Recommendations on the Duration of the Post-vaccination Observation Period for Influenza Vaccination during the COVID-19 Pandemic
Preamble
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (hereafter referred to as PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI Statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select Statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
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Publication Date: 2020-10-15
Related topics
Summary of the Information Contained in this NACI Statement
The following highlights key information for immunization providers. Please refer to the remainder of this statement for details.

# 1. What
- It is important to continue routine immunization programs during the COVID-19 pandemic, especially for the upcoming influenza season, which will prevent influenza-related morbidity and mortality and contribute to reducing the burden on the Canadian health care system. This is particularly important in anticipation of a potential resurgence in COVID-19 in the fall or winter months.
- During the COVID-19 pandemic, large crowds at influenza immunization clinics could contribute to increased SARS-CoV-2 transmission risks if not managed appropriately; therefore,  may be required.
- In addition to other public health and infection prevention and control measures, reducing the post-vaccination observation period in post-vaccination observation areas provides an option to reduce crowding. Decreasing close interactions among vaccine recipients and between vaccine recipients and clinic staff may help to mitigate against potential SARS-CoV-2 transmission in clinic settings. Vaccine recipients who do not meet the criteria for a reduced post-vaccination observation period will also benefit from a less crowded post-vaccination waiting area. This intervention may also allow more individuals to be vaccinated in a given time period (increase vaccination setting "throughput").

# 2. Who
- Settings providing influenza vaccinations for the upcoming influenza season during the COVID-19 pandemic.

# 3. How
1. NACI recommends that the current post-vaccination observation period, as specified in the Canadian Immunization Guide , should be maintained for influenza vaccination settings that can adhere to appropriate public health and infection prevention and control measures  to reduce SARS-CoV-2 transmission, particularly physical distancing (Strong NACI recommendation).
	- NACI concludes that there is fair evidence to maintain a 15-minute post-vaccination observation period during the COVID-19 pandemic for individuals with no known history of severe allergic reactions (including anaphylaxis) to any component of the influenza vaccine being considered for administration or any history of other immediate post-vaccination reactions (e.g., syncope with or without seizure) (Grade B Evidence).
2. NACI recommends that a shorter post-vaccination observation period, between 5 to 15 minutes after influenza immunization, may be considered during the COVID-19 pandemic, but only during times when appropriate physical distancing in post-vaccination waiting areas cannot otherwise be maintained due to the volume of individuals seeking immunization, and only when specific conditions are met (Discretionary NACI recommendation).
	- NACI concludes that there is insufficient evidence from retrospective, passive adverse event following immunization (AEFI) case series reports to support a reduced post-vaccination observation period. However, other factors may be taken into consideration to support a reduced post-vaccination observation period, if necessary for public health and infection prevention and control purposes (Grade I Evidence).
Endnotes \*
Endnotes \*
A shorter observation period may be considered only if the vaccine recipient meets the following conditions :
	- Past history of receipt of influenza vaccine and no known history of severe allergic reactions (including anaphylaxis) to any component of the influenza vaccine being considered for administration (note that novel technology vaccine recipients should be exempt from reduced post-observation period eligibility) .
	- No history of other immediate post-vaccination reactions (e.g., syncope with or without seizure) after receipt of any vaccines.
	- The vaccine recipient is accompanied by a parent/guardian (in the case of a child) or responsible adult who will act as a chaperone to monitor the vaccine recipient for a minimum of 15 minutes post-vaccination. In the case of two responsible adults, both can be vaccine recipients for the purposes of this criterion, if both agree to monitor the other post-vaccination.
	- The vaccine recipient will not be operating a motorized vehicle or self-propelled or motorized wheeled transportation (e.g., bicycle, skateboard, rollerblades, scooter), or machinery for a minimum of 15 minutes after vaccination.
	- The vaccine recipient and the parent/guardian or responsible adult chaperone are aware of when and how to seek post-vaccination advice and given instructions on what to do if assistance and medical services are required.
	- The vaccine recipient and the parent/guardian/responsible adult agree to remain in the post-vaccination waiting area for the post-vaccination observation period and to notify staff if the recipient feels or looks at all unwell before leaving. They should be informed that an individual exhibiting any symptom suggestive of an evolving AEFI at the end of the shortened post-observation period necessitates a longer period of observation in the clinic.

