each of 3 different exposures:

diphtheria-tetanus-pertussis (DTP) vaccination, hepatitis B vaccination, and

parenteral ceftriaxone. The strength of the association between IMHA and the

various exposures will be measured.

For Further Information Please Contact:

Belongia, MD

Marshfield Clinic Research Foundation

1000 North Oak Avenue

Marshfield, WI 54449

Phone: (715) 389-5549

Email: belongia.edward@...

36

NORTHERN CALIFORNIA KAISER PERMANENTE

Kaiser Permanente Vaccine Study Center

Oakland, California

Principal Investigators: B. Black, MD and Henry Shinefield, MD

Site Description

Northern California Kaiser Permanente has been a VSD site since the program's

inception in 1990. The Kaiser Permanente Vaccine Center conducts a wide range of

pediatric and adult immunization studies, including phase 2, 3 and 4 trials,

diverse prospective randomized studies, and observational studies of vaccine

safety. The multi-disciplinary VSD investigative team has expertise in

biostatistics, epidemiology, programming, pediatrics, internal medicine,

rheumatology, health economics, and conduct of both chart review and telephone

interview studies. The VSD research groups work extensively with the Kaiser

Permanente Division of Research that is noted for both epidemiologic and health

services research. The Center has access to one of the largest and most complete

clinical automated databases in the country and a large group of clinicians, who

cooperate in providing subspecialty expertise in vaccine safety studies.

Areas of VSD Research Activity

Areas of research interest include risk assessment of adverse events following

vaccination, the use of large linked data bases to provide rapid epidemiologic

and public health assessments, studies of genetic factors which might influence

the nature and risk of vaccine adverse events, statistical adjustments for

comparing populations with differing propensities to utilize care, the impact of

new vaccines or changing vaccine recommendations on vaccine coverage,

cost-benefit analyses and economic modeling. Current studies evaluating adverse

events following vaccination include an assessment of the risk of encephalopathy

following DTP vaccines, evaluation of a possible association of alopecia with

hepatitis B vaccination, the safety and benefit of influenza vaccination in

pregnancy, and the risk of and possible genetic factors predicting arthritis

following hepatitis B vaccination.

For Further Information Please Contact:

B. Black, MD

Kaiser Permanente Vaccine Study Center

1 Kaiser Plaza, 16th floor

Oakland, CA 94612

Phone: 510-267-7534

Email: steve.black@...

VSD Sites

37

UCLA CENTER FOR VACCINE RESEARCH/

SOUTHERN CALIFORNIA KAISER PERMANENTE HEALTH CARE PLAN

Los Angeles, California

Principal Investigators: Ken Zangwill, MD and I. Ward, MD

Site Description

The southern California VSD site is based in Los Angeles at the UCLA Center for

Vaccine Research and the Southern California Kaiser Permanente (SCKP) Health

Care Plan, the largest HMO in southern California. UCLA/SCKP investigators have

been active in vaccine research for more than 35 years, and have evaluated

nearly all licensed vaccines and many experimental formulations. The VSD team at

UCLA/SCKP includes several MDs, two PhD epidemiologists, a PhD biostatistician,

a MPH project coordinator, several Master's level data management and computer

programming staff, as well as staff involved with medical record review. Ongoing

academic relationships are maintained with many collaborators nationally and

internationally. In Los Angeles, these include the UCLA Schools of Medicine and

Public Health, California State University at Dominquez Hills, and the Los

Angeles

County Department of Health Services.

Areas of VSD Research Activity

Ongoing VSD studies being led by UCLA/SCKP include evaluations of several

potential vaccine-associate adverse events including aplastic anemia, acute

flaccid paralysis (initially related to oral polio vaccine), and neonatal and

infant mortality. UCLA/SCKP is also conducting studies of hepatitis A vaccine,

the safety of vaccination in premature infants, and the impact on gender on

vaccine safety. Lastly, UCLA/SCKP is currently piloting an innovative project

that develops real time computer linkages between the Kaiser immunization

tracking system and the national Vaccine Adverse Event Reporting system.

Successful integration of these systems may serve as a model nationally. The

UCLA/SCKP site also contributes to ongoing collaborative VSD projects including

assessment of influenza vaccine safety in children, thimerosal-containing

vaccines on infant neurodevelopment, and rapid surveillance for disease

detection of bioterroristic importance.

For Further Information Please Contact:

Ken Zangwill, MD

UCLA Center for Vaccine Research

1124 W. Carson Street

Torrance CA 90502

Phone: 310-781-3636

kzangwill@...

38

VSD Publications

2001, 2002 & 2003

Barlow WE. RL. Glasser JW. PH. RS. Mullooly JP. Black SB.

Shinefield HR. Ward JI. Marcy SM. DeStefano

F. Chen RT. Immanuel V. Pearson JA. Vadheim CM. Rebolledo V. Christakis D.

Benson PJ. N. Centers for Disease Control and

Prevention Vaccine Safety Datalink Working Group. The risk of seizures after

receipt of whole-cell pertussis or measles, mumps,

and rubella vaccine. New England Journal of Medicine 2001, 345:656-61.

Chang EJ, Zangwill KM, Lee H, Ward JI. Lack of association between rotavirus

infection and intussusception: implications for use

of attenuated rotavirus vaccines. Pediatr Infect Dis J 2002; 21:97-102

Chen RT, DeStefano F, Pless R, Mootrey G, Kramarz P, Hibbs B. Challenges and

Controversies in Immunization Safety. Infectious

Disease Clinics of North America 2001; 15: 21-39.

Coplan P. Black S. Rojas C. Shinefield H. Ray P. E. Guess H. Incidence and

hospitalization rates of varicella and herpes zoster

before varicella vaccine introduction: a baseline assessment of the shifting

epidemiology of varicella disease. Pediatric Infectious

Disease Journal 2001 20(7):641-5.

RL, Kramarz P, Bohlke K, RS, Mullooly J, Black S, Shinefield H,

Ward J, Marcy M, sen E, N, DeStefano

F, Chen R. Measles-Mumps-Rubella and Other Measles-Containing Vaccines Do Not

Increase the Risk for Inflammatory Bowel

Disease. A Case-Control Study From the Vaccine Safety Datalink Project. Arch

Pediatr Adolesc Med 2001;155:354-359.

RL, Lieu TA, Mell LK et al. Impact of the Change in Polio Vaccination

Schedule on Immunization Coverage rates: A Study in

Two Large Health Maintenance Organizations. Pediatrics 2001; 107: 671-676.

DeStefano F. Mullooly JP. Okoro CA. Chen RT. Marcy SM. Ward JI. Vadheim CM.

Black SB. Shinefield HR. RL. Bohlke K.

Childhood vaccinations, vaccination timing, and risk of type 1 diabetes

mellitus. Pediatrics 2001;108:e112-3.

Destefano, F., Gu, D., Kramarz, P., et al. Childhood Vaccinations and Risk of

Asthma. PIDJ 2002;21:498-504.

DeStefano F, Verstraeten T, LA; et al. Vaccinations and Risk of Central

Nervous System Demyelinating Diseases in Adults.

Archives of Neurology 2003. 60:504-509

LA, Austin G, Chen RT, Stout R, DeStefano F, Gorse GJ, Newman FK, Yu O,

Weniger BG. Safety and immunogenicity of

varying dosages of trivalent inactivated influenza vaccine administered by

needle-free jet injectors. Vaccine 2001;19:4703-9.

LA, Yu O, Heckbert S, et al. Influenza Vaccination Is Not Associated

With A Reduction In the Risk Of Recurrent Coronary

Events. AJE 2002;156:634-640.

LA. Neuzil KM. Yu O. Benson P. Barlow et al. Vaccine Safety Datalink.

Effectiveness of pneumococcal polysaccharide

vaccine in older adults. New England Journal of Medicine. 348(18):1747-55, 2003

May 1.

Kramarz P, France EK, Destefano F, Black SB, Shinefield H, Ward JI, Chang EJ,

Chen RT, Shatin D, Hill J, Lieu T, Orgren JM.

Population-based Study of Rotavirus Vaccination and Intussusception, PIDJ

2001:20; 410-6.

39

Kramarz P, DeStefano F, Gargiullo P, Chen RT, Lieu TA, RL, Mullooly JM,

Black SB, Shinefield HR, Bohlke K, Ward JI, Marcy

SM. Does influenza vaccination prevent asthma exacerbations in children? Journal

of Pediatrics. 2001;138(3):306-10

E, Shinefield HR, Woodruff BA, Black SB, DeStefano F, Chen RT, Ensor R.

Safety of neonatal hepatitis B vaccine administration.

Pediatr Infect Dis J 2001; 20: 1049-1054.

Lieu TA, RL, Capra AM, et al. Variation in Clinician Recommendations for

Multiple Injections During Adoptions of Inactivated

Polio Vaccine. Pediatrics 2001; 107:e49.

Lieu TA, Black SB, Ray GT, KE, Messonnier ML, Shinefield HR, Weniger BG.

The hidden costs of infant vaccination. Vaccine

2001;19:33-41.

Mullooly, J, Pearson J, Drew L, et al. Wheezing lower respiratory disease and

vaccination of full-term infants. Pharmacoepidemiology

and Drug Safety 2002; 11:21-30.

[Guest guest]

To add more ....IOM:

http://www.iom.edu/Object.File/Master/7/501/0.pdf

>

> Read this 2003 brochure about the Vaccine Safety Datalink. This

annual report is sent to health insurers that supply the VSD with data

on possible vaccine injuries.

>

>

>

> On page 7, paragraph 1, a casual reader might assume that consumer

reports of adverse reaction to vaccines are not taken seriously.

>

> http://www.ahip.org/content/fileviewer.aspx?docid=307 & linkid=3146

>

>

>

> Has anyone seen the Thimerosal case-control study mentioned?

>

>

>

> - Hokkanen

>

>

> ____________________________________

>

>

>

> 1

>

> THE VACCINE SAFETY DATALINK

>

> (VSD) PROJECT

>

> Annual Report for 2003

>

> 2

>

> With questions/comments or to request additional copies of this

report, please contact:

>

> Barbara Lardy

>

> America's Health Insurance Plans . 601 Pennsylvania Avenue, NW,

Suite 500 . Washington, DC . 20004

>

> 202-778-3229 or blardy@...

>

> © America's Health Insurance Plans, 2004

>

> Vision/Mission

>

> The vision of the Vaccine Safety Datalink (VSD) project is to

provide a powerful and cost-effective resource for the ongoing

evaluation of vaccine safety. The mission of the VSD project is to

carefully monitor vaccine safety through planned vaccine safety

studies and timely investigations of hypotheses.

