Adverse events following immunization (AEFI): Canadian Immunization Guide
Introduction
Evidence regarding vaccine safety generated throughout the vaccine life cycle helps to inform the risk-benefit discussion between immunization providers and potential vaccine recipients or their caregivers. Knowing about proven vaccine associations helps healthcare providers to assess clients who present with an illness in the post-immunization interval. Evidence addressing specific vaccine-associated adverse events (AEs) is discussed in .  describes the types of studies that inform vaccine safety and that can establish or refute that an event is caused by vaccine.
 Vaccinees and/or their parents/caregivers should be advised to notify their public health authority, vaccine provider or other healthcare provider about any concerns that arise following immunization. The provider can then assess these concerns and, if appropriate, complete an adverse event report. 
Adverse Events Following Immunization (AEFI) definitions
The definitions below align with those used by the Canadian Adverse Events Following Immunization Surveillance System (CAEFISS).
AEFI general definition: any untoward medical occurrence which follows administration of an active immunizing agent and which does not necessarily have a causal relationship with the use of a vaccine. The adverse event may be any unfavourable or unintended sign, abnormal laboratory finding, symptom or disease. The general definition of AEFI specifies that the event is not necessarily due to the vaccine. An AEFI can be classified by the following cause specific categories: 
- Vaccine product-related reaction: an AEFI that is caused or precipitated by a vaccine due to one or more of the inherent properties of the vaccine product (examples include vaccination site pain, fever and anaphylaxis).
- Vaccine quality defect-related reaction: an AEFI that is caused or precipitated by a vaccine that is due to one or more quality defects of the vaccine product, including its administration device as provided by the manufacturer. Quality defect is defined as any deviation of the vaccine product as manufactured from its set quality specifications. (Example: failure to inactivate polio virus in some Salk vaccine lots prepared by Cutter laboratories in 1955 resulting in poliovirus infection among some vaccinees.)
- Immunization error-related reaction: an AEFI that is caused by inappropriate usage and, therefore, by its nature is preventable. Inappropriate usage is defined as vaccine handling, prescribing and/or administration other than what is authorized and recommended in a given jurisdiction based on scientific evidence or expert recommendation. (Example: inappropriate administration of live measles vaccine to immunocompromised persons resulting in measles encephalitis or pneumonia.)
- Immunization triggered stress response: an AEFI arising from anxiety about the immunization (examples include syncope or hyperventilation).
- Coincidental event: an AEFI that is caused by something other than the vaccine product, immunization error, or immunization anxiety but where a temporal association with immunization exists. (Example: meningitis that occurs within days of MMR vaccination that upon investigation is shown to be caused by *Streptococcus pneumoniae- )
Serious AEFI: an AEFI that meets one or more of the following criteria: life-threatening, results in hospitalization, prolongation of an existing hospitalization, persistent or significant disability/incapacity, is a congenital anomaly/birth defect, fatal outcome. Any medical event which requires intervention to prevent one of the outcomes listed above may also be considered as serious.
Unexpected AEFI: An adverse event whose nature, severity, or outcome is not consistent with the term or description used in the approved Product Monograph should be considered unexpected. 
When and how to report an AEFI
 Timely AEFI reporting is essential to detect possible changes to the safety profile of all vaccines. The key criteria for reporting an AEFI are temporal association and has no other clear cause at the time of reporting. A causal relationship does not need to be proven. 
 Vaccine providers contribute to vaccine safety by reporting AEFI which allows further investigation of adverse events, but does not mean that an observed event was caused by either vaccine or immunization. It is important that all serious AEFI are reported without delay. It is also important to report unexpected AEFI. Expected common events such as vaccination site reactions or fever do not need to be reported. 
 Providers should follow local or provincial public health protocols and submit reports to the appropriate jurisdictional authority. In most jurisdictions (Ontario, Quebec, Nova Scotia, Manitoba, New Brunswick, Saskatchewan, Prince Edward Island and Northwest Territories, BC, Alberta and Nunavut) AEFI reporting is a legislated requirement. While all provinces and territories collect information similar to that in the national , some have developed their own unique reporting form as well as supplementary forms for specific AEFI: these forms should be used for reporting. 
 When supplementary or follow-up information becomes available after an AEFI report has been submitted, it can be provided using the same AEFI report form (specifying that it is a follow-up), and submitted by the same route. 
 Given the importance of serious AEFI reporting, all such reports are referred by provincial/territorial public health authorities to PHAC within 15 days of becoming aware of the event and processed at the national level within 2 working days. Market authorization holders are required to report serious events to Health Canada within the same 15 day timeframe. 
 Jurisdiction-specific information on the AEFI reporting requirements can be obtained by contacting the appropriate . 
Reporting adverse reactions following administration of a passive immunizing agent
To ensure the ongoing safety monitoring of passive immunizing agents in Canada, reporting of adverse reactions by health care providers is critical. When a serious or unexpected adverse reaction follows the administration of a passive immunizing agent, report the adverse drug reaction to the  using the  available on the program web page. The Canada Vigilance Program collects and assesses reports of suspected adverse reactions to health products, including biologics. If the passive immunizing agent was administered concurrently with an active immunizing agent, the adverse event should also be reported to the local or provincial public health immunization program in following local protocols.
