Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2022–2023

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Organization: Public Health Agency of Canada

Published: 2022-06-08

An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)

Important notice: Update to age indication for Influvac Tetra (BGP Pharma ULC, operating as Mylan, d.b.a. Viatris Canada):

Influvac Tetra egg-based, subunit, quadrivalent inactivated influenza vaccine is now authorized by Health Canada for use in 6 months and older. Refer to the product monograph for further details.

This updated authorized age for use supersedes the information for Influvac Tetra found in Table 2, Table 3 and various other sections within the National Advisory Committee on Immunization (NACI) Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2022–2023

Important notice: Update to age indication for Flucelvax Quad (Seqirus):

Flucelvax Quad (Seqirus) standard dose mammalian cell culture-based quadrivalent inactivated influenza vaccine is now authorized by Health Canada for use in persons 6 months and older. Refer to the product monograph for further details.

This updated authorized age for use supersedes the information for Flucelvax Quad found in Table 2, Table 3 and various other sections within the National Advisory Committee on Immunization (NACI) Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2022–2023

Table of Contents

  1. Introduction
  2. Canadian Immunization Guide chapter on influenza: clinical information for vaccine providers
  3. Particularly recommended vaccine recipients: additional information
  4. Vaccine preparations authorized for use in Canada: additional information
  5. Choice of seasonal influenza vaccine: additional information
  6. List of abbreviations
  7. Acknowledgments
  8. Appendix A: characteristics of influenza vaccines available for use in Canada, 2021–2022
  9. References

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 conflicts of interest.

I. Introduction

This document, the “Advisory Committee Statement: Canadian Immunization Guide Chapter on Influenza and National Advisory Committee on Immunization (NACI) Statement on Seasonal Influenza Vaccine for 2022–2023”, updates NACI's recommendations regarding the use of seasonal influenza vaccines.

I.1 New or Updated Information for 2022–2023

Use of seasonal influenza vaccine in the context of coronavirus disease 2019 (COVID-19)

Guidance on the use of seasonal influenza vaccine in the presence COVID-19

Seasonal influenza presents an ongoing disease burden in Canada during the fall and winter months, however the epidemiology of influenza has changed during the course of the pandemic. Influenza vaccine is the most effective way to prevent influenza illness and influenza-related complications, and will be an important component of managing health care system capacity during the influenza season in the context of any ongoing COVID-19 activity.

PHAC, in consultation with NACI and the Canadian Immunization Committee, has developed guidance on the administration of seasonal influenza vaccine to support provincial and territorial vaccine programs and primary care providers during the COVID-19 pandemic:

The guidance on this page is based on currently available scientific evidence and expert opinion and will be updated and added to as necessary throughout the influenza season as new evidence emerges. This web page should be considered in concert with recommendations regarding the use of seasonal influenza vaccines provided in this NACI Statement.

Guidance on concomitant administration of influenza and COVID-19 vaccines

NACI guidance outlines that administration of COVID-19 vaccines may occur at the same time as, or at any time before or after influenza immunization (including all seasonal influenza vaccines or LAIV) for those aged 12 years and older as of September 2021.

Readers should consult the current NACI COVID-19 guidance and the Canadian Immunization Guide (CIG) COVID-19 chapter for updated NACI guidance and further information on concomitant administration of COVID-19 vaccines with influenza vaccines and across all eligible age groups.

Inclusion of recombinant quadrivalent seasonal influenza vaccine

Supemtek™ (RIV4) is a recombinant quadrivalent seasonal influenza vaccine produced by Sanofi Pasteur that was authorized for use in Canada on January 14, 2021, in adults 18 years of age and older. Supemtek is the first and, to date, the only recombinant influenza vaccine licensed in Canada. Based on a review of available pre-licensure and post-market clinical trial and surveillance data, NACI has concluded that Supemtek may be considered for use among the quadrivalent influenza vaccines offered to adults 18 years of age and older (Discretionary NACI Recommendation). Refer to the NACI Supplemental Statement: Recombinant Influenza Vaccines, which will be forthcoming, for additional information supporting this recommendation.

Updated recommendations on mammalian cell culture-based quadrivalent influenza vaccine

Flucelvax Quad (IIV4-cc) is the first and, to date, the only mammalian cell culture-based inactivated seasonal influenza vaccine available for use in Canada. It was first authorized for use in Canada in adults and children 9 years of age and older on November 22, 2019. Recommendations and supporting evidence on the use of Flucelvax Quad in adults and children 9 years of age and older can be found in the NACI Supplemental Statement – Mammalian Cell Culture-Based Influenza Vaccines and were also incorporated into the Statement on Seasonal Influenza Vaccine for 2021–2022.

On March 8, 2021, Health Canada approved an expanded age indication for the use of Flucelvax Quad in children down to 2 years of age and older. Based on a review of Health Canada assessments of clinical trial evidence submitted by the manufacturer in support of the age indication extension, NACI has concluded that Flucelvax Quad may be considered among the quadrivalent influenza vaccines offered to adults and children 2 years of age and older. Refer to section IV.1 Inactivated Influenza Vaccine (IIV) later in the statement for additional information supporting this recommendation.