>

>

>

> " Sound immunization policies and recommendations affecting the

health of our nation depend upon the consistent monitoring of vaccines

and ongoing assessment of immunization benefits and risks. The Vaccine

Safety Datalink project is one of our most important tools to ensure

the safety and efficacy of vaccines. "

>

> Centers for Disease Control and Prevention

>

> 3

>

> 44

>

> 5

>

> Letter from America's Health Insurance Plans

............................................. 7

>

> Letter from Centers for Disease Control and Prevention/

>

> National Immunization Program

................................................. 9

>

> Introduction .......................................... 11

>

> VSD Priority Studies ........................................... 12

>

> Hepatitis B

>

> ? Autoimmune Thyroid Disease (ATD) Study

>

> ? Risk of Alopecia Following Hepatitis B Vaccination (Case/Control)

>

> ? Risk of Alopecia Following Hepatitis B Vaccination (Cohort)

>

> Influenza

>

> ? Influenza Vaccine and Bell's Palsy

>

> ? Pediatric Flu Study, Part II

>

> MMR

>

> ? Idiopathic Thrombocytopenia Purpura (ITP) and MMR Vaccination

>

> Vaccine Non-Specific

>

> ? Thimerosal Follow-Up Study

>

> ? Thimerosal / Autism Case-Control Study

>

> ? Rapid Cycle Analysis

>

> ? Sex-Based Analysis

>

> VSD Sites ............................................ 29

>

> Publications from 2001, 2002, 2003

........................................ 38

>

> Table of Contents

>

> 66

>

> 7

>

> Vaccines are important allies in the effort to prevent illness and

control the spread of many diseases. Yet, each year there are reports

that highlight possible side effects or other adverse events related

to vaccines. Such reports can lead to unwarranted public concern about

the risks of vaccines and lead to potential avoidance of vaccinations.

Such public actions can have a deleterious effect on the health of the

nation. It is critical to the health of our nation to have a

scientific system for collecting vaccine safety information from a

large population. The Vaccine Safety Datalink (VSD) project, with the

ultimate goal of protecting the public's health through the ongoing

monitoring of vaccine safety, provides just such a system.

>

> America's Health Insurance Plans (AHIP), providing health benefits

to over 200 million Americans, is proud to be a part of the CDC's VSD

project. For more than 20 years-predating the VSD project-researchers

in health plans have been involved in vaccine safety and efficacy

studies. Since the inception of the VSD project, researchers

affiliated with eight health plans have worked collaboratively with

CDC researchers to continue studying vaccine safety. Health plans and

insurers have long championed the use of preventive services,

especially vaccines, to improve health and prevent disease. AHIP

member plans consider vaccination to be an essential component for

ensuring a healthy nation and have been innovators in the design of

immunization programs to increase rates and timeliness of immunization

among infants, children, adolescents and adults. This annual report

highlights the continuing contributions being made to vaccine safety

by health plans serving as VSD participating sites.

>

> M. Ignagni

>

> President and CEO, America's Health Insurance Plans (AHIP)

>

> 7

>

> 88

>

> 9

>

> Vaccines are among the most successful and cost-effective public

health tools for preventing disease and death in the modern era. The

National Immunization Program (NIP) is devoted to undertaking and

promoting a wide range of scientific activities to support

immunization and prevent disease worldwide. However, no vaccine is

100% safe. When the majority of the population has been vaccinated and

the disease risk becomes rare, both real and perceived vaccine side

effects increase, which result in heightened public concern about the

safety of vaccines. A loss of public confidence in vaccines could

result in decreased vaccination levels, followed by epidemics of

disease. A timely, credible and effective immunization safety

monitoring system to determine which illnesses are caused by vaccines,

and which are not, must exist to maintain public confidence in

immunizations and prevent the return of disease epidemics. Within

NIP's Immunization Safety Branch (ISB), we are engaged in many

programs and activities to monitor the safety of vaccines. The Vaccine

Adverse Event Reporting System (VAERS), in collaboration with the Food

and Drug Administration, serves as an early warning system to detect

problems that may be related to vaccines. The Clinical Immunization

Safety Assessment (CISA) Network provides in-depth, standardized

clinical evaluations for individuals with unusual or severe vaccine

adverse events that might be reported to VAERS. The Brighton

Collaboration is a global collaboration which was established to

standardize case definitions for study of vaccines, thereby creating a

common " vocabulary " for vaccine safety research. Further vaccine

safety research for causal relationships is conducted within ISB

through the Vaccine Safety Datalink (VSD) Project, a large-linked

database containing comprehensive medical and immunization histories

of over 7.5 million people. The VSD enables population-based vaccine

safety research studies to compare the incidence of health problems

between vaccinated and unvaccinated people. In addition, the VSD

established a data sharing process to allow external researchers

access to datasets created through the VSD. Research conducted by the

Vaccine Acceptance Risk Perceptions (VARP) group determines how best

to disseminate information on the benefits and risks of vaccinations,

and the Vaccine Development (VAXDEV) activity works to develop safer

vaccines and delivery methods, especially needle-free jet injectors

for mass immunization campaigns. I am proud of the accomplishments we

have made to monitor the safety of vaccines as documented in this

report, conducted by CDC and in collaboration with the various

external partners like America's Health Insurance Plans (AHIP).

>

> I hope you will join me in supporting the research projects

conducted through our vaccine safety programs and activities.

>

> I thank you for your contributions and your support in the past

year, and welcome the opportunity to continue our collaboration in the

coming year.

>

> Sincerely,

>

> L. Cochi, MD, MPH

>

> Captain, United States Public Health Service

>

> Acting Director, National Immunization Program

>

> 9

>

> 10

>

> VSD Staff

>

> America's Health Insurance Plans (AHIP) Staff:

>

> Barbara Lardy, MPH, Vice President, Medical Affairs, Project Director

>

> Carmella Bocchino, RN, MBA, Sr. Vice President, Medical Affairs,

Management Liaison

>

> Fahey, MA. Deputy Director, VSD/CISA

>

> Daphnis, MPH, Program Manager, VSD

>

> Viggiano, Operations Manager, VSD/CISA

>

> Sharron , Research Associate/Contract Administrator, VSD/CISA

>

> Rick Ramsay, Sr. Associate Counsel & Compliance Officer

>

> Centers for Disease Control and Prevention,

>

> National Immunization Program, Immunization Safety Branch Staff:

>

> Chen, MD, MA , Chief

>

> Broom , Deputy Chief

>

> DeStefano, MD, MPH , Medical Epidemiologist

>

> Shay, MD, MPH, Medical Epidemiologist

>

> Margarette Kolczak, PhD, Epidemiologist

>

> , PhD, Epidemiologist

>

> Baggs, PhD, Epidemiologist

>

> nne Gee, MPH, Epidemiologist

>

> Jufu Chen, PhD, Epidemiologist

>

> Weintraub, MPH, Epidemiologist

>

> Charissa Densen, Program Analyst

>

> 11

>

> Introduction

>

> Source: Offit, and Bell, Louis, Vaccines: What You Should Know

>

> (Third Edition); (page 3); Wiley & Sons, Inc. 2003.

>

> Immunization is one of the greatest public health success stories of

all time. Every year, many serious childhood diseases are prevented by

using vaccines routinely recommended for newborns, infants and

children. Since the introduction of these vaccines, reported cases of

vaccinepreventable childhood diseases have decreased dramatically in

the United States and millions of lives have been saved. As a result,

most Americans today have only vague memories of diseases such as

polio, rubella, measles, diphtheria, meningitis and pertussis. Without

vaccines, the diseases we are now protected from could return to cause

serious illness or even death in many infants and children.

>

> Before Vaccines, Parents in the United States Could Expect that

Every Year:

>

> ? Polio would paralyze about 15,000 children.

>

> ? Rubella ( " German measles " ) would cause birth defects

>

> and mental retardation in as many as 20,000 newborns;

>

> ? Measles would infect about 4 million children, killing

>

> 3,000.

>

> ? Diphtheria would be one of the most common causes of death in

school-aged children.

>

> ? A bacterium called Hib would cause meningitis in 15,000 children,

leaving many with permanent brain damage.

>

> ? Pertussis ( " whooping cough " ) would kill 8,000 children.

>

> Although vaccines are widely considered to be important and safe

allies in the effort to prevent many serious diseases, vaccines are

not completely without risk of side effects or other adverse outcomes.

At several points in time during the past decade, the public has

expressed concern about possible side effects of vaccines and

questioned the safety of specific Source: Adapted from The Children's

Hospital of Philadelphia's Vaccine Education Center at

www.chop.edu/consumers/jsp/division/generic.jsp?id=75730

>

> vaccines. Most recently, there has been public concern over the use

of thimerosal (a mercury-containing preservative) in vaccines, reports

of severe side effects associated with the smallpox vaccine, and

studies suggesting a link between the measles-mumps-rubella (MMR)

vaccine and autism. In most instances, concerns about the risks of

specific vaccines can be addressed and reduced by providing

empirically-based information that allows the public to see that the

benefits of a specific vaccine outweigh its risks. However, such

information is dependent on a systematic approach for continually

monitoring and assessing the safety of specific vaccines in a variety

of populations.

>

> Do the Benefits Outweigh the Risks? The Case of Hepatitis B Vaccine

>

> Each year in the United States about 5,000 people die soon after

contracting hepatitis B virus. In addition, every year about 10,000

people become chronically infected with hepatitis B virus, putting

them at high risk for developing cirrhosis and liver cancer. In fact,

with the exception of influenza virus, hepatitis B virus causes more

severe disease and death in the United States than any other

vaccinepreventable disease.

>

> On the other hand, severe side effects associated with hepatitis B

vaccine are extremely rare. One of every 600,000 doses of the

hepatitis B vaccine will cause a severe allergic reaction called

anaphylaxis. Anaphylaxis usually occurs within 15 minutes of receiving

the vaccine and is treatable. To date, no one has died from this

reaction. Because hepatitis B virus is a common cause of severe

disease and death in the United States, and the hepatitis B vaccine

does not cause permanent damage or death, the benefits of the

hepatitis B vaccine clearly outweigh its risks.

>

> 12

>

> The Vaccine Safety Datalink (VSD) Project

>

> The Vaccine Safety Datalink (VSD) was established in 1990 as a

crucial part of the federal government's systematic effort to monitor

the safety of vaccines commonly used in the United States and to

reassure public confidence in vaccines. Through the VSD project,

researchers from the private and public sectors work together on

studies designed to monitor the safety of vaccines administered to

infants, children, adolescents and adults. Based at one of eight

participating sites or the Centers for Disease Control and Prevention

(CDC), the VSD researchers conduct studies that provide vital

information about the short and long-term effects of specific vaccines

on various populations. Collectively, the data from the VSD studies

are based on active surveillance of approximately seven million people

(2.5% of the total U.S. population).

