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Monitoring of Influenza Vaccine Safety in Healthy Children and Adults.ppt

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Monitoring of Influenza Vaccine Safety in Healthy Children and Adults.ppt Powered By Docstoc
					 Monitoring of Influenza
Vaccine Safety in Healthy
  Children and Adults

          John Iskander MD MPH
        Immunization Safety Office
    Office of the Chief Science Officer



                                          TM
      Outline of Presentation
• Overview of major U.S. post-licensure safety
  surveillance systems
   – Vaccine Adverse Event Reporting System (VAERS):
     passive, national
   – Vaccine Safety Datalink (VSD): active, population based

• Key recent studies
   – Pediatric inactivated vaccines (TIV)
   – Neurological adverse events
      • Bell’s palsy
      • Guillain-Barre Syndrome (GBS
   – Live attenuated influenza vaccine (LAIV)

                                                               TM
Key systems used to study
      vaccine safety




                            TM
Vaccine Preventable Disease
    (VPD) Surveillance

• A “3 legged stool”;
  monitoring for:

   – Disease levels
   – Vaccine coverage
   – Adverse events
     (AE)



                              TM
  Establishing Causal Link:
 Adverse Event and Vaccine
                                                        Illness or
                                                        Syndrome
                                                   Yes           No

Rate in vaccinated     a/a+b
                                             Yes    a            b

                               Vaccination
Rate in unvaccinated   c/c+d

                                             No     c            d




                                                                      TM
  The Vaccine Adverse Event
  Reporting System (VAERS)
• The “early warning system” of vaccine safety
  surveillance
• A national passive surveillance system jointly
  operated by the CDC and the FDA
• Established in 1990
• Accepts reports from physicians, other health
  care providers, and the public
• “Hypothesis generating”; seeking signals of
  potential concern
                                                   TM
       Influenza Vaccine Reports to
           VAERS, 7/1/90-6/31/04
                                                   Flu reports      net doses

                                                 year (vaccination       date)
3500                                                                                                                        90

                                                                                                                            80
3000

                                                                                                                            70
2500
                                                                                                                            60

2000                                                                                                                        50


1500                                                                                                                        40

                                                                                                                            30
1000
                                                                                                                            20

500
                                                                                                                            10

  0                                                                                                                         0
       90-91   91-92   92-93   93-94   94-95   95-96   96-97     97-98     98-99   99-00   00-01   01-02   002-03   03-04


                                                                                                                            TM
Influenza Reports by Age,
      7/1990 - 6/2004
           40
           35
           30
% report




           25
           20
           15
           10
            5
            0
                1-17   18-49   50-64   65+ missing
                        age-group (year)




                                                     TM
         Most Frequently Reported
       Influenza Vaccine Associated
           Events, 7/1990 - 6/2004
      • Children                            • Adults
          (<18 years old)                          (>18 years old)
          – Reactions at the                       – Reactions at the
            injection site                           injection site
          – Fever                                  – Vasodilatation
          – Pain and swelling                      – Fever
            at the injection site                  – Pain
          – Vasodilatation                         – Myalgia

•Reports typically involve more than one symptom
                                                                        TM
 The Vaccine Safety Datalink
           (VSD)
• 8 geographically diverse HMO’s that participate in
  a LLDB which tracks:

   – Vaccination (exposure)
   – Outpatient, emergency department (ED), hospital and
     lab data (health outcomes)
   – Demographic variables (confounders)

• Covers about 3% of U.S. population

• “Hypothesis testing” system
                                                           TM
    Investigation of safety
 concerns among expanded
target populations: studies in
       6-23 month olds



                                 TM
       Number of VAERS reports after TIV
        among children <2 years of age,
         according to influenza season




McMahon A, Iskander J, Haber P et al. Pediatrics. 2005 Feb;115(2):453-60   TM
      Conclusion: VAERS Reports in
       Children Aged < 2 after TIV

• The safety profile of TIV in children aged <2 years
  was similar before and after pediatricians were
  encouraged to vaccinate healthy children in this age
  group.

• The number of VAERS reports dramatically increased,
  most likely due to an increase in the number
  of doses administered

• The percentage of report subjects with underlying
  medical condition decreased in the last 3 years, but
  remains at 40%.