I.2 Abbreviations for Influenza Vaccines

The abbreviations used in this document for the different influenza vaccines are as follows:

Table 1. NACI influenza vaccine abbreviations
Influenza vaccine category Formulation Type Current NACI abbreviationTable 1 Footnote a
Inactivated influenza vaccine (IIV) Trivalent (IIV3) Standard doseTable 1 Footnote b, unadjuvanted, IM administered, egg-based IIV3-SD
AdjuvantedTable 1 Footnote c, IM administered, egg-based IIV3-Adj
High doseTable 1 Footnote d, unadjuvanted, IM administered, egg-based IIV3-HD
Quadrivalent (IIV4) Standard doseTable 1 Footnote b, unadjuvanted, IM administered, egg-based IIV4-SD
Standard doseTable 1 Footnote b, unadjuvanted, IM administered, cell culture-based IIV4-cc
High doseTable 1 Footnote d, unadjuvanted, IM administered, egg-based IIV4-HD
Recombinant influenza vaccine (RIV) Quadrivalent (RIV4) RecombinanteTable 1 Footnote e, unadjuvanted, IM administered RIV4
Live attenuated influenza vaccine (LAIV) Trivalent (LAIV3) Unadjuvanted, nasal spray, egg-based LAIV3
Quadrivalent (LAIV4) Unadjuvanted, nasal spray, egg-based LAIV4
Abbreviations: IIV: inactivated influenza vaccine; IIV3: trivalent inactivated influenza vaccine; IIV3-Adj: adjuvanted egg-based trivalent inactivated influenza vaccine; IIV3-HD: high-dose egg-based trivalent inactivated influenza vaccine; IIV3-SD: standard-dose egg-based trivalent inactivated influenza vaccine; IIV4: quadrivalent inactivated influenza vaccine; IIV4-cc: standard-dose cell culture-based quadrivalent inactivated influenza vaccine; IIV4-HD: high-dose egg-based quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose egg-based quadrivalent inactivated influenza vaccine; IM: intramuscular; LAIV: live attenuated influenza vaccine; LAIV3: egg-based trivalent live attenuated influenza vaccine; LAIV4: egg-based quadrivalent live attenuated influenza vaccine.
Table 1 Footnote a

The numeric suffix denotes the number of antigens contained in the vaccine (“3” refers to the trivalent formulation and “4” refers to the quadrivalent formulation). The hyphenated suffix “-SD” (where “SD” is used to denote “standard dose” for an IIV) is used when referring to IIV products that do not have an adjuvant, contain 15 µg hemagglutinin (HA) per strain and are administered as a 0.5 mL dose by intramuscular injection; “-cc” (where “cc” denotes “cell culture”) refers to an IIV product that is made from influenza virus grown in cell cultures instead of chicken eggs (Flucelvax Quad); “-Adj” (where “Adj” is used to abbreviate “adjuvanted”) refers to an IIV with an adjuvant (IIV3-Adj for Fluad or Fluad Pediatric); and “-HD” refers to an IIV that contains higher antigen content than 15 µg HA per strain standard IIV dose (IIV3-HD for Fluzone High-Dose or IIV4-HD for Fluzone High-Dose Quadrivalent).

Table 1 Return to footnote a referrer

Table 1 Footnote b

15 µg HA per strain.

Table 1 Return to footnote b referrer

Table 1 Footnote c

7.5 µg (in 0.25 mL) or 15 µg (in 0.5 mL) HA per strain.

Table 1 Return to footnote c referrer

Table 1 Footnote d

60 µg HA per strain.

Table 1 Return to footnote d referrer

Table 1 Footnote e

45 µg HA per strain.

Table 1 Return to footnote e referrer

I.3 Background

The World Health Organization’s (WHO) recommendations on the composition of influenza virus vaccines are typically available in February of each year for the upcoming season in the Northern Hemisphere. The WHO recommends that three influenza strains be included in the trivalent seasonal influenza vaccine: one influenza A(H1N1), one influenza A(H3N2), and one influenza B. Quadrivalent seasonal influenza vaccines should contain the three strains recommended for the trivalent vaccine, as well as an influenza B virus from the lineage that is not included in the trivalent vaccine.

Annual recommendations on the use of influenza vaccine in Canada are developed by the NACI Influenza Working Group (IWG) for consideration by NACI. Recommendations are developed based on a review of a variety of issues, which can include: the burden of influenza illness and the target populations for vaccination; efficacy, effectiveness, immunogenicity, and safety of influenza vaccines; vaccine schedules; and other aspects of influenza immunization. In addition, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing their recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels. These programmatic factors include economics, ethics, equity, feasibility, and acceptability. Details regarding NACI's evidence-based process for developing a statement are outlined in Evidence-based Recommendations for Immunization − Methods of the National Advisory Committee on Immunization.

Health care providers in Canada should offer the seasonal influenza vaccine as soon as feasible after it becomes available in the fall, since seasonal influenza activity may start as early as October in the Northern Hemisphere. Decisions regarding the precise timing of vaccination in a given setting or geographic area should be made according to local epidemiologic factors (influenza activity, timing, and intensity), opportune moments for vaccination, as well as programmatic considerations. Further advice regarding the timing of influenza vaccination programs may be obtained through consultation with local public health agencies.

Although vaccination before the onset of the influenza season is strongly preferred, influenza vaccine may still be administered up until the end of the season. Delayed administration may result in lost opportunities to prevent infection from exposures that occur prior to vaccination, and individuals seeking vaccination should be informed that vaccine administered during an influenza outbreak may not provide optimal protection. Vaccine providers should use every opportunity to administer influenza vaccine to individuals at risk who have not already been vaccinated during the current season, even after influenza activity has been documented in the community.

Every year, individuals with influenza and influenza-related complications increase the demand on the healthcare system in the fall and winter months. During the COVID-19 pandemic, influenza vaccination remains a critical tool to minimize the morbidity and mortality related to potential influenza and COVID-19 co-circulation and to reduce the burden on the Canadian health care system to enhance the capacity to respond to ongoing COVID-19 activity.

II. Canadian Immunization Guide Chapter on Influenza: Clinical Information for Vaccine Providers

The Canadian Immunization Guide (CIG) is written primarily for health care providers (frontline clinicians and public health practitioners) but it is also used by policy makers, program planners, and the general public. The CIG has been a trusted, reader-friendly summary of the vaccine statements provided by NACI since 1979.

