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Monitoring the Safety of Influenza A (H1N1) 2009 Monovalent Vaccines Claudia Vellozzi, MD, MPH Immunization Safety Office Division of Healthcare Quality Promotion Centers for Disease Control and Prevention Atlanta, GA November 18, 2009

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Monitoring the safety of influenza a h1n1 2009 monovalent vaccines l.jpg

Monitoring the Safety of Influenza A (H1N1) 2009 Monovalent Vaccines

Claudia Vellozzi, MD, MPH

Immunization Safety Office

Division of Healthcare Quality Promotion

Centers for Disease Control and PreventionAtlanta, GA

November 18, 2009

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Overall Objectives for 2009 H1N1 Vaccine Safety Monitoring

Identify clinically significant adverse events following receipt of 2009 HINI vaccine in a timely manner

Rapidly evaluate serious adverse events following receipt of 2009 H1N1 vaccine and determine public health importance

Evaluate if there is a risk of Guillain-Barré syndrome (GBS) associated with the 2009 H1N1 vaccine

Communicate vaccine safety information in a clear and transparent manner to healthcare providers, public health officials, and the public

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Today’s Objectives

  • Describe the CDC’s Immunization Safety Office surveillance systems for monitoring the safety of 2009 H1N1 vaccine

  • Provide preliminary data from each of these systems

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Vaccine Safety Datalink (VSD): Background

  • Established in 1990

  • A collaborative project among CDC and 8 managed care organizations (MCOs)

  • Allows for planned immunization safety studies as well as timely investigations arising from

    • hypotheses from medical literature and pre-licensure

    • reports to the Vaccine Adverse Event Reporting System (VAERS)

    • changes in immunization schedules, or the introduction of new vaccines

  • Since 2005, conducts routine Rapid Cycle Analysis (RCA) of newly licensed and approved vaccines or modifications to existing vaccine recommendations

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VSD Population

  • Collects medical care and vaccination data on more than 9.5 million members annually (3.1% of the US population)

  • As of 12/31/2008:

    • 2,252,024 children (<18) enrolled

      • 3.0% of US population

    • 7,245,835 adults (≥18) enrolled

      • 3.1% of US population

    • Average yearly birth cohort ~ 95,000

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Group Health Cooperative

Health Partners

Marshfield Clinic


Kaiser Permanente Colorado

So. CA Kaiser Permanente


VSD Sites: 2009

Northwest Kaiser Permanente

Harvard Pilgrim

No. CA Kaiser Permanente

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Hospital discharge diagnosis codes

Enrollment and demographics


Linked by Study IDs

Outpatient and Clinic visits

Birth and death certificate information

VSD Data Files + Chart Review

Immunizations Records

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VSD 2009 H1N1 Vaccine Safety Monitoring Specific Aims

  • Conduct rapid surveillance of 2009 H1N1 vaccine safety using

    • self controlled case series (SCCS) using binomial maximized sequential probability ratio tests (maxSPRT)

    • comparisons with historical seasonal influenza vaccines using Poisson maxSPRT

  • Conduct comprehensive analyses after immunization program is completed of associations between H1N1 vaccine and adverse events using a variety of statistical methods

    • Confirmatory Logistic Regression, SCCS, others (as needed)

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  • Vaccination

  • ------------------------------------------------------------------------------------------- Days -56 -15 0 42 84

  • Unexposed (pre)ExposedUnexposed (post)

  • SCCS Example

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    VSD 2009 H1N1 Vaccine Adverse Events under surveillance

    • GBS – first ever and first in a year diagnosis, complemented by chart review

    • Demyelinating disease

    • Disorders of the peripheral nervous system and neuropathies

    • Seizures (epilepsy, convulsions)

    • Encephalitis, myelitis, encephalomyelitis

    • Bell’s Palsy

    • Other cranial nerve disorders (Facial nerve disorders, Trigeminal nerve disorders)

    • Ataxia (other cerebellar ataxia, ataxia)

    • Anaphylaxis

    • Angioneurotic edema, Allergic Reaction, Urticaria

    • Myocarditis and pericarditis (LAIV only)

    • Hemorrhagic stroke (subarachnoid hemorrhage, intracerebral hemorrhage, other and unspecified intracranial hemorrhage)

