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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 – [email protected] – Telephone – (03) 9345 4143– Fax – (03) 9345 4163
Thank you
Monash Immunisation
• Refer to Monash Immunisation– Tel 9594 6320– Fax 9594 6325– [email protected]– Need referral– Level 2 (ground) Jessie Mac rooms area