The information in this section replaces the influenza chapter of the CIG. With a new NACI Statement on Seasonal Influenza Vaccine required each year, readers will have quick access to the information that they require within one document, whether it is the relevant influenza vaccine information written primarily for frontline vaccine providers as is found in this section, or the more detailed technical information that is found in the rest of this statement, commencing in Section III.

II.1 Key Information

The following highlights key information for vaccine providers. Please refer to the remainder of this statement for additional details.

What

Who

NACI makes the following recommendations for individual-level and public health program-level decision making. Individual-level recommendations are intended for people wishing to protect themselves from influenza or for vaccine providers wishing to advise individual patients about preventing influenza. Program-level recommendations are intended for provinces and territories responsible for making decisions on publicly funded immunization programs. Individual-level and program-level recommendations may differ, as the important factors to consider when recommending a vaccine for a population (e.g., population demographics, economic considerations) may be different than for an individual.

Recommendation for individual-level decision making

In infants less than 6 months of age influenza vaccine is less immunogenic than in older children and adults and does not confer sufficient protection to make the vaccine useful in this age groupFootnote 3. Currently, authorized influenza vaccines are not indicated for use in infants less than 6 months of age. For these reasons, NACI recommends that influenza vaccine should not be offered to infants less than 6 months of age. However, as infants less than 6 months of age are at high risk of influenza-related illness, the influenza vaccine should be offered to individuals who are pregnant, and any household contacts and care providers of infants (see List 1).

Recommendation for public health program-level decision-making

The national goal of the annual influenza immunization programs in Canada is to prevent serious illness caused by influenza and its complications, including death. Programmatic decisions to provide influenza vaccination to target populations as part of publicly funded provincial and territorial programs depend on many factors, such as cost-effectiveness evaluation and other programmatic and operational factors.

List 1: Groups for whom influenza vaccination is particularly recommended

People at high risk of influenza-related complications or hospitalization

  • All children 6–59 months of age
  • Adults and children with the following chronic health conditionsList 1 Footnote a:
    • cardiac or pulmonary disorders (includes bronchopulmonary dysplasia, cystic fibrosis, and asthma);
    • diabetes mellitus and other metabolic diseases;
    • cancer, immune compromising conditions (due to underlying disease, therapy, or both, such as solid organ transplant or hematopoietic stem cell transplant recipients);
    • renal disease;
    • anemia or hemoglobinopathy;
    • neurologic or neurodevelopment conditions (includes neuromuscular, neurovascular, neurodegenerative, neurodevelopmental conditions, and seizure disorders [and, for children, includes febrile seizures and isolated developmental delay], but excludes migraines and psychiatric conditions without neurological conditions);
    • morbid obesity (BMI of 40 and over); and
    • children 6 months to 18 years of age undergoing treatment for long periods with acetylsalicylic acid, because of the potential increase of Reye’s syndrome associated with influenza.
  • All pregnant individuals;
  • People of any age who are residents of nursing homes and other chronic care facilities;
  • Adults 65 years of age and older; and
  • Indigenous peoples.

People capable of transmitting influenza to those at high risk

  • Health care and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk;
  • Household contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated:
    • household contacts of individuals at high risk;
    • household contacts of infants less than 6 months of age, as these infants are at high risk but cannot receive influenza vaccine;
    • members of a household expecting a newborn during the influenza season;
  • Those providing regular child care to children 0–59 months of age, whether in or out of the home; and
  • Those who provide services within closed or relatively closed settings to people at high risk (e.g., crew on a ship).

Others

  • People who provide essential community services; and
  • People who are in direct contact with poultry infected with avian influenza during culling operations.
List 1 Footnote a

Refer to Immunization of Persons with Chronic Diseases and Immunization of Immunocompromised Persons in Part 3 of the CIG for additional information about vaccination of people with chronic diseases.

List 1 Return to footnote a referrer

How

The benefits and risks of influenza vaccination should be discussed prior to vaccination, including the risks of not being immunized.

Choice of influenza vaccine

A variety of influenza vaccines are authorized for use in Canada, some of which are authorized for use only in specific age groups. Therefore, the choice of influenza vaccine has become more complex. Refer to Section II.5 for recommendations on the choice of influenza vaccine by age group.

Dose and route of administration

The dose and route of administration vary by influenza vaccine product (see Section II.6 for details). For recommendations on which vaccines are recommended in different age groups, refer to Table 2.

Schedule

NACI recommends that:

Contraindications

For all influenza vaccines (IIV, RIV4 and LAIV), NACI recommends that influenza vaccination should not be given to:

For LAIV, in addition to the above-mentioned contraindications, NACI also recommends that LAIV should not be given to:

Refer to Contents of Immunizing Agents Available for Use in Canada in Part 1 of the CIG for a list of all vaccines authorized for use in Canada and their contents and to Vaccine Safety in Part 2 of the CIG for information regarding the management of adverse events (AEs), including anaphylaxis.

Precautions

NACI recommends that:

Refer to Section II.7 for additional information on influenza vaccine-related precautions

Concomitant administration with other vaccines

NACI recommends that:

Why

II.2 Epidemiology

Disease description

Influenza is a respiratory illness caused by the influenza A and B viruses in humans and can cause mild to severe illness, which can result in hospitalization or death. Certain populations, such as young children, older adults, and those with chronic health conditions, may be at higher risk for serious influenza complications such as viral pneumonia, secondary bacterial pneumonia, and worsening of underlying medical conditions.