    • Ischemic stroke (excludes transient ischemic attack)

    • Wheezing (LAIV only)

      • Asthma, wheezing, respiratory distress/insufficiency, other diseases of trachea/bronchi

      • Multiple definitions with and without bronchiolitis

  • Pregnancy Outcomes –

    • Spontaneous Abortions, Stillborn & Pre-eclampsia, eclampsia

  • Adjuvanted Outcomes –

    • Autoimmune hepatitis and Thrombocytopenia

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    VSD 2009 H1N1 Vaccine Pregnancy Studies

    • Active surveillance in pregnant women

      • Outcomes: Fever (>100° F),allergic reactions, miscarriage, stillbirth, premature labor and preeclampsia (includes 2 VSD sites)

    • Retrospective analysis evaluating the safety of 2009 H1N1 vaccines in pregnant women and their offspring (includes all VSD sites)

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    VSD 2009 H1N1 Vaccine Pregnancy Studies

    Conduct a survey of pregnant women who receive any combination of seasonal or H1N1 vaccines or refuse vaccination (includes one VSD site)

    Specific Aims

    • Assess where and when pregnant women are vaccinated and if not vaccinated—why not

    • Accurately capture pregnancy related start dates for future linkage with the electronic medical record

    • Assess non-medically attended AEs

      • Systemic and local reactions (Fever, chills, headache, swelling, etc.)

      • ILI and URI symptoms, GI symtoms, sleep disturbances, other

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    2009-10 Seasonal Trivalent Inactivated Influenza Vaccine (TIV): SCCS –preliminary results

    TotalDoses Administered– 2,045,127

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    2009-10 Seasonal TIV (TIV): SCCS –Historical Comparison-preliminary results

    Total Doses Administered: 2,045,127

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    2009 H1N1 MIV: (TIV): SCCS –Historical Comparison-Preliminary Results

    Total Doses Administered – 206,150

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    Summary (TIV): SCCS –

    • No potential associations or signals have been identified following the monitoring of 2009-10 Seasonal TIV (2,045,127) and LAIV (100,366) doses

    • 2009 H1N1 influenza vaccines have only recently begun to be administered in the VSD MCOs and data are insufficient to assess the safety of the vaccines

    • The VSD will continue to monitor both seasonal and H1N1 influenza vaccines on a weekly basis

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    EIP Guillain-Barr (TIV): SCCS –é Syndrome (GBS) Surveillance Project:Association of Influenza A (H1N1) 2009 Vaccine and GBS

    Eip gbs surveillance sites 2009 2010 l.jpg

    New York (TIV): SCCS –







    New Mexico


    Population: ~ 44.9 million

    EIP GBS Surveillance Sites, 2009-2010


    Eip guillain barr surveillance gbs surveillance project l.jpg
    EIP Guillain-Barr (TIV): SCCS –é Surveillance (GBS) Surveillance Project

    • CDC's Emerging Infections Program (EIP)

      • partnership of state and local health departments, academic centers, and CDC

      • performs surveillance and public health research on emerging infections

    • October 1, 2009 time limited surveillance for GBS

    • Objectives:

      • Rapidly detect cases of GBS and report (with vaccination status)

      • Assess and measure if there is an association between 2009 (H1N1) vaccine and GBS

    • Methods:

      • Population ~45 million persons (statewide in CT, MD, MN, NM, TN and selected regions of CA, CO, GA, NY, and OR)

      • Active network of neurologists and acute care facilities contacted weekly

      • Report all GBS cases, standardized case finding, medical record abstraction, patient interviews

      • Calculation of measures of association

    Eip guillain barre surveillance case finding l.jpg

    reported weekly (TIV): SCCS –

    to CDC

    10 EIP (40 million)


    1, 2


    Clinical Network *

    Active Case-Finding

    Possible Cases




    Patient Interviews

    Record review;

    contact provider;

    antecedent & vaccine history


    Hospital discharges

    Passive provider reporting

    (reportable condition)

    AAN educational initiative;





    Exclusion (non-cases)

    [Brighton not met or other neurologic diagnosis]


    at 14 days

    EIP Guillain-Barre Surveillance Case Finding

    * Weekly query with established network of neurology providers, sentinel pharmacies

