Influenza vaccine safety in Ontario

Assessing vaccine safety within Ontario’s Universal Influenza Immunization Program, 2012–2013 to 2014–2015

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Published by: The Public Health Agency of Canada
Issue: Volume 42-9: Scientific writing
Date published: September 1, 2016
ISSN: 1481-8531

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Volume 42-9, September 1, 2016: Scientific writing

Surveillance

Assessing vaccine safety within Ontario’s Universal Influenza Immunization Program, 2012–2013 to 2014–2015

Harris T¹*, Wong K¹, Nair J¹, Fediurek J¹, Deeks SL^1,2

Affiliations

¹ Public Health Ontario, Toronto, ON

² Dalla Lana School of Public Health, University of Toronto, Toronto, ON

Correspondence

tara.harris@oahpp.ca

Suggested citation

Harris T, Wong K, Nair J, Fediurek J, Deeks SL. Assessing vaccine safety within Ontario’s Universal Influenza Immunization Program, 2012-2013 to 2014-2015. Can Comm Dis Rep 2016;42:181-6. https://doi.org/10.14745/ccdr.v42i09a04

Abstract

Background: Influenza vaccine is recommended to prevent influenza-related morbidity and mortality. Post-marketing surveillance of adverse events following influenza vaccine is essential to monitor vaccine safety, inform immunization program planning and evaluation, and build confidence in immunization.

Objective: To summarize adverse events following immunization (AEFIs) reported after receipt of influenza vaccines administered within the Universal Influenza Immunization Program in Ontario.

Methods: AEFIs following administration of influenza vaccines between September 1, 2012 and August 31, 2015 were extracted from the Integrated Public Health Information System (iPHIS) on September 1, 2015. Events were grouped by provincial surveillance definitions. Reporting rates were calculated using provincial population estimates or net doses distributed as the denominator. The standard World Health Organization definition of serious AEFIs was used.

Results: There were 12.1 million doses of influenza vaccine distributed in Ontario and 528 AEFIs reported following influenza vaccines administered over three seasons. The annualized reporting rate was 4.4 per 100,000 doses distributed with a significant decreasing trend over time (p<0.05). The median age was 39.6 years (range six months-96 years); children under four years of age had the highest reporting rate (3.5 per 100,000 population). Disproportionate reporting among females was observed (76.5 percent), most notably in those 18 years and older. The most frequently reported events were injection site reactions (36.2 percent of reports). Others included allergic skin reactions (21.1 percent) and rashes (17.3 percent). Serious AEFIs were rare with a reporting rate of 1.6 per million doses distributed.

Conclusion: This assessment found a low rate of reported adverse events following influenza vaccines administered in Ontario. Most reported events were mild and resolved completely. The findings were consistent with the very good safety profile of influenza vaccines.

Introduction

Influenza is a respiratory infection which causes approximately 12,200 hospitalizations and 3,500 deaths in Canada each year^{Footnote 1}. Annual seasonal influenza vaccination is the most effective way to prevent influenza and its complications. There are multiple influenza vaccines authorized in Canada for use in individuals six months of age and older. Specific products include inactivated trivalent and quadrivalent vaccines (including adjuvanted and high-dose formulations) and live attenuated trivalent and quadrivalent vaccines with varying indications based on age and immune status^{Footnote 1}^{Footnote 2}. The National Advisory Committee on Immunization (NACI) recommends influenza vaccine to all individuals six months of age and older without contraindications, with particular focus on people at high risk of influenza-related complications or hospitalization and people capable of transmitting influenza to those at high risk^{Footnote 1}. Ontario has had a publicly-funded Universal Influenza Immunization Program since 2000^{Footnote 3}. All Ontarians six months of age and older, who live, work or go to school in the Province are eligible for yearly publicly-funded influenza vaccine. Most influenza vaccines in the Province are administered within the Universal Influenza Immunization Program, however influenza vaccine products which are authorized for use but not included in the public program may be purchased privately.

