Barré Syndrome and Influenza Vaccine

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(1)

Guillain

Guillain

-

-

Barr

Barr

é

é

Syndrome and Influenza

Syndrome and Influenza

Vaccine

Vaccine

James J. Sejvar, MD; Lawrence B. Schonberger, MD, MPH James J. Sejvar, MD; Lawrence B. Schonberger, MD, MPH

Division of Viral and Rickettsial Diseases Division of Viral and Rickettsial Diseases

National Center for Zoonotic, Vectorborne, and Enteric Diseases National Center for Zoonotic, Vectorborne, and Enteric Diseases

Centers for Disease Control and Prevention Centers for Disease Control and Prevention

Dina Pfeifer, MD, MSc Dina Pfeifer, MD, MSc

Department of Immunization, Vaccines, and Biologicals Department of Immunization, Vaccines, and Biologicals

World Health Organization World Health Organization

Guillain

Guillain-

-

Barré

Barr

é

Syndrome (GBS)

Syndrome (GBS)

ImmuneImmune--mediated polyradiculoneuropathymediated polyradiculoneuropathy

Acute Acute ––subacute subacute ““ascendingascending””limb weakness with decreased limb weakness with decreased reflexes

reflexes

Cranial nerve palsies, respiratory failureCranial nerve palsies, respiratory failure

Several potential mechanisms hypothesizedSeveral potential mechanisms hypothesized

Humoral or cellular immune response to antigenic stimulus, Humoral or cellular immune response to antigenic stimulus, resulting in attack on nerve self

resulting in attack on nerve self--proteinsproteins

Numerous infectious agents and immunizations temporally Numerous infectious agents and immunizations temporally associated

associated

Strongest association with Campylobacter jejuniStrongest association with Campylobacter jejuniinfection infection ––

“molecular mimicrymolecular mimicry””

Incidence increases with age, particularly over 50Incidence increases with age, particularly over 50

Characteristic clinical, laboratory, electrodiagnostic featuresCharacteristic clinical, laboratory, electrodiagnostic features

Outcome generally favorableOutcome generally favorable

Case fatality 5 Case fatality 5 ––10%10%

Neurologic sequelae in 20%Neurologic sequelae in 20%

(2)

GBS and Influenza Vaccine: Methods

GBS and Influenza Vaccine: Methods

All available literature reviewed (limited to controlled studiesAll available literature reviewed (limited to controlled studies))

Use of swineUse of swine--antigen containing influenza vaccines, including antigen containing influenza vaccines, including A/NJ/76 (H1N1), used pre

A/NJ/76 (H1N1), used pre--and postand post--1976 assessed1976 assessed

Archived WHO, CDC, CBER recordsArchived WHO, CDC, CBER records

AFEB recordsAFEB records

Personal communicationsPersonal communications

Comparison data on virologic, molecular characteristics of Comparison data on virologic, molecular characteristics of A/NJ/79 influenza virus, current A/CA/09 virus, other SW

A/NJ/79 influenza virus, current A/CA/09 virus, other SW--OI OI viruses

viruses

Best available data for Best available data for ““backgroundbackground””rates of GBSrates of GBS: :

1.0 1.0 ––1.7 / 100,000 population / year 1.7 / 100,000 population / year in developed countriesin developed countries

When possible, published rates converted to incidence / When possible, published rates converted to incidence / 100,000 for comparison

100,000 for comparison

GBS and A/NJ/76 (H1N1) Vaccine

GBS and A/NJ/76 (H1N1) Vaccine

1976: human1976: human--toto--human transmission of swinehuman transmission of swine--origin H1N1 origin H1N1

influenza virus on US military base

influenza virus on US military base

40 million doses of vaccine among US civilians, military40 million doses of vaccine among US civilians, military

Influenza epidemic never materializedInfluenza epidemic never materialized

““ClusterCluster””of GBS cases noted though AE surveillance early of GBS cases noted though AE surveillance early in campaign

in campaign

Campaign discontinued Dec. 16, 1976Campaign discontinued Dec. 16, 1976

Subsequent assessment of US civilians by CDC, state Subsequent assessment of US civilians by CDC, state health depts.

health depts.