>

> Although all VSD studies are designed to answer critical questions

about vaccine safety, each year a select number of studies is given a

special " priority " designation that indicates their vital importance

to the nation's health. VSD priority studies focus on vaccine safety,

are generally based on data collected from multiple sites, and are

allocated highest priority in the event that time or financial

resources become limited. In this report, we highlight ten priority

studies. The CDC's National Immunization Program (NIP) is charged with

the responsibility of providing leadership, expertise and ongoing

education about the development and delivery of an effective

immunization delivery program for the United States. As part of its

mission, NIP's Immunization Safety Branch supports epidemiologic

research to evaluate the safety, immunogenicity and efficacy of

vaccines recommended for routine human use after licensure by the U.S.

Food and Drug Administration (FDA). NIP provides leadership for the

planning, coordination and conduct of immunization activities across

the nation. Such activities include the provision of consultation,

training, statistical, promotional, educational and technical services

to assist health departments and other entities to implement effective

immunization programs.

>

> The CDC/NIP Immunization

>

> Safety Branch

>

> The Immunization Safety Branch of the CDC's National Immunization

Program is charged with enhancing the nation's capacity to monitor and

evaluate vaccine safety.

>

> Projects underway within the CDC/NIP Immunization Safety

>

> Branch include:

>

> ? Vaccine Safety Datalink (VSD) Project. To collaborate with

researchers in the private sector for the purpose of conducting

studies that monitor the safety of vaccines commonly used in the

United States.

>

> ? Clinical Immunization Safety Assessment (CISA) Network.

>

> To improve scientific understanding of vaccine safety issues at the

patient level and develop protocols to assist healthcare providers to

better manage situations in which adverse vaccine events occur.

>

> ? Vaccine Adverse Event Reporting System (VAERS). To monitor reports

of post-vaccination adverse events from health professionals, vaccine

manufacturers, and the general public for the purpose of identifying

new or rare vaccine side effects, increases in the occurrence of known

side effects, and patient risk factors for specific adverse events.

>

> ? Brighton Collaboration. The Brighton Collaboration is an

international voluntary collaboration to facilitate the development,

evaluation, and dissemination of high quality information about the

safety of human vaccines and to develop globally accepted and

implemented standardized case definitions of Adverse Events Following

Immunization (AEFIs).

>

> ? The Vaccine Acceptance Research Program (VARP). The Vaccine

Acceptance Research Program was conceived to better understand the way

in which individuals interpret risks and make decisions about

vaccination. The primary goal of this program is to develop and

evaluate interventions that help individuals make informed decisions

about vaccinations and help people understand the potential increased

risk of disease if a significant number of people refuse to be

vaccinated because of the current low disease prevalence.

>

> ? The Vaccine Development (VAXDEV). Unit promotes safer vaccine

administration methods such as needle-free injection technology,

through contract R & D for high-speed jet injectors, clinical studies,

and an information database, website, and news service. VAXDEV also

monitors new vaccines and technologies in development, and promotes

guidelines for improved vaccine labeling and packaging to minimize

medical errors, improve recordkeeping, and enhance surveillance of

vaccination adverse events.

>

> Participating VSD Sites

>

> ? Centers for Disease Control and Prevention

>

> National Immunization Program

>

> Immunization Safety Branch

>

> Atlanta, Georgia

>

> ? Group Health ative

>

> Center for Health Studies

>

> Seattle, Washington

>

> ? Harvard Pilgrim Health Care, Harvard

>

> Medical School and Harvard Vanguard

>

> Department of Ambulatory Care

>

> and Prevention

>

> Boston, Massachusetts

>

> ? HealthPartners Research Foundation

>

> Minneapolis, Minnesota

>

> ? Kaiser Permanente Colorado

>

> Clinical Research Unit

>

> Denver, Colorado

>

> ? Kaiser Permanente Northwest

>

> Center for Health Research

>

> Portland, Oregon

>

> ? Marshfield Clinic Research Foundation

>

> Marshfield, Wisconsin

>

> ? Northern California Kaiser Permanente

>

> Kaiser Permanente Vaccine Study Center

>

> Oakland, California

>

> ? UCLA Center for Vaccine Research /

>

> Southern California Kaiser Permanente

>

> Health Care Plan

>

> Los Angeles, California

>

> 13

>

> America's Health Insurance Plan (AHIP) (formerly known as the

>

> American Association of Health Plans) was selected by CDC to provide

>

> overall management and coordination for the VSD project. As part of

>

> its role in the VSD project, AHIP's responsibilities include:

>

> ? Maintain the strategic direction of the VSD projects;

>

> ? Monitor and review the quality of work associated with VSD

>

> projects and studies;

>

> ? Verify that all fiduciary responsibilities and budget

specifications are

>

> met; and

>

> ? Assure timely completion of all work and efforts associated with

>

> the scope of the VSD project.

>

> Hepatitis B: An Overview

>

> Hepatitis B is a virus that infects the liver. Each year in the

United States,

>

> approximately 300,000 people become infected with hepatitis B. Among

people

>

> who contract hepatitis B, about 5,000 die soon after they are

infected and another 10,000 develop long-term hepatitis that puts them

at risk for cirrhosis and cancer of the liver. A vaccine for hepatitis

B was first licensed for use in the United States in 1982. Since that

time, millions of adults, infants, and children have received the

hepatitis B vaccine. Side effects are rare. About three percent of

children develop pain and tenderness where the shot was given and one

percent develop low-grade fevers. An extremely rare side effect of

hepatitis B vaccine is anaphylaxis, which is treatable and estimated

to occur only once in every 600,000 doses.

>

>

>

> Vaccination and Risk of Autoimmune Thyroid Disorder: Is Hepatitis B

Vaccine Associated with Graves' Disease or Hashimoto's Thyroiditis?

>

> ISSUE

>

> Recent concerns have been raised about a possible association

between hepatitis B vaccine

>

> and occurrences of autoimmune thyroid diseases (ATD), such as

Graves' disease and Hashimoto's thyroiditis. The concerns are based in

part on case reports. Information from such reports is insufficient to

infer a causal link between hepatitis B vaccine and ATD because

reported cases may simply represent coincidental timing between

vaccination and the onset of ATD. Thus far, only a single case-control

study, published as an abstract in Pharmacoepidemiology and Drug

Safety, has addressed this question. Given the sparse data currently

available, and the potential implications of public concern regarding

these early reports of a possible association between hepatitis B

vaccine and ATD, confirmatory studies are needed.

>

> Hepatitis B

>

> 14

>

> VSD RESPONSE

>

> A group of VSD researchers has begun a collaborative study to

evaluate the association between receipt of hepatitis B vaccine and

risk of ATD, specifically Graves' disease orHashimoto's thyroiditis.

As part of the study, researchers will simultaneously conduct two

case-control studies among the adult populations of three HMOs

participating in the VSD project (Group Health ative, Kaiser

Permanente Northwest, and Northern California Kaiser Permanente). At

each participating site, automated data sources will be used to

identify persons with Graves' disease or Hashimoto's thyroiditis

(cases) and persons with no history of thyroid disease (controls).

Data will be confirmed by chart review, and persons identified as

eligible cases and controls will be contacted by telephone to obtain

additional information about vaccinations, identify relevant

covariates (i.e., family and personal history of select autoimmune

conditions), and estimate date of symptom onset among persons with ATD.

>

> The specific objectives of this VSD priority study are to:

>

> ? Evaluate the association between having ever received a hepatitis

B vaccine and risk of Graves' disease or Hashimoto's thyroiditis;

>

> ? Assess the association between receipt of hepatitis B vaccine

within intervals of

>

> <1 year, 1-5 years, and >5 years of the index date and risk of

Graves' disease or Hashimoto's thyroiditis;

>

> ? Evaluate the association between other adult vaccines and the risk

of Graves' disease or Hashimoto's thyroiditis;

>

> ? Assess the association between receipt of other adult vaccines

within intervals of

>

> <1 year, 1-5 years, and >5 years of the index date and risk of

Graves' disease or

>

> Hashimoto's thyroiditis.

>

> The results from this VSD priority study will provide the data

necessary to determine whether receipt of hepatitis B vaccine is

associated with an increased risk of autoimmune thyroid disease. The

study will also fill a gap in the study of autoimmune disorders

currently ongoing or recently completed through the VSD project.

>

> " By collecting complete information about hepatitis B vaccination

history from a well-defined study population, this study will confirm

or refute concerns raised by case reports. "

>

> Kari Bohlke, ScD, Principal Investigator, Group Health ative

>

> VSD Priority Study

>

> Research Team:

>

> KARI BOHLKE, ScD

>

> Principal Investigator

>

> Group Health ative

>

> LISA JACKSON, MD, MPH

>

> Group Health ative

>

> WILLIAM THOMPSON, PhD

>

> Centers for Disease Control

>

> and Prevention

>

> DAVID SHAY, MD, MPH

>

> Centers for Disease Control

>

> and Prevention

>

> JOHN MULLOOLY, PhD

>

> Kaiser Permanente Northwest

>

> STEVEN B. BLACK, MD

>

> Northern California

>

> Kaiser Permanente

>

> 15

>

> Alopecia Following Hepatitis B Vaccine in Adults and Adolescents: Is

Hepatitis B Vaccine Associated with an Increased Risk of Alopecia?

>

> ISSUE

>

> Recent reports submitted to VAERS suggest that alopecia areata (hair

loss) may rarely occur in persons who have received hepatitis B

vaccine. While the mechanisms responsible for alopecia following

vaccination are not certain, the condition could be immune-mediated.

>

> Therefore, CDC continues to conduct research to examine the effects

vaccines may have on the immune system in general and alopecia in

particular.

>

> VSD RESPONSE

>

> At Group Health ative (GHC), VSD researchers have been working

on a matched case-control study to assess the association between

receipt of hepatitis B vaccine and the risk of alopecia in adults and

adolescents. Chart reviews were used to validate outcome and exposure

status for cases and exposure status for controls. In the first phase

of the study, cases were drawn from those identified for an earlier

retrospective matched case-control analysis that GHC conducted using

automated data and controls were matched to cases 5:1 by age, sex, and

length of enrollment in GHC prior to the index date. Analyses from the

first phase were based on 206 cases and 610 controls, and there was

inadequate power to detect an association between alopecia and

vaccination (if one exists). Since some associations between alopecia

and vaccination have been suggested, the VSD Adult Studies Work Group

approved GHC's proposal to expand the analysis to include at least two

additional years of data. This second phase of the study is currently

underway.

>

> The specific objective of this VSD priority study is to:

>

> ? Evaluate the association between receipt of hepatitis B vaccine

and risk of alopecia.