# 4. Why
- A vaccination clinic setting that is able to maintain recommended public health and infection prevention and control measures, such as physical distancing in post-vaccination areas, is unlikely to achieve significant additional reductions in the risk of SARS-CoV-2 transmission by implementing a shorter post-vaccination observation period.
- A vaccination clinic setting that at times is unable to maintain recommended physical distancing in post-vaccination areas may consider implementing a shorter post-vaccination observation period to reduce the risk of SARS-CoV-2 transmission under specified conditions.
- Serious adverse events in the minutes following immunization that may require medical intervention are relatively rare.
I. Introduction
A cluster of cases of pneumonia of unknown origin was reported from Wuhan, Hubei Province, China in December 2019. These cases were determined to be due to a novel coronavirus (SARS-CoV-2) that causes a disease now referred to as coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) characterized COVID-19 as a pandemic on March 11, 2020.
Canadian provinces and territories instituted a series of public health measures to limit SARS-CoV-2 transmission and to reduce the burden on the healthcare system, including the temporary deferral of non-essential medical services. Recognizing the need to continue routine immunization programs during the pandemic, the Public Health Agency of Canada (PHAC), with consultation from the National Advisory Committee on Immunization (NACI) and the Canadian Immunization Committee, released interim guidance on , as well as guidance on  to reduce the risk of SARS-CoV-2 transmission in a variety of immunization clinic settings.
There are a variety of process modifications (administrative, environmental and engineering controls, and personal protective measures) that can be implemented in the vaccination clinic setting to prevent SARS-CoV-2 transmission, such as promoting physical distancing (at least two metres) among vaccine recipients, and staff and their co-workers. Another possible measure may be to reduce the post-vaccination observation period for rare, but serious AEFIs. Reducing the amount of time vaccine recipients spend in the vaccination clinic post-vaccination could reduce the opportunity for SARS-CoV-2 transmission from an unrecognized, infectious COVID-19 case. However, any consideration of a reduction in post-vaccination observation period must weigh the potential risk of delayed identification of an adverse event that may require immediate medical intervention against the potential benefits of reducing the risk of SARS-CoV-2 transmission and allowing more individuals to be vaccinated (increase vaccination clinic "throughput") in a given time period.
In Canada, it is recommended that vaccine recipients remain under observation for at least 15 minutes after vaccination, unless there is a specific concern about a possible vaccine allergy in which case a 30-minute post-vaccination observation period is considered a safer interval. Guidelines for post-vaccination observation in other countries vary . In April 2020, the Australian Technical Advisory Group on Immunization (ATAGI) released a recommendation that the post-vaccination observation period could be reduced from 15 minutes to 5 minutes in immunization clinics where adequate physical distancing was not possible, as long as specific criteria were met. The ATAGI guidance was based on a targeted review of the literature and expert opinion.

# Guidance objective
The objectives of this NACI statement are to review the evidence on the timing of onset of serious AEFIs (anaphylaxis, syncope with or without seizure). These data will be used to assess the potential impact of a reduction in the post-vaccination observation period on the risk of delayed identification of a serious adverse event that may require immediate medical intervention, balanced against the potential benefits of reducing SARS-CoV-2 transmission in influenza vaccination settings and allowing more individuals to be vaccinated in a given time period. The analysis will be used to provide guidance to provincial and territorial immunization programs and frontline clinicians on the duration of the post-vaccination observation period for influenza vaccination during the COVID-19 pandemic.
II. Methods

# Rapid literature review
In preparation for influenza vaccination clinics in fall 2020, a rapid review of literature was conducted to determine the likelihood of missing serious AEFIs (anaphylaxis, syncope with or without seizure) with shorter post-vaccination observation periods. The rapid review's search strategy was developed in conjunction with a federal Reference Librarian and was used to search a single electronic database for studies on the timing of serious AEFIs in children and adults (all ages and populations).

# Research question
What is the minimum observation period needed post-vaccination to observe serious AEFI?
P (population):
Individuals 6 months of age and older
I (intervention):
Observation period post-vaccination, any vaccine
C (comparison):
N/A
O (outcomes):
Time to onset of serious AEFI
The electronic database (EMBASE) was searched from inception to May 22, 2020 using the following search terms: seizure, syncope, anaphylaxis, adverse event, immunization, vaccination reaction, allergic reaction, and post-vaccination reaction. Searches were restricted to articles published in English and French. Two reviewers (NF, PDP) independently screened the titles and abstracts and full-text of eligible articles, but not in duplicate. The PRISMA Flow Diagram is shown in . The complete search strategy is available upon request.
Studies were included if they met the following criteria:
- The study recorded the specific time of onset of at least a subset of AEFIs and reported events that occurred within 30 minutes of vaccination; and
- The study assessed the incidence of the following serious AEFIs:
	+ anaphylaxis, syncope with or without seizure.
Studies were excluded if they met one or more of the following criteria:
- The study was in a language other than English or French;
- The article was an editorial, opinion, conference abstract or news report;
- The minimum observation period for AEFIs was greater than 30 minutes; or
- The study did not report the time to onset of serious AEFIs.
The eligible studies that were identified were divided amongst three reviewers (NF, PDP, GC). The reviewers independently extracted data from their assigned studies into evidence tables and appraised the risk of bias of the studies. The data extraction and risk of bias assessments were not done in duplicate for any of the eligible studies.
The extracted data were used to summarize key study characteristics and to analyze the studies for risk of bias, using a modified Institute of Health Economics Tool (IHE), as all included studies were case reports or case series. A narrative synthesis of the extracted data was created to summarize the outcomes of interest (number of AEFIs, severity, time to onset, and incidence, if reported). As not all of the identified articles evaluated outcomes by severity, the number of serious reports identified were compiled from reports that were explicitly classified as serious, as well as from inference from stated sequelae of individual cases that would meet usual serious outcome definitions (e.g., death, life-threatening illness, hospitalization, prolonged hospitalization, permanent disability).

