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Canadian Immunization Guide

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Part 2
Vaccine Safety

Vaccine Safety

As vaccine preventable infections have decreased, the spotlight of public and media concern has shifted to vaccine safety. Since vaccines are usually given to healthy people, especially children, tolerance for adverse events following immunization is low. Perceived vaccine safety risks receive as much media attention as real safety risks and can be difficult to dispel despite credible scientific evidence. Loss of confidence in the safety of vaccines threatens the continued success of immunization programs.

Vaccine pharmacovigilance has been defined as the science and activities related to the detection, assessment, understanding and communication of adverse events following immunization (AEFI) and other vaccine-related or immunization-related issues, and to the prevention of untoward effects of the vaccine or immunization. Health care providers have essential and pivotal roles to play in vaccine pharmacovigilance, including gaining and maintaining public confidence in the safety of vaccines.

Health care providers can develop competency in pharmacovigilance by:

This chapter provides a general overview of pharmacovigilance concepts and activities in Canada as well as a summary of key information and resources related to the three immunization competencies listed above. Refer to the summary of key information information related to vaccine pharmacovigilance in Canada.

The vaccine-specific chapters in Part 4 of this Guide contain key condensed pre-authorization and post-marketing evidence-based safety data. Detailed vaccine safety data are included in the relevant National Advisory Committee on Immunization (NACI) statements and in the vaccine’s product monograph available through Health Canada’s Drug Product DatabaseExternal Link.  Refer to the Appendix for a definition of abbreviations used in this chapter.

Key information related to vaccine pharmacovigilance in Canada

What:

Vaccine pharmacovigilance is defined as the science and activities related to the detection, assessment, understanding and communication of AEFI and other vaccine-related or immunization–related issues, and to the prevention of untoward effects of the vaccine or immunization.

Why:

To minimize the risk and maximize the benefit of vaccines and immunization

Who:

Government regulators, vaccine industry, public health officials, health care professionals, and consumers all have roles and responsibilities for pharmacovigilance (see Table 1)

How:

  • Health Canada regulators have processes in place to maximize vaccine safety throughout the product life cycle – i.e., pre-marketing and post-marketing.
  • It isn’t possible to detect all vaccine side effects through pre-marketing studies, especially if the side effects are very rare (less than 1 in 10,000 subjects). Thus, continuous monitoring of the safety of marketed vaccines is essential for detection of and timely response to vaccine safety signals. A vaccine safety signal is any information that arises from one or multiple sources which suggests a new potentially causal association, or a new aspect of a known adverse reaction (increased severity and/or increased frequency), between immunization and an event or set of related events, that is judged to be of sufficient concern to justify verification and, as appropriate, remedial action.
  • The Canadian Adverse Event Following Immunization Surveillance System (CAEFISS) is a joint effort of provincial/territorial (P/T) and federal public health authorities and their partners.
  • Health care providers should report, without delay, all serious or unexpected AEFI to public health according to jurisdictional guidelines:
    • AEFI: any untoward medical occurrence which follows immunization and which does not necessarily have a causal relationship with the usage of a vaccine. The adverse event may be any unfavourable or unintended sign, abnormal laboratory finding, symptom or disease.
    • Serious adverse event (SAE): one which is life-threatening and/or which results in any one or more of the following: hospitalization, prolongation of an existing hospitalization, permanent disability, congenital abnormality, fatal outcome.
    • ‘unexpected’ AEFI: one which is not included in the official product label (as listed in the package leaflet and/or product monograph)
  • While prompt reporting of serious and/or unexpected AEFI is essential to detect emerging signals and monitor vaccine safety, one or even many AEFI reports do not constitute proof that a vaccine causes an AEFI. Causality assessment requires scientific or epidemiologic evidence to answer the question ‘Can it?’ and then accurate diagnosis and thorough investigation to try to answer the question ‘Did it?’

Vaccine pharmacovigilance activities in Canada

Overview

Vaccine safety assessment and monitoring is a continuum that spans all phases of the vaccine product ‘life cycle’ from discovery through market authorization and beyond.  Many stakeholders (Refer to Table 1) and activities (Refer to Table 2) are involved. Some stakeholders such as vaccine manufacturers and regulatory authorities have roles and responsibilities throughout the product life cycle, whereas others such as public health authorities and vaccine providers are involved later in the process, from about the time the product is authorized for marketing in Canada.

A great deal is learned about vaccine safety during the testing period prior to market authorization. Testing proceeds in a step wise fashion from non-human to human studies. Clinical trials in humans start out small but increase in size and progressively assess immunogenicity, appropriate dose and schedule, safety and finally efficacy.  Regulatory oversight is in place to ensure that all phases of testing and production are done in accordance with rigorous standards (Good Laboratory Practices, Good Clinical Practices, Good Manufacturing Processes).

With sufficient evidence that the product has a positive benefit to risk profile, regulators will authorize a new vaccine for marketing. About the same time national expert advisory groups such as NACI review the evidence to develop recommendations for use and public health authorities use a standard framework to determine whether or not publicly-funded immunization programs should be instituted.  