Active, national caseActive, national case--finding between December 16, finding between December 16,

1976 and Jan 31, 1977

1976 and Jan 31, 1977

GBS among adult vaccinees compared to nonGBS among adult vaccinees compared to non--vaccinees vaccinees

(

(3)

1. Based on 8 controlled assessments,

1. Based on 8 controlled assessments,

A/NJ/76 (H1N1) influenza vaccine associated

A/NJ/76 (H1N1) influenza vaccine associated

with increased risk of GBS in adults

with increased risk of GBS in adults

RR of

RR of

7.6

7.6

(95% CI 6.7 –

(95% CI 6.7

8.6)

8.6)

Reporting rate of 8.6 cases / 100,000

Reporting rate of

8.6 cases / 100,000

/ yr

/ yr

Non-

Non

-vaccinees: 1.7 / 100,000 / yr

vaccinees: 1.7 / 100,000 / yr

Attributable risk of 0.95 / 100,000

Attributable risk of

0.95 / 100,000

vaccinees

vaccinees

Features consistent with biological plausibility

Features consistent with biological plausibility

Risk concentrated within first 6 weeks of

Risk concentrated within first 6 weeks of

vaccination (peak at week 2

vaccination (peak at week 2 –

3)

3)

Not a lot-

Not a lot

-

or manufacturer-

or manufacturer

-

specific phenomenon

specific phenomenon

Several re-

Several re

-analyses with same conclusions

analyses with same conclusions

2. There are limited data on GBS risk among

2. There are limited data on GBS risk among

other populations receiving vaccine.

other populations receiving vaccine.

U.S. MilitaryU.S. Military

A/NJ/76 formulation (bivalent) same as civilian, but higher doseA/NJ/76 formulation (bivalent) same as civilian, but higher dose(1.0 ml (1.0 ml vs. 0.5 ml); also received B vaccine

vs. 0.5 ml); also received B vaccine

Single study: Single study: ““no increased risk of the magnitude reported by CDCno increased risk of the magnitude reported by CDC””; ; limitations in data*

limitations in data*

No additional controlled data No additional controlled data

Use of A/NJ/76 vaccine outside USUse of A/NJ/76 vaccine outside US

UK: ? Anecdotal reports, but no confirmationUK: ? Anecdotal reports, but no confirmation

Canada: 800,000 doses of monovalent and bivalent vaccine distribCanada: 800,000 doses of monovalent and bivalent vaccine distributeduted

Limited mechanisms to detect risk of GBS; small population of Limited mechanisms to detect risk of GBS; small population of vaccinees

vaccinees

NetherlandsNetherlands

2.4 million doses apparently delivered2.4 million doses apparently delivered

None apparently usedNone apparently used

(4)

3. There are limited data on risk of GBS

3. There are limited data on risk of GBS

from swine

from swine

-

-

antigen

antigen

-

-

containing influenza

containing influenza

vaccines pre

vaccines pre

--

--

1976

1976

1955 1955 ––1969: Swine antigen (A/swine/Iowa/1976/31 H1N1) 1969: Swine antigen (A/swine/Iowa/1976/31 H1N1)

routinely incorporated into U.S. military vaccines

routinely incorporated into U.S. military vaccines

1956 1956 ––1959: same antigen incorporated in some civilian 1959: same antigen incorporated in some civilian

vaccines

vaccines

No suggestion of increased riskNo suggestion of increased risk

Limited passive surveillance infrastructureLimited passive surveillance infrastructure

No systematic assessmentsNo systematic assessments

In limited exposed population, no risk of sufficient In limited exposed population, no risk of sufficient concern enough to be reported to public health

concern enough to be reported to public health

authorities or published

authorities or published

Swine antigens not used since 1976 (Netherlands 1977?)Swine antigens not used since 1976 (Netherlands 1977?)

4. Most data suggest little, if any, significant

4. Most data suggest little, if any, significant

risk of GBS following subsequent influenza

risk of GBS following subsequent influenza

vaccines

vaccines

Association between other influenza vaccine formulations and GBSAssociation between other influenza vaccine formulations and GBSless clearless clear

9 9 wellwell--designed,designed,controlled assessments between 1977 and 2009controlled assessments between 1977 and 2009

Two suggesting a small but statistically significant increase inTwo suggesting a small but statistically significant increase inrisk of GBSrisk of GBS

Lasky et al*: Lasky et al*:

increased risk following influenza vaccine for combined 1992increased risk following influenza vaccine for combined 1992--93 and 93 and 1993

1993--94 seasons (RR 1.7; 95% CI 1.0 94 seasons (RR 1.7; 95% CI 1.0 ––2.4; AR 0.06 / 100,000 2.4; AR 0.06 / 100,000 vaccinations);

vaccinations);

no such risk with each season separately. no such risk with each season separately.