# Canadian Adverse Events Following Immunization Surveillance System
The Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) database was searched for AEFI reports of anaphylaxis, syncope, and afebrile seizure associated with a date of vaccine administration between 2014 and 2018. The Medical Dictionary for Regulatory Activities (MedDRA) terms used to code CAEFISS reports were used to search CAEFISS for reports for the three outcomes of interest. Reports of anaphylaxis had to meet the Brighton Collaboration definition for anaphylaxis  and the individual in the report managed as such. CAEFISS uses the World Health Organization definition of a serious AEFI: an event that is life threatening, results in hospitalization or a prolongation of hospitalization, persistent or significant disability or where the outcome is a birth defect or death. Reports that did not include a time to onset of symptoms were excluded.
The time to symptom onset for each AEFI was summarized by 5-minute intervals within the first 15 minutes post-vaccination, if available; and the time of onset that includes 25%, 50%, 75%, 95%, and 100% of all reports. These summary measures were analyzed by age groups: less than 2 years, 2 to less than 7 years, 7 to less than 18 years, 18 to less than 50 years, 50 to less than 65 years, 65 years and older, all ages, and by all reports versus serious AEFI.

# Qualitative assessment of reducing the post-vaccination observation period
It is challenging to accurately quantify the impact of a reduction in the post-vaccination observation period on the risk for SARS-CoV-2 transmission in a vaccination setting. This is particularly the case because the clinic settings in Canada are diverse; community prevalence of SARS-CoV-2 varies between communities and fluctuates over time within communities; and because this measure would be one of several public health and infection prevention and control measures implemented to reduce the risk of transmission in these settings. Consequently, a qualitative assessment of this intervention was undertaken to weigh the potential risk of any potential delay in identifying serious AEFIs that may require immediate medical intervention against the potential benefit of reducing the risk of SARS-CoV-2 transmission and enhancing the ability to vaccinate more individuals during a given time period (increase vaccination clinic "throughput").

# Recommendation Development
The draft statement was developed through the NACI Influenza Working Group and in consultation with the NACI Vaccine Safety Working Group. These three analyses, outlined above, were then used by NACI to draft recommendations on whether to reduce the duration of post-vaccination observation period in the context of the COVID-19 pandemic. NACI critically appraised the available evidence and approved the final recommendation on August 13, 2020.
III.Onset of adverse events following immunization
Twenty-two studies on time to onset of serious AEFI were identified through the rapid review. All studies were evaluated for risk of bias using a modified IHE tool and all were deemed to be at serious risk of bias, except two studies, which were deemed to be at unclear risk of bias. Both studies with unclear risk of bias described the incidence of anaphylaxis after vaccine administration using a restricted set of ICD-9 codes to search a health care database, a process deemed to be more sensitive at identifying anaphylaxis episodes than relying on reports submitted to passive AEFI reporting systems. McNeil et al. used the same code set used by Bohlke et al., but supplemented their search with allergy codes combined with epinephrine-dispensing codes. The majority of the included articles used data from passive surveillance systems, and had limitations such as underreporting, insufficient information on cases reported, lack of denominators and inconsistent case definitions. For measurement of whether the intervention of interest was described, articles were considered to be of low bias if they reported the vaccine name and manufacturer and whether this was the first or subsequent immunization dose, if relevant. A visual summary of the risk of bias assessments is provided in .
The findings from the rapid review must be interpreted with caution in light of the findings of the risk of bias assessment for the articles identified in the rapid review and the inherent limitations of data obtained from retrospective case series studies that rely on passive AEFI surveillance systems. For example, the voluntary nature of reporting in most of these systems can lead to underreporting of AEFIs; the retrospective nature of these studies may make it difficult to obtain the necessary clinical data to verify outcomes and to determine that outcomes meet case definitions; the studies may also not have access to data on the sequelae for individuals in case reports, which may lead to an underestimation of the seriousness of some outcomes. There is often no access to denominator data (i.e., the number of vaccine doses distributed or ideally the number of doses administered) to estimate the incidence of outcomes. Also estimates of incidence based on relatively few case reports may be unreliable (i.e., relatively few additional case reports can significantly alter the calculated rate) and rates generated in heterogeneous populations may not be comparable.