>

> The results from this VSD priority study will increase our knowledge

about vaccine side

>

> effects and contribute to a greater understanding of the impact

vaccines may have on the

>

> immune system.

>

> Hepatitis B

>

> VSD Priority Study

>

> Research Team:

>

> LISA JACKSON, MD, MPH

>

> Principal Investigator

>

> Group Health ative

>

> BARBARA CARSTE, MPH

>

> Group Health ative

>

> 16

>

> 17

>

> Risk of Alopecia Following Hepatitis B Vaccination:

>

> A Preliminary Cohort Analysis of 15-59 Year Olds

>

> ISSUE

>

> Recent studies suggest that alopecia areata (hair loss) may rarely

occur in persons who have received hepatitis B vaccine. While the

mechanisms responsible for alopecia followingvaccination are not

certain, the condition could be immune-mediated. Therefore,

CDCcontinues to conduct research to examine the effects vaccines may

have on the immune system in general and alopecia in particular.

>

> VSD RESPONSE

>

> Researchers at Northern California Kaiser Permanente (NCKP) are

conducting a cohort study to assess the risk of alopecia following

hepatitis B vaccination among persons aged 15 to 59 years. The study

has involved a cohort of persons continuously enrolled in NCKP from

1/1/95 to 12/31/99. Automated data on clinic visits were collected for

the cohort and persons with visits for hair loss prior to their

follow-up start date were excluded. Vaccine data were collected from

an automated immunization database, and the relative risk for alopecia

by type of vaccine exposure (i.e., hepatitus B, tetanus/diptheria,

influenza) was estimated. Although a statistically significant

association was seen for alopecia in persons exposed to hepatitis B

vaccine, similar results were seen in comparisons between persons

exposed vs. unexposed to Td. These same results were not found in

persons exposed to flu vaccine. The similarities in alopecia rates in

the HepB and Td vaccine exposed groups suggest the possibility of

unidentified confounders, possibly related to utilization patterns.

Further analyses will be necessary to identify potential confounders.

The relatively high incidence of alopecia diagnoses seen in the NCKP

automated clinic data compared to published incidence rates for

alopecia as well as results of earlier chart review studies suggest a

possible lack of specificity in the automated data for alopecia. Chart

reviews will be necessary to verify rates of alopecia in exposed vs.

unexposed groups.

>

> VSD Priority Study

>

> Research Team:

>

> STEVEN B. BLACK, MD

>

> Principal Investigator

>

> Northern California

>

> Kaiser Permanente

>

> HENRY SHINEFIELD, MD

>

> Northern California

>

> Kaiser Permanente

>

> " This study is a good example of the pairing of the VAERS and the

VSD for evaluations of vaccine safety. In this case, VAERS reports

suggested a possible link between hepatitis B vaccine, or other

vaccines, and alopecia areata in children and adults. As a follow-up

to this signal, a controlled epidemiologic study was initiated in the

VSD. "

>

> , MD, MPH, Principal Investigator, Group Health ative

>

> 18

>

> Influenza: An Overview

>

> Commonly known as the flu, influenza is a virus that infects the

respiratory system. Every year in the United States, about 115,000

people are hospitalized and about 20,000 people die from severe

pneumonia caused by influenza. Most of the deaths caused by influenza

occur in people 65 or older. However, young children are more likely

than adults to be hospitalized with infections caused by influenza. An

influenza vaccine is given to people who are at high risk for

developing severe influenza. Recently, CDC advised that all children

between 6 months and 23 months of age should also receive the

influenza vaccine. Known side effects from influenza vaccine are

extremely rare. The influenza vaccine causes fever, muscle aches and

fatigue in less than one percent of people given the vaccine.

>

> Influenza Vaccine and Bell's Palsy:

>

> Does Influenza Vaccine Increase the Risk of Bell's Palsy?

>

> ISSUE

>

> Bell's palsy is a common neurological disorder that accounts for up

to 75% of all peripheral facial palsies. Although the etiology of

Bell's palsy is not clear, one of the theories put forward involves an

autoimmune etiology. Following the introduction of a newly licensed

intranasal influenza vaccine in Switzerland in October 2000, 46 cases

of Bell's palsy were noted among people who received the vaccine. The

situation warranted a thorough investigation to determine whether

there is any association between influenza vaccine and Bell's palsy.

>

> Influenza

>

> VSD Priority Study

>

> Research Team:

>

> WEIGONG ZHOU, MD, PhD

>

> Principal Investigator

>

> Centers for Disease Control

>

> and Prevention

>

> LISA JACKSON, MD, MPH

>

> Group Health ative

>

> STEVEN B. BLACK, MD

>

> Northern California

>

> Kaiser Permanente

>

> FEIFEI WEI, PhD

>

> HealthPartners

>

> Research Foundation

>

> JAMES DONAHUE, DVM, PhD

>

> Marshfield Clinic

>

> Research Foundation

>

> ALLISON NALEWAY, PhD

>

> Kaiser Permanente Northwest

>

> 19

>

> VSD RESPONSE

>

> A group of VSD researchers are currently conducting a case-control

study to investigate the possible association between use of the

intranasal influenza vaccine and Bell's palsy. As part of the study,

researchers will identify people with Bell's palsy who are members of

HMOs participating in the VSD project. At each participating site,

medical records of persons with Bell's palsy will be reviewed to

assess exposure to influenza vaccine, hepatitis B vaccine, Td vaccine,

and other vaccines. Data will be analyzed to calculate relative risk

of Bell's palsy following vaccination and the incidence of Bell's

palsy will be assessed in vaccinated and unvaccinated populations.

>

> The specific objectives of this VSD priority study are to:

>

> ? Investigate whether or not receipt of influenza vaccine increases

the risk for Bell's palsy;

>

> ? Assess the extent to which receipt of other vaccines are risk

factors for Bell's palsy.

>

> The results from this VSD priority study will contribute to the

ongoing investigation of the association between influenza vaccine and

Bell's palsy. The study will also contribute to our understanding of

the interaction between autoimmune disorders and vaccines. " This study

will investigate any association between influenza vaccine and Bell's

palsy to ensure the safety of the general public. "

>

> , MD, MPH, Group Health ative

>

> 20

>

> Safety of the Trivalent Inactivated Influenza Vaccine Among

>

> Children Ages 6-23 Months: A Population-Based Study,

>

> 1993-2003

>

> ISSUE

>

> During the influenza season of 2002/2003, CDC encouraged the

vaccination of healthy children aged 6 to 23 months for the first time

ever. The decision to encourage vaccination of children against

influenza was largely based on the increased risk for hospitalization

due to influenza that was seen among children in this age group. The

decision was also based on new evidence that universal vaccination of

school children may prevent influenza in the population of adults over

65 years of age through " herd immunity. " In October 2003, the Advisory

Committee on Immunization Practices (ACIP) voted to formally recommend

vaccination against influenza for all healthy children ages 6-23

months. In deciding on this recommendation, national policy groups

based their decision partly on existing data on the safety of the

Trivalent Influenza Vaccine (TIV) in young children. However, they

have also requested ongoing surveillance for possible rare adverse

events due to this vaccine.

>

> VSD RESPONSE

>

> VSD researchers are currently working on a study that will provide

the data needed to accurately assess the safety of the Trivalent

Influenza Vaccine (TIV). Researchers will study a large cohort of

young children who received the Trivalent Influenza Vaccine (TIV) over

a period of 10 years (1993 - 2003) for evidence of any increased risk

of adverse events requiring medical attention following vaccination.

The study will include all children aged 6 to 23 months of age who

received at least one TIV vaccination between 1993 and 2003, and who

were continuously enrolled in the Vaccine Safety Datalink

participating site at least 42 days prior to and 70 days following

vaccination. Approximately 25,000 children are expected to be included

in the study. All inpatient, outpatient, and emergency department

visits will be used to identify patterns of medically attended events

(MAEs) occurring within three " risk windows " following influenza

vaccination (i.e., 0-2 days, 1-14 days, 15-42 days).

>

> Influenza

>

> VSD Priority Study

>

> Research Team:

>

> SIMON HAMBIDGE, MD, PhD

>

> Principal Investigator

>

> Kaiser Permanente Colorado

>

> JASON GLANZ, MS

>

> Kaiser Permanente Colorado

>

> STAN XU, PhD

>

> Kaiser Permanente Colorado

>

> ERIC FRANCE, MD, MSPH

>

> Kaiser Permanente Colorado

>

> LISA JACKSON, MD, MPH

>

> Group Health ative

>

> STEVEN B. BLACK, MD

>

> Northern California

>

> Kaiser Permanente

>

> JOHN MULLOOLY, PhD

>

> Kaiser Permanente Northwest

>

> TRACY LIEU, MD, MPH

>

> Harvard Pilgrim Health Care

>

> MIKE GOODMAN, PhD

>

> Health Partners

>

> Research Foundation

>

> KEN ZANGWILL, MD

>

> UCLA Center for Vaccine Research /

>

> Southern California Kaiser Permanente

>

> Health Care Plan

>

> JAMES DONAHUE, DVM, PhD

>

> Marshfield Clinic

>

> Research Foundation

>

> DAVID SHAY, MD, MPH

>

> Centers for Disease Control

>

> and Prevention

>

> 21

>

> The specific objectives of this VSD priority study are to:

>

> ? Investigate whether or not receipt of the Trivalent Influenza

Vaccine (TIV) in young children increases the risk for medically

attended events (MAEs) in the postvaccination period;

>

> ? Classify MAEs following TIV as either immediate (day 0 to 2),

acute (day 1 to 14), or delayed (day 15 to 42);

>

> ? Assess the risk of MAEs after the second seasonal influenza

vaccination, and in the subset of children who are at high risk for

complications from influenza infection.

>

> The preliminary results from this VSD priority study will be

presented to the ACIP in February and June of 2004. Final study

results are likely to have a strong influence on future vaccine

policies and ACIP recommendations.

>

> " The influenza vaccine will prevent an enormous amount of illness

and suffering in infants and young children. All studies to date show

the vaccine to be safe and effective in this population. Our study

aims to further examine the safety of the influenza vaccine in very

young children by looking for rare events that might occur after

vaccination. "

>

> Simon J. Hambidge, MD, PhD, Co-Investigator, Kaiser Permanente Colorado

>

> Measles-Mumps-Rubella: An Overview

>

> MEASLES

>

> Measles is a very contagious disease caused by a virus that usually

begins with a cough, runny nose, fever, and " pink eye. " A rash then

appears on the face, spreads to the rest of the body, and lasts for

about five days. Many children develop severe dehydration from the

infection. About five percent of children infected with the measles

virus develop pneumonia. In older children, measles can cause

encephalitis, which can lead to brain damage. Although only about one

out of every thousand children infected with measles develops

encephalitis, permanent brain damage will occur in about 25 percent of

those children.