Influenza vaccines are generally safe and well tolerated. For influenza vaccines administered by intramuscular injection, the most common side effect is pain at the injection site, which affects between 40 to 60 percent of healthy adults, but is generally mild and resolves within a few days^{Footnote 4}^{Footnote 5}. Higher frequencies of injection site reactions are observed for adjuvanted and high-dose formulations. The occurrence of serious adverse events is rare and includes anaphylaxis and Guillain-Barré syndrome (GBS)^{Footnote 1}. Post-marketing surveillance of influenza vaccines is essential to continue to demonstrate vaccine safety over time, to inform evaluation and build confidence in influenza immunization programs. Information from public health surveillance of adverse events following immunization (AEFIs) provides relevant and timely information to address concerns about vaccine safety, which have been shown to be a key barrier influencing vaccine acceptance among the general population^{Footnote 6}^{Footnote 7}^{Footnote 8} and health care workers^{Footnote 9}^{Footnote 10}^{Footnote 11}.

Our objective is to summarize influenza AEFIs reported in Ontario during three recent influenza seasons to support a comprehensive evaluation of the Universal Influenza Immunization Program in Ontario.

Methods

Definitions

A confirmed AEFI is defined as "Any reported event in a vaccine recipient which follows immunization that cannot be clearly attributed to other causes. A causal relationship with the administration of the vaccine does not need to be proven"^{Footnote 12}. Adverse events are defined according to event-specific provincial surveillance criteria^{Footnote 12}. AEFIs are further defined as serious if they meet the World Health Organization standard definition which specifies that a serious AEFI is one that results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect^{Footnote 13}^{Footnote 14}. Other important medical events include: anaphylaxis, encephalitis, acute disseminated encephalomyelitis, myelitis, meningitis, GBS, acute cerebellar ataxia and thrombocytopenia. These events do not meet the above definition of serious and were measured and presented separately. Reports of events managed as anaphylaxis were further assessed using the Brighton Collaboration case definition and diagnostic levels of certainty^{Footnote 15}.

In Ontario, reporting of AEFIs by specific health professionals (e.g., physicians, nurses and pharmacists) is mandated by provincial public health legislation ^{Footnote 16}; however, voluntary reporting from vaccine recipients or their caregivers also occurs. Reports of AEFIs are received by local public health units (PHUs) who investigate and enter information according to provincial surveillance guidelines into the Integrated Public Health Information System (iPHIS), the electronic reporting system for reportable diseases and AEFIs in Ontario.

The review included all AEFIs reported following administration of influenza vaccines administered within the Universal Influenza Immunization Program between September 1, 2012 and August 31, 2015. Data was extracted from iPHIS on September 1, 2015. Vaccine products utilized within the Universal Influenza Immunization Program between 2012-2013 and 2014-15 were trivalent inactivated vaccines including: Fluviral^®, Agriflu^®, Vaxigrip^®, Fluzone^® (2014-2015 only) and Fluad^® (for 65 years and older who reside in long-term care facilities). Reports following administration of live attenuated influenza vaccine only were excluded, as they represented a very small number of reports (n=4) and were not part of the Universal Influenza Immunization Program during the reporting period.

Proportions were based on reports with completed data in iPHIS, therefore the denominator varies by variable. Temporal trends were assessed by influenza season, defined as September 1 to August 31 for the purposes of provincial influenza AEFI surveillance. AEFI reporting rates were calculated using both doses distributed and population-based denominators. Reporting rates were calculated over time and by event-type using net doses distributed within the publicly-funded program as the denominator. This was calculated based on estimates of net vaccine distribution data provided by the Ontario Government Pharmaceutical and Medical Supply Service which is adjusted for wasted or returned reusable vaccine. Reporting rates were calculated by demographic groups (e.g., age, sex and geography) using population-based denominators in the absence of information about dose distribution within these groups. Population denominators were based on 2012 and 2013 estimates for the 2012-2013 and 2013-2014 influenza seasons, respectively and 2014 projections for the 2014-2015 season^{Footnote 17}^{Footnote 18}. A statistical analysis was performed using SAS version 9.3 and Microsoft Excel 2010. Trends in incidence rate over the entire study period were assessed using Poisson regression and p-values less than 0.05 were considered statistically significant. This project was approved by the Public Health Ontario Ethics Review Board.

