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

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

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

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 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 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 d Nolan et al JAMA 2010

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

LESSON 6 : EXPECT THE UNEXPECTED

Princess Margaret Hospital- Perth WA 2008 2009 2010 Influenza vaccine (previous 72 hours) 3 36 No influenza vaccine 31 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. 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. TIV, trivalent inactivated influenza vaccine. 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:e000016 www.tga.gov.au

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

Febrile seizures following influenza vaccine in Australian children in 2010 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 www.ncirs.edu.au 15

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

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’

JURISDICTIONS NRA

JURISDICTIONS NRA/Central

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

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 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

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.

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; 367:1173-1180, Rodrigues, Int J Epi 2002

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

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

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

“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.”

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

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

Monash Immunisation 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

Clinical support for providers and patients How to report? 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 Need to add contact details for online/email, phone/fax contact

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