Vaccine Safety Update and introduction to

Monash ImmunisationJim Buttery

Infectious Diseases, MCH Monash Immunisation, MMC

Director of Research, MCHSAEFVIC, MCRI

Outline National• Australia TIV 2010

experience– Signal detection– Investigations for association– Investigations for cause

• Changes since 2010 to improve– Surveillance– Signal detection– Investigations– Communication

• Flu• MMRV• Primary care…

2013 safety initiatives

BCG• 2012….2013….

Monash Immunisation

Febrile seizures

• Common 2-3% of all children– Usual trigger minor infection eg URTI, influenza

• Usually 6m-5y of age– Brief < 5 minutes– Benign- no neurologic sequalae

• Can recur in 1/3• Increased risk described following

– MMR, MMRV – influenza vaccine

Febrile convulsions post influenza vaccines

• Classically 7-11 hours post vaccine• Febrile convulsion rates:

– USA 0.03 (0.16 over 7 days) per 1,000 doses

• Risk increased if co-administered with PCV13

http://www.cdc.gov/flu/Leroy et al Vaccine 2012

TIV in Australian Children

Australia• Funded for special risk groups only

– Contracting/provision administered by states– Estimated coverage 5%

• Not required on ACIR Immunisation Register• Coverage hard to determine• Data mostly held in primary care practices

– Vaccination usually starts March/April• Inactivated TIV

– CSL Fluvax/ Fluvax Jnr / Panvax (H1N109)– Other international manufacturers

Chin et al, Eurosurveillance 2012

TIV in Australian Children

Australia• Funded for special risk groups only

– Contracting/provision administered by states– Estimated coverage 5%

West Australia• 3 young children deaths ascribed to flu 2007• State funding all children 6m-5y from 2008• Coverage 30-35%

2010 TIV: Pre-licensure safety data• Seasonal vaccine

– No RCTs for this batch

• Panvax H1N109 trials 2009 with 15µg dose– 1/82 children <3y severe fever (1.2%, 95%CI 0.2-6.6)

• 4/79 with 30µg dose (5.1%, 95%CI 2-12.3)

Disease yes

Disease no

Vaccine yes

a b

Vaccine no

c dNolan et al JAMA 2010

0

1

1/03

/10

8/03

/10

15/03

/10

22/03

/10

29/03

/10

5/04

/10

12/04

/10

19/04

/10

26/04

/10

2010 timeline

8th March: Trivalent vaccine launched

Fluvax Junior and Fluvax: CSLInfluvac: Solvay Pharmaceuticals

Vaxigrip: Sanofi Pasteur

13th April: TGA notified

22nd April: WA suspends preschool influenza vaccination program

Reports of febrile convulsions presenting to ED follow TIV

23rd April: TGA suspends national flu vaccination

program

Courtesy Chris Blyth, PMH

LESSON 6 : EXPECT THE UNEXPECTED

Princess Margaret Hospital- Perth WA

2008 2009 2010

Influenza vaccine

(previous 72 hours)

0 3 36

No influenza vaccine 31 47 47

Slide courtesy Chris Blyth

WA investigations

• State ED database EDIS: 9 Perth EDs– All admissions coding for febrile seizure r56.0

• TIV delivery estimated using provider questionnaire for rates

• Reactogenicity of 3 vaccines used determined by retrospective cohort study from 1 clinic

Armstrong P K et al. BMJ Open 2011;1:e000016

Presentations of children under 5 years of age with febrile convulsions (ICD-10 code R56.0) to nine Perth hospital emergency departments, 1 January to 2 May 2010.

Armstrong P K et al. BMJ Open 2011;1:e000016

©2011 by British Medical Journal Publishing Group

West Australia Febrile Convulsions

• est max of 18 816 doses of TIV administered– 63 febrile convulsions recorded– estimated rate 3.3/1000 doses (95% CI 2.6 to 4.2)

• TGA– 7/1,000 for FLUVAX (adult) vaccine– 10/1,000 for FLUVAX JUNIOR– 0 for INFLUVAC from 1,450 doses administered

• >200 x the only population-based published estimate

Armstrong P K et al. BMJ Open 2011;1:e000016www.tga.gov.au

2011-2012: WA influenza vaccination

Courtesy CDCD; DoH WA

N Wood, R Menzies, P McIntyre, H Wang, H Gidding, M Gold, J Buttery, N Crawford, D Tran, P Richmond, C Blyth

www.ncirs.edu.au

Febrile seizures following influenza vaccine in Australian children in 2010

Self controlled case series analysis

Interval post flu vaccine to febrile seizure

Days post flu vaccine

n=38 had febrile seizure within 48 hours47% aged 12 to 23 months

SCCS analysis

• CSL seasonal fluvax and FS within 48 hours compared to non risk period– IRR = 15.2 (95%CI 7.3-31.4)

