How do we know vaccines are safe ? Safety inferred because of an absence of adverse reactions • We detect Adverse Events Following Immunisation • Then perform cause specific classification to differentiate an event which is a reaction from a co-incidental event.
CIOMS/ WHO cause specific definition of AEFIs An AEFI that is caused or precipitated by An AEFI that is a vaccine that An AEFI that is caused by caused or is due to one An AEFI that is An AEFI something precipitated by caused by or more quality arising from other than the a vaccine due defects of the Inappropriate anxiety about vaccine to one or more vaccine vaccine the product, product handling, of the inherent immunization. immunization properties of including its prescribing or error or administration the vaccine administration. immunization product. device as anxiety provided by the manufacturer.
How do we differentiate an adverse vaccine/ immunisation reaction from a co-incidental event ? A/Professor Michael Gold Head Allergy and Immunology Women’s and Children’s Health Network and Discipline of Paediatrics University of Adelaide
Outline • AEFI surveillance systems – Components • Causality assessment – For a clusters of cases (Aggregate) – For individual cases (Case Based)
Why should we have a country specific or regional AEFI surveillance system ? – Incomplete safety information because; • Country specific schedules • Genetic predisposition – Eg Narcolepsy Adjuvant Pandemic Influenza Vaccine – HLA DQB1-0602 • Novel vaccine use in limited countries
Nohynek H 1 AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One. 2012;7(3):e33536. doi: 10.1371/journal.pone.0033536. Epub 2012 Mar 28.
Why should we have a country specific or regional AEFI surveillance system ? – Responding to local community concern
Why should we have a country specific or regional AEFI surveillance system ? – Vaccine quality defects • Vaccine manufacture - batch related defects – Immunisation error • Programme error – Differentiate local co-incidental events from reactions • Background rates of disease • Eg Introduction of a new vaccine in a malaria endemic region vs same vaccine introduced into non-malaria region
Components of an AEFI surveillance system • Ascertainment of AEFI reports • Ascertainment of AEFI reports • Ascertainment of AEFI reports – Passive, Active, Passive Stimulated • Report management – Coding, classification, data entry, storage • Analysis – Analysis, causality assessment, signal detection – Hypothesis generation • Action – Investigation, corrective action, communication (feed-back),
Q1. How can industry compliance with GMP be strengthened ? Current estimates are that there will be approximately 30 vaccine products "newly pre-qualified" and introduced into immunisation programmes in the middle/low income countries and will include Rotavirus, HPV, PCV, Influenza vaccine 1995-2008 – manufacturers doubled to 136
Q2. How can vaccine pharmacovigilance be strengthened ? • Resources – AEFI reporting, evaluation and action (investigation, education, research, communication) • Involves and co-ordination of all stakeholders – NRA – Immunisation Programme (EPI) – Government – Industry – Experts - Academia • Ownership
Q3. How can vaccine pharmacovigilance be governed and include all stakeholders (industry) ? • Universally recommended, healthy individuals, vulnerable populations.......... • Higher level of trust • Cannot have trust without good governance
South Australian officials 'hiding' flu vaccination statistics Tory Shepherd, Health reporter From: The Advertiser April 30, 2010 1:14PM
Q4. How can Post Licensure Surveillance systems be strengthened and complementary systems developed ?