>

> The measles vaccine was first administered in the United States in

1963 and hundreds of millions of doses have been administered since

that time. Due to the measles vaccine, measles infections are now

uncommon in the United States. Yet, in the late 1980's and early

1990's, an outbreak of measles swept across the United States. More

than 11,000 children were hospitalized and 120 died from measles

during that outbreak. The outbreak of the 1980's and 1990's served as

a reminder of the devastating effect that measles can have on children

and communities.

>

> MUMPS

>

> Mumps is a virus that typically infects children and causes a

painful swelling of the salivary or parotid glands (located just below

the ears). Mumps can also infect the brain (encephalitis) and lining

of the brain (meningitis). In addition, mumps can infect an unborn

child during the first trimester of pregnancy and cause fetal death.

Before the mumps vaccine, the mumps virus was the most common cause of

viral meningitis and deafness. Since the mumps vaccine, only about 500

cases of mumps virus are reported in the United States each year (down

from 200,000 cases prior to the vaccine). The mumps vaccine is not

known to cause any serious reactions and is therefore considered a

very safe

>

> vaccine.

>

> RUBELLA

>

> Rubella, like measles and mumps, is a virus that typically infects

children. Rubella, also known as German

>

> measles, begins with fever, swollen glands, and a light rash on the

face. Although usually harmless, the rubella virus

>

> occasionally causes encephalitis and can cause a decrease in

platelets. The rubella virus is most harmful in pregnant women.

>

> Up to 85% of infants whose mothers are infected with rubella in the

first trimester of pregnancy will have blindness, deafness,

>

> heart defects, or mental retardation.

>

> Between 1964 and 1965 there were about 12 million cases of rubella

in the United States, resulting in birth defects in about 20,000

>

> children. Since the rubella vaccine has been available in the United

States, the number of birth defects due to rubella has decreased

>

> to about five per year. There are no known serious side effects from

the rubella vaccine.

>

> Measles-Mumps-Rubella

>

> 22

>

> 23

>

> Idiopathic Thrombocytopenia Purpura (ITP) and MMR

>

> Vaccination: Is there an Increased Risk of ITP Following

>

> MMR Vaccination?

>

> ISSUE

>

> Idiopathic thrombocytopenia purpura (ITP) is an acquired disease

that is caused by the destruction or impaired production of platelets.

In children who are otherwise healthy, the acute onset of

thrombocytopenia is commonly characterized as ITP. Over the last

several years, there has been growing concern that the live virus

measles-mumps-rubella (MMR) vaccination is associated with an

increased incidence of idiopathic thrombocytopenia purpura

>

> (ITP). Two studies published in 2001 and in 2003 demonstrated a

significant risk of ITP following the receipt of MMR vaccination.

These studies, however, were based on only 28 and 23 cases, respectively.

>

> VSD RESPONSE

>

> To better quantify the relationship between MMR vaccination and ITP,

VSD researchers are currently investigating the association in a large

cohort of children. Researchers will use inpatient, outpatient and

laboratory data to identify children with a diagnosis of ITP during a

specified period of time. Medical charts will then be reviewed to

verify cases of ITP and collect information on vaccination history.

Analyses will be performed to assess the risk of ITP following MMR

vaccination.

>

> The specific objectives of this VSD priority study are to:

>

> ? Evaluate the risk of ITP following recent MMR vaccination in

children between the ages of 1 to 2, 4 to 6, and 11 to 13 years of age;

>

> ? Identify periods of greatest risk for ITP within a six-week window

after MMR vaccination;

>

> ? Explore the level of increased risk of ITP following the second

dose of MMR;

>

> ? Assess the risk of recurrence of ITP following MMR vaccination.

>

> The results of this VSD priority study will provide the most

accurate assessment of the association between MMR vaccination and

ITP. Thus, the study will have a significant impact on MMR vaccine

recommendations, policies, and clinical practice.

>

> " We believe this study will prove to be the most definitive

investigation to examine the relationship between MMR vaccination and

the onset of ITP to date " .

>

> K. France, MD, MSPH, Principal Investigator, Kaiser Permanente

Colorado

>

> VSD Priority Study

>

> Research Team:

>

> ERIC FRANCE, MD, MSPH

>

> Principal Investigator

>

> Kaiser Permanente Colorado

>

> JASON GLANZ, MS

>

> Kaiser Permanente Colorado

>

> SIMON HAMBIDGE, MD, PhD

>

> Kaiser Permanente Colorado

>

> KRISTI YAMASAKI, PharmD

>

> Kaiser Permanente Colorado

>

> MARSHA RAEBEL, PharmD

>

> Kaiser Permanente Colorado

>

> LISA JACKSON, MD, MPH

>

> Group Health ative

>

> STEVEN B. BLACK, MD

>

> Northern California Kaiser Permanente

>

> JOHN MULLOOLY, PhD

>

> Kaiser Permanente Northwest

>

> KEN ZANGWILL, MD

>

> UCLA Center for Vaccine Research /

>

> Southern California Kaiser Permanente

>

> Health Care Plan

>

> S. MICHAEL MARCY, MD

>

> Southern California Kaiser Permanente

>

> TRACY LIEU, MD, MPH

>

> Harvard Pilgrim Health Care

>

> JAMES DONAHUE, DVM, PhD

>

> Marshfield Clinic Research Foundation

>

> MIKE GOODMAN, PhD

>

> HealthPartners Research Foundation

>

> DAVID SHAY, MD, MPH

>

> Centers for Disease Control

>

> and Prevention

>

> 24

>

> Vaccine Non-Specific Studies

>

> Four of the VSD priority studies are non-vaccine specific in that

the research questions pertain to multiple vaccines or the overall

process of evaluating vaccine safety. Two of these studies are

designed to assess the effect of thimerosal on child health and

development.

>

> Thimerosal, a mercury-containing preservative, has been the focus of

intense scrutiny by the U.S. Congress and the news media following its

removal from all routinely recommended childhood vaccines in 2001.

Prior to that time, thimerosal was added to multidose vials of

vaccines such as diphtheria-tetanus-acellular pertussis (DtaP),

hepatitis B, and Haemophilus influenzae type B (Hib) to prevent

bacterial or fungal contamination. There continues to be concern that

thimerosal contained in vaccines administered prior to 2001 might have

harmed children.

>

> The remaining two vaccine non-specific priority studies are aimed at

improving the overall process associated with evaluating vaccine

safety. One is a feasibility study to assess the extent to which VSD

data can be used to provide real-time data and evidence to the CDC and

other organizations (e.g., the FDA) about the presence and rate of

adverse events following vaccination. The other study is concerned

with evaluating sex-based differences in reporting of adverse effects

associated with administration of vaccines.

>

> Infant Environmental Exposures and Neurodevelopmental

>

> Outcomes: A Thimerosal Follow-up Study

>

> ISSUE

>

> In 2001, the Immunization Safety Review Committee of the Institute

of Medicine (IOM) concluded that although a relationship between

thimerosal-containing vaccines and neurodevelopmental disorders was

biologically plausible, the evidence was insufficient to either

accept or reject a causal relationship. The IOM report recommended

follow-up studies of children who had participated in randomized

trials of acellular pertussis trials to further investigate the

possible relationship between the amount of thimerosal received in

different trial study arms and subsequent neurodevelopmental disorders.

>

> Vaccine Non-Specific Studies

>

> VSD Priority Study

>

> Research Team:

>

> IMMUNIZATION SAFETY BRANCH

>

> CENTERS FOR DISEASE CONTROL

>

> AND PREVENTION

>

> JOHN DUNN, MD, MPH

>

> Group Health ative

>

> LISA JACKSON, MD, MPH

>

> Group Health ative

>

> STEVEN B. BLACK, MD

>

> Northern California

>

> Kaiser Permanente

>

> S. MICHAEL MARCY, MD

>

> Southern California

>

> Kaiser Permanente

>

> TRACY LIEU, MD, MPH

>

> Harvard Pilgrim Health Care

>

> ABT ASSOCIATES, INC.

>

> 25

>

> VSD RESPONSE

>

> VSD researchers are currently collaborating on a retrospective

cohort study that will provide additional data needed to assess the

relationship between thimerosal and neurodevelopmental disorders. As

part of this VSD priority study, researchers will administer a

neuropsychological test to a cohort of children aged 7 to 10 years

whose vaccinations in the first year of life could have contained

thimerosal. Outcomes will include speech and language skills, fine

motor coordination, motor tics, academic and intellectual functioning,

and ADHD symptomology.

>

> Results will be stratified by level of thimerosal exposure.

>

> The specific objectives of this VSD priority study are to:

>

> ? Investigate the possible relationship between the amount of

thimerosal received in different trial study arms and subsequent

neurodevelopmental disorders;

>

> ? Compare the neuropsychological performance of children exposed to

different quantities of thimerosal from vaccines administered during

the first year of life. The results of this VSD priority study are

likely to have important policy implications.

>

> 26

>

> Thimerosal and Autism: A Case Control Study

>

> to Investigate the Relationship Between Exposure

>

> to Thimerosal and Onset of Autism

>

> ISSUE

>

> Over the past decade, autism prevalence rates have been rising.

Although there is no evidence that any vaccine or vaccine additive

increases the risk of developing autism, there has been considerable

concern among parents and others regarding vaccines and autism. In

2001, the Institute of Medicine (IOM) established an independent

expert committee to review the possible link between the MMR vaccine

and autism. The committee concluded that the vast

>

> majority of cases of autism cannot be caused by MMR vaccine and

therefore MMR vaccine cannot be used to explain the increasing trend

in autism diagnoses.

>

> VSD RESPONSE

>

> Due to public concerns, VSD researchers have begun a case-control

study to rigorously examine the association between thimerosal and

autism. As part of the study, researchers will use automated data and

registries to identify children with autism (cases) and without autism

(controls). In-person examinations, telephone interviews, medical

chart reviews, and immunization tracking systems will be used to

collect information on vaccine history and other possible covariates.

>

> The specific objectives of this VSD priority study are to:

>

> ? Determine whether exposure to thimerosal in infancy or in-utero is

related to development of autism;

>

> ? Evaluate whether exposure to thimerosal in infancy is related to

development of the subclass of autism predominantly associated with

regression.

>

> This IOM-recommended VSD study will be the first rigorous,

epidemiological study conducted on the issue of thimerosal and autism.

Data from this VSD priority study should provide the best available

scientific information on whether or not there is a possible causal

association between exposure to thimerosal and development of autism.