Infectious agent

There are two main types of influenza virus that cause seasonal epidemics in humans: A and B. Influenza A viruses are classified into subtypes based on two surface proteins: hemagglutinin (HA) and neuraminidase (NA). Three subtypes of HA (H1, H2, and H3) and two subtypes of NA (N1 and N2) are recognized among influenza A viruses as having caused widespread human disease over the decades. Immunity to the HA and NA proteins reduces the likelihood of infection and together with immunity to the internal viral proteins, lessens the severity of disease if infection occurs.

Influenza B viruses have evolved into two antigenically distinct lineages since the mid-1980s, represented by B/Yamagata/16/88-like and B/Victoria/2/87-like viruses. Viruses from both the B/Yamagata and B/Victoria lineages contribute variably to influenza illness each year. Globally, influenza circulation has been at a historical low since the onset of the COVID-19 pandemic, and with the implementation of non-pharmaceutical public health measures against COVID-19 in Canada. There has been a virtual absence of any B/Yamagata detections globallyFootnote 5.

Over time, antigenic variation (antigenic drift) of strains occurs within an influenza A subtype or a B lineage. The ever-present possibility of antigenic drift, which may occur in one or more influenza virus strains, requires seasonal influenza vaccines to be reformulated annually, with one or more vaccine strains changing in most seasons.

Transmission

Influenza is primarily transmitted by aerosols and droplets spread through coughing or sneezing, and through direct or indirect contact with respiratory secretions.

The incubation period of seasonal influenza is usually about 2 days but can range from 1–4 daysFootnote 6. Adults may be able to spread influenza to others from 1 day before symptom onset to approximately 5 days after symptoms start. Children and people with weakened immune systems may be infectious longer.

Risk factors

The people at greatest risk of influenza-related complications are adults and children with chronic health conditions (see List 1), residents of nursing homes and other chronic care facilities, adults 65 years of age and older, children 0–59 months of age, pregnant individuals, and Indigenous peoples.

Seasonal and temporal patterns

Influenza activity in Canada is usually low in the late spring and summer, begins to increase over the fall, and peaks in the winter months. Depending on the year, one or more peaks may occur as early as the fall and into the spring. Influenza season in Canada can last for many months, and more than one influenza strain typically circulates each season.

Spectrum of clinical illness

Symptoms typically include the sudden onset of fever, cough, and muscle aches. Other common symptoms include headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. Most people will recover within a week or 10 days. More rarely, central nervous system involvement, acute myositis, myocarditis or pericarditis have been described. In addition, complications including pneumonia, respiratory failure, cardiovascular complications, or worsening of underlying chronic medical conditions may occur.

Disease incidence

Global

Worldwide, annual epidemics result in approximately one billion cases of influenza, three to five million cases of severe illness, and 290,000 to 650,000 deaths. Prior to the COVID-19 pandemic, the global annual attack rate was estimated to be 5–10% in adults and 20–30% in childrenFootnote 1. For current international influenza activity information, refer to WHO's Global Influenza Program website.

National

Together, influenza and pneumonia are ranked among the top 10 leading causes of death in CanadaFootnote 7. The FluWatch program is Canada's national surveillance system, which monitors the spread of influenza and influenza-like illnesses (ILI) continually throughout the year. In the five seasons prior to the COVID-19 pandemic (2014–2015 to 2018-2019 season), an average of 40,000 laboratory-confirmed cases of influenza were reported to FluWatch each year. Although the burden of influenza can vary from year to year, it is estimated that there are an average of 12,200 hospitalizations related to influenza and approximately 3,500 deaths attributable to influenza annuallyFootnote 8Footnote 9. Current influenza activity information can be found on the FluWatch website.

It should be noted that the incidence of influenza is often underreported since the illness may be confused with other viral illnesses and many people with ILI do not seek medical care or have viral diagnostic testing done.

II.3 Vaccine Products Authorized for Use in Canada

This section describes the influenza vaccine products that are authorized for use in Canada for the 2022–2023 season. All influenza vaccines available in Canada have been authorized by Health Canada. However, not all products authorized for use are necessarily available in the marketplace. The vaccine manufacturers determine whether they will make any or all of their products available in a given market. Provincial and territorial health authorities then determine which of the products available for purchase will be used in their respective publicly funded influenza immunization programs and for which population groups.

The antigenic characteristics of circulating influenza virus strains provide the basis for selecting the strains included in each year's vaccine. Vaccine selection by the WHO generally occurs more than 6 months prior to the start of the influenza season to allow time for the vaccine manufacturers to produce the required quantity of vaccine. All manufacturers that distribute influenza vaccine products in Canada confirm to Health Canada that the vaccines to be marketed in Canada for the upcoming influenza season contain the WHO's recommended antigenic strains for the Northern Hemisphere. Vaccine producers may use antigenically equivalent strains because of their growth properties. The strains recommended for egg-based products may differ somewhat from the strains chosen for cell-culture based products to account for differences in the production platforms.

There are three categories of influenza vaccine authorized for use in Canada: IIV, RIV, and LAIV. Trivalent (3-strain) vaccines contain one A(H1N1) strain, one A(H3N2) strain, and one influenza B strain from one of the two lineages. Quadrivalent (4-strain) vaccines contain the strains in the trivalent vaccine plus an influenza B strain from the other lineage. Most influenza vaccines currently authorized for use in Canada are made from influenza viruses grown in chicken eggs. However, there are two exceptions. The influenza viruses used to produce Flucelvax Quad are propagated in a mammalian cell line (Madin-Darby Canine Kidney cells), while the Supemtek vaccine technology uses recombinant HA produced in a proprietary insect cell line using a baculovirus vector for protein expression.

A summary of the characteristics of influenza vaccines available in Canada during the 2022–2023 influenza season can be found in Appendix A. For complete prescribing information, readers should consult the product monographs available through Health Canada's Drug Product Database.