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    Descriptive Epidemiology of GBS Active Case Finding, Oct 1-Nov 9, 2009


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    Select Methods Using Vaccine Coverage Data 2009

    • Observed vs. historical GBS rates

      • Compares observed no. GBS cases occurring within 42 days of H1N1 vaccination to expected no. among vaccinees

      • Earliest incidence metric

      • Limitations:

        • historical rate comparison (may not be valid comparison, different case finding)

        • Initially only crude, or age-specific with assumptions on vaccine administration

        • With BFRSS data, fewer assumptions needed for age-specific comparisons

    • GBS rates in vaccinated vs. unvaccinated persons

      • Use BFRSS vaccine coverage data, calculate person-time exposed and unexposed to vaccine, calculate rates

      • Strength: rates in vaccinated and unvaccinated persons will both be calculated from active surveillance data

      • Limitations

        • BRFSS data not available until mid-November and may only be available at the state level (not EIP catchment area specific)

    • GBS rates in H1N1 vaccinated vs. seasonal vaccine recipients

      • Use BFRSS vaccine coverage data

      • Age-adjust

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    Real Time Immunization Monitoring System (RTIMS) 2009


    • Johns Hopkins Bloomberg School of Public Health (JHU)

    • CDC ISO (AHIP)

    • WorldAPP (WA)

    • State and local health departments (HD)

    • Hospitals, schools, clinics, pharmacies

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    RTIMS 2009

    • Automated web-based surveillance system

    • Captures self reported data from vaccine recipients

    • Predecessor: Telewatch

      • Used for monitoring patients with chronic diseases

      • Modified for monitoring yellow fever vaccine1

      • Piloted for influenza vaccine November 2008

    • Capacity:

      • On line and database: 1-10 million vaccine recipients

      • Follow-up personnel: expandable

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    Objectives 2009

    To monitor influenza vaccine recipients for adverse events (early signal detection)

    To identify host factors associated with adverse events

    To compare rates of adverse events associated with different influenza vaccine products

    To expedite reporting of AEs to VAERS

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    Study Population 2009

    Seasonal & 2009 H1N1 Influenza vaccine recipients

    Target population – Pregnant women, health care workers, school aged children

    State & local health departments, hospitals, schools and OB clinics

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    Timeline for Surveys 2009




    Follow up





    Day 2 Day 7 Day 42

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    Study Information Card 2009Provided at Time of Vaccination

    Front Back

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    RTIMS Information Flow 2009

    Permission to Contact

    at Time of Vaccination








    website sign-up


    CDC, JHU, HDs



    Data entry



    RTIMS Survey

    3-4 min initial

    <1 min follow-up

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    4,730 Baseline Surveys 2009by Risk Group and Genderas of Nov 9, 2009

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    Type of Vaccine Received 2009by Risk Groupas of Nov 9, 2009

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    Diagnoses after Flu Vaccine 2009by Vaccineas of Nov 9, 2009

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    Limitations 2009

    • Surveys after vaccination

    • Possible selection bias:

      • Females more likely to participate

      • Persons with reactions more likely to complete?

      • Drop outs?

    • Some reluctance to have VAERS form filed

      • name and contact information

    • Active solicitation of symptoms

      • Some multiple symptoms

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    Acknowledgements 2009

    • VSD

      • Eric Weintraub

      • James Baggs

      • Frank DeStefano

    • CDC/EIP

      • Melissa Viray

      • Paige Lewis

      • Oliver Morgan

      • Scott Fridkin

    • RTIMS

      • Neal Halsey

      • Rosanna Setse

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    CDC 2009


    SAS Programs, Logs, Output, & Analytical Datasets



    The VSD Distributed Data Model

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    VSD 2009 H1N1 Vaccine Study Design and Analytic Plan 2009

    • Challenges for studying the safety of influenza vaccines

      • Confounding by indication

      • Vaccine recommendations have expanded and changed

      • Influenza vaccines are often given over a very short period of time.