Results

There were 528 AEFIs reported following influenza vaccines administered within the Universal Influenza Immunization Program in Ontario between September 1, 2012 and August 31, 2015. During this time period, over 12.1 million net doses of Universal Influenza Immunization Program vaccine were distributed, for an annualized reporting rate of 4.4 per 100,000 doses distributed. A significant decreasing trend in the reporting rate by season was observed, with a marked drop in the reporting rate in 2014-2015, compared to 2012-2013 and 2013-2014 (p<0.05) (Figure 1).

Figure 1: Number of influenza AEFIs and reporting rate (per 100,000 doses distributed) in Ontario, 2012-2013 to 2014-2015

All Flumist doses from manufacturer (assumed that PDCCH pilot included)
Flumist only
Count Flumist AEFIs	1	2	1
Doses distributed (all Flumist from manufacturer)	7,580	10,240	13,380
Rate	13.19	19.53	7.47

OGP distribution minus 280 doses of Flumist distributed in 2013-14 for PCCHU pilot
All publicly funded (excluding PCCHU Flumist pilot)
AEFI count	202	197	129
Doses distributed	4,020,830	3,999,990	4,108,661
Reporting rate	5.02	4.93	3.14

OGP distribution minus 280 doses of Flumist distributed in 2013-14 for PCCHU pilot, plus total Flumist distribution from manufacturer
All combined (All publicly funded + Flumist doses from AstraZeneca)
Count all flu AEFIs (including Flumist)	203	199	130
Doses distributed	4,028,410	4,010,230	4,122,041
Reporting rate	5.04	4.96	3.15

All OGP (publicly funded plus PCCHU Flumist pilot)
Count Flu AEFIs (all combined)	203	199	130
Doses distributed (OGP all)	4,020,830	4,000,270	4,108,661
Rate	5.05	4.97	3.16

Individuals with AEFIs ranged in age from six months to 96 years (median 39.6 years). Over half of all reports (58.2 percent) were in adults 18-64 years of age; however, the highest age-specific reporting rates were in children less than four years and five to nine years of age (3.5 and 2.8 per 100,000 population, respectively) (Table 1). Reporting rates within age group decreased over the three seasons with significant decreases in children less than four and adults 50 to 64 years of age. Disproportionate reporting among females was observed (76.5 percent overall), particularly in adult age groups (93.3 and 86.5 percent in 18-49 and 50-64 year olds, respectively). The highest female-to-male reporting rate ratios were in adults 18-49 and 50-64 years of age (13.8 and 6.2, respectively). Geographically, reporting rates by PHU varied widely from zero to 9.9 per 100,000 population with no noted pattern.

**Table 1: Number of influenza AEFIs, percent and reporting rate in Ontario, by age group, 2012-2013 to 2014-2015**
Age Category (years)^Footnote1	Count^{Footnote 2}	Percent of AEFIs^{Footnote 2}	Percent of population^Footnote3	Reporting rate (per 100,000 population)^Footnote4
≤4	75	14.3	5.3	3.49
5-9	61	11.6	5.4	2.78
10-17	22	4.2	9.0	0.59
18-49	180	34.2	43.8	1.00
50-64	126	24.0	20.9	1.50
65-79	50	9.5	11.5	1.11
80+	12	2.3	4.2	0.72
Total	526	100.0	100.0	1.29
Table 1 footnote 1 Age - Date of influenza vaccine administration - date of birth Return to footnote1 Referrer Table 1 footnote 2 Total AEFIs = 528 (Two AEFI reports excluded for unknown age) Return to first footnote2 Referrer Table 1 footnote 3 Using 2014-2015 population projections (N=13,672,718) Return to footnote3 Referrer Table 1 footnote 4 Reporting rate is calculated using the following denominators: 2012 population estimates for 2012-2013, 2013 for 2013-2014 and 2014 projections for 2014-2015 Return to footnote4 Referrer