Inactivated influenza vaccine (IIV)

IIVs currently authorized for use in Canada are a mix of split virus and subunit vaccines. In split virus vaccines, the virus has been disrupted by a detergent. In subunit vaccines, HA and NA have been further purified by removal of other viral components. All IIVs currently available in Canada are produced in eggs, with the exception of Flucelvax Quad (IIV4-cc), which is a mammalian cell culture-based quadrivalent inactivated, subunit influenza vaccine that is prepared from viruses propagated in mammalian cell lines [proprietary 33016-PF Madin-Darby Canine Kidney (MDCK) cell lines] adapted to grow freely in suspension in culture medium. The production of IIV4-cc does not depend on egg supply as it does not require egg-grown candidate vaccine viruses.

The IIVs available in Canada are in a standard dose formulation or in a formulation designed to enhance the immune response in specific age groups, through the use of a higher dose of HA antigen or the inclusion of an adjuvant. Refer to Basic Immunology and Vaccinology in Part 1 of the CIG for more information about inactivated vaccines.

Standard-dose IIVs are available in Canada as quadrivalent formulations (IIV4-SD: Afluria Tetra, Flulaval Tetra, Fluzone Quadrivalent, and Influvac Tetra; IIV4-cc: Flucelvax Quad). These vaccines are unadjuvanted, contain a standard dose of antigen (15 µg HA per strain), and are administered as a 0.5 mL dose by IM injection. Influvac Tetra may be administered by IM or deep subcutaneous injection.

The adjuvanted IIVs (IIV-Adj) currently authorized for use in Canada are trivalent subunit IIVs that contain the adjuvant MF59, which is an oil-in-water emulsion composed of squalene as the oil phase that is stabilized with the surfactants polysorbate 80 and sorbitan triolate in citrate buffer. IIV-Adj contains 7.5 µg HA per strain administered as a 0.25 mL dose by IM injection for children 6–23 months of age (Fluad Pediatric) or 15 µg HA per strain administered as a 0.5 mL dose by IM injection for adults 65 years of age and older (Fluad). Other IIVs do not contain an adjuvant.

There is one high-dose IIV (IIV-HD) currently authorized for use in Canada; a quadrivalent unadjuvanted, split virus IIV that contains 60 µg HA per strain and is administered as a 0.7 mL dose by IM injection (Fluzone High-Dose Quadrivalent).

Recombinant influenza vaccine (RIV)

There is currently only one RIV authorized for use in Canada: Supemtek™ (RIV4), a quadrivalent unadjuvanted, baculovirus-expressed seasonal influenza vaccine that contains 45 µg HA per strain and is administered as a 0.5 mL dose by IM injection for adults 18 years of age and older. RIV contains recombinant HAs produced in an insect cell line using genetic sequences from cell-derived influenza viruses. The production of RIV does not depend on egg supply as it does not require egg-grown candidate vaccine viruses.

Live attenuated influenza vaccine (LAIV)

LAIV is given as an intranasal spray. The influenza viruses contained in LAIV are attenuated so that they do not cause influenza and are cold-adapted and temperature sensitive, so that they replicate in the nasal mucosa rather than the lower respiratory tract. LAIV contains standardized quantities of fluorescent focus units (FFU) of live attenuated reassortants and is given as a 0.2 mL dose (0.1 mL in each nostril).

A quadrivalent product (LAIV4; FluMist Quadrivalent) is authorized for use in Canada for children 2–17 years of age and adults 18–59 years of age. The trivalent formulation (LAIV3) is no longer available in Canada.

II.4 Efficacy, Effectiveness, and Immunogenicity

Efficacy and effectiveness

Influenza vaccine has been shown in randomized controlled clinical trials to be efficacious in providing protection against influenza infection and illness. However, the effectiveness of the vaccine—that is, how it performs in settings that are more reflective of usual health care practice—can vary from season to season and by influenza vaccine strain type and subtype. Influenza vaccine effectiveness (VE) depends on how well the vaccine strains match with circulating influenza viruses, the type and subtype of the circulating virus, as well as the health and age of the individual receiving the vaccine. Even when there is a less-than-ideal match or lower VE against one strain, the possibility of lower VE should not preclude vaccination, particularly for people at high risk of influenza-related complications and hospitalization, since vaccinated individuals are still more likely to be protected compared to those who are unvaccinated.

Immunogenicity

Antibody response after vaccination depends on several factors, including the age of the recipient, prior and subsequent exposure to antigens, and the presence of immune compromising conditions. Protective levels of humoral antibodies, which correlate with protection against influenza infection, are generally achieved by 2 weeks after vaccination; however, there may be some protection afforded before that time.

II.5 Choice of Seasonal Influenza Vaccine

The decision to include specific influenza vaccines as part of publicly funded provincial and territorial programs depends on several factors, including cost-effectiveness evaluation and other programmatic and operational factors, such as implementation strategies. Not all products will be made available in all jurisdictions and availability of some products may be limited; therefore, officials in individual provinces and territories should be consulted regarding the products available in individual jurisdictions.

With the availability of influenza vaccines that are designed to enhance immunogenicity in specific age groups, the choice of product has become more complex.