• CSL fluvax and FS within 48 hours AND age adjustment– <2 years old

• IRR = 15.2 (95%CI 7.3-31.6)

– > 2 years old• IRR = 0.7 (95%CI 0.17-2.7)

AEFI reporting: Australia

• Differences between states– Strengths/weaknesses– Funding– Clinical links etc

• Relation to TGA– Communication– Potential delays

• ACSOM (ADRAC)– Review cycles– ‘surge capability’

NRA

JURISDICTIONS

JURISDICTIONS NRA/Central

2011-2012: finding solutions

Professor John HorvathFormer Chief Medical Officer

Professor Bryant StokesFormer WA Chief Medical Officer

FEDERAL INQUIRY: TGA WA PARLIAMENTARY INQUIRY

Recommendations• States retain reporting• Harmonise AEFI reporting

for states– Form– methods

• User friendly timely internet reporting

• Increase consumer and health professional awareness

• Build flags into internet reporting for rate changes

• Define surveillance objectives

• Priority for e-health– vaccines administered

• Denominator data– Safety monitoring data

• Establish national vaccine safety committee

• Establish agreed protocols for action– Triggers– Signal investigation methods

• De-identified AEFI reports available for open review

Progress• States retain reporting• Harmonise AEFI reporting

for states– Form– methods

• User friendly timely internet reporting

• Increase consumer and health professional awareness

• Build flags into internet reporting for rate changes

• Define surveillance objectives

• Priority for e-health– vaccines administered

• Denominator data– Safety monitoring data

• Establish national vaccine safety committee

• Establish agreed protocols for action– Triggers– Signal investigation methods

• De-identified AEFI reports available for open review

New for 2013

Flu 2013• Multicentre comparative

study of paediatric TIV preparations– NCIRS led

MMRV• Trial of fever rates post-

immunisation from GP software (pilot) (also Flu)– SAEFVIC– Canning tool- interested

practices needed• MD, BP, Practyx

HPV

• Enhanced surveillance in schools and LGA– SAEFVIC

Safety of environmental excursions

SS 10 months old

• Healthy term infant• No significant past history• BCG Vaccination 16/12/2010

– One week later, travelled to Kerala, India (23/12/10)

• unwell 3 weeks into trip (10/1/11)– Fever, cough, rhinorrhea – Inflamed BCG scar, slight discharge

SS 10 months old

• 2 weeks later– left anterior axillary lymphadenopathy (21/1/11)– Ongoing fevers

• Progressive increase in left axillary LNs– Non-tender

• Returned to Australia at end of Jan 2011

SS 10 months old

History•Born in Melbourne•Only child•Immunised per schedule•No known TB / chronic cough contacts

ID Clinic Feb 2012

• Firm, possibly fluctuant• Multiple shotty cervial

lymph nodes• No other lymphadenopathy• Unremarkable general

examination

Investigations

• Increased fluctuance on clincal review

Managment• Excision of lymph node abscess• 4 month course of daily rifampicin 100mg and

isoniazid 100mg– Well tolerated

• Histopathology – granulomatous infection• Mycobacteria PCR positive

• Residual lymphadenopathy resolved over 3/12• Small LN palpable at end of treatment course• Notified to SAEFVIC

BCG: History• BCG is named after the two

French investigators responsible for developing the vaccine from an attenuated strain of Mycobacterium bovis.

• Isolated from a cow with TB• They presented their results to

the Academie de Sciences in 1908• Subcultured every 3 weeks for 13

years..

Oils aint oils- from WHO website:

• The BCG vaccines that are currently in use are produced at several (seven?) sites throughout the world. These vaccines are not identical. To what extent they differ in efficacy and safety in humans is not clear at present. Some differences in molecular and genetic characteristics are known. What is not known is if the "BCG" from one manufacturer is "better" than one produced at another site. Each BCG is now known by the location where it is produced.

Current BCG recommendations• ATSI neonates living in regions of high TB

incidence, • neonates born to parents with leprosy or a family

history of leprosy, • children <5 years of age who will be travelling to

live in countries of high TB prevalence for longer than 3 months

• embalmers, • healthcare workers involved in conducting

autopsies.

State and Territory guidelines should be consulted for the following groups

• healthcare workers who may be at high risk of exposure to drug-resistant cases,

• neonates weighing <2.5 kg, • children ≥5 years and <16 years of age who

will be travelling or living for extended periods in countries with a high prevalence of tuberculosis.