Investigating and managing AEFI
It is important to use standard case definitions for AEFI investigation and reporting. The Canadian Adverse Event Following Immunization Surveillance System (CAEFISS) AEFI report form has been structured to facilitate establishing whether or not reported events meet standard case definitions for AEFIs considered to be of special public health importance (e.g., anaphylaxis, hypotonic-hyporesponsive episode, febrile seizure, intussusception).
 It is also important to consider and investigate coincidental causes of an AEFI. This can be done after the initial report with additional relevant information provided at a later date. Establishing that an adverse event was actually coincidental and not causal is important for making appropriate decisions about future immunizations for a given individual. For more information, refer to the WHOs  
 The Canadian Immunization Guide provides specific information on management of selected AEFI and/or special populations. Additional guidance may be found through Federal/Provincial/Territorial immunization program authorities, and, in several provinces, AEFI expert assessment is available via the Canadian Immunization Research Networks . For more information on AEFI management, refer to SIC Networks  
Proof of causal association
The goal of adverse event investigation and reporting is to determine whether these events are associated with the vaccine or immunization. Vaccine attributable risk is defined as the difference between the frequency of the event in the vaccinated compared to the unvaccinated population. Determination of vaccine attributable risk is primarily done through research studies. 
 A placebo-controlled randomized control trial is the most rigorous study design, especially those using a cross-over design. An elegant example of such a design is a Finnish study involving 581 twin pairs where one twin of each pair was first given the measles-mumps-rubella (MMR) vaccine and 3 weeks later given a placebo. The other twin in the pair first received placebo and 3 weeks later the MMR vaccine. This was done in a double-blinded fashion (i.e., neither the researchers nor the subject caretakers knew whether a given injection was MMR vaccine or placebo). Adverse events were monitored for 21 days after immunization. The results of this classic study are shown in Table 3 and demonstrate two key points. First, fever is a common childhood event affecting 16% to 18% of the placebo group  i.e., a temporally associated coincidental event, related neither to vaccine nor to immunization. Secondly, the risk of fever attributable to MMR vaccine is 2% to 6% and occurs in the interval from 7 to 12 days after immunization.
Calculated from data presented in Table II in Peltola H, Heinonen OP. *Frequency of true adverse reactions to measles-mumps-rubella vaccine.- Reprinted with permission from Elsevier Science. Lancet 1986;1(8487):939-42.
An epidemiologic cohort design is another way to measure vaccine attributable risk (or risk difference). In Canada, this type of design was used to study the frequency of adverse events among a cohort of children given three successive doses of hepatitis B vaccine. The measured outcomes were the number of illnesses or clinical symptoms compatible with any adverse event recorded during one week intervals from 4 weeks before to 3 weeks after each vaccine dose. Recorded adverse events increased in the week after hepatitis B immunization but returned to pre-vaccination levels thereafter. The attributable increase in adverse events due to hepatitis B vaccine was limited to the first week after immunization and was 44%, 26% and 38% after doses 1, 2 and 3 respectively.
 The self-controlled case series design is a powerful method for determining vaccine attributable risk for very rare adverse events. The risk of an event occurring during a defined period following vaccine exposure is compared to the risk of the event occurring in the same individual during intervals of similar length but without vaccine exposure. This technique has been successfully applied to address vaccine safety controversies (e.g., lack of causal link between MMR or thimerosal-containing vaccines and autism) as well as to quantify the attributable risk for some rare events that have been causally linked to vaccine such as thrombocytopenia following measles containing vaccines. 
Individual case causality assessment of AEFI
It is nearly impossible to assess causality without a thorough investigation, near to the time an event occurs. This is especially important for serious as well as unexpected AEFI, and it underscores the important role that immunization and other healthcare providers have in managing AEFI. 
 The WHO guidelines for individual case assessment are an important tool for determining causality based on standardized case definitions that are provided by the Brighton Collaboration.
 The stepwise algorithm provided in the guidelines takes into consideration evidence for known vaccine product-related reactions as well as individual case history and other details which may point to anxiety, immunization error or coincidental root cause for the AEFI. In addition to helping identify actions that are needed to rule out coincidental causes of an AEFI and make decisions about the safety of repeated immunization in individuals, these guidelines can also be used by program administrators to guide the investigation of AEFI clusters, and identify possible new vaccine  adverse event associations which may require further study. 
 In addition, challenge  dechallenge  rechallenge events may also be used to establish causality. This applies much more frequently to drugs than to vaccines. An example would be drug-associated rashes which appear after starting a drug (challenge), disappear after stopping the drug (dechallenge), and reappear upon re-exposure to the same drug (rechallenge). Given the immunologic properties of vaccines, dechallenge is difficult to achieve. The American Health and Medicine Division has accepted challenge  rechallenge events as mechanistic evidence that tetanus toxoid may cause Guillain-Barre Syndrome. This was based on a single case report of a man who developed GBS within 2 weeks following exposure to tetanus toxoid vaccine on three separate occasions.
 While individual case investigation may be able to establish a vaccine  adverse event causal association, it cannot determine vaccine attributable risk.