1. Vaccine Safety Update and introduction to Monash Immunisation
Jim Buttery
Infectious Diseases, MCH
Monash Immunisation, MMC
Director of Research, MCH
SAEFVIC, MCRI

2. Outline National 2013 safety initiatives Australia TIV 2010 experience
Signal detection
Investigations for association
Investigations for cause
Changes since 2010 to improve
Surveillance
Investigations
Communication
Flu
MMRV
Primary care…
BCG
2012….2013….
Monash Immunisation

3. Febrile seizures Common 2-3% of all children Usually 6m-5y of age
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

4. 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
Leroy et al Vaccine 2012

5. TIV in Australian Children
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

6. TIV in Australian Children
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%

7. 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 )
4/79 with 30µg dose (5.1%, 95%CI )
Disease yes
Disease no
Vaccine yes a b
Vaccine no c d
Nolan et al JAMA 2010

8. 2010 timeline 13th April: TGA notified
8th March: Trivalent vaccine launched
Fluvax Junior and Fluvax: CSL
Influvac: Solvay Pharmaceuticals
Vaxigrip: Sanofi Pasteur
Reports of febrile convulsions presenting to ED follow TIV
22nd April: WA suspends preschool influenza vaccination program
23rd April: TGA suspends national flu vaccination program
Courtesy Chris Blyth, PMH

9. LESSON 6 : EXPECT THE UNEXPECTED

10. Princess Margaret Hospital- Perth WA
2008
2009
2010
Influenza vaccine
(previous 72 hours) 3 36
No influenza vaccine 31 47
Slide courtesy Chris Blyth

11. 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

12. 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.
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 TIV, trivalent inactivated influenza vaccine.
Armstrong P K et al. BMJ Open 2011;1:e000016
©2011 by British Medical Journal Publishing Group

13. 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:e000016

14. 2011-2012: WA influenza vaccination
Courtesy CDCD; DoH WA

15. Febrile seizures following influenza vaccine in Australian children in Self controlled case series analysis
N Wood, R Menzies, P McIntyre, H Wang, H Gidding,
M Gold, J Buttery, N Crawford, D Tran, P Richmond, C Blyth 15

16. Interval post flu vaccine to febrile seizure
n=38 had febrile seizure within 48 hours
47% aged 12 to 23 months
Days post flu vaccine

17. SCCS analysis
CSL seasonal fluvax and FS within 48 hours compared to non risk period
IRR = 15.2 (95%CI )
CSL fluvax and FS within 48 hours AND age adjustment
<2 years old
IRR = 15.2 (95%CI )
> 2 years old
IRR = 0.7 (95%CI )

18. AEFI reporting: Australia
Differences between states
Strengths/weaknesses
Funding
Clinical links etc
Relation to TGA
Communication
Potential delays
ACSOM (ADRAC)
Review cycles
‘surge capability’

19. JURISDICTIONS
NRA

20. JURISDICTIONS
NRA/Central

21. 2011-2012: finding solutions FEDERAL INQUIRY: TGA
WA PARLIAMENTARY INQUIRY
Professor Bryant Stokes
Former WA Chief Medical Officer
Professor John Horvath
Former Chief Medical Officer

22. 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

23. 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

24. New for 2013
Flu 2013
MMRV
Multicentre comparative study of paediatric TIV preparations
NCIRS led
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

25. Safety of environmental excursions

26. 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

27. 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

28. SS 10 months old History Born in Melbourne Only child
Immunised per schedule
No known TB / chronic cough contacts

29. ID Clinic Feb 2012 Firm, possibly fluctuant
Multiple shotty cervial lymph nodes
No other lymphadenopathy
Unremarkable general examination

30. Investigations
Increased fluctuance on clincal review

31. 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

32. 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..

33. 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.

34. 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.

35. 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.

36. EFFICACY: BCG IS EFFECTIVE IN PREVENTING SEVERE TB IN CHIDREN
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: ,
Rodrigues, Int J Epi 2002

37. 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

38. BCG History: The Lübeck disaster
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

39. REVISED PAEDIATRIC BCG DISEASE CLASSIFICATION
Local disease
Abscess
Dual disease
M. tb and BCG
Regional disease
Adenitis
BCG IRIS
Following HAART
Disseminated disease
Beyond regional
Hesseling et al, Clin Infect Dis 2006

40. “SAGE agreed that the BCG position paper should be
updated to reflect this change and provide guidance
to national policy-making bodies, recognizing the
complexity 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.”

41. SAEFVIC: BCG AEFI
N=59

42. SAEFVIC BCG AEFI n=59 male/female : 40/19 age age at vaccination
mean: 2.66 years
median: 0.90 
range:  
 ”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?!!!”

43. SAEFVIC: BCG AEFI

44. 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

45. 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

46. 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

47. An all age immunisation service for high risk patients
Monash Immunisation
An all age immunisation service for high risk patients

48. Monash Immunisation
All age service – established January 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

49. 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

50. Clinical support for providers and patients How to report?
AEFI reports
Clinical support for providers and patients
How to report?
Online – –
Telephone – (03)
Fax – (03)
Need to add contact details for online/ , phone/fax contact

51. Thank you

52. Monash Immunisation Refer to Monash Immunisation Tel 9594 6320
Fax
Need referral
Level 2 (ground) Jessie Mac rooms area