# III.1 Anaphylaxis

## Rapid literature review

### Time to symptom onset of anaphylaxis
There were 16 articles (12 retrospective case series            , 4 case reports   ) identified in the rapid review that provide data on the timing of reports of anaphylaxis following vaccine administration. The retrospective case series primarily use AEFI surveillance systems to examine reports of anaphylaxis in vaccine recipients. Across all of the identified articles, 981 reports of anaphylactic reactions were described, with 816 (83%) reports assessed against the Brighton Collaboration definition of anaphylaxis and the criteria for the three levels of diagnostic certainty (level 1: 413 reports; level 2: 372; level 3: 14; other/level not reported: 17). Of the 981 reports of anaphylaxis, 729 (74%) of the reports were classified as serious.
Overall, 873 (89%) of the anaphylaxis reports had some time to symptom onset recorded, of which the majority (492/873, 56%) occurred within 30 minutes of vaccination. The majority of the data (735/873, 84%) came from a single study using reports from the US Department of Health and Human Service's Vaccine Adverse Events Reporting System (VAERS) database, which categorized onset times into relatively broad time intervals (within 30 minutes, 30-119 minutes, 2-4 hours, 4-8 hours and 8-24 hours).
There were 8 retrospective case series         and 3 case reports    that identified 55 reports that provided descriptions of or actual times to anaphylaxis symptom onset in intervals within the first 15 minutes post-vaccination. Of these 55 reports, 35 (64%) occurred between 0 and 5 minutes post-vaccination, 4 (7%) "within minutes" or "within a few minutes," 9 (16%) between 5 and 10 minutes, 1 (2%) between 10 and 15 minutes, and 6 (11%) within 5 to 15 minutes.
Three of the retrospective case series studies    provided summary measures of the time to anaphylaxis symptom onset after vaccination. Baxter et al. evaluated the Australian Surveillance of Adverse Events following Vaccination in the Community (SAEFVIC) database for reports of anaphylaxis occurring within the first 60 minutes following immunization in preschool aged (<5 years) children. The study found all 12 identified anaphylaxis reports had a time of symptom onset of 0-40 minutes, with an average of 7.5 minutes and a median of 5 minutes. Su et al., using anaphylaxis case reports from VAERS from 1990-2016, found 828 case reports that occurred within 1 day post-vaccination. These reports had a median time of onset after vaccination of 20 minutes (ranging from <1 minute to 24 hours). And finally Pahud et al., examining serious, non-fatal adverse events reported to VAERS following receipt of 2009 H1N1 vaccine in children (<18 years of age) from October 2009-January 2010 found 12 true allergic reactions (i.e., not just reports of anaphylaxis) occurred within 3 hours of vaccination with a median of 30 minutes (range: 5 minutes-3 hours).

### Estimates of anaphylaxis incidence based on literature
There were 6 retrospective case series       that had access to the data on the number of vaccine doses either distributed or administered during the period of the study; these data were used to calculate either overall or vaccine-specific estimates of anaphylaxis incidence during the study period.
The incidence of anaphylaxis was fairly consistent across studies, although there was some variation. The variation could be due to the small number of anaphylaxis case reports and the different denominators used to calculate incidence (doses distributed or doses administered). McNeil et al. reported an overall incidence of anaphylaxis in children and adults of 1.31 per 1,000,000 doses administered. Two other studies calculated the incidence of anaphylaxis in children <18 years of age; estimates ranged from 0.65 to 1.3 per 1,000,000 doses .
Four studies reported incidence estimates for specific vaccines that varied significantly by vaccine and by study (0.1 to 26 per 1,000,000 doses)   . The highest reported incidence was from a study based on anaphylaxis reports submitted to the New South Wales Health Immunization Unit for human papillomavirus (HPV) vaccine and the lowest reported incidence was for influenza vaccine based on reports submitted to VAERS. Incidence of anaphylaxis estimates after administration of influenza vaccine was 0.1 to 1.8 per 1,000,000 doses (administered or distributed) .

## Canadian Adverse Events Following Immunization Surveillance System

### Time to symptom onset of anaphylaxis
Of the 136 reports of anaphylaxis identified, 112 (82%) were classified as serious. Just over half of all the anaphylaxis reports occurred in individuals 7 to less than 18 years of age (n=30, 22%) and 18 to less than 50 years of age (n=46, 34%). There were fewer numbers of AEFI reports in each of the other age groups (range: 9-20 AEFI reports per age group).
For all ages combined, 25% of anaphylaxis reports had onset within 5 minutes of vaccination, increasing to 50% of reported cases by 15 minutes post-vaccination, with an overall median time to symptom onset of 15 minutes (range: 1 minute to 48 hours). The proportion of individuals with symptom onset within the first 15 minutes post-vaccination did not vary significantly by age grouping, with the exception of children less than 2 years of age (6 minutes vs 15 minutes for all ages) and individuals 50 to less than 65 years of age (45 minutes vs 15 minutes) (). When comparing the time to symptom onset for all anaphylaxis reports compared to reports classified as serious, similar trends were found. For all ages combined, 29% of case reports had onset of symptoms by 5 minutes post-vaccination, 46% by 10 minutes post-vaccination and 54% by 15 minutes post-vaccination. These proportions did not differ significantly by age grouping, with the exception of children less than 2 years of age (50% by 5 minutes, 67% by 15 minutes) and individuals 50 to less than 65 years of age (8% by 5 minutes, 31% by 15 minutes) (data not shown), reflecting the differences in median time to symptom onset in these age groups ().

# III.2 Syncope and Seizure
As seizures may occur secondary to syncopal episodes, the two outcomes are considered together in this section.