Despite all the knowledge gained about a product by the time market authorization is given, there is still more to learn about the safety profile in terms of rare side effects or risk for increased frequency of adverse events. Thus ongoing monitoring of vaccine safety is standard throughout the life cycle and it may be necessary to do special studies to learn more about the safety profile or to investigate issues of concern that may emerge in the post-market period.

Regulatory activities also continue in the post-market period to ensure that all new lots of the product match the properties of those on which marketing approval was based and that product production is consistent and of high quality.

More detail on the specific processes and stakeholder activities in Canada that contribute to vaccine safety are provided below. 

Regulatory quality oversight and pharmacovigilance activities

Health Canada’s Health Products and Food Branch (HPFB) has the mandate to take an integrated approach to managing the health-related risks and benefits of health products and food by:

  • minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food; and
  • promoting conditions that enable Canadians to make healthy choices and providing information so that they can make informed decisions about their health.

The following provides a brief summary of how this is done.

Authorization for marketing a vaccine in Canada

Health Canada's Biologics and Genetic Therapies Directorate (BGTD) is the Canadian federal authority that regulates biological drugs, including vaccines. Before manufacturers or sponsors are eligible to market a product in Canada, they must submit a "New Drug Submission".  This submission contains extensive information and data about the vaccine's safety, efficacy and quality, including the results of the preclinical and clinical studies, details regarding the production of the vaccine, packaging and labelling details, and information regarding therapeutic claims and side effects.  The quality evaluation of the submission includes an onsite evaluation of the production facilities as well as laboratory testing of samples from three to five consecutive lots (or batches of vaccine production) to verify manufacturing consistency.  

Upon careful review of the all the evidence, the BGTD determines whether the benefits of the vaccine outweigh its risks, and the risks can be mitigated. (i.e. risks decreased and their impact reduced), in accordance with Canada's Food and Drugs Act and RegulationsExternal Link. If the submission meets all requirements, the BGTD will issue a Notice of ComplianceExternal Link and a Drug Identification Number (DIN)External Link for market authorization.

Compliance with Good Manufacturing Practice (GMP) is an additional Health Canada requirement for selling vaccines in Canada.  The Health Products and Food Branch Inspectorate (HPFBI) ensures this compliance through issuance of Establishment Licenses via its own GMP inspections or through Mutual Recognition Agreements with international regulatory bodies such as the European Medicines Agency.

Quality monitoring activities

Vaccine lot release program

The purpose of the lot release program is to ensure to the extent possible that each newly manufactured batch of vaccine matches the lots used to generate the safety and efficacy data for market authorization.  Each vaccine lot is subject to the lot release program before sale in Canada. Specifically, an official document containing results of key quality control tests performed throughout the manufacturing process of each individual lot must be submitted to and is reviewed by Health Canada before a release letter is issued to allow the sale of the lot on the Canadian market. Moreover, as part of its lot release program, Health Canada performs testing of most vaccine lots as per its Lot Release GuidelinesExternal Link. In addition, vaccine manufacturers must submit a Yearly Biological Product Report, which summarizes the quality information for all the lots manufactured in their facility for each product. These strategies allow Health Canada to assess how well the manufacturing process is controlled and that the quality control tests remain suitable.

In addition, regular GMP inspections are conducted to ensure continued compliance to Good Manufacturing Practice and renewal of establishment licenses for vaccine manufacturing facilities.

Safety monitoring activities

Canada Vigilance ProgramExternal Link
Market authorization holders (i.e., the sponsors or manufacturers that have the legal authority to market their drug in Canada) are required to report serious adverse reactions to the Canada Vigilance Program, as mandated by the Food and Drugs Act and Regulations. This information is one of the tools that enable Health Canada to monitor the safety profile of vaccines to determine if their benefits continue to outweigh their risks.

Safety reports

The Food and Drugs Act and Regulations require market authorization holders to analyze adverse drug reaction data for safety concerns and prepare an annual summary report which represents a comprehensive assessment of the worldwide safety data of the vaccine. Market authorization holders must also notify Health Canada if they become aware of a significant change in the product benefit-risk profile.

Safety reports are assessed by Health Canada and, if specific safety issues are identified, additional safety information may be requested.

Risk management plans (RMP)

A risk management plan summarizes known important safety information about a health product; identifies gaps in knowledge; outlines how known and potential safety concerns will be monitored by the market authorization holder; and provides a proposal to minimize any identified or potential risk. Health Canada reviews the RMP when the market authorization holder is seeking authorization to market a new vaccine in Canada but can also request that a RMP be submitted at other times.

Product risk/benefit assessments

Health Canada can ask the market authorization holder to submit a benefit-risk assessment of a therapeutic health product when the benefit-risk profile of a product has changed. Health Canada evaluators reviewing benefit-risk assessments use science-based procedures to determine whether the benefits outweigh the risks or whether the product needs regulatory intervention.