Most adverse events were reported following administration of influenza vaccine only (93.6 percent; n=494); 34 reports involved co-administration with other vaccines, most commonly, pneumococcal polysaccharide 23-valent (Pneu-P-23) vaccine (n=15) and tetanus, diphtheria, acellular pertussis (Tdap) vaccine (n=7). The most frequently reported events were injection site reactions which were documented in 36.2 percent of all reports. Other frequently reported types of events included allergic skin reactions (21.1 percent) and rashes (17.3 percent) (Table 2). The highest event-specific reporting rates were similar to reporting volume with the highest rates for pain, redness and swelling at the injection site, allergic skin reactions and rash (1.3, 0.9 and 0.8 per 100,000 doses distributed, respectively). Medically important events (n=27) included anaphylaxis (n=22), thrombocytopenia (n=1) and acute rhabdomyolosis (n=1) as well as three serious events described below. Reports of events managed as anaphylaxis ranged in age from four to 84 years, were predominantly (81.8 percent; n=18) female and none were classified as serious. Eight (36.4 percent) met the Brighton Collaboration anaphylaxis case definition (one level I, six level II, one level III) and the remaining 14 reports (63.6 percent) did not contain sufficient evidence to meet the definition. Based on events that met the Brighton definition, the reporting rate of anaphylaxis was 0.7 per one million doses distributed.

**Table 2: Number, percent distribution and reporting rate of influenza vaccine AEFIs in Ontario, by adverse event category, 2012-2013 to 2014-2015**
Adverse event type^{Table 2 Footnote 1}	Adverse event^{Table 2 Footnote 2}	Number of AEFI reports^{Table 2 Footnote 3}	Reporting rate^{Table 2 Footnote 4}	Percent of all AEFI reports^{Table 2 Footnote 3}	Number of serious reports
Injection site reactions	Total	190	1.6	36.2	8
	Cellulitis	30	0.2	5.7	6
	Infected Abscess	2	< 0.1	0.4	1
	Nodule	4	< 0.1	0.8	0
	Pain/redness/swelling at the injection site^{Table 2 Footnote 1}	162	1.3	30.9	3
	Pain/redness/swelling extending beyond nearest joint	40	0.3	7.6	1
	Pain/redness/swelling <4 days^{Table 2 Footnote 5}	7	0.1	1.3	0
	Pain/redness/swelling ≥4 days	129	1.1	24.6	2
	Sterile abscess	2	< 0.1	0.4	0
Systemic reactions	Total	156	1.3	29.7	7
	Adenopathy/lymphadenopathy	10	0.1	1.9	0
	Arthritis/arthralgia	16	0.1	3	1
	Fever ≥ 38 °C in conjunction with another reportable event	42	0.3	8	6
	Hypotonic-hypo-responsive episode (HHE)	1	< 0.1	0.2	0
	Parotitis	1	< 0.1	0.2	0
	Persistent crying/screaming	1	< 0.1	0.2	0
	Rash	91	0.8	17.3	1
	Severe vomiting/diarrhea^{Table 2 Footnote 6}	14	0.1	2.7	1
	Syncope with injury^{Table 2 Footnote 6}	1	< 0.1	0.2	0
	Thrombocytopenia	1	< 0.1	0.2	0
Allergic events	Total	145	1.2	27.6	1
	Allergic reaction - skin	111	0.9	21.1	1
	Allergic reaction - other^{Table 2 Footnote 5}	6	< 0.1	1.1	0
	Event managed as anaphylaxis^{Table 2 Footnote 6}	22	0.2	4.2	0
	Oculorespiratory syndrome (ORS)	11	0.1	2.1	0
Neurologic events	Total	32	0.3	6.1	8
	Anaesthesia/paraesthesia^{Table 2 Footnote 6}	10	0.1	1.9	2
	Bell's palsy	4	< 0.1	0.8	0
	Convulsions/seizures	9	0.1	1.7	3
	Encephalopathy/encephalitis	2	< 0.1	0.4	1
	Guillian-Barré syndrome (GBS)	3	< 0.1	0.6	2
	Paralysis other than Bell's palsy	4	< 0.1	0.8	0
Other severe/unusual events	Total	105	0.9	20.0	8
Table 2 footnote 1 Adverse event categories represent groupings of specific types of adverse events and are not mutually exclusive. For category totals, reports with more than one specific event within a category are counted only once. Thus category totals will not be the sum to the total of specific adverse events overall or within a category Return to first footnote1 Referrer Table 2 footnote 2 Includes only those adverse events where the count was at least one Return to first footnote2 Referrer Table 2 footnote 3 Each AEFI report may contain one or more specific adverse events which are not mutually exclusive. Percentages will not sum to 100%. The denominator is the total number of confirmed AEFI reports between 2012-2013 and 2014-2015 influenza season. Three reports were associated with zero adverse events, thus was excluded from the total confirmed AEFI reports in this specific analysis (n=525) Return to first footnote3 Referrer Table 2 footnote 4 Reporting rates are calculated using total dose distributed between 2012-2013 and 2014-2015 influenza seasons Return to first footnote4 Referrer Table 2 footnote 5 Includes the values "Pain/redness or swelling lasting less than four days", "Allergic reaction - cardiovascular" and Allergic reaction - respiratory" which were discontinued in iPHIS on January 1, 2013 Return to first footnote5 Referrer Table 2 footnote 6 These events were implemented as new values added to the "adverse event reaction(s)" field in iPHIS on Jan.1, 2013 Return to first footnote6 Referrer