   – Asthma is the most frequent underlying medical condition.
                                                                 TM
     VSD Screening Analysis
• Safety of Trivalent Inactivated Influenza Vaccine (TIV)
  Among Children: A Population-Based Study
  Kaiser Permanente Colorado
  (E. France et al, Arch Pediatr Adolescent Med,
  November 2004)

• Objective: To screen a large cohort of children who
  received the TIV for evidence of medically attended
  events (MAE) following vaccination (“hypothesis
  generating”)

• Total cohort 251,600 children < 18; received 438,167
  doses of TIV across 6 influenza seasons

                                                            TM
Method: Retrospective Analysis using “self control"


                          Risk Period:
                           Days 1-14




                        Flu
                     Vaccination         Control Group 2:
  Control Group 1:
   Days -28   -14      Day 0               Days 15 - 28


                                                          TM
    VSD Study Conclusions for
         6-23 month olds

• No signal of a serious medical outcome occurring
  more often in the two weeks following influenza
  vaccination

• No neurologic outcomes identified in the two
  week period following vaccination

• Impetigo signal identified (n=9), no obvious
  pattern in site of infection

                                                     TM
  Rare serious events:
Guillain-Barré Syndrome
 (GBS) and Bell’s Palsy
      as examples



                          TM
      A/New Jersey/1976 “Swine
        Flu” Vaccine and GBS
• 1976 National Influenza Immunization Program A/New Jersey
  “Swine Flu” mass vaccination campaign mounted due to fear of
  flu pandemic

• Program to provide vaccine for most of the adult U.S.
  population and for at risk children

• Program halted following reports of GBS after vaccine

• Later studies confirmed association between A/NJ/1976
  vaccine and GBS
   – Attributable risk (AR) estimates for GBS in the 6 weeks after vaccination

      ranged from 4.9 to 11.7 cases per million vaccinated
                                                                                 TM
 GBS and the 1992-1993 and
1993-1994 Influenza Vaccines
• Case-Control study conducted due to doubling of GBS
  reports after influenza vaccine seen in VAERS in
  1993-94 season

• No significant increase in risk of vaccine-associated
  GBS from 92-93 to 93-94 vaccines

• For both seasons combined, adjusted relative risk of 1.7
  (95% CI 1.0-2.8) suggests slightly more than one
  additional case of GBS per million persons vaccinated

   – Lasky et al. NEJM. 1998 Dec 17;339(25):1797-802


                                                             TM
 GBS and non-GBS Reporting
  Rates Following Influenza
Vaccination, VAERS 1990-2003
                                                                                                                                                                      GBS
                       0.18                                                                                                           3                               non-GBS




                                                                                                                                            Non-GBS reporting rate,
 GBS reporting rates




                       0.16
                                                                                                                                      2.5
    vaccinations




                       0.14
    per 100,000




                                                                                                                                                per 1000,000
                                                                                                                                                 vaccinations
                       0.12                                                                                                           2
                        0.1
                                                                                                                                      1.5
                       0.08
                       0.06                                                                                                           1
                       0.04
                       0.02
                                                                                                                                      0.5
                         0                                                                                                            0
                              90-91
                                      91-92
                                              92-93
                                                      93-94
                                                              94-95
                                                                      95-96
                                                                              96-97
                                                                                      97-98
                                                                                              98-99
                                                                                                      99-00
                                                                                                              00-01
                                                                                                                      01-02
                                                                                                                              02-03


                                                      Influenza season
    Haber P et al. JAMA. 2004 Nov 24;292(20):2478-81
                                                                                                                                                                                TM
GBS Reporting Rates by Age
and Influenza Season, VAERS
          1990-2003
                    0.25
Rates per 100,000




                     0.2
   vaccinations




                    0.15                                                                                                           18-49
                                                                                                                                   50-64
                     0.1                                                                                                           65+

                    0.05


                      0
                           90-91

                                   91-92

                                           92-93

                                                   93-94

                                                           94-95

                                                                   95-96

                                                                           96-97

                                                                                   97-98

                                                                                           98-99

                                                                                                   99-00

                                                                                                           00-01

                                                                                                                   01-02

                                                                                                                           02-03
                                                           Influenza season


                                                                                                                                           TM
 Influenza Vaccine and GBS:
 Systematic Evidence Review
• Institute of Medicine reviewed evidence for causal
  link between influenza vaccines and GBS in 2003