Canadian Adverse Event Following Immunization Surveillance System (CAEFISS)

CAEFISS is a collaborative post-marketing federal/provincial/territorial (F/P/T) surveillance system with the following objectives:

  • to continuously monitor the safety of marketed vaccines in Canada;
  • to identify increases in the frequency or severity of previously identified vaccine-related reactions;
  • to identify previously unknown AEFI that could possibly be related to a vaccine (unexpected AEFI);
  • to identify areas that require further investigation and/or research; and
  • to provide timely information on AEFI reporting profiles for vaccines marketed in Canada that can help inform immunization-related decisions.

CAEFISS includes spontaneous, enhanced and active AEFI reporting processes. Each province and territory has their own reporting system that includes activities at the local/regional as well as the provincial/territorial level. (Refer to the FPT contact information for AEFI-related questions) All provincial and territorial systems are part of CAEFISS.  Spontaneous AEFI reports may come from health care professionals, market authorization holders and the public. F/P/T immunization program authorities encourage vaccine providers and others to report AEFI of particular public health importance and sometimes conduct enhanced AEFI surveillance as part of new publicly-funded immunization programs or as a response to possible emerging vaccine safety signals. In some jurisdictions (Ontario, Quebec, Nova Scotia, Manitoba, New Brunswick, Saskatchewan, Prince Edward Island and Northwest Territories) AEFI reporting is a legislated requirement.

There is also an active syndromic surveillance component to CAEFFIS. This is provided by the Immunization Monitoring Program – ACT-ive (IMPACT) which is described below.

Immunization Monitoring Program – ACT-ive (IMPACT)

IMPACTExternal Link is a pediatric, hospital-based network funded by PHAC and administered by the Canadian Paediatric Society. IMPACT conducts a national surveillance network for adverse events following immunization, vaccine failures and selected vaccine preventable diseases in children. The 12 IMPACT hospitals encompass approximately 90% of tertiary care pediatric beds in Canada. Nurse monitors actively search for children admitted to IMPACT hospitals with neurologic and other high priority adverse events. The nurse monitors determine whether these events have followed immunization within a timeframe that could implicate vaccine as a possible cause. All such AEFI are reported to PHAC as well as to local public health officials.

How and when to report an AEFI

Vaccinees and/or their parents/caregivers should be advised to notify their 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. Providers submit reports to the appropriate jurisdictional authority (e.g. to local or provincial public health). In all cases, these are then reported to the federal authorities so each AEFI can be added into the national CAEFISS database. Refer to the FPT contact information for AEFI-related questions which also contains the AEFI Reporting Form and a user guide.

The main purpose of post-marketing AEFI surveillance is to detect vaccine safety signals. The key criteria for reporting an AEFI are temporal association and a suspicion that the vaccine or immunization may have caused the event. One need not be sure that the AEFI was caused by either vaccine or immunization nor does an AEFI report prove causation. Unexpected events that are not listed in the product monograph should be reported. Expected common events such as vaccination site reactions or fever need not be reported unless they are more severe or frequent than usual. Part 4 of this Guide provides information on expected common adverse events for vaccines marketed in Canada.

Of greatest priority for timely reporting are serious AEFI (life-threatening and/or which result in any one or more of the following: hospitalization, prolongation of an existing hospitalization, permanent disability, congenital abnormality, fatal outcome). Serious events should be investigated for other causes as appropriate, but reporting should be done without delay. Follow-ups can be sent using the same AEFI report form (specifying that it is a follow-up), and submitted by the same route, once the investigation is complete.

The national Adverse Events Following Immunization Report Form and User Guide to the Completion and Submission of the AEFI Reports provide detailed guidance for reporting an AEFI.

AEFI report flow and associated activities

Local public health officials are usually the first to receive an AEFI report. Key activities include review by a public health professional for individual public health action related to the advisability of additional doses of implicated vaccine(s). Efforts may also be made to gather additional information, validate a report diagnosis, and follow up investigation results and/or final outcome of the AEFI. In some settings, the reports are entered into an electronic database. Vaccine safety issues such as unexpected events or increases in severity or frequency of expected AEFI, especially vaccination site reactions or allergic events, may first be recognized at the local level. Such concerns are communicated to appropriate regional and/or provincial/territorial personnel for further assessment and investigation if needed.

Provincial/territorial immunization programs receive and review all AEFI reports to carry out jurisdictional level analysis including estimation of rates of occurrence of specific AEFI and, in some cases, preparation of periodic jurisdictional summaries. With a larger volume of reports than is seen at local levels, this is another opportunity to identify possible safety signals and take action as appropriate. Actions may include: undertaking additional epidemiological investigation; consulting with experts, advising federal public health or regulatory authorities; or creating an AEFI alert to notify and seek input from all F/P/T vaccine safety leads (refer to Vaccine Vigilance Working Group). In addition to being the lead on jurisdictional pharmacovigilance activities, P/T vaccine safety coordinators remove personal identifiers in AEFI reports and send the reports to PHAC. Serious AEFI reports are forwarded to PHAC within 15 days or less.