• Protection

• Consistent 60-80% protection against disseminated tuberculosis (TBM, miliary TB) in HIV-negative and unexposed young children

• Variable protection: pulmonary TB, limited impact transmission

• Revaccination: no benefit

• Cost-effective

• Limited efficacy data in HIV-infected infants

• High TB incidence HIV-infected infants (small subpopulation): 25 fold higher in HIV-infected infants

• HAART: reduces risk of TB in HIV-infected infants Trunz, Fine, Dye. The Lancet 2006; 367:1173-1180, Rodrigues, Int J Epi 2002

EFFICACY: BCG IS EFFECTIVE IN PREVENTING SEVERE TB IN CHIDREN

BCG History: The Lübeck disaster

• Dec 1929 & April 1930– 251 of 412 infants born in

Lübeck, Germany, received three doses of BCG vaccine by the mouth during the first ten days of life.

– 72 died of tuberculosis• most of them in two to five

months, and all but one before the end of the first year

• In addition, 135 suffered from clinical tuberculosis but eventually recovered

• 44 became tuberculin-positive but remained well • Of 251 children, 207 (82.5%) died or developed

tuberculosis• later recognized that this batch was accidentally

contaminated with a virulent strain of M. tuberculosis

BCG History: The Lübeck disaster

Revised paediatric BCG disease classification

Local disease

Abscess

Disseminated disease

Beyond regional

Regional disease

Adenitis

BCG IRIS

Following HAART

Dual disease

M. tb and BCG

REVISED PAEDIATRIC BCG DISEASE CLASSIFICATION

Hesseling et al, Clin Infect Dis 2006

“SAGE agreed that the BCG position paper should beupdated to reflect this change and provide guidanceto national policy-making bodies, recognizing thecomplexity of the decision-making process and the lack of information as well as the necessary infrastructure to perform adequate risk assessment in individual children.

Among HIV-infected children, the benefits of potentially preventing severe TB are outweighed by the risks associated with the use of BCG vaccine. GACVS therefore advised WHO to change its recommendation such that children who are known to be HIV-infected, even if asymptomatic, should no longer be immunized with BCG vaccine.”

SAEFVIC: BCG AEFI

N=59

SAEFVIC BCG AEFI n=59

• male/female : 40/19• age

– age at vaccination• mean: 2.66 years• median: 0.90

• range: 0.06-22.78

• ”Wow – wonder if there is anything to support whether men get vaccinated more often and therefore this is a reflection of vaccine administration .. or do men just complain about their AEFI more?!!!”

SAEFVIC: BCG AEFI

BCG withdrawal Sept 2012

• Sanofi-Aventis Australia Pty Ltd has recalled batches of its Bacillus Calmette-Guerin vaccine amid concerns its sterility cannot be assured because of an “environmental monitoring excursion” during manufacture

BCG recall

• BCG Connaught- 4 batches used since April• Reviewed SAEFVIC data

– 59 children since 2007• 21 had batch information available

– 18 since April 2012• 7 Implicated batches • 5 x non withdrawn batches• 6 x no batches available- overseas or not able to be

contacted or no batch number recorded

Pragmatics: BCG

• BCG Connaught strain replaced with BCG Denmark strain– Denmark higher rate disseminated disease in HIV– ?other AE– 100 dose vials rather than 10 dose

• Distribution now limited to RCH and Monash– New BCG clinics at Monash Immunisation

• Jo Tully and Tim Davis

Monash Immunisation

An all age immunisation service for high risk patients

All age service – established January 2012- first within Australia

Nurse-led outpatient drop-in centre operating each week day

Service run by clinical nurses who specialise in immunisation management and education

Access to specialised adult and paediatric immunisation physicians.

Provide vaccinations under the National Immunisation Program

Clinical research

Monash Immunisation

Immunisation of current inpatients and outpatients

Provide immunisations to high risk groups– Immunosuppressed patients and patients on immunosuppressive therapies.– Oncology– Respiratory and Cardiac– Transplant – RSV immunoglobulin– Antenatal and Postnatal– Premature babies– Families of high risk patients

Assist with complex immunisation issues for patients

Phone support and information.

Education/advise to health care providers, children, adults and their families

Monash Immunisation

• AEFI reports• Clinical support for providers and patients• How to report?

– Online – www.saefvic.org.au – Email – saefvic@mcri.edu.au – Telephone – (03) 9345 4143– Fax – (03) 9345 4163

Thank you

Monash Immunisation

• Refer to Monash Immunisation– Tel 9594 6320– Fax 9594 6325– Immunisation@southernhealth.org.au– Need referral– Level 2 (ground) Jessie Mac rooms area