      • Individuals may have received vaccine outside their MCO (count as unvaccinated)

      • Seasonality of adverse events may confound interpretation

    • To address the challenges to monitor 2009 H1N1 safety more than one approach will be included in both:

      • Rapid Cycle Analyses (RCA) weekly surveillance (near real time and critical to rapid safety assessment)

      • End of season analysis

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    VSD 2009 H1N1 Vaccine Adverse Event Definitions safety

    • Risk periods (windows)

      • AE-specific as described in published studies or biologic plausibility

      • Length of windows – vary from 2 to 60 days

      • Day of vaccination included in the risk period if it is biologically plausible for AE to occur same day of vaccination (e.g., anaphylaxis).

    • To improve the specificity

      • Limit to AEs occuring in inpatient or ED settings

      • First event to occur in a year

    • For AEs that may have more than one “new” onset in a year a shorter period of time will be included in analysis (ex;wheezing, seizures)

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    How the VSD Evaluates Signals safety

    • Check data quality

    • Check inputs, background incidences, i.e. temporal trends

    • Check whether comparison groups are defined appropriately

    • Conduct the analysis using a different control group (e.g., concurrent vs. historical) or different vaccine

    • Conduct a temporal scan to see if outcomes cluster during a post-vaccination time window

    • Conduct a definitive study using logistic regression analysis

    • Review charts to confirm or exclude cases as true cases

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    Weekly maxSPRT Results for GBS, safetyAge ≥6 Months, 2007/08 Season

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    Centers For Disease Control, VSD team safety

    James Baggs, PhD

    Julianne Gee, MPH

    Natalie McCarthy, MPH

    Eric Weintraub, MPH

    Kaiser Permanente of No. California (NCK),

    Oakland CA

    Roger Baxter, MD

    Nicky Klein, MD, PhD

    Ned Lewis

    Northwest Kaiser Permanente (NWK),

    Portland OR

    Allison Naleway, PhD

    John Mullooly, PhD

    Karen Riedlinger

    Lois Drew

    Harvard Pilgrim /Harv. Vanguard (HAR)

    Boston, MA

    Tracy Lieu, MD, MPH

    Richard Platt, MD, MSc

    Katherine Yih, PhD, MPH

    Richard Fox

    Grace Lee, MD, MPH

    Sharon Greene, MD, MPH

    Group Health Cooperative (GHC), Seattle WA

    Lisa Jackson, MD, MPH

    Jennifer Nelson, PhD

    Lora Bounds

    Marshfield Clinic Rsch. Foundation (MFC)

    Marshfield WI

    Edward Belongia, MD

    James Donahue, MD

    Nick Berger

    Health Partners Rsch Foundation (HPM)

    Minneapolis MN

    Jim Nordin, MD

    Amy Butani

    Kaiser Permanente of Colorado (KPC)

    Denver, CO

    Simon Hambidge, MD, PhD

    Jason Glanz, MS, PhD

    David McClure, PhD

    Matt Daley, MD

    David Ryerson

    So. California Kaiser Permanente (SCK), CA

    Los Angeles, CA

    Steven Jacobson, MD, PhD

    Wansu Chen, MS

    Sungching Glenn, MS

    VSD Investigators and Collaborators - Partial List

    Sites include > 125 staff working on VSD

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    Case Only Methods safety:

    Descriptive Epidemiology

    Observed vs. Background Rates of GBS:

    Crude and Age-Specific Comparisons

    Estimated GBS Rates in Vaccinated vs. Unvaccinated Persons:

    Crude and Age-Specific Comparisons

    Case-Cohort analysis

    BRFSS Vaccine Coverage Data Available

    Potential Analytic Studies:

    Self Control Case Series (SCCS)









    EIP Guillain-Barre Surveillance Timeline

    Vaccine Delivered

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    4,790 Completed Baseline Surveys safetyby Risk Group and Age Groupas of Nov 9, 2009

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    Diagnoses after Flu Vaccine safetyby Genderas of Nov 9, 2009

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    Daily Visits to safety

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    Links clicked on to arrive at safety

    HITS Entry Link________________________________________________________


    3486 Unknown

    1240 http://

    1123 Entered URL directly

    917 http://

    589 http://

    564 http://

    358 http://

    327 http://

    303 http://

    178 http://

    105 http://

    103 http://

    94 http://

    >60% of traffic comes from the CDC

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    2009-10 Seasonal TIV safetyHistorical Comparison-preliminary results

    Total Doses Administered: 2,045,127