Adverse Events Following Immunization (AEFI) Quarterly Report for 2014 – Q2

Safety assessment summary for this Quarter:

• No vaccine safety concerns were identified in Quarter 2 for 2014.
• All serious cases were reviewed and found either to be expected (based on known vaccine-related adverse reactions) or to have alternate explanations, such as community acquired infection; exposures to other agents, such as antibiotics; or pre-existing problems like cardiac disease.
• There appears to be a decrease in AEFI reports received this quarter - this reflects a gap in reporting from jurisdictions that are implementing new electronic reporting systems. We expect an increase in reports received in subsequent quarters to balance this gap.
• There was an increase in reports received this quarter due to intussusception following rotavirus vaccine. It is likely that the increased number of reports reflects an increased utilization of the vaccine. See Table 5 and the discussion preceding it for more information.

Vaccines are closely monitored in Canada at all phases of the vaccine product 'life cycle' from discovery through market authorization (pre-market) and beyond, as people begin using them (post-market). Many stakeholders are involved in various activities related to vaccine safety assessment and monitoring including the federal government, provincial, territorial and local public health authorities, health care providers, vaccine industry and the public. The Public Health Agency of Canada (the Agency) conducts vigilant post-market safety surveillance through a national reporting system, the Canadian Adverse Events Following Immunization Surveillance System (CAEFISS).

The primary purpose of vaccine post market surveillance is to detect safety concerns. These concerns include a possible increase in the severity or frequency of expected reactions, or occurrence of one or more unexpected events (i.e. an event that is not consistent with Canadian product information or labelling). This allows immunization providers and public health immunization program providers to take public health action at the level of the:

• individual (e.g. further investigation to confirm a diagnosis and determine possible causes, consultation to rule out allergy to one or more vaccine components, or evaluate whether or not to give subsequent doses of a vaccine), and/or
• immunization program (e.g. investigation of a cluster of adverse events, review of procedures to ensure that vaccine storage requirements have been strictly followed, or consider a change in policy to adopt a less reactogenic vaccine).

The Agency also shares adverse event following immunization (AEFI) data with Health Canada, the vaccine regulator in Canada, to enable regulatory action related to vaccines marketed in Canada (such as issuing communications to immunization providers or the public regarding the safety concern or requiring additional information or investigation by the vaccine distributor).

Regular vaccine safety surveillance quarterly reports summarizing CAEFISS data were initiated by the Agency in 2014. The first Quarterly Report, summarized all reports of adverse events following immunization (AEFI) received by the Agency in 2014 from Jan 1st to March 31st (Quarter 1), regardless of the date the vaccine was actually given. This Quarter 2 Report provides a similar summary for all reports received from April 1st to June 30th. A new feature of this and subsequent Reports for 2014 is the provision of cumulative data spanning the entire year from January 1st to the end of the reporting quarter (June 30th for this report). This provides a focus on each individual quarter but also tracks the trends as Quarterly Reports accumulate during the calendar year.

Both the current (Q2) and cumulative (Q1 and Q2) quarterly data are compared to an average of all reports received during the same periods of time (Quarter 2 alone and cumulative from Jan 1st to Jun 30th for the average for the last three years (2011- 2013).

Notes on Interpretation: An AEFI is defined as "any untoward medical occurrence which follows immunization and which does not necessarily have a causal relationship with the usage of the vaccine. The adverse event may be any unfavorable or unintended sign, abnormal laboratory finding, symptom or disease". AEFI reports submitted to the Public Health Agency of Canada represent a suspicion, opinion or observation by the reporter as opposed to an assertion or proof that the vaccine may have caused the event. For most events a clear causal relationship is difficult to establish. Additional limitations to AEFI report data include varied reporting standards and underreporting, lack of certainty regarding the diagnostic validity of a reported event, missing information regarding other potential causes and other reporting biases. In short, this information should not be used to estimate the incidence of adverse events.

Results Highlighted for Quarter 2 of 2014

Cumulative counts included in this Quarterly Report (Q2) include reports received from April 1^st to June 30^th 2014 and comparisons are made to the average number of reports received in the same quarter over the previous three calendar years (2011-2013). The reports analysed for 2014 were extracted from the CAEFISS database on August 28^th 2014 and for 2011-2013 on April 29^th 2014 by the Public Health Agency of Canada (the Agency).

Frequency of serious and non-serious AEFI Reports by Age Group

The age distribution for serious AEFI reports received in Q2 for 2014 was similar to that seen in previous years. For non-serious AEFI reports, the proportion involving children aged <7 years appeared to be lower in Q2 of 2014 than in previous years (39.6% versus 51.7%) and higher in adults 18 years and older (41.6% versus 30.6%). This trend is likely artifactual and related to reporting issues referred to above. The jurisdictions whose reports have been delayed by technical issues also happen to have the highest reporting rates for young children. The consistency in SAE between Q2 of 2014 and previous years for those under 18 years of age is because these data are collected by IMP-ACT, and they report adverse events directly to the Agency.

Most common vaccines identified in Adverse Events Following Immunization (AEFI) Reports

The most commonly identified vaccines in AEFI reports are summarized below in table and graph format. Table 3 lists the most commonly implicated vaccines among AEFI reports received for Q2 of 2014 relative to the average number for 2011-2013. Figure 3 provides a cumulative summary of the same data collected in 2014 (Q1 and Q2) compared to the average in 2011-2013. Of note are the apparent lower frequency of non-serious adverse event reports in Q2 compared to 2011-2013 average for DTaP-IPV-Hib, Pneu-C, Men-C, MMR, Var. These lower numbers for childhood vaccines (as opposed to those given to adults) are most likely due to delays in reporting and will be captured in subsequent quarterly reports.