The Vaccine Safety Section at PHAC receives AEFI reports from multiple sources (from provinces, federal jurisdictions, IMPACT, and manufacturers), identifies duplications and collates them into a national database. Serious events are given priority and are processed within 2 business days. The key activities at the national level include coding of AEFI using the international Medical Dictionary for Regulatory Activities (MedDRA) and medical case review to detect vaccine safety signals including any unexpected or unusual AEFI. Analyses are done regularly to search for vaccine safety signals and information is shared with Health Canada. Reports are produced for F/P/T and NACI review.

Vaccine Vigilance Working Group (VVWG)

This group includes members representing all federal (First Nations and Inuit Health Branch [FNIHB], National Defence and the Canadian Forces [DND], Royal Canadian Mounted Police [RCMP], Correctional Services of Canada [CSC]) and P/T immunization programs as well as Health Canada regulators and IMPACT. The working group reports to the Canadian Immunization Committee and its activities include:

  • preparation of national guidelines and procedures for monitoring and management of AEFIs in Canada;
  • providing a national forum to identify, share and promote best practices regarding vaccine pharamcovigilance; and
  • providing a national vaccine safety sentinel network that can rapidly share and disseminate information to appropriate stakeholders regarding vaccine safety issues or signals

Table 1 provides an overview of the key stakeholder roles and responsibilities for pharmacovigilance in Canada.  It is important to note that to be effective there needs to be good communication among the key stakeholders. For example, scientists and regulators need to give information to health care providers, and health care providers need to give information to public health authorities who in turn collate and analyse information for regulators, healthcare providers, scientists and consumers.

Table 1: Key stakeholder roles and responsibilities for pharmacovigilance in Canada
Stakeholder Specific group Role/responsibility
Table 1 - Footnote 1
Good Manufacturing Practice:  guidelines to ensure that the vaccine production process:
  • uses starting materials that are characterized with defined origin and acceptable quality;
  • is validated by demonstration that all specifications of all steps are met at least 3 times in a row;
  • is consistent with each new lot having the same characteristics of lots used in pre-authorization clinical trials that established safety and efficacy; and
  • is done in a licensed establishment.
Table 1 - Footnote 2
Good Laboratory Practice: guidelines to ensure uniformity, consistency, reliability, reproducibility, quality and integrity of chemical pre-clinical safety testing
Table 1 - Footnote 3
Good Clinical Practice: standards for the conduct of clinical trials
Table 1 - Footnote 4
Federal jurisdictions include: First Nations and Inuit Health Branch (FNIHB), Department of National Defense (DND), Royal Canadian Mounted Police (RCMP) and Correctional Services of Canada (CSC).
Health Canada regulators (Health Products and Food Branch, HPFB) Biologics and Genetic Therapies Directorate (BGTD)
  • Requires sufficient evidence of safety, efficacy and quality to authorize vaccine for sale in Canada
  • Vaccine lot release program
  • Reviews/approves post-marketing product changes that could impact quality, safety or efficacy
Marketed Health Products Directorate (MHPD)
  • Collects suspected adverse reaction reports from market authorization holders
  • Conducts risk-benefit assessment
  • Reviews safety data submitted by market authorization holders (adverse reaction reports, safety reports, issue-specific safety reports, risk management plans, etc.)
  • Issues risk communications
Health Products and Food Branch Inspectorate
  • Provides establishment licensing and inspections
  • During inspections, monitors and enforces vaccine industry compliance with the Food and Drugs Act and Regulations, including Good Manufacturing PracticeTable 1 - Footnote 1
Vaccine industry Vaccine market authorization holders
  • Monitor the safety of their vaccines
  • Comply with the Food and Drugs Act and Regulations, including Good Laboratory PracticeTable 1 - Footnote 2, Good Clinical PracticeTable 1 - Footnote 3, and Good Manufacturing Practice
Public health authorities Public Health Agency of Canada
  • Collates, codes, reviews, analyzes and communicates national level AEFI report data from multiple sources
FederalTable 1 - Footnote 4/Provincial/Territorial (F/P/T) Health Jurisdictions (immunization programs)
  • AEFI surveillance at the F/P/T jurisdictional level 
  • F/P/T vaccine safety signal detection/investigation
  • Share de-identified AEFI report data with PHAC
Local public health officials
  • Report AEFIs to P/T public health officials
  • Individual public health action after an AEFI (e.g., AEFI validation and/or investigation; decisions on future re-immunization)
Health professionals Scientists, expert clinicians and networks
  • Conduct research and contribute to surveillance of vaccine and immunization safety
Members of the National Advisory Committee on Immunization
  • Review evidence on vaccine risk and benefit to provide expert recommendations for vaccine use
Vaccine providers and other health care providers, as appropriate to their clinical and/or public health professional practice
  • Administer vaccine
  • Identify, report and manage AEFI as part of their clinical and/or public health professional practice
Consumers Vaccinees and their care providers
  • Seek information needed to make decisions about vaccination
  • Notify their healthcare provider about AEFIs to enable prompt assessment, appropriate management, and timely reporting if indicated.