## Rapid literature review

### Time to symptom onset of syncope or seizure
There were 8 articles (7 retrospective case series       , 1 case report) identified in the rapid review that provide data on the outcomes of either syncope or seizure following vaccine administration. The retrospective case series studies all utilized AEFI surveillance systems to evaluate reports of syncope or seizure in vaccine recipients. In the 8 articles that identified reports of syncope or seizure, there were 1,180 reports of syncope alone (i.e., not associated with any reported seizure activity), 199 reports of seizures associated with syncopal episodes ("syncopal seizures"), and 16 reports of seizures alone (either afebrile or febrile) for a total of 1,395 reports. Of the 1,395 reports, 103 (7%) were considered serious (97 syncope alone, 1 syncopal seizure, and 5 febrile seizures).
Of the 1,180 reported cases of syncope alone, 453 (38%) had some indication of time to symptom onset. The range of reported onset times varied from within 5 minutes to 2 days; however, 340 (75%) of the syncopal case reports with a recorded time to symptom onset occurred within the first 15 minutes post-vaccination. Twenty-four (5%) of these reports were from four studies     using retrospective case series data: 15 (63%) cases had onset from 0-5 minutes post-vaccination and 1 (4%) case with onset within 10-15 minutes. The time of onset of the remaining 8 cases were not provided in the same 5-minute time intervals: 4 (17%) occurred within 10 minutes of vaccination and 4 (17%) within 15 minutes of vaccination.
Among the studies identified, a fifth study also using retrospective case series data provided the largest number of syncopal case reports with symptom onset within the first 15 minutes post-vaccination. This study by Braun et al evaluated reports of syncope occurring within 12 hours of immunization submitted to VAERS and injury reports for syncope-related falls from the US National Vaccine Injury Compensation Program in individuals of any age from 1990-October 1995. Of the 571 reports that had a recorded time to symptom onset (81.9% of total reports), 323 (63.2%) occurred within 5 minutes of vaccination, increasing to 416 (81.4%) within 10 minutes, and 454 (88.8%) within 15 minutes of vaccination. Of the 454 syncopal episodes, 153 were associated with "tonic or clonic movements" ("syncopal seizures"): 138 (30. 4%) within 15 minutes of vaccination and 15 (12.8%) greater than 15 minutes after vaccination. Of note, 67 (9.6%) cases reported subsequent hospitalization. Six individuals sustained head injuries after syncope-induced falls, which included skull fractures, cerebral contusions, cerebral hematomata and one case of major cerebral hemorrhage. Three of the injuries necessitated neurosurgery to alleviate cerebral swelling or bleeding and 2 individuals still had significant neurologic deficits up to 2 years after the incidents. All 6 of these head injuries occurred from syncopal events within 15 minutes after vaccination.
In the study by Sutherland et al., there were 10 secondary injuries recorded among the 26 serious syncopal reports: head injuries after syncopal falls (n=9), including one death of a 15-year-old boy due to intracranial hemorrhage, and a motor vehicle incident after a loss of consciousness while driving (n=1). Seven (70%) of the injuries occurred within 15 minutes of vaccination.
A description of the time to symptom onset was available for 154 (77%) of the 199 reports of seizures associated with syncopal episodes ("syncopal seizures") and for all 16 (100%) reports of seizures alone. Two articles provided the data on syncopal seizure following vaccine administration  . Braun et al. reported 153 syncopal reports with associated "tonic or clonic movements": 138 (90.2%) occurred within 15 minutes of vaccination and 15 (9.8%) occurred greater than 15 minutes after vaccination. The remaining case which was reported in the second study occurred at 0 minutes post-vaccination (i.e., immediately). The 16 cases of seizure alone were identified in two studies . Crawford et al analyzed detailed clinical information on SAEFVIC case reports of syncope and seizures after quadrivalent HPV vaccination in females 12-26 years of age vaccinated as part of the Australian National HPV Vaccination Program from May 2007-April 2009. The study identified 31 episodes of syncope with associated seizures, but the time to seizure onset was reported only for 3 reports of afebrile seizure, all in individuals with confirmed underlying epilepsy. There were no deaths reported in the study population, but there were 7 injuries reported: head injuries (n=5), mouth bleeding (n=1) and a T5/T6 vertebral fracture (n=1). The study by Milstien et al. identified 13 reports that met the US Food and Drug Administration (FDA) case definition for a potentially vaccine-associated convulsion, four afebrile convulsions and nine febrile convulsions. The time of onset for the afebrile convulsions was 30 minutes, 2 hours, 24 hours and 2 days after vaccination.

### Estimates of syncope and/or seizure incidence based on literature
There were 3 retrospective case series studies that had access to the data on the number of vaccine doses either distributed or administered during the period of the study, allowing for calculation of either overall or vaccine-specific syncope or seizure incidence during the study period  .
In an analysis of SAEFVIC case reports of syncope and seizures after quadrivalent HPV vaccination as part of the Australian National HPV Vaccination Program, Crawford et al. estimated an incidence of 7.8 and 2.6 per 100,000 doses of vaccine distributed for syncope and syncopal seizures respectively.Subelj et al. estimated the incidence of syncope and seizures associated with syncope to be 13.4 and 3.4 per 100,000 doses, respectively, based on 4 years of data from mandatory reports to the National Institute of Public Health of a school-based four-valent HPV (HPV4) vaccine program targeting girls 11-14 years of age in Slovenia. Sutherland et al evaluated reports of "syncope" or "syncope vasovagal" occurring in individuals 5 years of age on the same day as vaccination submitted to the VAERS surveillance system from January 1, 2005-July 31, 2007 and compared the rates of syncopal events to the rate of VAERS reports received from 2002-2004. The rates of syncopal events per 1,000,000 doses of vaccines distributed in the US during the respective study periods was increased in 2005-2006 (0.31-0.54) compared to 2002-2004 (0.28-0.35), as were the proportion of reports from females (77.5% vs 61.6%) and persons 11-18 years of age (62.0% vs 47.3%).