Juurlink et al#: Juurlink et al#:

increased risk of GBS following presumed influenza vaccination increased risk of GBS following presumed influenza vaccination over over period of 1993

period of 1993 ––2004 (RR 1.45, 95% CI 1.05 2004 (RR 1.45, 95% CI 1.05 ––1.99)1.99)

No increase in incidence of hospital admissions for GBS followinNo increase in incidence of hospital admissions for GBS following g universal influenza vaccination in Ontario in 2000.

universal influenza vaccination in Ontario in 2000.

Differences in methodologies, case ascertainment methods, analysDifferences in methodologies, case ascertainment methods, analyseses

No clear, consistent associationNo clear, consistent association

Potential GBS risk likely outweighed by influenzaPotential GBS risk likely outweighed by influenza--associated morbidity / mortality associated morbidity / mortality in any particular season

in any particular season

(5)

5. Biological data on possible mechanisms

5. Biological data on possible mechanisms

for association of GBS and A/NJ/76 (H1N1)

for association of GBS and A/NJ/76 (H1N1)

vaccine are largely absent

vaccine are largely absent

No association with particular human leukocyte

No association with particular human leukocyte

antigen (HLA) haplotypes

antigen (HLA) haplotypes

A/NJ/76 vaccine,

A/NJ/76 vaccine,

but also other formulations

but also other formulations

,

,

induces anti

induces anti-

-myelin ganglioside antibodies in

myelin ganglioside antibodies in

mice

mice

(Nachamkin et al. 2008)

(Nachamkin et al. 2008)

Provides biological basis, but significance

Provides biological basis, but significance

unclear

unclear

No robust data suggesting a biological basis for

No robust data suggesting a biological basis for

association

association

*Kaslow et al. Neurology 1987;37:685 #J Infect Dis 2008;198:226

6. There are both molecular and antigenic

6. There are both molecular and antigenic

similarities and differences between A/NJ/76

similarities and differences between A/NJ/76

(H1N1) and 2009 A/H1N1 viruses

(H1N1) and 2009 A/H1N1 viruses

A/NJ/76 (HswN1): “

A/NJ/76 (HswN1):

“classical

classical”

swine influenza virus

swine influenza virus

All gene segments derived from viruses since 1930

All gene segments derived from viruses since 1930

2009 A/H1N1: novel combination of gene segments

2009 A/H1N1: novel combination of gene segments

6 genes –

6 genes

“triple reassortant

triple reassortant”

”; gene segments from

; gene segments from

swine H1N1, North American avian and human

swine H1N1, North American avian and human

H3N2

H3N2

NA, M –

NA, M

Eurasian lineage of Hsw1N1 viruses

Eurasian lineage of Hsw1N1 viruses

HA antigenically and genetically different from

HA antigenically and genetically different from

A/NJ/76

A/NJ/76

Biological properties of 2009 A/H1N1 HA and NA not

Biological properties of 2009 A/H1N1 HA and NA not

fully characterized

(6)

Conclusions (1)

Conclusions (1)

A/NJ/76 (H1N1) influenza vaccine associated with increased A/NJ/76 (H1N1) influenza vaccine associated with increased risk of GBS in adults 6

risk of GBS in adults 6 --8 weeks following vaccine in US 8 weeks following vaccine in US civilians

civilians

Reasons unknownReasons unknown

No clear biological explanationNo clear biological explanation

Data on risk of GBS following other swineData on risk of GBS following other swine--antigen antigen containing vaccines too limited to allow for conclusions

containing vaccines too limited to allow for conclusions

Most data suggest little or no risk of GBS following Most data suggest little or no risk of GBS following subsequent influenza vaccines

subsequent influenza vaccines

A/NJ/76 (H1N1) and 2009 A(H1N1) viruses differ A/NJ/76 (H1N1) and 2009 A(H1N1) viruses differ virologically and antigenically

virologically and antigenically

Without biological underpinning for 1976 event, unclear Without biological underpinning for 1976 event, unclear what significance any similarities might have on risk of

what significance any similarities might have on risk of

vaccine

vaccine

Conclusions (2)