Choice of influenza vaccine by age group

Recommendations for individual-level decision making
Recommendations for public health program-level decision making
Table 2: Recommendations on choice of influenza vaccine type for individual- and public health program-level decision making by age group
Recipient by age group Vaccine types authorized for use Recommendations on choice of influenza vaccine

6–23 months

  • A quadrivalent influenza vaccine authorized for this age group should be used in infants and young children without contraindications, given the burden of influenza B disease in this age group and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine.
  • If a quadrivalent vaccine is not available, any of the available trivalent vaccines licensed for this age group should be used

2–17 yearsTable 2 Footnote b

  • An age appropriate quadrivalent influenza vaccine (IIV4-SD, LAIV4, or IIV4-cc) should be used in children without contraindications or precautions (see text below applicable to LAIV), including those with chronic health conditions, given the burden of influenza B disease in this age group and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine.
  • LAIV4 may be given to children with:
    • stable, non-severe asthma;
    • cystic fibrosis who are not being treated with immunosuppressive drugs (e.g., prolonged systemic corticosteroids); and
    • stable HIV infection, if the child is currently being treated with ART (i.e., HAART) and has adequate immune function.
  • LAIV should not be used in children or adolescents for whom it is contraindicated or for whom there are warning and precautions such as those with:
    • severe asthma (defined as currently on oral or high-dose inhaled glucocorticosteroids or active wheezing);
    • medically attended wheezing in the 7 days prior to vaccination;
    • current receipt of aspirin or aspirin-containing therapy;
    • immune compromising conditions, with the exception of stable HIV infection, i.e., if the child is treated with HAART (for at least 4 months) and has adequate immune function.
    • pregnancy
      • In pregnancy, IIV4-SD or IIV4-cc should be used instead.
  • If IIV4-SD, IIV4-cc, and LAIV4 are not available, IIV3-SD should be used.

18–59 years

  • Any of the available influenza vaccines authorized for this age group should be used in adults 18-59 years without contraindications or precautions, noting the following consideration and exceptions:
    • There is some evidence that IIV may provide better efficacy than LAIV in healthy adults; and
  • LAIV is not recommended for:
    • pregnant individuals;
    • adults with any of the chronic health conditions identified in List 1, including immune compromising conditions; and
    • health care workers

60–64 years

  • Any of the available influenza vaccines authorized for this age group should be used in adults 60-64 years without contraindications.

65 years and olderTable 2 Footnote c

Individual-level decision-making

  • IIV-HD should be used over IIV-SD, given the burden of influenza A(H3N2) disease and the good evidence of IIV3-HD providing better protection compared to IIV3-SD in adults 65 years of age and older.
    • Other than a recommendation for using IIV-HD over IIV-SD formulations, NACI has not made comparative individual-level recommendations on the use of the other available vaccines in this age group. In the absence of a specific product, any of the available age appropriate influenza vaccines should be used.

Public health program-level decision-making

  • Any of the available influenza vaccines authorized in this age group should be used.
    • There is insufficient evidence on the incremental value of different influenza vaccines (i.e. cost-effectiveness assessments have not been performed by NACI) to make comparative public health program-level recommendations on the use of the available vaccines.
Abbreviations: ART: antiretroviral therapy; HAART: highly active antiretroviral therapy; IIV: inactivated influenza vaccine; IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-cc: quadrivalent mammalian cell –culture-based inactivated influenza vaccine; IIV4-HD: high-dose quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; RIV4: quadrivalent recombinant influenza vaccine; LAIV: live attenuated influenza vaccine; LAIV4: quadrivalent live attenuated influenza vaccine.
Table 2 Footnote a

IIV3-SD formulations will not be available for use in Canada during the 2022-2023 influenza season

Table 2 Return to footnote a referrer

Table 2 Footnote b

Refer to Table 4 for a summary of vaccine characteristics of LAIV compared with IIV in children 2–17 years of age.

Table 2 Return to footnote b referrer

Table 2 Footnote c

Refer to Table 5 for a comparison of the vaccine characteristics of influenza vaccine types available for use in adults 65 years of age and older.

Table 2 Return to footnote c referrer

Table 2 Footnote d

IIV3-HD formulations will not be authorized or available for use in Canada during the 2022-2023 influenza season.

Table 2 Return to footnote d referrer

II.6 Vaccine Administration

Dose, route of administration, and schedule

With the variety of influenza vaccines available for use in Canada, it is important for vaccine providers to note the specific differences in age indication, route of administration, dosage, and schedule for the products that they will be using (see Table 3). Key relevant details and differences between vaccine products are also highlighted in Appendix A.

For influenza vaccines given by the IM route, the anterolateral thigh muscle is the recommended site in infants 6–12 months of age. The anterolateral thigh or the deltoid muscle can be used for toddlers and older children. The deltoid muscle of the arm is the preferred injection site in adolescents and adults. For more information on vaccine administration, please refer to Vaccine Administration Practices in Part 1 of the CIG.

Table 3: Recommended dose and route of administration, by age, for influenza vaccine types authorized for the 2022–2023 influenza season
Age group Influenza vaccine type (route of administration) Number of doses required
IIV3-SDTable 3 Footnote a or IIV4-SDTable 3 Footnote b
(IM)
IIV4-ccTable 3 Footnote c
(IM)
IIV3-AdjTable 3 Footnote d
(IM)
IIV4-HDTable 3 Footnote e
(IM)
RIV4Table 3 Footnote f
(IM)
LAIV4Table 3 Footnote g
(intranasal)
6–23 months 0.5 mLTable 3 Footnote h - 0.25 mL - - - 1 or 2Table 3 Footnote i
2–8 years 0.5 mL - - - - 0.2 mL
(0.1 mL per nostril)
1 or 2Table 3 Footnote i
9–17 years 0.5 mL 0.5 mL - - - 0.2 mL
(0.1 mL per nostril)
1
18–59 years 0.5 mL 0.5 mL - - 0.5 mL 0.2 mL
(0.1 mL per nostril)
1
60–64 years 0.5 mL 0.5 mL - - 0.5 mL - 1
65 years and older 0.5 mL 0.5 mL 0.5 mL 0.7 mL 0.5 mL - 1

Abbreviations: IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV4-cc: quadrivalent mammalian cell-culture based inactivated influenza vaccine; IIV4-HD: high-dose quadrivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; RIV4: quadrivalent recombinant influenza vaccine; IM: intramuscular; LAIV4: quadrivalent live attenuated influenza vaccine.

