CDC CDC Influenza Vaccine Safety Influenza Vaccine Safety MonitoringMonitoring

Immunization Safety Office (ISO)

Penina Haber John Iskander

Authors have no financial and other conflict of interest

Outline Influenza vaccine usage in the US Vaccine Adverse Event reporting system (VAERS) Influenza season CDC annual seasonal influenza vaccine monitoring:

collaborative project with FDA Challenges:

vaccine schedules, multiple products, new cohort of vaccinee

Summary CDC-FDA influenza vaccine scientific publications

Trivalent Inactivated Influenza Vaccine (TIV)

The most widely used vaccine in adults in the US

The only vaccine annually administered to adults and children

Monitoring seasonal use of influenza vaccine remains the cornerstone of public health strategies to reduce morbidity and mortality of influenza virus infections

* >18 years

Vaccine Adverse Event Reporting System (VAERS)

National passive surveillance ~receives 25,000 reports per year Operated jointly by CDC and FDA Reports are received from Health care

providers, manufacturers, immunization programs, patients and parents

VAERS accepts all reports of any adverse event occurring after any U.S. licensed vaccines

Influenza Season Influenza season: is defined as for all

reports with vaccination date from July first of year one to June 30th of the following year

Serious reports: Reports involving hospitalizations, prolongation of hospitalization, death, life-threatening illness or permanent disability (according to CFR)

Non-serious reports: all other reports

Case Definition

Brighton Collaboration is a global effort to promote comparability of vaccine safety data through primarily developing case definitions and guidelines for adverse events following immunization [AEFI].

e.g. GBS, anaphylaxis's, local reactions, seizures http://www.brightoncollaboration.org/internet/en/index.html

Influenza Vaccine Monitoring Monitoring of adverse events reports following

influenza vaccine, a joint effort with FDA include: Daily e-mail alerts and review of new serious

adverse event reports (AE’s) Weekly electronic summary tables and line lists:

reports by severity level, most frequently reported AE’s by age-group and products

Safety profiles - comparing the different influenza products by age and most frequently reported outcomes

Comparing death, non-fatal and GBS reports the current seasons vs. previous seasons (at a specific date each season)

Influenza Vaccine Monitoring (continued)

Weekly conference calls with FDA to review most recent reports of interest, reporting trends and potential concerns (signals)

Since 1994, verification (questionnaire) of all suspected GBS reports to VAERS following all influenza vaccine (all ages)

Influenza Vaccine Monitoring: Challenges

Influenza vaccine composition changes each season

Denominator data (doses administered) Not available by age and/or vaccine combination

Increased complexity Vaccination in age groups who previously were not

widely vaccinated Increase number of vaccine manufacturers and

number of AE’s Timely safety evaluation of new products and

potential new/rare AE’s

Annual Influenza Vaccination Recommendations Since 2000

2000: All adults 50 and older 2004:

All children aged 6 - 23 months All contacts of children aged 0 - 23 months All women who will be pregnant during influenza season

2005: All persons with any condition that can compromise respiratory function or the handling of respiratory secretions

2006: All children aged 24 - 59 months and their household contacts and out-of-home caregivers

2008: All children aged 6 months through 18 years

Approved Influenza Vaccines, United States, 2008-09 Season

VaccineTrade Name

Manufacturer Presentation Age Group Thimerosal Preservative

TIV Fluzone Sanofi Pasteur

.25 mL prefilled syringe 6 - 35 mo None

0.5 mL prefilled syringe > 36 mo None

0.5 mL vial; > 36 mo None

5.0 mLmulti-dose vial

> 6 mo Yes

TIV Afluria CSL

0.5 mLprefilled syringe > 18 years

None

5.0 multi-dose vial Yes

TIV Fluvirin Novartis Vaccine

0.5 mLprefilled syringe

> 4 years

Preservative free(<1 mcg mercury/dose)

5.0 mLmulti-dose vial

Yes

TIV Fluarix GSK0.5 mL

prefilled syringe> 18 years

Preservative free(<1 mcg mercury/dose)

TIV FluLaval GSK/IDB5.0 mL

multi-dose vial> 18 years Yes

LAIV FluMist MedImmune Single-dose sprayer2 - 49 years,

healthyNone

Cumulative Monthly Influenza Vaccine Distribution

(*Through 12/28/2007)

70.4

57.1

0

20

40

60

80

100

120

July Aug Sept Oct Nov Dec Jan Feb

2000 2002 2004-05 2005-06 2006 2007

Do

ses

(Mill

ion

s)

83.0 81.2

102.5

*

115.4

Most Frequently Reported Adverse Events (VAERS), 1990 - 2008

Serious AEs (N=3199) Guillain-Barré-syndrome

(20%) Fever (19%) Asthenia (17%) Paresthesia (14%) Pain (13%)

Non-serious AEs (N=21549) Pain (17%) Fever (16%) Injection site pain (14%) Pruritus (12%) Myalgia (10%)