## Canadian Adverse Events Following Immunization Surveillance System

### Time to symptom onset of syncope or seizure
Of the 52 reports of syncope, 20 (38%) were classified as serious. Individuals 7 to less than 18 years of age (n=33, 65%) and 18 to less than 50 years of age (n=8, 16%) accounted for the majority of all 52 reports. There were very few AEFI reports in each of the remaining age groups (N is between 2 and 4 for each).
For all ages combined, 25% of syncope reports had onset within 1 minute of vaccination, increasing to 50% of reported cases by 3 minutes post-vaccination and 75% within 15 minutes, with an overall median time to symptom onset of 3 minutes (range: 1 minute to 29 days) (). The proportions were similar for syncope reports classified as serious (data not shown).
There were 61 reports of afebrile seizure between 2014 and 2018, 50 (82%) of which were classified as serious. The majority (74%) of reports were in individuals less than 2 years of age. There were very few AEFI reports in the other age groups. For all ages combined, the median time to onset of afebrile seizure was 21 hours (range: 1 minute to 29 days). Only for the group of individuals 7 to less than 18 years were a significant proportion (25%) of afebrile seizures reported to have occurred within 2 minutes of vaccination, based on a small number of case reports (n=8).

# III.3 Risk-benefit assessment
The rationale for potentially considering a reduction in the post-vaccination observation period in influenza vaccination settings during the COVID-19 pandemic is to reduce the duration of time vaccine recipients spend together with others in post-vaccination areas and to potentially reduce the number of contacts recipients encounter in vaccination settings. This could then reduce the opportunity for SARS-CoV-2 transmission from an unrecognized, infectious COVID-19 case and allow more individuals to be vaccinated (increase vaccination clinic "throughput") in a given time period. However, it is very challenging to quantify the impact of a reduction in the post-vaccination observation period on the risk for SARS-CoV-2 transmission, independent of other public health and infection prevention and control measures (engineering, environmental and administrative controls, and personal protective equipment) that are likely to be implemented in influenza vaccination settings during the COVID-19 pandemic. In addition, there will be differences in the risk of transmission in various settings due to variability in disease prevalence at different locations and at different points in time. Any consideration of a reduction in post-vaccination observation period would be a deviation from the current standard practice in Canadian provinces and territories. The current standard of a 15-minute post-vaccination observation period is intended to identify serious AEFIs that may require immediate medical intervention. This must be weighed against the potential benefits of reducing risk of SARS-CoV-2 transmission and allowing more individuals to be vaccinated (increase vaccination clinic "throughput") in a given time period.

## Potential benefits of a reduced post-vaccination observation period
- Reduction in crowding within post-vaccination waiting areas of vaccination clinics will improve the likelihood of maintaining physical distancing among vaccine recipients and between vaccine recipients and clinic staff.
- Less waiting post-vaccination may encourage members of the public to attend vaccination clinics if there is perceived to be less risk of COVID-19 infection due to less crowding in the vaccination clinics areas and if there is less time overall required to get vaccinated. Perceptions of reduced risk of infection will be enhanced by the other infection prevention and control measures taken in the context of COVID-19 that will also reduce crowding within the vaccination clinic setting (e.g., scheduled vaccination appointments, arrival just in time for appointments, screening of clinic staff and attendees).
- A reduced number of individuals in the post-vaccination waiting areas would benefit vaccine recipients who do not meet the criteria for a reduced post-vaccination observation period, and may remain in the vaccination setting for the standard 15-minute observation period or a 30-minute observation period if there is a specific concern about possible vaccine allergy.
- A reduced post-vaccination period may allow more individuals to be vaccinated (increase vaccination clinic "throughput") in a given time period and also allow vaccine recipients to be in contact with fewer individuals.

## Potential risks of a reduced post-vaccination observation period
- There would be a small but potentially increased risk of delayed identification of an adverse event that may require immediate medical intervention (e.g., anaphylaxis and syncope with or without seizure).
- Reducing the post-vaccination observation period may have only a relatively modest, independent impact in reducing the risk of SARS-CoV-2 transmission in the vaccination clinic setting during the COVID-19 pandemic when compared with the other public health and infection prevention and control measures (e.g., environmental and engineering controls, administrative processes, personal protective equipment). The overall risk will also depend upon factors such as local disease prevalence at the time of the immunization clinics.
- The reduction in the post-vaccination observation period may be perceived as an action being taken primarily to improve clinic efficiency rather than an important infection prevention measure.
IV. Recommendations
Following a thorough review of the evidence summarized above, NACI has made two recommendations for public health program decision-making. These recommendations are based on currently available scientific evidence and expert opinion and are relevant only during the COVID-19 pandemic, after which the current guidance for the post-vaccination observation period as identified in Part 2 of the Canadian Immunization Guide should be followed.
In considering these recommendations and for the purposes of publicly funded program implementation, provinces and territories may take into account economic factors and other local operational factors (e.g. current immunization programs, resources). Recognizing that there are differences in operational contexts across Canada, jurisdictions are advised to refer to the local epidemiology of COVID-19 and additional PHAC guidance to determine the relative merits of modifying the post-vaccination observation period. NACI will continue to monitor the scientific literature for developments related to post-vaccination observation period and will update recommendations as evidence evolves, if required.
Please note:
- A *strong recommendation- applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.
- A *discretionary recommendation- may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.