There were 20 serious AEFI reports across all seasons, representing 3.8 percent of all AEFIs and a reporting rate of 1.6 per million doses distributed. The proportion of reports that were classified as serious by season steadily decreased (5.0, 3.6 and 2.3 percent for 2012-2013 to 2014-2015, respectively) as did the serious reporting rate (from 2.5 per million doses distributed in 2012-2013 to 1.8 and 0.7 per million doses distributed in 2013-2014 and 2014-2015, respectively). The age range of serious reports was one to 81 years with the greatest number of reports in older adults 50-64 and 65-79 years, as well as children one to four years of age (four reports each). Females accounted for 60 percent of serious reports. The most frequent type of event among serious AEFIs was cellulitis (requiring hospital admission for treatment with IV antibiotics) (n=6). Other serious events included seizures (n=2; one febrile in a child, one afebrile in an adult), anaesthesia/paraesthesia (n=2), GBS (n=3), bilateral panuveitis (n=2; one also diagnosed with GBS), encephalitis (n=1), chronic inflammatory demyelinating process (n=1), polymyalgia rheumatic (n=1), febrile rash illness (n=1), infective abscess (n=1) and one report of sudden onset of mobility limitation with spontaneous resolution. No deaths were reported.

Out of all AEFIs, the majority were reported by health care professionals (63.8 percent: 25.3 percent from physicians and 38.5 percent from other health professionals), followed by self-reports and reports by family members (12.1 percent, 8.2 percent, respectively). For those reports with health care utilization information completed, 68.2 percent (n=353) sought outpatient medical consultation, 23.1 percent (n=121) were seen in the emergency department and 3.9 percent (n=20) were hospitalized. In most cases, the individual was recovered at the time of reporting (70.0 percent, n=336), 26.0 percent were not yet recovered (but full recovery was expected) and 4.0 percent (n=19) were documented as having residual effects. Among all reports, two were noted as being pregnant; both were mild, non-serious events which resolved completely. There were six AEFI reports where an immunization error was noted. All involved incorrect injection technique (e.g., intramuscular injection administered too high, needle length too short) resulting in prolonged pain at the injection site and one serious report of cellulitis.

