Australian Adverse Event Following

Immunisation-Clinical Assessment Network

[AEFI-CAN]

ASID workshop: Wednesday 8th May 2018

Nigel Crawford & Nicholas Wood on behalf of the Network

Topics

• AEFI CAN: What is it?

• Adverse events following immunisation

• Adult cases [Monash]

• Serious Adverse Neurological Events [SANE]

• Rash & Hypersensitivity

AEFI CAN: What is it?

• Previously informal network - paediatricians discussing AEFI- national teleconference • 6-weekly

• Pilot funding from DH Canberra in 2013-14 • 4vHPV vaccine for males• formalised the network

• Includes TGA representatives & DH Immunisation section (Canberra)

• Co-ordinated by the Victorian vaccine safety service (SAEFVIC)

• Co- chairs: Nigel Crawford and Nick Wood

Specialist immunisation clinics (SIC) 1990s

• The majority (421/469) were revaccinated, with only one child having a significant neurological event; this was transient (HHE) and resolved spontaneously.

Clinical evaluation AEFI

ADC 2000;83:128-131

Christopher Blyth, Peter Richmond, Karen Hawkins, Patricia Cuthbert, Ushma Wadia, Andrew McLean-Tooke

Madeleine Hall, Alberto Pinzon, Leanne Philips, Sophie Wen

Michael Gold, Abigail Cheung, Jovanka King, Iann Homer, Mary Walker

David Durrheim, Patrick Cashman, Ben Smith, Jody Stephenson, Karen Orr; Kristine Macartney, Lucy Deng, Nicholas Woods, Michael Boyle, Rani Bhatia. AusVaxSafety

Carolyn Banks, Catherine Campbell, Nicola Irwin. TGA

Sean Beggs

Nigel Crawford, Jim Buttery, Margie Danchin, Kirsten Perrett, Adele Harris, Michelle Giles, Tony Korman

AEFI-CAN Investigators

CDI. 2011;35(4):294-98.

AEFI CAN database

https://www.aefican.org.au/

SAEFVIC Telehealth Consultations

Tony Korman and Adele Harris

Maternal dTpa vaccine

• 35 year old Female 28 weeks pregnant received Boostrix® vaccine

• 10 days post vaccine red lump at injection site

• Over next few weeks developed an annular lesion with raised red edge (target lesion) and became itchy

4 weeks post vaccine 8 weeks post vaccine 10 weeks post vaccine

• DDx: ? Erythema Multiforme ?Fungal infection• Fungal scraping isolated Trichophyton

tonsurans• Resolved slowly over many weeks

ISR post Menactra• 19 yo Female

• Administered dose 1 Menactra

• That night localised redness

• Approx 32 hours later noticed increased redness, swelling and itch at injection site

• Regular Panadol for pain relief

• Seen by GP who diagnosed cellulitis and commenced oral antibiotics

• Slowly resolved over next week

Serious Adverse Neurological Events [SANE]

• Transverse myelitis

• Acute Disseminated Encephalomyelitis (ADEM)

• Guillain Barre syndrome (GBS)

Results• Vaccine safety datalink (VSD)- United States

• Following nearly 64 million vaccine doses:

• only 7 cases of TM

• and 8 cases of ADEM were vaccinated during the primary exposure window ‘5–28 days’ prior to onset

• TM-no statistically significant increased risk of immunization

• ADEM, there was no statistically significant increased risk following any vaccine except for dTap (2 exposed cases)

• OR ADEM onset was 15.8 (95% CI, 1.2–471.6; P = .04)

• Estimated excess risk was 0.385 (95% CI, −.04 to 1.16) cases per million doses.

Baxter et al. CID. 2016

• Investigator led- study

• Supported by bioCSL [now Seqirus]

• GBS is a condition of acute flaccid paralysis (weakness)

• Causes• Infectious

• including campylobacter & wild type influenza

• Post-infectious (auto-immune)

• Significant morbidity• 20% having persistent and significant

disability

Why an issue?2009

H1N1/09 Influenzapandemic

1976

H1N1 vaccine hadan increased risk of Guillain-Barre

syndrome

GUILLAIN-BARRE SYNDROME FOLLOWING VACCINATION IN THE NATIONAL INFLUENZA IMMUNIZATION PROGRAM, UNITED STATES1976–1977

American Journal of Epidemiology 1979

The Johns Hopkins University School of Hygiene and Public Health

LAWRENCE B. SCHONBERGER et al.