Conclusions (2)

1976: No significant influenza disease

1976: No significant influenza disease

2009: Already associated with morbidity

2009: Already associated with morbidity

and mortality

and mortality

Future epidemiology, potential virulence

Future epidemiology, potential virulence

unknown

unknown

Risk in 1976 may have been acceptable in

Risk in 1976 may have been acceptable in

the setting of significant influenza

the setting of significant influenza

-

-associated disease

(7)

Acknowlegments

Acknowlegments

John D Grabenstein, RPh, PhD Col (ret) USA; Senior John D Grabenstein, RPh, PhD Col (ret) USA; Senior

Director, Adult Vaccine Medical Affairs, Merck Vaccines &

Director, Adult Vaccine Medical Affairs, Merck Vaccines &

Infectious Diseases.

Infectious Diseases.

Philip K. Russell, M.D.Major General (ret) USAPhilip K. Russell, M.D.Major General (ret) USA

Teresa Hammett, Division of Viral and Rickettsial Diseases, Teresa Hammett, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention

Centers for Disease Control and Prevention

Dr. Cathy Parker, Biologics and Genetic Therapies Dr. Cathy Parker, Biologics and Genetic Therapies Directorate Health Canada

Directorate Health Canada

Dr. Mair Powell, Medicines and Healthcare products Dr. Mair Powell, Medicines and Healthcare products Regulatory Agency, United Kingdom of Great Britain &

Regulatory Agency, United Kingdom of Great Britain &

Northern Ireland

Northern Ireland

Dr. Bettie Voordouw, Medicines Evaluation Board, Dr. Bettie Voordouw, Medicines Evaluation Board, Netherlands.

Netherlands.

Additional Slides

Additional Slides

(8)

GBS and Influenza Illness

GBS and Influenza Illness

Case reports of GBS following influenza /

Case reports of GBS following influenza /

ILI

ILI

No substantial evidence of strong

No substantial evidence of strong

association

association

No seasonal pattern of GBS

No seasonal pattern of GBS

No increase in GBS following large

No increase in GBS following large

epidemics

epidemics

Several reports suggest risk, but data

Several reports suggest risk, but data

conflicting

conflicting

Vaccine

Vaccine-

-

Associated Neurologic

Associated Neurologic

Disease

Disease

Neurologic AE Neurotropic Post-Immunization Immune-Mediated Central Nervous System Central Nervous System Peripheral Nervous System “Idiosyncratic”

(9)

“Phylogeny

Phylogeny

of GBSs

of GBSs

Guillain-Barré Syndromes Acute Inflammatory Demyelinating Type (AIDP)

Acute motor axonal

Type (AMAN) Fisher syndrome

(Secondary axonal Degeneration)

Acute motor and Sensory axonal type

(10)

Guillain

Guillain-

-

Barré

Barr

é

Syndrome

Syndrome

Acute inflammatory demyelinating polyradiculopathyAcute inflammatory demyelinating polyradiculopathy--

--most common form of GBS in North America, Europe

most common form of GBS in North America, Europe

Primarily axonal form more common in developing Primarily axonal form more common in developing world

world

Incidence 0.5 Incidence 0.5 ––4 / 100,000, depending on study design; 4 / 100,000, depending on study design; incidence increases with age

incidence increases with age

Demyelination > axonal damage; cross Demyelination > axonal damage; cross --reactive epitopes reactive epitopes

on peripheral myelin sheath or axons

on peripheral myelin sheath or axons

Various structural glycoproteins on myelin / axons Various structural glycoproteins on myelin / axons induce antigenic response

induce antigenic response

Antecedent viralAntecedent viral--like illness or immunization reported in like illness or immunization reported in over 2/3

over 2/3

GBS

GBS

Acute Acute ––subacute onset of weaknesssubacute onset of weakness––evolve over days to weeksevolve over days to weeks

MostMost––maximal deficit within 2 weeksmaximal deficit within 2 weeks

HypoHypo--or areflexiaor areflexia

““AscendingAscending””weaknessweakness——legs to arms; generally symmetriclegs to arms; generally symmetric