Pediatric VAERS Reports Following TIV by Season and Age

0

50

100

150

200

250

300

350

400

450

500

<1990

1990-1

991

1991-1

992

1992-1

993

1993-1

994

1994-1

995

1995-1

996

1996-1

997

1997-1

998

1998-1

999

1999-2

000

2000-2

001

2001-2

002

2002-2

003

2003-2

004

2004-2

005

2005-2

006

2006-2

007

2007-2

008*

Season of Influenza Vaccination

* Reports received as of July 2008

Nu

mb

er

of

Rep

ort

s 2 to 5 years

5 to 17 years

Summary Seasonal annual monitoring of influenza

vaccine AE’s is well coordinated among CDC and FDA

CDCFDA collaborative monitoring of influenza AE’s addresses all aspects of vaccine safety activities: Public/ media response Daily review Analytical review (safety profile, reporting

rates calculations) Weekly and monthly calls Scientific publications (e.g., peer-review,

letters to the editor, MMWR)

VAERS system enables CDC-FDA to monitor and assess the safety of various influenza products in timely manner (e.g., GBS)

Expansion of annual influenza recommendation are challenging and complex

Summary - Continued

CDC-FDA Influenza Vaccine Safety(Publications)

Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barré syndrome and the 1992-1993 and 1993-1994 influenza vaccines. N Engl J Med 1998 Dec 17; 339 (25): 1797-802

Haber P, DeStefano F, Angulo F, Iskander J, Shadomy S, Chen RT. Guillain-Barré- syndrome (GBS) following influenza vaccine. JAMA. 2004; 292: 2478-2481

Zhou W, Pool V, DeStefano F, Iskander J, Haber P, Chen RT, VAERS team. 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. Phamacoepi Drug Safety. 2004; 13:505-510

Izurieta H, Haber P, Wise R, Iskander J, Pratt D, Mink C, Chang S, Braun MM, Ball, R. Early postmarketing  surveillance of live, cold-adapted, intranasal influenza vaccine. JAMA. Dec 2005; 294:2720-2725

McMahon AW, Iskander J, Haber P, Chang S, Woo EJ, Braun MM, Ball R. Adverse events after inactivated influenza vaccination among children less than 2 years of age: analysis of reports from the Vaccine Adverse Event Reporting System, 1990-2003. Pediatrics. 2005;115(2):453-60.

Iskander J, Broder K. Monitoring the safety of annual and pandemic influenza vaccines: lessons from the US experience. Expert Review of Vaccines 2008;7(1):75–82.

CDC-FDA Influenza Vaccine Safety(Publications) - Continued

VAERS influenza team CDC/FDA Lewis Page (ISO) Dale Burwen (FDA) Gary Euler (ISD) Tony Fiore (NCIRD) Greg Wallace (ISD)

Acknowledgements

Thank You

GBS and the Association with the Swine Influenza Vaccine - (1976-1977)

Concerns about the risk of developing GBS after influenza vaccination have been present since the association was first noticed during 1976-77 (swine influenza) vaccination campaign Relative risks ranged from 4.0-7.6 for 6-or 8 weeks

periods after vaccinations. Subsequent studies of GBS and influenza

vaccines found low relative risks that were not statistically significant.

Lasky et. al Study Study was initiated du to doubling of GBS

reports to VAERS during 1992-93 and 1993-94 seasons

Study conducted among patients given DX of GBS in 4 states

The relative risk of GBS associated with vaccination adjusted for age, sex and vaccine season was 1.7 for the 2 seasons combined

Attributable risk of 1 additional case of GBS per million individuals vaccinated.

Reporting Rates Of GBS and Non-GBS* Following Influenza Vaccination, VAERS

July 1990 – June 2005

0

0.02

0.04

0.06

0.08

0.1

0.12

0.14

0.16

0.18

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

03

-04

04

-05

Influenza season

GB

S r

eport

ing r

ate

s p

er

100,0

00 v

acc

inati

ons

0

0.5

1

1.5

2

2.5

3

Non-G

BS r

eport

ing r

ate

, per

1000,0

00 v

acc

inati

ons

GBSnon-GBS

** Heber et. Al., JAMA. 2004; 292 : 2478-2481

Adults >18 years; Guillain-Barre-

Syndrome (GBS) accounted for a quarter

of all the serious reports and showed a

significant decline over time

VAERS Flu GBS Follow-up Study, VAERS 1994 - 2003

# Schonberger et al. reported prior illness in 62% unvaccinated vs. 33% in vaccinated

Results N Percentage %

All Reports 323 100

GBS Diagnosis – Verified 264 82

Non-GBS - Verified 26 8

Lost to Follow-up 33 10

Prior Influenza Vaccination 105 33

Prior illness within 4 weeks # 76 24

Onset-Interval of GBS and Non-GBS Following influenza Vaccine in VAERS

1990-2003

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8

onset-interval (week)

% o

f rep

orts

GBS Non-GBS