What was the risk in 1976?

• relative risk of 7.6 (95% CI 6.7–8.6)

• within 0-42 days of vaccination

• estimated one additional case of GBS per 100,000 persons vaccinated

Why did it occur?

• Suspected GM1 antibody- but no sera from patients to confirm 1976 hypothesis

• Animal models:• Rabbits developed anti-GM1 Ab and flaccid limb weakness when

sensitised with C. jejuni

• Low homogeny between HINI 1976 c/w 2009:

• of 88.6% by nucleotide sequence

• 90.8% by amino acid sequence

Yuki N, et al. PNAS 2004;101:11404-9

Nachamkin et al. J Infect Dis. 2008 Jul 15;198(2):226-33

GBS in Australia

• Annual incidence: 2.5 per 100,000 population (560 per year in Australia, ~140 per year in Victoria)

• Males are at higher risk

• Incidence increases with age

[AIHW-ATAGI 2009]

Victorian Background rates

GBS Active: study procedures

• 10 key hospitals managing GBS in Victoria

• Adult Neurologist: Lynette Kiers

• Review all GBS cases (Brighton def)• Levels 1-4 (clinical; CSF; NCS)

• Study duration 1-year [9/09-9/10]• H1N1 Panvax [CSL]

• Seasonal Trivalent Influenza Vaccine

• WHO supported international collaboration

SCCS

Slide acknowledgement Caitlin Dodd

GBS Active: Results

MJA. 2012;197(10):574-78.

GBS Active: Results

• The RI of GBS following monovalent H1N1 vaccination was 3.4 (95% CI, 0.8–15.0)

• For TIV, there was one case in the risk period

• RI 0.69 (95% CI, 0.08–5.64)

MJA. 2012;197(10):574-78.

Global GBS Active study

Dodd et al. Vaccine . 2013 Sep 13;31(40):4448-58. doi: 10.1016/j.vaccine.2013.06.032

Global GBS Active study

Dodd et al. International collaborative case series safety monitoring for pandemic 2009 H1N1 vaccines:

estimation of the risk of Guillain-Barré syndrome [abstract]. 2012 Aug 23-26; Barcelona, Spain

International GBS Active study

• The approximate twofold increase in the of risk GBS in the 42 days post-vaccination translates into ~ 1–3excess cases of GBS per million people vaccinated.

Dodd et al. Vaccine . 2013 Sep 13;31(40):4448-58. doi: 10.1016/j.vaccine.2013.06.032

https://www.cdc.gov/vaccinesafety/concerns/history/gbs-menactra-faqs.html

ADEM case dTpa

Vaccine rash & hypersensitivity (allergy)

Vaccine hypersensitivity

Flow chart of clinical evaluation through trial.

Liew Woei Kang et al. BMJ 2008;337:bmj.a2642

©2008 by British Medical Journal Publishing Group

BCCD Level of Certainty

Diagnostic Criteria Number of cases meeting criteria

Level 1 ≥1 major dermatological AND ≥1 major cardiovascular

0

≥1 major dermatological ≥AND 1 major respiratory

9

Level 2 ≥1 major cardiovascular AND ≥1 major respiratory

0

≥1 major cardiovascular/respiratory AND ≥1 minor criterion involving ≥1 different system

3

≥1 major dermatological AND ≥1 minor cardiovascular/respiratory

12

Level 3 ≥1 minor cardiovascular OR respiratory AND ≤1 minor criteria from ≥2 different systems

1

Level 4 Reported anaphylaxis with insufficient evidence to meet case definition

1

Level 5 Not a case of anaphylaxis 1

Anaphylaxis- Brighton criteria

Cheng et al. Vaccine, 2016

AEFI CAN: Are you interested?