Evaluation of vaccine safety and quality throughout the product life cycle

Prior to the 1960s, it was erroneously thought that everything that could be known about a product could be learned prior to product authorization. It is now known that while sufficient evidence of safety, efficacy and quality is an absolute requirement for regulators to grant authorization for marketing a product, sufficient evidence does not mean knowing everything that can be known about a product. It is impossible to learn everything about a product prior to authorization and efforts to do so delay proven product benefit from being realized in the population.

Pre-marketing studies are rigorously controlled to ensure that results are valid and reproducible. As a result, subjects in these studies are usually healthy with no underlying conditions. Post-marketing surveillance studies may be needed to determine whether the safety profile is the same in other target populations, such as the immunocompromised or those born prematurely or those with asthma, diabetes or other chronic diseases. In order to detect very rare adverse events (frequency of less than 1 in 10,000 subjects) it is necessary to have 30,000 to over 100,000 subjects in a controlled study. This is rarely practical or possible and would delay the introduction of a proven effective vaccine into the population. The concept of a life cycle for vaccines and other marketed products underscores the fact that knowledge regarding product safety and efficacy must be sought after, as well as before, marketing authorization.

Table 2 describes what is learned about vaccine safety throughout the vaccine life cycle and the accompanying regulatory requirements to ensure data and product quality.

Table 2: Evaluation of safety and quality throughout the vaccine life cycle
Vaccine life cycle phase Usual number of subjects Regulatory requirement Why it is done
Pre-marketing evaluation prior to issuance of the Notice of Compliance (NOC)
Table 2 - Footnote 1
Good Laboratory Practice: guidelines to ensure uniformity, consistency, reliability, reproducibility, quality and integrity of chemical pre-clinical safety testing
Table 2 - Footnote 2
Good Clinical Practice: standards for the conduct of clinical trials
Table 2 - Footnote 3
Good Manufacturing Practice: guidelines to ensure that the vaccine production process:
  • uses starting materials that are characterized with defined origin and acceptable quality;
  • is validated by demonstration that all specifications of all steps are met at least 3 times in a row;
  • is consistent with each new lot having the same characteristics of lots used in pre-authorization clinical trials that established safety and efficacy; and
  • is done in a licensed establishment.
Pre-clinical testing None Compliance with the Food and Drugs Act and Regulations, Good Laboratory Practice (GLP)Table 2 - Footnote 1
  • Provides information on possible efficacy and safety in laboratory and animal testing
Clinical trials
  • Phase I: 10 – less than 100
  • Phase II: 100-1,000
  • Phase III: 1,000-30,000
Compliance with the Food and Drugs Act and Regulations, Good Clinical Practice (GCP)Table 2 - Footnote 2
  • Provides safety and efficacy data on humans
  • Phase I: very common adverse reactions (occurring in 10% or more of doses)
  • Phase II: common adverse reactions (occurring in 1% to less than 10% of doses)
  • Phase III: uncommon (occurring in 0.1% to less than 1% of subjects) and some rare (occurring in 0.01% to less than 0.1% of subjects) adverse reactions
Validation of manufacturing process, and control Not applicable Compliance with the Food and Drugs Act and Regulations, including Good Manufacturing Practice (GMP)Table 2 - Footnote 3 as well as with WHO, ICH and other international quality guidance documents
  • Assesses quality of vaccine production process:
    • All steps in the manufacturing process from seed lot production to delivery  as well as quality control tests must be validated
  • Documentation on production process, quality  control and facilities must be submitted to the regulator for review prior to approval
On-site evaluation of the manufacturing process Not applicable Compliance with the Food and Drugs Act and Regulations, including GMP as well as with WHO, ICH and other international quality guidance documents
  • Monitors quality of vaccine production:
    • Health Canada product specialists are sent to the manufacturing site to assess the manufacturing process
Consistency testing Not applicable Compliance with the Food and Drugs Act and Regulations, including GMP
  • Ensures quality of vaccine:
    • Samples from at least 3 consecutive lots are tested in Health Canada laboratories to ensure that the product is manufactured consistently
Establishment licensing Not applicable Compliance with the Food and Drugs Act and Regulations, GMP
  • Ensures that the facilities in which the product (the active pharmaceutical ingredient) is manufactured are appropriate to the specifications that apply to that product.
Post-marketing regulatory oversight (post-NOC) and pharmacovigilance activities
Lot release program Not applicable Compliance with the Food and Drugs Act and Regulations
  • Ensures that each marketed lot of vaccine does not differ from vaccine lots shown to be safe and effective in clinical trials
Establishment inspections Not applicable Compliance with the Food and Drugs Act and Regulations, including GMP
  • Ensures that the facilities in which the product (the active pharmaceutical ingredient) is manufactured are appropriate to the specifications that apply to that product.4
  • Generally inspections occur every 2 to 3 years; however can be more or less frequent depending on the type of activity and product.
Post-marketing studies to address gaps in the vaccine safety profile that could not be learned via pre-marketing testing Phase IV: 100 to many thousands (depending on study objective) There is no regulatory requirement, but it is suggested as part of guidance from Health Canada. May conduct large population-based epidemiologic studies to assess a signal and test hypotheses (accept or reject) related to a causal association between vaccine and adverse event.
  • Expand data on vaccine safety profile in target population in case some rare adverse events not detected during pre-marketing phase
  • Assess safety profile in special populations not studied as part of pre-authorization trials (e.g., immunocompromised, diabetics etc.)
  • Study possible interactions with other vaccines
AEFI  surveillance systems Spontaneous, enhanced and/or active AEFI reporting systems Compliance with the Food and Drugs Act and Regulations by market authorization holders CAEFISS activities are undertaken voluntarily, although some P/T require AEFI reporting as part of their public health legislation
  • Detect new vaccine safety signals which could be:
  • increased severity or frequency of previously known adverse reactions
  • unexpected adverse reactions
  • Conduct special investigations to determine root cause of vaccine safety signals
Studies designed to test hypotheses related to vaccine-adverse event associations Population-based epidemiologic studies and/or randomized controlled trials May be requested by regulators in response to new safety signals
  • Test hypothesis that a vaccine can cause an AEFI, including very rare events (less than 1 in 10,000 subjects)