• 1976 Swine Flu (A/NJ/1976) vaccine
   – Evidence favors a causal relationship

• All other years
   – Evidence inadequate to accept or reject a causal
     relationship

• IOM recommendations:
   – Analysis of 1976 Swine Flu vaccine, if available, for
     presence of possible causative agents for GBS

                                                             TM
Bell’s Palsy: Initial Signal

• Nasalflu (Berna Biotech) introduced mainly to the
  German- speaking part of Switzerland in 10/2000
   – Inactivated intranasal vaccine
• 46 cases of Bell’s palsy among recipients of Nasalflu
  were reported between 10/2000 and 4/2001
• Substantial media coverage 3/2001+
• Distribution suspended
• Case-control investigation initiated 5/2001
• Nasalflu Berna exposure (ever exposed)
  significantly increased the risk for Bell’s palsy:

                                 OR            95% CI
Nasalflu Berna                   114          15 - 830


                                                          TM
   Follow-up study in VAERS
• A Potential Signal of Bell’s Palsy after Parenteral
  Inactivated Influenza Vaccines: Reports to the Vaccine
  Adverse Event Reporting System (VAERS) - United States,
  1991-2001 (Pharmacoepi and Drug Safety 2004; 13: 505-510)
  Weigong Zhou MD, PhD et al.


   – 154 verifiable Bell’s palsy reports after influenza
     vaccines in VAERS from 1991 – 2001.
   – These reports may signal a possible association
     between influenza vaccines and an increased risk of
     Bell’s palsy.
   – A population-based controlled study has been
     undertaken in the VSD


                                                              TM
Figure 1. Onset Interval* of Bell’s palsy after influenza vaccines in the
Vaccine Adverse Event Reporting System (VAERS)
               45
               40
               35
               30
  % of Total




               25
               20
               15
               10
               5
               0
                      0        1-3      4-10     11-30     31-60     60+       Unk
                                          Onset Interval (Day)
               Bell's palsy after flu vaccines   All Adverse Events after all vaccines
                                                                                         TM
   Investigation of safety
concerns for a newly licensed
  product: LAIV (fluMist®)



                                TM
    Safety surveillance for LAIV in
          VAERS: Overview
• One million fluMist® doses distributed during first
  season*
      *Source: Minutes ACIP meeting, February 21-22, 2004

• Reports received from 9/1/2003 – 5/10/2004:
   – 278 (28 per 100,000 doses distributed)

• 23 (8%) serious events, including hypersensitivity
  reactions, respiratory, and neurological events
   – No deaths reported

     (Data in press by Izurieta et al)                      TM
         Summary of 1st year LAIV
           safety surveillance
• Overall reassuring findings:
   – No deaths or secondary transmission to immunodeficient
     contacts reported
   – Small proportion (8%) of reports were serious
   – Most findings expected based on results from clinical trials

• Notable events:
   – 15% of reports indicate use outside of labeled
     recommendations
   – Serious events in patients with history of wheezing/asthma
   – Hypersensitivity reactions including possible anaphylaxis
   – 1 GBS case; causal relationship to vaccination not known


                                                                    TM
      Safety challenges with
      expanded vaccine use
• Use of existing safety systems, or development
  of new freestanding ones?
• Limited resources
   – As an example, VAERS currently operates with annual
     funding of $0.009 per capita
• Development of clinical networks
   – Clinical Immunization Safety Assessment Network
     (CISA)
• Routine denominator capture
• Quantifying common events
   – VAERS not optimal due to underreporting; diary cards,
     active surveillance are options

                                                             TM
          Potential Solutions
• Linked numerator/denominator capture
   – VSD “rapid cycle” analysis
   – Linkages with immunization registries
• Enhancements to VAERS
   – Web-based reporting (since 2002), more complete
     reporting, enhanced follow-up, “data mining”
• Bar coding of vaccines and linking with vaccinee
  records
• Ready access to baseline rates of anticipated
  adverse events of interest (VSD, other sources)

                                                       TM
                   Conclusions
• Systems are in place to monitor vaccine safety
   – New enhancements will play a key role

• Self-limited local and systemic reactions to
  influenza vaccine relatively common

• Rare events like GBS, causal or coincidental, will
  likely require focused study

• Expanded influenza vaccine use will pose special
  vaccine safety challenges

   – More safety data, likely of greater complexity
   – Linking of data systems necessary
   – Resource and personnel availability key to response
                                                           TM

				
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