• 6-weekly case discussion- 1-hour Telecall

• Confidentiality agreement

• Adult clinical services

• New vaccines [Influenza; Shingles]

• adult vaccine allergy service

• Jurisdictional dependent

AEFI-CAN

Christopher Blyth, Peter Richmond, Karen Hawkins, Patricia Cuthbert, Ushma Wadia, Andrew McLean-Tooke

Madeleine Hall, Alberto Pinzon, Leanne Philips, Sophie Wen

Michael Gold, Abigail Cheung, Jovanka King, Iann Homer, Mary Walker

David Durrheim, Patrick Cashman, Ben Smith, Jody Stephenson, Karen Orr; Kristine Macartney, Lucy Deng, Nicholas Woods, Michael Boyle, Rani Bhatia. AusVaxSafety

Carolyn Banks, Catherine Campbell, Nicola Irwin. TGA

Sean Beggs

Nigel Crawford, Jim Buttery, Margie Danchin, Kirsten Perrett, Adele Harris, Michelle Giles, Tony Korman

AEFI-CAN Investigators

FEBRILE SEIZURES

Febrile seizure study

• NHMRC supported (A$630,000)

• Epilepsy experts

• Sam Berkowitz and Ingrid Scheffer

• Australian AEFI-CAN Clinical Network sites

• PI – Nicholas Wood

[NCIRS, Westmead, Sydney]

Australia’s vaccine safety scare – 2010

ROOT CAUSE analysis:

- viral lipid-mediated delivery of short,

fragmented viral RNA - key trigger

- Inadequate virus splitting

Rockman et al, 2 publications Vaccine 2014

2010: Unexpected Febrile Seizures in Children with

bioCSL Fluvax® (Australian Influenza vaccine)

Unexpected febrile seizures in children aged <5 years, esp 6-24 months

Temporary national suspension of all flu vaccination in children - 5 months

5-7 febrile seizures per 1000 vaccinated children

- 2 children with permanent brain damage

only with ONE BRAND: bioCSL Fluvax® / Fluvax Junior®

Especially in Western Australia

• only state providing free vaccine to all children

Dramatic effects on parental confidence in flu vaccine and flu vaccine

coverage – 2 government reviews

What are febrile seizures?

most common seizures in childhood

affect 2–5% of the pediatric population

Risk factors

• febrile infections. some vaccinations, lower gestational age, low birth weight

and genetic factors

~ 30% of children with first FS have a second episode, often within 2 years

Known risk factors for recurrence

• younger age at first FS, family history, low temperature of fever at first FS

Long-term morbidity and mortality is extremely low.

Risk of epilepsy after simple FS only slightly > than risk in the general population

Influenza vaccine coverage & parents attitude in WA

Blyth C et al. The impact of pandemic A(H1N1)pdm09 influenza and vaccine-associated

adverse events on parental attitudes and influenza vaccine uptake in young children. Vaccine,

2014; 32,4075–81

Parents attitude: Influenza vaccine is safe

Agree : 60% in 2008-2009 vs. 30% in 2010-2012

Disagree: 3% 2008-2009 vs. 14% in 2010-2012

Fig. Influenza vaccine uptake among children in WA

bioCSL root cause analysis

Reactogenic strains. A/H1N1pdm09, B Brisbane

Poor splitting (Sodium taurine deoxycholate used by bioCSL only)

Viral RNA fragments retained

Excessive cytokine response

Trials underway of reformulated CSL Flu vaccine with increased TDOC for B

strains

Quadrivalent Sequirus vaccine used in adults > 18 years

Other outcomes…

More detailed assessments of risk of FS post vaccination

New ACTIVE SURVEILLANCE

• for flu vaccine safety: AusVax Safety

• Specifically for FS post other/all vaccines in childhood (e.g. MMR-V)

Background

It is not known whether there are underlying physiologic or

immunologic differences between febrile seizures (FS) triggered by

vaccines versus other causes.

Furthermore, while secular and individual-level factors have been

associated with FS risk, they are rarely evaluated simultaneously

NHMRC project grant

Febrile seizures following vaccination in children: How

common are they and what is the long-term clinical

outcome? And genetic associations?

Lead: Associate Professor Nick Wood

NCIRS: Kristine Macartney and Karen Orr

Collaborators:

• Professors Ingrid Scheffer and Sam Berkowitz,

Melbourne Epilepsy Centre

• Developmental specialist: Belinda Barton

• 3 other paediatric centres:

- Nigel Crawford and Jim Buttery (Victoria)

- Mike Gold (SA), Peter Richmond (WA)

Clinical and development assessment

Long term follow-up and outcomes

Testing for panel of epilepsy-associated genetic markers

[SCN1A]