>

> Vaccine Non-Specific Studies

>

> " The hypothesis that thimerosal exposure may be related to the

development of autism has created considerable concern among parents,

particularly the parents of autistic children. The VSD study of

thimerosal and autism will provide critically needed objective

scientific information to address these concerns and guide public policy. "

>

> Croen, PhD, Northern California Kaiser Permanente

>

> VSD Priority Study

>

> Research Team:

>

> IMMUNIZATION SAFETY BRANCH

>

> CENTERS FOR DISEASE CONTROL

>

> AND PREVENTION

>

> LISA CROEN, PhD

>

> Northern California

>

> Kaiser Permanente

>

> S. MICHAEL MARCY, MD

>

> Southern California

>

> Kaiser Permanente

>

> TRACY LIEU, MD, MPH

>

> Harvard Pilgrim Health Care

>

> ABT ASSOCIATES, INC.

>

> 27

>

> Sex-Based Differences in Reporting of

>

> Potential Vaccine-Associated Adverse Events

>

> ISSUE

>

> Sex-based differences are well documented in many biologic systems,

including immunology. In 2001, the Institute of Medicine (IOM)

recommended that research analyses, including those concerned with

vaccine safety, consider potential differences between men and women.

Some of this interest was generated by anthrax vaccine trials in which

females experienced a greater incidence of adverse events following

vaccination. Sex-based differences in vaccine-related adverse events

have also been noted in studies of measles, acellular pertussis, DTaP,

and influenza vaccines. In these studies, women usually experience

greater reactogenicity than men. Much of these data, however, are

either uncontrolled, include small sample sizes, and/or do not

evaluatea large spectrum of possible adverse outcomes. In addition,

most large phase II and III studies do not report adverse events by

sex. The VSD project provides a useful infrastructure to evaluate

sex-specific vaccine safety in all age groups, using population-based

data.

>

> VSD RESPONSE

>

> In response to the IOM recommendation, VSD researchers have been

collaborating on a study to examine potential inequality in the sex

distribution of local and/or systemic adverse events following

vaccination. In this VSD priority study, researchers are using

inpatient and outpatient data from health plans to conduct

sex-specific analyses as follows: 1) for all routineand individual

vaccines, by age and time interval post-vaccination; and 2) evaluation

withadjustment for outcomes that are known to have a predilection for

one or the other sex. Preliminary results from this large study

indicate that there may be sex-based differences in the incidence of

adverse events related to vaccination. In general, females appear to

be at higher risk than men and are more likely to be identified with

one of several systemic conditions after vaccination including

syncope, hematologic abnormalities, asthma and autoimmune conditions.

Further work to clarify incidence rates, adjustment for various

confounders includingage and HMO, timing of the event after

vaccination, and certainty of diagnosis is ongoing. This priority VSD

study will provide insight into the extent to which there are

sex-baseddifferences in the reporting of vaccine-related adverse

events. We hope these data will assist the IOM in raising awareness in

the scientific community of the potential for sex-based differences in

adverse events following vaccination. This topic is not currently

emphasized in preclinical and post-licensure trials of new vaccines.

>

> VSD Priority Study

>

> Research Team:

>

> KEN ZANGWILL, MD

>

> Principal Investigator

>

> UCLA Center for Vaccine Research /

>

> Southern California

>

> Kaiser Permanente Health Plan

>

> MARTIN LEE, PHD

>

> Biostatistician

>

> UCLA Center for Vaccine Research /

>

> Southern California

>

> Kaiser Permanente Health Plan

>

> S. MICHAEL MARCY, MD

>

> Co-Investigator

>

> UCLA Center for Vaccine Research /

>

> Southern California

>

> Kaiser Permanente Health Plan

>

> JOEL WARD, MD

>

> Co-Investigator

>

> UCLA Center for Vaccine Research /

>

> Southern California

>

> Kaiser Permanente Health Plan

>

> " A fuller understanding of potential differences between men and

women regarding adverse responses to vaccination should

>

> lead to greater reporting and investigation of this issue in large

pre and post-licensure trials of new vaccines. "

>

> Ken Zangwill, MD, Principal Investigator, UCLA Center for Vaccine

Research / Southern California Kaiser Permanente

>

> 28

>

> Rapid Cycle Analysis of Vaccine Safety Data: Can VSD

>

> Data Be Used to Simulate a Rapid Cycle Analysis?

>

> ISSUE

>

> Recent events in the United States highlight the importance of

setting up omputerized reporting systems to detect adverse events in

real time. The primary goal of such an adverse events reporting system

would be to minimize lag time between the onset of vaccine adverse

events and the proper evaluation, management and treatment of

individuals experiencing such events. A secondary goal of such a

system would be to provide real-time data to the Centers for Disease

Control and Prevention (CDC) regarding rates of adverse events

following vaccination, along with an assessment of the severity of the

events. The need for such a system was highlighted when the newly

licensed rotavirus vaccine was found to be associated with an

increased risk of intussusception following vaccination.

>

> VSD RESPONSE

>

> VSD researchers have been collaborating on a study to assess the

feasibility of using VSD data to develop computerized reporting

systems that can detect adverse vaccine-related events in real time.

As part of the study, researchers restructured the existing VSD cycle

datasets into a format that would simulate how data would appear if

received on a weekly basis in a rapid cycle analysis project. By doing

so, researchers were able to evaluate the feasibility of the VSD to

deal with three major challenges facing rapid cycle data analysis:

outcome definition, rapid and routine creation of analytic datasets

based on automated data, and statistical analysis of signal detection.

>

> The specific objectives of this VSD priority study were to:

>

> ? Simulate a rapid cycle analysis framework within the VSD dataset;

>

> ? Evaluate VSD data " as if " analysis had been carried out on a

weekly basis;

>

> ? Assess capability to find known or presumed signals for adverse

events.

>

> Early results from this study indicate that it is feasible to use

VSD data to conduct rapid cycle analysis of routinely collected

vaccine data. The VSD data could provide the basis for a

population-based, non-biased surveillance system for vaccine safety.

>

> " This study demonstrates that it is feasible to develop systems for

rapid and routine assessment of new vaccine safety. Such systems can

provide valuable population based estimates of vaccine adverse event

rates in a more timely manner than is currently available. "

>

> , MD, MPH, Principal Investigator, Northern California

Kaiser Permanente

>

> VSD Priority Study

>

> Research Team:

>

> ROBERT DAVIS, MD, MPH

>

> Principal Investigator

>

> Northern California

>

> Kaiser Permanente

>

> JIM NORDIN, MD

>

> HealthPartners

>

> Research Foundation

>

> MICHAEL GOODMAN, PhD

>

> HealthPartners

>

> Research Foundation

>

> RICHARD PLATT, MD, MSc

>

> Harvard Pilgrim Health Care

>

> DAVID SHAY, MD, MPH

>

> Centers for Disease Control

>

> and Prevention

>

> NED LEWIS, MPH

>

> Northern California

>

> Kaiser Permanente

>

> DEBRA P. RITZWOLLER, PhD

>

> Kaiser Permanente Colorado

>

> MARGARETTE KOLCZAK, PhD

>

> Centers for Disease Control

>

> and Prevention

>

> Vaccine Non-Specific Studies

>

> 29

>

> VSD Sites

>

> CENTERS FOR DISEASE CONTROL AND PREVENTION

>

> National Immunization Program

>

> Immunization Safety Branch

>

> Atlanta, GA

>

> Branch Chief: Chen, MD

>

> Site Description

>

> The Immunization Safety Branch (ISB) is the funding organization for

the Vaccine Safety Datalink (VSD) and the Clinical Immunization Safety

Assessment (CISA) centers. The ISB provides scientific leadership and

fully collaborates in all aspects of VSD and CISA activities. ISB

scientists serve as principal or co-investigators on several VSD and

CISA research studies. The ISB has the largest group of scientists

worldwide to assess and minimize (whenever possible) the risks

associated with immunization programs in the United States (and

elsewhere upon request). Besides conducting epidemiologic activities

related to surveillance and evaluation of the safety of routine

vaccinations, ISB also develops new surveillance methodologies (e.g.,

data mining, syndromic surveillance), assists policy makers in

rational vaccine use, and identifies optimal ways to communicate

vaccine risks and benefits. Most recently, ISB has begun conducting

surveillance for the safety of vaccinations used to protect against

bioterrorism agents such as anthrax and smallpox.

>

> Areas of VSD Research Activity

>

> ISB scientists are involved in a wide array of immunization safety

studies, including high-profile issues like intussusception

afterrotavirus vaccination and risks associated with thimerosal in

vaccines. Other recent studies have included the occurrence of a newly

identified oculorespiratory syndrome after influenza vaccine,

identification of risk factors for serious reactions to the yellow

fever vaccine, safety of acellular pertussis vaccines in managed care

organizations, safety and effectiveness of influenza vaccine in

asthmatic children, and whether hepatitis B vaccination is associated

with multiple sclerosis.

>

> Possibilities for new projects include: 1) assessing trends in

prevalence of neurodevelopmental disabilities and risk factors in

managed care populations; 2) assessing opportunities for using twins

in vaccine safety studies; 3) investigating safety of new pediatric

>

> combination vaccines; 4) assessing safety of live intranasal

influenza vaccines; 5) case control studies of risk factors for

smallpox vaccine adverse events; 6) assessment of extensive limb

swelling after DTaP vaccine boosters.

>

> For Further Information Please Contact:

>

> T. (Bob) Chen, MD

>

> Immunization Safety Branch

>

> National Immunization Program

>

> Centers for Disease Control and Prevention

>

> Phone: 404-639-8256

>

> Email: bchen@...

>

> 30

>

> GROUP HEALTH COOPERATIVE

>

> Center for Health Studies

>

> Seattle, Washington

>

> Principal Investigator: A. , MD, MPH

>

> Site Description

>

> Group Health ative has been a VSD site since the project's

inception in 1990 and Group Health investigators have played an active

role in the design, conduct, analysis, interpretation, and reporting

of VSD research. Sources of data for VSD studies at Group Health

include administrative databases, chart abstraction, and patient

interview. Group Health has long standing administrative

>

> databases recording information on immunizations, diagnoses assigned

to outpatient and inpatient medical encounters, pharmacy

prescriptions, and laboratory results. These databases record data for

Group Health's population of 400,000 people over periods ranging from

12 to 30 years, depending on the data source, and provide millions of

cumulative person-years of information for research purposes. Group

Health's VSD team includes epidemiologists, biostatisticians, project

managers, programmers, and research assistants. The Group Health VSD

study team is part of Group Health's Center for Health Studies, an

internationally recognized academically focused research organization

that conducts primarily government funded clinical, epidemiologic, and

health services research.

>

> The Center includes 21 MD and PhD investigators, over 200 staff

members, and receives approximately $20 million in annual grant

>

> funding.