Types of AEFI surveillance Passive Stimulated passive Active surveillance surveillance • Reporting of AEFI • Passive • Systematic search by HCW and the surveillance + or scan for defined public ongoing reminders AEFI in target & education of populations (clinic, • AEFI needs to be HCW for AEFI hospital, recognized cases community) • Under-reporting is • May be focused on common selected AEFI
Stimulated passive surveillance system Periodic • Useful where AEFI reminders, surveillance is new education • Involving doctors in clinical & settings can increase feedback reporting of serious AEFI to detect & report • “Zero-reporting” may be a useful cases
Active surveillance Systematic • Active search for safety signals: search/scan cases, risks or syndromes (HHE, intussusceptions, etc) for defined AEFI in target • Time and resource consuming populations • Higher sensitivity, but lower (health unit, coverage clinic, hospital, • Prone to biases unless blinded observers community)
How to do active surveillance continued Based on • Review hospital and clinic records for selected AEFI search for • Complete reporting form when a AEFI patient meets the criteria Based on • Follow up patients after specific search for vaccination vaccine • Inquires about any AEFI (specific targets) and complete reporting form received Collation and analysis of completed report forms
Vaccines safety; effect of supervision or SMS on reporting rates of adverse events following immunization (AEFI) with meningitis vaccine (MenAfriVac™): a randomized controlled trial. Ateudjieu J 1. Vaccine. 2014 Sep 29;32(43):5662-8. doi: 1016/j.vaccine. 2014.08.012. Epub 2014 Aug 23. To assess the effect of: (i) sending weekly SMS, or (ii) weekly supervisory visits on AEFI reporting rate during a meningitis immunization campaign conducted in Cameroon in 2012 using the meningitis A conjugate vaccine (MenAfriVac™). A total of 348 (77.2%) of 451 health facility were included, and 116 assigned to each of three groups The incidence rate of reported AEFI per 100 health facility per week was – 20.0 (15.9-24.1) in the SMS group , – 40.2 (34.4-46.0) in supervision group – 13.6 (10.1-16.9) in the control group.
Q5. How to improve health care and vaccine provider knowledge, attitude and practice about safety and surveillance ? “For all vaccines, the attitude of the physician, nurse …is very influential in the decision to vaccinate a child… * * Swennen B et al. Analysis of factors influencing vaccine uptake: Vaccine 2002;20 S5-S7. * Ansari M et al. Reducing resistance against polio drops. JRSH 2007;127:276-9 Hak E at al.. Vaccine 2005; 23: 3103-7.Pearce et al. BMJ 2008 336 (7647): 754 .
• 29 Health Professionals • 46% of ED consultants not aware of a system of reporting, all nurses aware • Variation in what to report as an AEFI – Nurse, GP, ED consultant – Eg ED only report life threatening, did not report febrile seizures • GP and ED no training, all nurses trained
Vaccine Product Related Reaction Limitations of passive surveillance
Vaccine Product Related Reaction Limitations of passive surveillance Febrile seizures per 1,000 vaccines Fluvax Jr Western Australia 9 Australia 5 Panvax Australia 0.08-0.17 USA CDC Vaccine 0.16 Datalink
Q6. How can we co-ordinate and strengthen global safety surveillance efforts ? • Global implications of safety concerns – MMR and autism (Industrialised) – HPV vaccine and Fiji (ID-NID) – Pentavalent vaccine and death • (NID-ID) • Global Surveillance and communication
Q7. How do we engage the community to communicate and monitor vaccine safety ?
Solutions Pharmacovigilance in Africa • Improving knowledge – Community, health providers • Improving co-ordination – NRA/EPI/Government/NGO/Industry • Novel methods of surveillance – Passive vs Stimulated vs Active sentinel • Mobile phone technology • Establishing regional networks – Regional causality assessment committee, NITAGS • Sustaining surveillance capacity after clinical trials • Opportunities with the polio end game
Causality and Causality assessment Causality* Causality • Is the relationship Assessment between two events (the cause and the effect), • Determining if such a where the second event is relationship exists and if so to a consequence of the first what extent *A direct cause is a factor in absence of which the effect would not occur (necessary cause ). *Sometimes, there are multiple factors that can precipitate or function as co- factors for the effect (event) to occur.
Causality assessment for AEFI • Why ? To avoid automatically concluding that “the event happened after vaccination, therefore it happened because of vaccination”… • For a collection of AEFI reports (aggregate) • For an individual AEFI report (case based)
Co-incidental or causal (reaction) ? Passive AEFI surveillance does not establish causality Event/Illness/Syndrome • Unique lab result yes no • Unique clinical syndrome yes Vaccination • Epidemiological study • NEED A RELATIVE RISK no • ABSOLUTE RISK
Adverse vaccine reactions Unique Laboratory results • Culture of live attenuated vaccine organism
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