Adverse Events Following Immunization (AEFI) Reported by Main Reason and Seriousness

Classification of AEFIs for Report Purposes: all AEFI reports are reviewed daily by health professionals to assign a main reason for reporting and the associated severity. The classification adheres closely to the national AEFI reporting form in order to provide meaningful feedback to public health authorities, health professionals and the public regarding the adverse event reporting profile. The main categories used when reporting an AEFI, and those reflected on the graph below, are defined as:

• Reactions at or near the vaccination site: most reported events involve inflammation at or near the site of vaccination. Further details can be found in section 9(a) of the reporting form
• Allergic or Allergic-like Events: the most severe allergic event, anaphylaxis, is rare (≤1 episode per 100,000 doses administered) Further details can be found in section 9(b) of the reporting form
• Neurologic events: seizures are the most commonly reported neurologic event especially in infants and toddlers who are prone to have seizures in association with fever. Such events are reported in Canada relatively frequently because they are actively sought and reported by the IMP-ACT network. Further details can be found in section 9(c) of the reporting form.
• Rash only: to be classified as 'rash only', the rash is the only sign or symptom reported. This would include hives that onset any time after immunization but are accompanied by no other signs or symptoms. Hives are a frequent occurrence in childhood and a cause is often not found
• Other events specified on the CAEFISS report form: this could include other events such as persistent crying (continuous or unaltered crying ≥ 3 hours, intussusception, hypotonic-hyporesponsive episodes (HHE), Further details can be found in section 9(d) of the reporting form.

Events not clearly falling into one of the categories listed above are classified into one of four additional categories:

• Systemic events: these are primarily events involving many body systems often accompanied by fever. Any recognized syndromes are classified as systemic events and include such illnesses as Kawasaki syndrome, Steven-Johnson syndrome, Henoch-Schonlein purpura, fibromyalgia and serum sickness. In addition evidence for infection of one or more body parts (respiratory infection, bladder infection, etc.) are included in this category as are instances of rash that is non-allergic in origin and is accompanied by other signs and symptoms such as fever, cough and conjunctivitis. General symptoms such as fatigue, malaise, lethargy, headache, myalgias including influenza-like illnesses are classified as systemic events. Finally fever as the only adverse event reported is included in this category.
• Vaccination anxiety related events: this includes fainting (syncope) with or without seizure-like movements which may briefly accompany a fainting episode. Other events included in this category are clusters of events often seen within minutes of immunization indicative of anxiety such as pallor, shakiness, feeling cold, hyperventilation, etc.
• Miscellaneous other events: all other adverse events that don't fit into any of the above categories are captured as miscellaneous events. These may be further categorized by the predominant body system they fall under such as gastrointestinal, cardiac, genitourinary, etc.
• Vaccination error without an associated AEFI: on occasion reports are submitted of an error in immunization without any associated adverse event. Examples include use of an expired product or incorrect administration of a product (e.g. giving a vaccine into the muscle when it should have been injected subcutaneously).

The main reason for reporting serious (SAE) and non-serious (non-SAE) AEFI for Q2 of 2014 compared to the 2011-2013 average is shown in Table 4. Figure 4 provides a cumulative summary of the same data collected in 2014 (Q1 and Q2) compared to the average in 2011-2013. While the total numbers of non-SAE reports were less in Q1 and Q2 of 2014 than previous years, the distribution by main reason for reporting was similar. The most frequently reported non-SAE were reactions at or near the vaccination site, rash as the only event, allergic or allergic like events and systemic events. The vast majority of all reports were non-serious.

Analysis of Serious Adverse Events Following Immunization (SAE) Reports received by the Agency

The type of serious adverse events (SAE) reported are described below. Table 5 summarizes the type of SAE reported in Q2 of 2014 compared to the 2011-2013 average. Figure 5 provides a cumulative summary of the same data collected in 2014 (Q1 and Q2) compared to the average in 2011-2013.

There were a total of 37 SAE reports in Q2 of 2014 (8.1% of 459 reports total). The average for Q2 from 2011 to 2013 was 54 serious reports (6% of 841 reports total). As noted in Q1, the single most common reason for reporting SAEs in Q2 were seizures usually accompanied by fever. Febrile seizures are actively sought by the pediatric hospital-based Immunization Monitoring Program-Active (IMP-ACT) network which regularly provides over half of all serious AEFI reported to the Agency for children. Febrile seizures are known to occur after immunization with live attenuated vaccines such as MMR or MMRV as often as once for every 2600 vaccinations given. The events are short-lived and not associated with long term adverse outcomes.

The only category with several more Q2 reports in 2014 than in previous years was intussusception (5 in Q2 of 2014 versus 0-2 in previous years). All 5 reports involved infants who had received rotavirus vaccine alone (n=2) or with other regularly scheduled infant vaccines (n=3). The interval from vaccination to symptom onset was 3-4 days for 2 cases, both following dose 1. For the other 3 cases, the onset was 54 days after dose 1, 19 days after dose 2 and an unknown interval after dose 2. All 5 infants made a full recovery. There is a known, albeit rare risk of intussusception (estimated range of 1-7 cases/100,000 doses of vaccine) following rotavirus vaccination. However, there are many other causes of intussusception, and the overall benefit of rotavirus vaccine outweighs the risk. It is most likely that the increased number of intussusception reports reflects an increased utilization of rotavirus vaccine in public health programs across Canada. Nevertheless, intussusception continues to be monitored across Canada.