Table 3 Footnote a

IIV3-SD formulations (Agriflu [6 months and older] and Influvac [3 years and older]) are authorized but will not be available for use in Canada during the 2022-2023 influenza season.

Table 3 Return to footnote a referrer

Table 3 Footnote b

Afluria Tetra (5 years and older), Flulaval Tetra (6 months and older), Fluzone Quadrivalent (6 months and older), Influvac Tetra (3 years and older).

Table 3 Return to footnote b referrer

Table 3 Footnote c

Flucelvax Quad (2 years and older)

Table 3 Return to footnote c referrer

Table 3 Footnote d

Fluad Pediatric (6–23 months) or Fluad (65 years and older)

Table 3 Return to footnote d referrer

Table 3 Footnote e

Fluzone High-Dose Quadrivalent (65 years and older)

Table 3 Return to footnote e referrer

Table 3 Footnote f

Supemtek™ (18 years and older)

Table 3 Return to footnote f referrer

Table 3 Footnote g

FluMist Quadrivalent (2–59 years)

Table 3 Return to footnote g referrer

Table 3 Footnote h

Evidence suggests moderate improvement in antibody response in infants, without an increase in reactogenicity, with the use of full vaccine doses (0.5 mL) for unadjuvanted inactivated influenza vaccinesFootnote 10Footnote 11. This moderate improvement in antibody response without an increase in reactogenicity is the basis for the full dose recommendation for unadjuvanted inactivated vaccine for all ages. For more information, refer to Statement on Seasonal Influenza Vaccine for 2011–2012.

Table 3 Return to footnote h referrer

Table 3 Footnote i

Children 6 months to less than 9 years of age receiving seasonal influenza vaccine for the first time in their life should be given 2 doses of influenza vaccine, with a minimum interval of 4 weeks between doses. Children 6 months to less than 9 years of age who have been properly vaccinated with one or more doses of seasonal influenza vaccine in the past should receive 1 dose of influenza vaccine per season thereafter.

Table 3 Return to footnote i referrer

Booster doses and revaccination

Booster doses are not required within the same influenza season. However, children 6 months to less than 9 years of age who have not previously received the seasonal influenza vaccine require 2 doses of influenza vaccine, with a minimum of 4 weeks between doses (see Table 3). Only one dose of influenza vaccine per season is recommended for everyone else. Two doses of seasonal influenza vaccine in older adults do not appear to improve the immune response to the vaccine compared to one doseFootnote 12.

Serological testing

Serologic testing is not necessary or recommended before or after receiving seasonal influenza vaccine.

Storage requirements

Influenza vaccine should be stored at +2°C to +8°C and should not be frozen. Refer to the individual product monographs for further details. Refer to Storage and Handling of Immunizing Agents in Part 1 of the CIG for additional information.

Concomitant administration with other vaccines

All seasonal influenza vaccines, including LAIV, may be given at the same time as, or at any time before or after administration of other vaccines (either live or inactivated), including COVID-19 vaccines for those aged 12 years and older as of September 2021. Refer to the CIG and latest NACI COVID-19 vaccine guidance for any additional emerging guidance on concomitant administration with COVID-19 vaccines as new products emerge or there are COVID-19 age eligibility expansions.

In theory, the administration of two live vaccines sequentially within less than 4 weeks could reduce the efficacy of the second vaccine. Studies have been done showing no interference when administering LAIV3 concomitantly with: measles, mumps, rubella (MMR); measles, mumps, rubella, varicella (MMRV); or live oral polio vaccinesFootnote 13Footnote 14Footnote 15. No studies have been done to assess the possibility of interference between LAIV and other live vaccines during concomitant administration, or on LAIV effectiveness given before or after other live vaccines. Additional information regarding simultaneous administration with other vaccines can be found in Section IV.5 of this statement.

Given the lack of data for immune interference, and based on expert opinion, NACI recommends that LAIV can be given together with or at any time before or after the administration of any other live attenuated or inactivated vaccine. However, some vaccine providers may continue to choose to give LAIV and other live vaccines separated by at least 4 weeks, based on the theoretical possibility of immune interference, although NACI does not believe that this precaution is necessary for LAIV. The use of an inactivated influenza vaccine would avoid this theoretical concern. Note that the timing rules related to two parenteral live vaccines (e.g., MMR and varicella vaccines) still apply. For more information regarding vaccination administration timing rules, please refer to Timing of Vaccine Administration in Part 1 of the CIG.

When more than one injection is given at a single clinic visit, it is preferable to administer them in different limbs. If it is not possible to do so, injections given in one limb should be separated by a distance of at least 2.5 cm (1 inch). A separate needle and syringe should be used for each injection.

The target groups for influenza and pneumococcal polysaccharide vaccines overlap considerably. Vaccine providers should take the opportunity to vaccinate eligible people against pneumococcal disease when influenza vaccine is given.

Concomitant administration with other adjuvanted vaccines

Data are limited regarding coadministration of adjuvanted vaccines with other adjuvanted or nonadjuvanted vaccines.

RZV is an example of a recombinant adjuvanted subunit herpes zoster vaccine (Shingrix, GlaxoSmithKline) that is authorized for use in Canada in adults 50 years of age and older; therefore, the target age group for herpes zoster vaccine and influenza vaccine overlap. RZV has been shown to be safe and effective when given concomitantly with unadjuvanted, standard dose influenza vaccinesFootnote 4. However, no studies have been conducted that have assessed the co-administration of RZV with adjuvanted or high dose influenza vaccineFootnote 16. It should be noted that RZV and IIV-adj currently authorized for use in Canada contain the adjuvants AS01B and MF59 respectively. How these adjuvants may interact when RZV and IIV-adj are administered concomitantly is not known and some providers may prefer to use non-adjuvanted influenza vaccine in this situation.