# IV.1 Recommendations for Public Health Program Level Decision-Making
1. NACI recommends that the current post-vaccination observation period, as specified in the Canadian Immunization Guide, should be maintained for influenza vaccination settings that can adhere to appropriate public health and infection prevention and control measures to reduce SARS-CoV-2 transmission, particularly physical distancing (Strong NACI recommendation).
	- NACI concludes that there is fair evidence to maintain a 15-minute post-vaccination observation period during the COVID-19 pandemic for individuals with no known history of severe allergic reactions (including anaphylaxis) to any component of the influenza vaccine being considered for administration or any history of other immediate post-vaccination reactions (e.g., syncope with or without seizure) (Grade B Evidence).Evidence and Rationale
	- A 15-minute post-vaccination observation period is the Canadian standard for individuals with no known history of prior severe allergic reaction or any other immediate post-vaccination reactions.
	- A vaccination clinic setting that is able to maintain recommended public health and infection prevention and control measures, including physical distancing in post-vaccination areas, is unlikely to achieve significant additional reductions in the risk of SARS-CoV-2 transmission by implementing a shorter post-vaccination observation period.
2. NACI recommends that a shorter post-vaccination observation period, between 5 to 15 minutes after influenza immunization, may be considered during the COVID-19 pandemic, but only during times when appropriate physical distancing in post-vaccination waiting areas cannot otherwise be maintained due to the volume of individuals seeking immunization, and only when specific conditions are met  (Discretionary NACI recommendation).
	- NACI concludes that there is insufficient evidence from retrospective, passive adverse event following immunization (AEFI) case series reports to support a reduced post-vaccination observation period. However, other factors may be taken into consideration to support a reduced post-vaccination observation period, if necessary for public health and infection prevention and control purposes (Grade I Evidence).
Endnotes \*
Endnotes \*
A shorter observation period may be considered only if the vaccine recipient meets the following conditions :
	- Past history of receipt of influenza vaccine and no known history of severe allergic reactions (including anaphylaxis) to any component of the influenza vaccine being considered for administration (note that novel technology vaccine recipients should be exempt from reduced post-observation period eligibility).
	- No history of other immediate post-vaccination reactions (e.g., syncope with or without seizure) after receipt of any vaccines.
	- The vaccine recipient is accompanied by a parent/guardian (in the case of a child) or responsible adult who will act as chaperone to monitor the vaccine recipient for a minimum of 15 minutes post-vaccination. In the case of two responsible adults, both can be vaccine recipients for the purposes of this criterion, if both agree to monitor the other post-vaccination.
	- The vaccine recipient will not be operating a motorized vehicle or self-propelled or motorized wheeled transportation (e.g., bicycle, skateboard, rollerblades, scooter), or machinery for a minimum of 15 minutes after vaccination.
	- The vaccine recipient and the parent/guardian or responsible adult chaperone are aware of when and how to seek post-vaccination advice and given instructions on what to do if assistance and medical services are required.
	- The vaccine recipient and the parent/guardian/responsible adult agree to remain in the post-vaccination waiting area for the reduced post-vaccination observation period and to notify staff if the recipient feels or looks at all unwell before leaving the clinic. They should be informed that an individual exhibiting any symptom suggestive of an evolving AEFI at the end of the shortened post-observation period necessitates a longer period of observation in the clinic.
Evidence and Rationale
- Public health and infection prevention and control measures (i.e., engineering, environmental and administrative controls, and personal protective equipment) should be implemented to reduce the risk for SARS-CoV-2 transmission.
- A consideration to reduce the post-vaccination observation period must weigh the potential risk of any delay in identifying serious adverse events that may require immediate medical intervention against the potential benefits of reducing contacts with others and the associated risk of SARS-CoV-2 transmission; and potentially allowing more individuals to be vaccinated in a given time period. It is recognized that several factors may influence decision-making and applicability of recommendations:
	+ The community levels of SARS-CoV-2 transmission at the time of vaccination clinics will influence the risk of SARS-CoV-2 transmission in the vaccination setting. This risk will vary by and within jurisdictions over time.
	+ Unanticipated or unprecedented increases in the number of individuals presenting for immunization in clinic settings at a given time could temporarily overwhelm the other public health and infection prevention measures in place.
	+ It is unknown how much a reduced post-vaccination observation period, independent of other public health and infection prevention and control measures, contributes to reducing the risk of SARS-CoV-2 transmission in the vaccination setting.
- The evidence from retrospective, passive AEFI case series reports is insufficient to support a reduced post-vaccination observation period.
	+ Overall estimates of anaphylaxis incidence using retrospective case series data from passive AEFI surveillance systems varied, but were consistent with estimates of anaphylaxis incidence for commonly administered vaccines (1 per 100,000 to 1 per 1,000,000 doses) cited by the World Allergy Organization in its International Consensus statement on allergic reactions to vaccines.