Vaccine - Adverse event causality: can it? Did it? Will it?

Causality assessment can be used to answer three different questions related to vaccine causing an adverse event: Can it? Did it? Will it?

Can it? – vaccine attributable risk

”Can it?” uses scientific and epidemiologic methods, usually in large populations, to prove that there is a causal association between a vaccine and an adverse event. When the answer to “can it?” is yes, investigators also hope to identify the attributable risk related to the vaccine.

Ideally, the goal of safety studies is to determine vaccine attributable risk, defined as the difference between the frequency of an event in the vaccinated compared to unvaccinated population. Special study designs are needed to determine attributable risk such as those described below. While the first two studies were completed several years ago they remain relevant and are excellent examples of study designs that can inform vaccine safety.

The most rigorous study design is a placebo-controlled randomized control trial, 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 measles-mumps-rubella (MMR) vaccine and 3 weeks later given a placebo whereas 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.

Table 3: Placebo-controlled randomized cross-over design to determine proportion of fever attributable to MMR vaccineTable 3 - Footnote *
Days after injection
1 - 6 7 - 8 9 - 10 11 - 12 13 - 21
Table 3 - Footnote *
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.
MMR vaccine 17.2% 20.3% 24.0% 19.9% 16.2%
Placebo 17.0% 18.0% 17.9% 17.5% 16.5%
Difference or attributable risk 0.2% 2.3% 6.1% 2.4% – 0.3%

An epidemiologic cohort design is another way to measure vaccine attributable risk. A Canadian example is shown in Figure 1. In this case, the study cohort was children immunized with 3 doses of hepatitis B vaccine and 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. Therefore this means that there is a 44% increase risk of adverse events in the first week after the first dose of vaccine which is determined to be due to vaccine.

Figure 1: Cohort study design to determine proportion of adverse events attributable to hepatitis B vaccineFigure 1 - Footnote *

Figure 1: Adverse Events Chart

Some bars represent relative attributable risk (AR=44%, AR=26%, AR=38%)
Arrows indicate vaccination.

Figure 1 - Footnote *
Reproduced with permission of the American Journal of Public Health from De Serres G. et al. Importance of attributing risk in monitoring adverse events after immunization: hepatitis B vaccination in children. Am J Public Health 2001;91(2):313-15.

Text Equivalent - Figure 1

Determining vaccine attributable risk for very rare adverse events (less than 1 in 10,000 subjects) is difficult. In controlled trials, study populations of 30,000 or more are needed. Once a vaccine with proven efficacy has been authorized and marketed in Canada, it is unethical to include placebo groups in studies among people for whom the vaccine is recommended. Thus, special epidemiologic methods   are needed   to try to control bias, especially related to non-random distribution of immunization in the population.  

One powerful method for determining vaccine attributable risk for very rare adverse events is the self-controlled case series design which compares the risk of an event occurring during a defined risk period following vaccine exposure to other time intervals in the same individual’s life where no vaccine exposure occurred. 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 (refer to Institute of Medicine).

Did it? - AEFI cluster and individual case causality assessment

In investigating AEFI clusters and individual cases, reviewers are trying to answer the question “Did it?” (i.e., did one or more administered vaccines cause the observed adverse event or would the event have happened anyway even if the vaccine hadn’t been given).