Sensory abnormalitiesSensory abnormalities

Ascending pain or dysesthesiasAscending pain or dysesthesias

Objective numbness generally absentObjective numbness generally absent

Autonomic dysfunctionAutonomic dysfunction

Tachy / bradycardia, hypotension, arrhythmiasTachy / bradycardia, hypotension, arrhythmias

Cytoalbuminologic dissociation Cytoalbuminologic dissociation ––elevated CSF protein in elevated CSF protein in

absence of pleocytosis

absence of pleocytosis

Characteristic electrophysiologic profile Characteristic electrophysiologic profile ––reduced conduction reduced conduction velocities and decreased amplitudes indicative of demyelination

velocities and decreased amplitudes indicative of demyelination

(11)

GBS and Glycoconjugate Antibodies

GBS and Glycoconjugate Antibodies

Gangliosides: glycosphingolipids in plasma membrane of Gangliosides: glycosphingolipids in plasma membrane of tissues

tissues

Major surface molecules of PNS & CNS tissuesMajor surface molecules of PNS & CNS tissues

Strong association of antiganglioside antibodies with GBS; Strong association of antiganglioside antibodies with GBS; thought to play a role in pathogenesis

thought to play a role in pathogenesis

AntiAnti--GM1: AMANGM1: AMAN

AntiAnti--GQ1b: FSGQ1b: FS

Natural infection with certain serotypes of Natural infection with certain serotypes of Campylobacter Campylobacter jejuni

jejuni associated with GBSassociated with GBS

CrossCross--reactive antibodies to gangliosides and reactive antibodies to gangliosides and C. jejuniC. jejuni

lipopolysaccharide moieties

lipopolysaccharide moieties

Biological plausibility?Biological plausibility?

GBS

GBS

Outcome generally favorable; complete recovery

Outcome generally favorable; complete recovery

with or without treatment

with or without treatment

Advanced age, mechanical ventilation

Advanced age, mechanical ventilation

associated with poorer outcome

associated with poorer outcome

Treatment modifies disease progression and

Treatment modifies disease progression and

outcome

outcome

Intravenous immune globulin (IVIG)

Intravenous immune globulin (IVIG)

Plasmapheresis

Plasmapheresis

(12)

GBS vs. CIDP

GBS vs. CIDP

GBS

GBS

CIDP

CIDP

Antibodies

Antibodies AIDP: VariableAIDP: Variable AMAN: GM1 AMAN: GM1 FS: GQ1b FS: GQ1b No antibodies No antibodies Antecedent event

Antecedent event 70%70% NoneNone Course

Course MonophasicMonophasic Relapsing / remittingRelapsing / remitting Treatment

Treatment IVIG, PLEXIVIG, PLEX Steroids, IVIG, PLEXSteroids, IVIG, PLEX Pathology

Pathology Axonal and demyelinatingAxonal and demyelinating DemyelinatingDemyelinating

Differentiation between GBS and CIDP requires longitudinal

follow-up to identify relapses and remissions

GBS and Vaccines

GBS and Vaccines

Influenza

Influenza

1976 swine influenza: small but significant risk for GBS (1 1976 swine influenza: small but significant risk for GBS (1 additional case / 100,000 vaccinees) 1

additional case / 100,000 vaccinees) 1 ––6 weeks post6 weeks post- -immunization

immunization

IOM: IOM: ““evidence favors a causal association...evidence favors a causal association...””

Association between other influenza vaccine formulations and Association between other influenza vaccine formulations and immunizations less clear

immunizations less clear

19 19 wellwell--designed,designed,controlled studies in the literature between controlled studies in the literature between 1977 and 2009

1977 and 2009

22(Lasky et al., 1998 [flu]; Kinnunen et al., 1989 [OPV]) (Lasky et al., 1998 [flu]; Kinnunen et al., 1989 [OPV]) suggest slightly increased risk...(maximal odds ratio 1.7)

suggest slightly increased risk...(maximal odds ratio 1.7)

No clear, consistent associationNo clear, consistent association

Biological data: swine influenza vaccine, Biological data: swine influenza vaccine, but also other but also other formulations

formulations, induces anti, induces anti--myelin ganglioside antibodies in mice myelin ganglioside antibodies in mice (Nachamkin et al. 2008)

(Nachamkin et al. 2008)

Figure

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References

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