>

> Areas of Research Activity

>

> Group Health VSD researchers have led and participated in multiple

VSD studies of vaccine safety and effectiveness. Recent VSD studies

conducted at Group Health include a multi-site descriptive study of

the risk of anaphylaxis in children and adolescentsfollowing

vaccination, a multi-site case-control study of the risk of autoimmune

thyroid disease following hepatitis B vaccination,an inception cohort

study of the association between influenza vaccination and risk of

recurrent cardiovascular events in adults, a comparison of DT rates of

use and reasons for use during DTP and DTaP eras, and a cohort study

of the effectiveness of pneumococcal polysaccharide vaccine in the

elderly.

>

> For Further Information Please Contact:

>

> , MD, MPH

>

> GHC Center for Health Studies

>

> 1730 Minor Avenue, Suite 1600

>

> Seattle, WA 98101

>

> Phone: 206- 442-5216

>

> Email: jackson.l@...

>

> VSD Sites

>

> 31

>

> HARVARD PILGRIM HEALTH CARE, HARVARD MEDICAL SCHOOL AND HARVARD VANGUARD

>

> Department of Ambulatory Care and Prevention

>

> Boston, Massachusetts

>

> Principal Investigators: Lieu, MD, MPH, and Platt, MD, MS

>

> Site Description

>

> The Harvard VSD site is located in the Department of Ambulatory Care

and Prevention, a unique partnership between Harvard

>

> Pilgrim Health Care, Harvard Medical School and Harvard Vanguard.

The core study population for the VSD Project at Harvard

>

> is patients of Harvard Vanguard Medical Associates, a

multi-specialty physician group with 14 centers in the greater Boston

area.

>

> The site has a fully computerized medical record that has been used

with the core study population since 1969, ensuring maximally accurate

vaccine administration data and access to full-text outpatient medical

records. The VSD's association with Harvard offers special

opportunities to collaborate with colleagues in the Department of

Epidemiologyat the Harvard School of Public Health and adds to the

geographic diversity to the VSD population. The Harvard site also

contributes methodologic and technologic innovation through the

expertise of its investigators in time-series analysis, health

economics, and bioterrorism surveillance methods. The site also has

close ties to Children's Hospital Boston, one of the nation's premier

institutions in pediatric research and teaching.

>

> Areas of VSD Research Activity

>

> Each year, the Harvard VSD Team initiates several studies that focus

on a broad range of topics related to vaccine safety. Recently

completed studies include a smallpox study that identified vaccine

safety as a key factor in hospital workers' projected decisions about

acceptance or rejection of smallpox vaccination, and an influenza

study that determined the incidence of outpatient visits associated

with influenza among young children in the Harvard VSD cohort. Ongoing

VSD studies include a Pneumococcal vaccination study evaluating the

impact of the introduction of pneumococcal conjugate vaccine on

immunization up-to-date status, a study of the association between

thimerosal exposure from vaccines and neurodevelopmental outcomes in

children, and an evaluation of the impact of shifts in practice for

multiple immunizations on the risk of fever.

>

> For Further Information Please Contact:

>

> Lieu, MD, MPH

>

> Department of Ambulatory Care and Prevention

>

> Harvard Pilgrim Health Care, Harvard Medical School and Harvard Vanguard

>

> 133 Brookline Ave., 6th floor

>

> Boston, MA 02215

>

> Phone: 617-509-9949

>

> Email: tracy_lieu@...

>

> 32

>

> VSD Sites

>

> HEALTHPARTNERS RESEARCH FOUNDATION

>

> Minneapolis, Minnesota

>

> Principal Investigator: J. Goodman, PhD

>

> Site Description

>

> HealthPartners Research Foundation (HPRF) is a nonprofit research

center that conducts public domain research as an independent part of

the HealthPartners family of companies. HPRF joined the VSD project in

March of 2001 and serves as a pediatric-only site that focuses on all

areas of vaccine safety in children. HealthPartners is a mixed-model

HMO with a large network of owned and contracted clinics, medical and

dental centers. The VSD population is drawn from the two largest

HealthPartners clinics serving more than 600,000 enrollees.

HealthPartners serves a diverse population of urban, suburban, and

rural residents, including low socioeconomic populations in the

Minneapolis-St. metropolitan area. HPRF has a wealth of experience

using administrative databases in vaccine-related,

pharmacoepidemiology, pharmacoeconomic, and other large link database

studies. HealthPartners' computerized information services system

provides a fully integrated structure that captures inpatient and

outpatient claims and encounters, electronic physician notes, and

laboratory, pharmacy, emergency room, and urgent care data that can be

accessed by the HPRF VSD staff. HPRF investigators also have access to

electronic physician notes containing information not present in any

other administrative data system. HealthPartners implemented an

Epicare electronicmedical record in the 2003 and has had an

immunization registry since 1997.

>

> Areas of VSD Research Activity

>

> HPRF's multi-specialty VSD team consists of bio-statisticians,

pediatricians, an economist, an epidemiologist, programmers, support

staff and contracts with well-known vaccine researchers. The HPRF VSD

team initiates and participates in several studies that focus on a

wide range of vaccine safety topics. Some of our recent studies

include a study of rotavirus vaccine and intussusception, an

examination of the health consequences that result from exemption from

immunization, an assessment of the safety of Yellow Fever vaccine in

children and adults, and a feasibility study to enable real time

surveillance using automated data to rapidly detect vaccine adverse

events.

>

> For Further Information Please Contact:

>

> J. Goodman, PhD

>

> HealthPartners Research Foundation

>

> 8100 34th Avenue South, MS 23302G

>

> Minneapolis, MN 55440-1524

>

> Phone: 952-967-5039

>

> Email: michael.j.goodman@...

>

> 33

>

> KAISER PERMANENTE COLORADO

>

> Clinical Research Unit

>

> Denver, Colorado

>

> Principal Investigator: France, MD, MSPH

>

> Site Description

>

> Kaiser Permanente Colorado (KPC) has been a Vaccine Safety Datalink

(VSD) site since 2000. The KPC site includes multi-disciplinary

>

> expertise in pediatrics, biostatistics, epidemiology,

pharmacoepidemiology, prevention, and health economics. The VSD research

>

> team is located within the Clinical Research Unit of KPC, which has

a high level of active grant support in a broad range of health

>

> services research areas, and clinical trials research. The KPC

Clinical Research Unit is also involved with a wide range of pediatric

>

> studies including phase 3 and 4 trials, and prospective randomized

studies of vaccine safety.

>

> Areas of VSD Research Activity

>

> KPC's areas of research interest include the impact of new vaccines

or changing vaccine recommendations on vaccine coverage or vaccine

policy, methodology research, and epidemiologic assessments. The KPC

site first became involved with the VSD following Dr. France's work

with the group that helped to delineate the relationship between

vaccination against rotavirus and intussusception in young children.

Current research studies at the KPC site include assessing the safety

of the trivalent inactivated influenza vaccine among the pediatric

>

> population, evaluating the possible association of idiopathic

thrombocytopenic purpura with the measles, mumps, and rubella

vaccination, the possible benefit of influenza vaccination in

pregnancy on infant outcomes, and comparing four study designs used to

examine the association between vaccination and acute adverse events.

KPC is also interested in methodology research to develop analytic

methods to minimize or assess bias in observational epidemiologic

studies. Work includes comparing conditional models to longitudinal

models used in vaccine safety studies, and evaluating the validity and

stability of four types of study designs used to examine the

association between vaccination and acute adverse events. Future plans

include using HLA typing from cord bloods to look at adverse events

and investigating the concept of the " healthy vaccinee effect " .

>

> For Further Information Please Contact:

>

> France, MD, MSPH

>

> Kaiser Permanente Colorado

>

> Clinical Research Unit

>

> 2550 S. Road

>

> Aurora, CO 80014

>

> Phone: (303) 636-3151

>

> Email: eric.k.france@...

>

> 34

>

> KAISER PERMANENTE NORTHWEST

>

> Center for Health Research

>

> Portland, Oregon

>

> Principal Investigator: Mullooly, PhD

>

> Site Description

>

> Kaiser Permanente Northwest (KPNW) has been a Vaccine Safety

Datalink (VSD) site since the research program's inception in

>

> 1990, and conducts a wide range of pediatric and adult immunization

studies. The multi-discipline VSD investigative team includes

>

> biostatistics, epidemiology, pediatrics and internal medicine,

allergy/immunology, pharmaco-epidemiology, and health economics.

>

> The VSD research group exists within the larger Center for Health

Research that is noted for epidemiologic and health services

>

> research in many areas.

>

> Areas of VSD Research Activity

>

> Areas of research activity include risk assessment of adverse events

following vaccination, data quality assessment of automated

immunization and diagnosis databases, statistical adjustments for

misclassification, vaccine coverage and compliance, vaccine

effectiveness, impacts of vaccination programs, medical care costs of

infectious diseases, cost-effectiveness of vaccination programs,

household transmission of infectious diseases, and infectious disease

transmission modeling. Current studies of adverse events following

vaccination include wheezing in premature infants following hepatitis

B vaccination, childhood asthma and atopy, and local and systemic

adverse events following pediatric flu vaccination. Kaiser Permanente

Northwest also leads the VSD data quality work group. Data quality

studies include those related to assessing the completeness and

accuracy of automated vaccination and vaccination exemption records,

temperatures, fever codes, and inpatient and outpatient pneumonia

>

> codes.

>

> For Further Information Please Contact:

>

> Mullooly, PhD

>

> Kaiser Permanente Center for Health Research

>

> 3800 N. Interstate

>

> Portland, OR 97227

>

> Phone: 503-335-6768

>

> Email: john.mullooly@...