An AEFI is reported based on a suspicion as opposed to a certainty that a given vaccine caused a given adverse event. The actual cause of the AEFI could be one or more of the following based on terms that have been defined by the Council for International Organizations of Medical Sciences (CIOMS) – World Health Organization (WHO) Working Group on Vaccine Pharmacovigilance:

  • 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. For example:
    • common to very common AEFI:  vaccination site pain and swelling, fever
    • uncommon AEFI:  hypotonic-hyporesponsive events (HHE) after infant vaccines;
    • rare AEFI:  febrile seizure after MMR vaccine
    • very rare AEFI:  anaphylaxis after any vaccine
  • 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.  An example of this occurred in 1955 when Cutter laboratories failed to completely inactivate polio virus in Salk vaccine lots leading to cases of polio infection.   This event led to much stronger regulatory oversight of vaccine production and the implementation of Good Manufacturing Practices. With the current level of regulatory oversight to assess vaccine quality, a vaccine quality defect-related reaction is now rare.  Nonetheless, the possibility must be considered and a high level of a vigilance maintained when new signals emerge.
  • 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. An example of this is the development of a sterile nodule at the vaccination site because of using needles that are too short.  When needles are too short, it results in subcutaneous deposition of alum-containing vaccine meant to be injected intramuscularly which can result in a sterile nodule.
  • Immunization anxiety-related reaction: an AEFI arising from anxiety about the immunization (e.g., syncope or hyperventilation).
  • Coincidental event: an AEFI that is caused by something other than the vaccine product, immunization error, or immunization anxiety (e.g., acute infection that may have been incubating but not clinically apparent at the time of immunization; emergence of a genetic disorder not yet diagnosed at the time of immunization.)

Each of the above types of adverse events must be considered as a possible ‘root cause’ whenever a vaccine safety signal is detected and verified. Sometimes it cannot be exactly determined what the root cause was. Depending on the seriousness of the signal it may be necessary to take immediate regulatory action (e.g., lot quarantine or recall) and/or public health action (e.g., suspend or modify immunization program) pending results of the investigation. A signal investigation requires a cooperative effort from multiple stakeholders including F/P/T public health officials, Health Canada regulators, vaccine market authorization holders and, often, vaccine researchers.

Will it? - applying vaccine safety evidence to risk communication

Evidence regarding vaccine safety, as generated throughout the vaccine life cycle helps to inform the risk-benefit discussion between health care providers and potential vaccine recipients or their caregivers. Of greatest use is the determination of vaccine attributable risk.  For example, to the question: Will MMR vaccine cause thrombocytopenia? Based on large epidemiologic studies, one can say that MMR vaccine will cause thrombocytopenia once for every 30,000 to 40,000 doses given. Evidence addressing other adverse events can be found in vaccine-specific chapters in Part 4 of this Guide.

Global Partners

Vaccine pharmacovigilance is a global effort with many participants. Canada’s global partners in vaccine pharmacovigilance are briefly described below with a link to more detailed information.

World Health Organization (WHO)

The WHO has a mandate from member states to develop, establish and promote international standards with respect to a wide variety of products including biologics such as vaccines. Since 1965, the WHO has had a global program for International Drug Monitoring which is run out of the Uppsala Monitoring CentreExternal Link in Sweden. The main objective of the program is safety signal detection at a global level.

In 1999 the WHO established the Global Advisory Committee on Vaccine SafetyExternal Link (GACVS) to provide independent evidence-based responses to safety issues of global concern. The expert committee meets twice yearly (usually June and December) and publishes their conclusions and recommendations shortly thereafter in the WHO Weekly Epidemiological Record. The GACVS also maintains a subject-specific topic index at their website. As part of their work, GACVS established the Vaccine Safety NetExternal Link which identifies and promotes websites on vaccine safety that adhere to good information practices.

Council for International Organizations of Medical Sciences (CIOMS)

The Council for International Organizations of Medical SciencesExternal Link is an international, non-governmental, non-profit organization established jointly by WHO and UNESCO in 1949 to facilitate and promote international activities in the field of biomedical sciences, including making recommendations on the assessment and monitoring of adverse reactions. The WHO and CIOMS jointly formed a Working Group to develop definitions relevant to vaccine pharmacovigilanceExternal Link which were published in 2012.

Brighton Collaboration

The Brighton Collaboration is a global expert network which seeks to create methodological standards for vaccine pharmacovigilance including standardized case definitions of AEFIExternal Link. These case definitions have been adopted by the VVWG and are captured to some extent in the national Adverse Events Following Immunization Report Form.

Institute of Medicine (IOM)

The IOMExternal Link was formed in 1970 by the United States National Academy of Sciences (NAS) and functions as an independent, expert professional body that examines issues of relevance to the health of the public. Since 2001, an absolute criterion for membership on IOM Immunization Safety Review Committees has been lack of any association with vaccine manufacturers or their parent organizations and no prior function as a legal expert witness.