Discussion

This assessment of adverse events following influenza immunization reported in Ontario during three recent influenza seasons is consistent with the well-established safety profile of influenza vaccines. Ontario's influenza AEFI reporting rate of 4.4 per 100,000 doses distributed between the 2012-2013 and 2014-2015 seasons represents one of the lowest vaccine-specific reporting rates of all publicly-funded vaccines in the Province ^{Footnote 19}. This rate was also lower than the most recently reported national influenza AEFI reporting rate (8.9 per 100,000 doses distributed; 2012-2013 to 2014-2015) ^{Footnote 20} suggesting under-reporting in Ontario compared to other Canadian jurisdictions.

The decrease in reporting rate observed in 2014-2015 compared to previous years was unexpected and not fully understood. It was however, consistent with a decrease observed nationally during the same season. Some of the decrease could have been due to changes in provincial AEFI case definitions, which occurred during the first season in 2013 (e.g., limiting reporting of events involving pain, redness or swelling at the injection site to those that persist for four days or longer). Delayed reporting may play a role although in Ontario the proportion of late reports (e.g., reported after August 31) for 2012-2013 and 2013-2014 was minimal (3.5 and 1.5 percent, respectively) and a similar proportion of delayed reports for the 2014-2015 season would still result in a lower AEFI rate.

Age group-specific population-based reporting rates of influenza AEFIs were generally as expected with higher rates and proportions of AEFIs (compared to population distribution) in the youngest age groups. The observed female predominance in AEFI reporting has been previously noted in Ontario ^{Footnote 21}^{Footnote 22} and in other passive AEFI surveillance systems ^{Footnote 23}^{Footnote 24}^{Footnote 25} although it appears particularly striking in this current assessment (93.3 and 86.5 percent in 18-49 and 50-64 year olds, respectively). The reasons for this phenomenon are likely multi-factorial. Differences in vaccine uptake between males and females may play a role, especially as health care workers (a target group for influenza vaccine) are more likely to be female. However, provincial estimates from the Canada Community Health Survey (12 years of age and older; influenza immunization, less than one year ago) suggest only a slight female predominance among those immunized (54.1 percent were female) ^{Footnote 26}. Other potential factors include: differences between males and females in health care seeking behavior ^{Footnote 27}^{Footnote 28}^{Footnote 29} once an AEFI occurs and different biologic response to vaccines ^{Footnote 30}^{Footnote 31}. The difference in AEFI reporting by sex was less pronounced for serious AEFIs among which 60 percent were female.

Injection site reactions were the most frequently reported type of event in this assessment which is consistent with clinical trials and post-marketing surveillance of influenza vaccine products administered by intramuscular injection^{Footnote 4}^{Footnote 5}^{Footnote 23}^{Footnote 32}. Unlike the relatively high volume of injection site reactions among all AEFIs, the rate of reporting was quite low (1.6 per 100,000 doses distributed). While this rate likely underestimates the actual occurrence of localized reactions, some degree of under-reporting is expected for these events which are typically mild and resolve on their own. Allergic events were also frequently reported, most of which were allergic skin reactions which is consistent with previous AEFI assessments^{Footnote 19}^{Footnote 20}^{Footnote 23}. A small number of allergic events were classified as an event managed as anaphylaxis. Based on reports that met the Brighton definition, the reporting rate of anaphylaxis was comparable, albeit slightly lower than the expected rate of anaphylaxis following influenza vaccines which has been estimated at about one per million doses of vaccine^{Footnote 33}^{Footnote 34}.