>

> VSD Sites

>

> 35

>

> MARSHFIELD CLINIC RESEARCH FOUNDATION

>

> Vaccine Safety Datalink Site

>

> Marshfield, Wisconsin

>

> Principal Investigator: Belongia, MD

>

> Site Description

>

> Marshfield Clinic is the largest private group medical practice in

Wisconsin and one of the largest in the United States. Although the

primary service area includes northern, central, and western

Wisconsin, and the Upper Peninsula of Michigan, patients from every

county in Wisconsin, every state in the nation, and 24 foreign

countries were seen within the Clinic system last fiscal year. The

Marshfield Clinic and the Marshfield Clinic Research Foundation, the

nonprofit research division of the Marshfield Clinic, have

participated in the VSD project since March 2001. Strengths of the

Marshfield Clinic for vaccine safety research include access to a

stable rural population, an electronic medical record with a

sophisticated diagnosis coding system (with mapping to ICD codes), a

real-time electronic immunization registry used by public and private

providers, and an epidemiology research group with experience in

vaccine safety research and infectious disease epidemiology. Areas of

VSD Research Activity Current studies of adverse events following

vaccination that are directed by investigators at the Marshfield

Clinic include two investigations related to the small pox vaccination

program. For one study, the main objectives are to determine the

prevalence of diagnosed atopic dermatitis and eczema in a defined

population, estimate the proportion of people who would be at

increased risk of developing eczema vaccinatum if they or their

household contacts were vaccinated, and determine if adults are able

to accurately recall past diagnoses of atopic dermatitis for

themselves, their children, or other members of their households. A

second smallpox study will determine the sensitivity of a

self-administered screening instrument to identify health care workers

who should not receive smallpox vaccine, using the medical record as

the gold standard. MCRF is also leading a study to determine if

immune-mediated hemolytic anemia (IMHA) in children is related to each

of 3 different exposures: diphtheria-tetanus-pertussis (DTP)

vaccination, hepatitis B vaccination, and parenteral ceftriaxone. The

strength of the association between IMHA and the various exposures

will be measured.

>

> For Further Information Please Contact:

>

> Belongia, MD

>

> Marshfield Clinic Research Foundation

>

> 1000 North Oak Avenue

>

> Marshfield, WI 54449

>

> Phone: (715) 389-5549

>

> Email: belongia.edward@...

>

> 36

>

> NORTHERN CALIFORNIA KAISER PERMANENTE

>

> Kaiser Permanente Vaccine Study Center

>

> Oakland, California

>

> Principal Investigators: B. Black, MD and Henry Shinefield, MD

>

> Site Description

>

> Northern California Kaiser Permanente has been a VSD site since the

program's inception in 1990. The Kaiser Permanente Vaccine Center

conducts a wide range of pediatric and adult immunization studies,

including phase 2, 3 and 4 trials, diverse prospective randomized

studies, and observational studies of vaccine safety. The

multi-disciplinary VSD investigative team has expertise in

biostatistics, epidemiology, programming, pediatrics, internal

medicine, rheumatology, health economics, and conduct of both chart

review and telephone interview studies. The VSD research groups work

extensively with the Kaiser Permanente Division of Research that is

noted for both epidemiologic and health services research. The Center

has access to one of the largest and most complete clinical automated

databases in the country and a large group of clinicians, who

cooperate in providing subspecialty expertise in vaccine safety studies.

>

> Areas of VSD Research Activity

>

> Areas of research interest include risk assessment of adverse events

following vaccination, the use of large linked data bases to provide

rapid epidemiologic and public health assessments, studies of genetic

factors which might influence the nature and risk of vaccine adverse

events, statistical adjustments for comparing populations with

differing propensities to utilize care, the impact of new vaccines or

changing vaccine recommendations on vaccine coverage, cost-benefit

analyses and economic modeling. Current studies evaluating adverse

events following vaccination include an assessment of the risk of

encephalopathy following DTP vaccines, evaluation of a possible

association of alopecia with hepatitis B vaccination, the safety and

benefit of influenza vaccination in pregnancy, and the risk of and

possible genetic factors predicting arthritis following hepatitis B

vaccination.

>

> For Further Information Please Contact:

>

> B. Black, MD

>

> Kaiser Permanente Vaccine Study Center

>

> 1 Kaiser Plaza, 16th floor

>

> Oakland, CA 94612

>

> Phone: 510-267-7534

>

> Email: steve.black@...

>

> VSD Sites

>

> 37

>

> UCLA CENTER FOR VACCINE RESEARCH/

>

> SOUTHERN CALIFORNIA KAISER PERMANENTE HEALTH CARE PLAN

>

> Los Angeles, California

>

> Principal Investigators: Ken Zangwill, MD and I. Ward, MD

>

> Site Description

>

> The southern California VSD site is based in Los Angeles at the UCLA

Center for Vaccine Research and the Southern California Kaiser

Permanente (SCKP) Health Care Plan, the largest HMO in southern

California. UCLA/SCKP investigators have been active in vaccine

research for more than 35 years, and have evaluated nearly all

licensed vaccines and many experimental formulations. The VSD team at

UCLA/SCKP includes several MDs, two PhD epidemiologists, a PhD

biostatistician, a MPH project coordinator, several Master's level

data management and computer programming staff, as well as staff

involved with medical record review. Ongoing academic relationships

are maintained with many collaborators nationally and internationally.

In Los Angeles, these include the UCLA Schools of Medicine and Public

Health, California State University at Dominquez Hills, and the Los

Angeles

>

> County Department of Health Services.

>

> Areas of VSD Research Activity

>

> Ongoing VSD studies being led by UCLA/SCKP include evaluations of

several potential vaccine-associate adverse events including aplastic

anemia, acute flaccid paralysis (initially related to oral polio

vaccine), and neonatal and infant mortality. UCLA/SCKP is also

conducting studies of hepatitis A vaccine, the safety of vaccination

in premature infants, and the impact on gender on vaccine safety.

Lastly, UCLA/SCKP is currently piloting an innovative project that

develops real time computer linkages between the Kaiser immunization

tracking system and the national Vaccine Adverse Event Reporting

system. Successful integration of these systems may serve as a model

nationally. The UCLA/SCKP site also contributes to ongoing

collaborative VSD projects including assessment of influenza vaccine

safety in children, thimerosal-containing vaccines on infant

neurodevelopment, and rapid surveillance for disease detection of

bioterroristic importance.

>

> For Further Information Please Contact:

>

> Ken Zangwill, MD

>

> UCLA Center for Vaccine Research

>

> 1124 W. Carson Street

>

> Torrance CA 90502

>

> Phone: 310-781-3636

>

> kzangwill@...

>

> 38

>

> VSD Publications

>

> 2001, 2002 & 2003

>

> Barlow WE. RL. Glasser JW. PH. RS. Mullooly

JP. Black SB. Shinefield HR. Ward JI. Marcy SM. DeStefano

>

> F. Chen RT. Immanuel V. Pearson JA. Vadheim CM. Rebolledo V.

Christakis D. Benson PJ. N. Centers for Disease Control and

>

> Prevention Vaccine Safety Datalink Working Group. The risk of

seizures after receipt of whole-cell pertussis or measles, mumps,

>

> and rubella vaccine. New England Journal of Medicine 2001, 345:656-61.

>

> Chang EJ, Zangwill KM, Lee H, Ward JI. Lack of association between

rotavirus infection and intussusception: implications for use

>

> of attenuated rotavirus vaccines. Pediatr Infect Dis J 2002; 21:97-102

>

> Chen RT, DeStefano F, Pless R, Mootrey G, Kramarz P, Hibbs B.

Challenges and Controversies in Immunization Safety. Infectious

>

> Disease Clinics of North America 2001; 15: 21-39.

>

> Coplan P. Black S. Rojas C. Shinefield H. Ray P. E. Guess H.

Incidence and hospitalization rates of varicella and herpes zoster

>

> before varicella vaccine introduction: a baseline assessment of the

shifting epidemiology of varicella disease. Pediatric Infectious

>

> Disease Journal 2001 20(7):641-5.

>

> RL, Kramarz P, Bohlke K, RS, Mullooly J, Black S,

Shinefield H, Ward J, Marcy M, sen E, N, DeStefano

>

> F, Chen R. Measles-Mumps-Rubella and Other Measles-Containing

Vaccines Do Not Increase the Risk for Inflammatory Bowel

>

> Disease. A Case-Control Study From the Vaccine Safety Datalink

Project. Arch Pediatr Adolesc Med 2001;155:354-359.

>

> RL, Lieu TA, Mell LK et al. Impact of the Change in Polio

Vaccination Schedule on Immunization Coverage rates: A Study in

>

> Two Large Health Maintenance Organizations. Pediatrics 2001; 107:

671-676.

>

> DeStefano F. Mullooly JP. Okoro CA. Chen RT. Marcy SM. Ward JI.

Vadheim CM. Black SB. Shinefield HR. RL. Bohlke K.

>

> Childhood vaccinations, vaccination timing, and risk of type 1

diabetes mellitus. Pediatrics 2001;108:e112-3.

>

> Destefano, F., Gu, D., Kramarz, P., et al. Childhood Vaccinations

and Risk of Asthma. PIDJ 2002;21:498-504.

>

> DeStefano F, Verstraeten T, LA; et al. Vaccinations and Risk

of Central Nervous System Demyelinating Diseases in Adults.

>

> Archives of Neurology 2003. 60:504-509

>

> LA, Austin G, Chen RT, Stout R, DeStefano F, Gorse GJ,

Newman FK, Yu O, Weniger BG. Safety and immunogenicity of

>

> varying dosages of trivalent inactivated influenza vaccine

administered by needle-free jet injectors. Vaccine 2001;19:4703-9.

>

> LA, Yu O, Heckbert S, et al. Influenza Vaccination Is Not

Associated With A Reduction In the Risk Of Recurrent Coronary

>

> Events. AJE 2002;156:634-640.

>

> LA. Neuzil KM. Yu O. Benson P. Barlow et al. Vaccine Safety

Datalink. Effectiveness of pneumococcal polysaccharide

>

> vaccine in older adults. New England Journal of Medicine.

348(18):1747-55, 2003 May 1.

>

> Kramarz P, France EK, Destefano F, Black SB, Shinefield H, Ward JI,

Chang EJ, Chen RT, Shatin D, Hill J, Lieu T, Orgren JM.

>

> Population-based Study of Rotavirus Vaccination and Intussusception,

PIDJ 2001:20; 410-6.

>

> 39

>

> Kramarz P, DeStefano F, Gargiullo P, Chen RT, Lieu TA, RL,

Mullooly JM, Black SB, Shinefield HR, Bohlke K, Ward JI, Marcy

>

> SM. Does influenza vaccination prevent asthma exacerbations in

children? Journal of Pediatrics. 2001;138(3):306-10

>

> E, Shinefield HR, Woodruff BA, Black SB, DeStefano F, Chen RT,

Ensor R. Safety of neonatal hepatitis B vaccine administration.

>

> Pediatr Infect Dis J 2001; 20: 1049-1054.

>

> Lieu TA, RL, Capra AM, et al. Variation in Clinician

Recommendations for Multiple Injections During Adoptions of Inactivated

>

> Polio Vaccine. Pediatrics 2001; 107:e49.

>

> Lieu TA, Black SB, Ray GT, KE, Messonnier ML, Shinefield HR,

Weniger BG. The hidden costs of infant vaccination. Vaccine

>

> 2001;19:33-41.

>

> Mullooly, J, Pearson J, Drew L, et al. Wheezing lower respiratory

disease and vaccination of full-term infants. Pharmacoepidemiology

>

> and Drug Safety 2002; 11:21-30.

>

>

>