For each issue studied, the IOM Immunization Safety Committee reviews all pertinent theoretical, experimental, clinical and epidemiologic evidence and hears presentations from the public and health professionals. The Committee starts from a neutral position, with no prior assumption regarding a positive or negative connection between the vaccine and the issue at hand. The scientific evidence is then reviewed, and biologic mechanisms for a possible causal association carefully considered. Prior to publication, each report is reviewed by an independent expert panel, chosen by the NAS and the IOM but anonymous to the Committee. Reviewer’s comments are given due consideration, but ultimately the final published report represents the consensus of the IOM safety panel alone. The IOM website provides access to all committee reports, including the most recent reports published in 2011 The 2011 Committee reportExternal Link considered the scientific evidence related to the safety of eight vaccines (MMR, varicella, influenza, human papillomavirus [HPV], hepatitis A, hepatitis B, meningococcal polysaccharide, meningococcal conjugate, and diphtheria toxoid-tetanus toxoid-acellular pertussis [DTaP]-containing vaccines). The 2013 Committee reportExternal Link focused on the safety of the United States immunization schedule for infants and children.

Selected References

Advisory Committee on Population Health and Health Security. Final report: National Immunization Strategy, 2003. Accessed November 2012.

Berkovic SF, Harkin L, McMahon JM et al. De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study. Lancet Neurol 2006;5:488-92.

Council for International Organizations of Medical Sciences (CIOMS). Report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance: Definition and Application of Terms for Vaccine Pharmacovigilance (PDF document)External Link. 2012. Accessed December 2012.

Dellepiane N, Griffiths E, Milstien JB. New challenges in assuring vaccine quality. Bulletin WHO 2000;78(2):155-62.

De Serres G, Skowronski DM, Guay M et al. Recurrence risk of oculorespiratory syndrome after influenza vaccination: randomized controlled trial of previously affected persons. Arch Intern Med. 2004 Nov 8;164(20):2266-72. Erratum in: Arch Intern Med. 2005 Jan 24;165(2):145.

De Serres G. et al. Importance of attributing risk in monitoring adverse events after immunization: hepatitis B vaccination in children. Am J Public Health 2001;91(2):313-15.

Folb PI, Bernatowska E, Chen R. et al. A global perspective on vaccine safety and public health: the Global Advisory Committee on Vaccine Safety (PDF document)External Link. Am J Public Health 2004;94(11):1926-31. Accessed November 2012.

Immunize Canada. Fact sheet: Immunization Information on the Internet:
Can you trust what you read? Accessed November 2012. English version (PDF document)External Link; French version (PDF document)External Link.

Institute of Medicine. 2011. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press.

Offit PA. The Cutter Incident – How America’s First Polio Vaccine Led to the Growing Vaccine Crisis. 2005. Yale University Press, New Haven and London.

Peltola H, Heinonen OP. Frequency of true adverse reactions to measles-mumps-rubella vaccine. Lancet 1986;1(8487):939-42.

Public Health Agency of Canada.  F/P/T contact information for AEFI-related questions. Accessed April 28, 2013.

World Health Organization Global Advisory Committee on Vaccine Safety. Bi-annual meeting reports, including summary lists of the topics discussed and full text detailsExternal Link. Accessed November 2012.

World Health Organization Vaccine Safety NetExternal Link. Accessed November 2012 at:

World Health Organization. Guidelines for preparing core clinical safety information on drugs - report of the Council for International Organizations of Medical Sciences (CIOMS) Working Group III. Geneva: WHO, 1994. (Chapter 5, Good Safety Information Practice).

Appendix of abbreviations

Abbreviation Definition
AEFI Adverse event(s) following immunization
AR Attributable risk
BGTD Biologics and Genetic Therapies Directorate
CAEFISS Canadian Adverse Event Following Immunization Surveillance System
CIOMS Council for International Organizations of Medical Sciences
CNPHI Canadian Network for Public Health Intelligence
CSC Correctional Services of Canada
DIN Drug identification number
DND National Defence and the Canadian Forces
DTaP Diphtheria toxoid-tetanus toxoid-reduced acellular pertussis
F/P/T Federal/provincial/territorial
FNIHB First Nations and Inuit Health Branch
GACVS Global Advisory Committee on Vaccine Safety
GCP Good Clinical Practice
GLP Good Laboratory Practice
GMP Good Manufacturing Practice
HHE Hypotonic-hyporesponsive events
HPFB Health Products and Food Branch
HPV Human papillomavirus
IMPACT Immunization Monitoring Program – ACT-ive
IOM Institute of Medicine
MedDRA Medical Dictionary for Regulatory Activities
MHPD Marketed Health Products Directorate
MMR Measles-mumps-rubella vaccine
NACI National Advisory Committee on Immunization
NAS United States National Academy of Sciences
NOC Notice of Compliance
P/T Provincial/territorial
PHAC Public Health Agency of Canada
RCMP Royal Canadian Mounted Police
RMP Risk management plan
SAE Serious adverse event
UNESCO United Nations Educational, Scientific and Cultural Organization
VVWG Vaccine Vigilance Working Group
WHO World Health Organization

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