As expected, serious events following influenza vaccine during this time period were rare and most often related to events known to be rarely reported following receipt of influenza vaccines. For example, GBS is a rare event which is consistently reported in post-marketing surveillance of influenza vaccines, including in Ontario where there were three reports of GBS following influenza vaccine over three years. While the evidence considering influenza vaccination and GBS is inadequate to accept or reject a causal association^{Footnote 35}, the absolute risk of approximately one excess case per one million vaccines^{Footnote 36}^{Footnote 37}^{Footnote 38} is much lower than that associated with influenza disease^{Footnote 39}^{Footnote 40}. Of note, there were two reports of bilateral panuveitis during this time period which have been described in more detail by Manusow and colleagues^{Footnote 41}. Panuveitis is a rare condition most often associated with infectious or inflammatory causes^{Footnote 42} although there is no known causal association with vaccines^{Footnote 43}.

Limitations of this analysis include those which are inherent to many passive AEFI surveillance systems such as data quality, completeness and reporting bias^{Footnote 23}^{Footnote 24}. Under-reporting of AEFIs has been previously demonstrated to be more prominent in Ontario compared to other jurisdictions^{Footnote 19} and is again suggested here. Reporting rates were calculated using the total population or doses distributed as the denominator, both of which are proxies for doses administered in the absence of a provincial population-based immunization registry. Although doses distributed are widely used in analyses of passive AEFI surveillance systems^{Footnote 23}^{Footnote 24}, it can underestimate AEFI reporting rates if vaccine wastage is not well captured or understood. Trend analysis includes only three seasons therefore interpretation may be limited. Analyses of additional seasons over a longer time period will further inform ongoing assessment of trends in AEFI reporting.

Conclusion

This assessment found that influenza vaccines administered within the Universal Influenza Immunization Program in Ontario resulted in a low rate of reported adverse events. Most reported events were mild and resolved completely. No unexpected safety issues were identified. These findings are consistent with the very good safety profile of influenza vaccines used in Canada and internationally. Continued surveillance is important to monitor for safety signals and reporting trends over time, particularly with the introduction of new influenza vaccines and to maintain professional and public confidence in influenza vaccine safety. Further analysis is needed to understand the decreasing rate over time and under-reporting within the surveillance system to optimize AEFI surveillance data in Ontario.

Acknowledgements

Sincere thanks is extended to public health unit staff across the province for their efforts in investigation and reporting of AEFIs which are essential to the evaluation of the Universal Influenza Immunization Program and influenza vaccine safety in Ontario.

Conflict of interest

None.

Funding

Funding for this project was provided by Public Health Ontario.

References

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Footnote 10

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Footnote 12

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Footnote 13

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Footnote 14

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Footnote 15

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Footnote 16

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Footnote 18

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Footnote 19

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Footnote 21

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Footnote 22

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Footnote 23

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Footnote 24

Zhou W, Pool V, Iskander JK, English-Bullard R, Ball R, Wise RP, et al. Surveillance for safety after immunization: Vaccine Adverse Event Reporting System (VAERS): United States, 1991-2001. MMWR Surveill Summ 2003 Jan 24;52(1):1-24.

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Footnote 25

Lawrence G, Boyd I, McIntyre P, Isaacs D. Surveillance of adverse events following immunisation: Australia 2002 to 2003. Commun Dis Intell Q Rep 2004;28(3):324-338.

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Footnote 26

Statistics Canada. Table 105-0501. Health indicator profile, annual estimates, by age group and sex, Canada, provinces, territories, health regions (2013 boundaries) and peer groups. CANSIM. Ottawa ON: Statistics Canada; 2016. [updated 2016 Apr 22]. http://www5.statcan.gc.ca/cansim/a26?lang=eng&id=1050501.

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Footnote 27

Bertakis KD, Azari R, Helms LJ, Callahan EJ, Robbins JA. Gender differences in the utilization of health care services. J Fam Pract 2000 Feb;49(2):147-152.