	+ Estimates for the incidence of syncope using passive case series data ranged widely, but were consistently much higher than for anaphylaxis.
	+ The data from the rapid review indicate that a shortened post-vaccination observation period may still identify a majority of syncopal episodes, but not the majority of episodes of anaphylaxis.
		- The study by Braun et al that evaluated the largest number of reports of syncope found 63.2% occurred within 5 minutes of vaccination, increasing to 416 (81.4%) within 10 minutes, and 454 (88.8%) within 15 minutes of vaccination. CAEFISS data, for all ages combined, found 25% of syncope reports had onset within 1 minute of vaccination, increasing to 50% of reported cases by 3 minutes post-vaccination and 75% within 15 minutes, with an overall median time to symptom onset of 3 minutes (range: 1 minute to 29 days).
		- A little over half of all anaphylaxis reports with a recorded time of symptom onset occurred within 30 minutes of vaccination, but the proportion of those reports occurring during the first 15 minutes post-vaccination was not reported. From the case series containing the largest number of anaphylaxis reports, the median time to anaphylaxis onset after vaccination was 20 minutes (range: from <1 minute-24 hours). CAEFISS reports, for all ages combined, found 25% of anaphylaxis reports had onset within 5 minutes of vaccination, increasing to 50% of reported cases by 15 minutes post-vaccination, with an overall median time to symptom onset of 15 minutes (range: 1 minute to 48 hours). Similar trends were found for anaphylaxis reports classified as serious.
- Use of a shortened post-vaccination observation period should be accompanied by safeguards, as outlined in the recommendation, to minimize situations that would place the vaccine recipient at risk for unintended injury should an adverse event occur after the shortened observation period, but within the standard 15-minute post-vaccination observation period.
"should/should not be offered"- Known/Anticipated advantages outweigh known/anticipated disadvantages ("should"),
OR Known/Anticipated disadvantages outweigh known/anticipated advantages ("should not")
- Implication: A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present
"may be considered"- Known/Anticipated advantages closely balanced with known/anticipated disadvantages, OR uncertainty in the evidence of advantages and disadvantages exists
- Implication: A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable
General design specific criteria are outlined in Harris et al. (2001)..
Australia
SAEFVIC passive surveillance system
US
US
VAERS passive surveillance system
Australia
Australia
SAEFVIC passive surveillance system
Overall incidence following HPV4 vaccination was 7.8 per 100,000 doses distributed for syncope and 2.6 per 100,000 for syncopal seizures.
Of the 94 syncopal episodes, 67% (63/94) had syncope alone, and 33% (31/94) had associated seizure activity, of which 23% (7/31) had urinary incontinence. The HPV4 vaccine was given alone in 85% (82/97) of reports, with concomitant vaccines including: hepatitis B (6); diphtheria-tetanus-acellular pertussis (6); varicella (1); and varicella and hepatitis B vaccine (2).
US
Vaccine Injury Comensation Program
US
US
Two cases of anaphylactic-like reactions were reported. One case was in a 3-year-old boy who became pale and hypotensive and began to wheeze five minutes after vaccination. The other case was in a 4-year-old boy who became nauseated, pale, and bradycardia; circumoral cyanosis developed 20 minutes after vaccination. Both cases responded quickly to epinephrine and oxygen.
Syncope
Seven reports of syncope were identified, three that noted treatment with epinephrine and/or Benadryl. All but three episodes occurred within ten minutes of vaccination (others occurred at 30 minutes, 2 hours, and 24 hours). All episodes were in children 3 to 5 years of age.
Seizure
US
VAERS passive surveillance system
Finland
Passive surveillance system
30 suspected cases of anaphylaxis were identified, all of which appeared within 20 minutes of vaccination, except one case who developed symptoms several hours after vaccination.
Seizure
Switzerland
Passive surveillance system
US
VAERS passive surveillance system
Slovenia
 8 syncope events, accounting for 3.8% of all AEFIs reported, were identified. Incidence was 13.4 per 100,000 HPV4 vaccine doses distributed. Two syncope episodes were deemed serious. One event had an immediate onset, and another occurred 5 minutes following vaccine administration.
Seizure
US
VAERS passive surveillance system
US
VAERS passive surveillance system
107 reports of syncope/presyncope and unintentional injury on the day of vaccination were identified. 100 of the reported injuries occurred within 20 minutes of vaccination. There were three reports of serious head injury, including one that was deemed fatal due to vasovagal syncope.
Following the third dose of hepatitis B vaccine, a 15-year-old boy with no antecedent of event or medical problems, experienced vasovagal syncope several minutes after vaccination. He fell backward and hit his head, momentarily lost consciousness, then complained of pain in the chest and arms. Then, he reportedly had convulsions and went into cardiopulmonary arrest.
Passive surveillance system database
Funding:
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A 71-year-old women with documented allergies to red meat required emergency department treatment and epinephrine administration upon receipt of live attenuated herpes zoster virus vaccine containing the Oka VZV strain. The vaccine was administered in a local pharmacy and within minutes she had a sensation of mental clouding progressing to lightheadedness, wheezing, and throat tightness.
Funding:
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