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Footnote 28

Galdas PM, Cheater F, Marshall P. Men and health help-seeking behaviour: Literature review. J Adv Nurs 2005 Mar;49(6):616-623.

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Footnote 29

Smith J, Braunack-Mayer A, Wittert G. What do we know about men's help-seeking and health service use? Med J Aust 2006;184(2):81-83.

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Footnote 30

Klein SL, Jedlicka A, Pekosz A. The Xs and Y of immune responses to viral vaccines. Lancet Infect Dis 2010 May;10(5):338-349.

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Footnote 31

Klein SL, Poland GA. Personalized vaccinology: One size and dose might not fit both sexes. Vaccine 2013 May 28;31(23):2599-2600.

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Footnote 32

Centers for Disease Control and Prevention (CDC). Prevention and control of seasonal influenza with vaccines. Recommendations of the Advisory Committee on Immunization Practices—United States, 2013-2014. MMWR Recomm Rep 2013 Sep 20;62(RR-07):1-43.

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Footnote 33

McNeil MM, Weintraub ES, Duffy J, Sukumaran L, Jacobsen SJ, Klein NP, et al. Risk of anaphylaxis after vaccination in children and adults. J Allergy Clin Immunol 2015 Sep 28.

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Footnote 34

Bohlke K, Davis RL, Marcy SM, Braun MM, DeStefano F, Black SB, et al. Risk of anaphylaxis after vaccination of children and adolescents. Pediatrics 2003 Oct;112(4):815-820.

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Footnote 35

Stratton K, Ford A, Rusch E, Wright Clayton E. National Academy of Sciences. Adverse effects of vaccines: Evidence and causality. Washington DC: NAM; 2011. http://www.nap.edu/catalog/13164/adverse-effects-of-vaccines-evidence-and-causality.

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Footnote 36

Haber P, DeStefano F, Angulo F, et al. Guillain-Barré syndrome following influenza vaccination. JAMA 2004 Nov;292:2478-81.

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Footnote 37

Juurlink D, Stukel T, Kwong J, et al. Guillain-Barré syndrome after influenza vaccination in adults: A population-based study. Arch Intern Med 2006;166:2217-21.

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Footnote 38

Prothro C, Kudish K, Fielin M. Preliminary results: Surveillance for Guillain-Barré syndrome after receipt of influenza A (H1N1) 2009 monovalent vaccine - United States, 2009-2010. MMWR. 2010;59:657-61.

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Footnote 39

Kwong J, Vasa P, Campitelli M, et al. Risk of Guillain-Barré syndrome after seasonal influenza vaccination and influenza health-care encounters: A self-controlled study. Lancet Infect Dis 2013;13(9):769-76.

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Footnote 40

Hawken S, Kwong JC, Deeks SL, Crowcroft NS, McGeer AJ, Ducharme R, et al. Simulation study of the effect of influenza and influenza vaccination on risk of acquiring Guillain-Barré syndrome. Emerg Infect Dis 2015 Feb;21(2):224-231.

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Footnote 41

Manusow JS, Rai A, Yeh S, Mandelcorn ED. Two cases of panuveitis with orbital inflammatory syndrome after influenza vaccination. Can J Ophthalmol 2015 Oct;50(5):e71-4.

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Footnote 42

Rosenbaum J. Uveitis: Etiology, clinical manifestations, and diagnosis. Alphen aan den Rijn NL: Wolters Kluwer; 2015. http://www.uptodate.com/contents/uveitis-etiology-clinical-manifestations-and-diagnosis?source=search_result&search=uveitis&selectedTitle=1~150.

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Footnote 43

National Academies of Sciences, Engineering and Medicine. Adverse effects of vaccines: Evidence and causality. Washington DC: NAM; 2011. http://www.nationalacademies.org/hmd/Reports/2011/Adverse-Effects-of-Vaccines-Evidence-and-Causality.aspx.

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