NACI will continue to review the evidence and update guidance accordingly.

II.7 Vaccine Safety and Adverse Events

Post-marketing surveillance of influenza vaccines in Canada has shown that seasonal influenza vaccines have a safe and stable profile. In addition to routine surveillance, every year during the seasonal influenza vaccination campaigns, PHAC and the Federal/Provincial/Territorial Vaccine Vigilance Working Group (VVWG) of the Canadian Immunization Committee conduct weekly expedited surveillance of adverse events following immunization (AEFI) for current influenza vaccines in order to identify vaccine safety signals in a timely manner. Refer to the Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) web page for more information on post-marketing surveillance and AEFIs in Canada. In addition, the Canadian National Vaccine Safety (CANVAS) Network, a national network of sites across Canada for active vaccine safety surveillance, collects and analyzes information on AEFIs after influenza vaccination to provide influenza vaccine safety information to public health authorities during the core weeks of the annual influenza vaccination campaign.

All influenza vaccines currently authorized for use in Canada are considered safe for use in people with latex allergies. The multi-dose vial formulations of inactivated influenza vaccine that are authorized for use in Canada contain minute quantities of thimerosal, which is used as a preservative Footnote 17Footnote 18 to keep the product sterile. Large cohort studies of administrative health databases have found no association between childhood vaccination with thimerosal-containing vaccines and neurodevelopmental outcomes, including autistic-spectrum disordersFootnote 19. All single dose formulations of IIV and LAIV are thimerosal-free. Refer to Vaccine Safety in Part 2 of the CIG for additional information.

Common adverse events

With IM administered influenza vaccines, injection site reactions are common but are generally classified as mild and transient. IIV3-Adj tends to produce more extensive injection site reactions than unadjuvanted IIV3, but these reactions are also generally mild and resolve spontaneously within a few days. IIV-HD tends to induce higher rates of systemic reactions compared to IIV-SD, but most of these reactions are mild and short-lived. Recombinant vaccines appear to have a similar safety profile to IIVs. The most common AEs experienced by recipients of LAIV3 are nasal congestion and runny nose, which are also reported for LAIV4. Refer to the relevant subsections of Section IV for additional information.

Less common and serious or severe adverse events

Serious adverse events (SAEs) are rare following influenza vaccination, and in most cases, data are insufficient to determine a causal association. Allergic responses to influenza vaccine are a rare consequence of hypersensitivity to some components of the vaccine or its container. Refer to Section IV.5 below for additional information.

Other reported adverse events and conditions

Guillain-Barré syndrome

Studies suggest that the absolute risk of Guillain-Barré syndrome (GBS) in the period following seasonal and A(H1N1)pdm09 influenza vaccination is about one excess case per million vaccinationsFootnote 20Footnote 21, and that the risk of GBS associated with influenza illness (about 17 cases per million influenza-coded health care encounters, which are a proxy for influenza illness) is higher than that associated with influenza vaccinationFootnote 21.

Although the evidence considering influenza vaccination and GBS is inadequate to accept or reject a causal relation between GBS in adults and seasonal influenza vaccination, avoiding subsequent influenza vaccination of individuals known to have had GBS without other known etiology within 6 weeks of a previous influenza vaccination appears prudent at this time. However, the potential risk of GBS recurrence associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination.

Oculorespiratory syndrome

Oculorespiratory syndrome (ORS), the presence of bilateral red eyes and one or more associated respiratory symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, or sore throat) that starts within 24 hours of vaccination, with or without facial oedema, was identified during the 2000–2001 influenza seasonFootnote 22. Since then, there have been far fewer cases per year reported to CAEFISSFootnote 23. ORS is not considered to be an allergic response. People who have an occurrence or recurrence of ORS upon vaccination do not necessarily experience further episodes with future vaccinations.

Individuals who have experienced ORS without lower respiratory tract symptoms may be safely revaccinated with influenza vaccine. Individuals who experienced ORS with lower respiratory tract symptoms should have an expert review. Health care providers who are unsure whether an individual previously experienced ORS versus an immunoglobulin E (IgE) mediated hypersensitivity immune response should seek advice. Data on clinically significant AEs do not support the preference of one vaccine product over another when revaccinating those who have previously experienced ORS.

Allergic reactions to previous vaccine doses

Expert review of the benefits and risks of vaccination should be sought for those who have previously experienced severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of influenza vaccination, an apparent significant allergic reaction to the vaccine, or any other symptoms that could indicate a significant allergic reaction (e.g., throat constriction, difficulty swallowing) that raise concern regarding the safety of revaccination. This advice may be obtained from experts in infectious disease, allergy, and immunology, or public health that can be found in various health settings, including the Special Immunization Clinic (SIC) network.

In view of the considerable morbidity and mortality associated with influenza and rarity of true vaccine allergy, a diagnosis of allergy to an influenza vaccine should not be made without confirmation, which may involve consultation with an allergy or immunology expert.

Drug interactions

Although influenza vaccine can inhibit the clearance of warfarin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in people receiving influenza vaccine. Statins have effects on the immune system in addition to their therapeutic cholesterol-lowering actions. Two published studies have found that adults who are regular statin users (at least 65 years of ageFootnote 24 in one study and 45 years and older in the otherFootnote 25 ) had an apparent decreased response to influenza vaccination as measured by reduced geometric mean titres (GMT)Footnote 24 or reduced VE against medically attended acute respiratory illnessFootnote 25. Statins are widely used in the same adult populations who are also at-risk for influenza-related complications and hospitalizations. Therefore, if these preliminary findings are confirmed in future studies, concomitant statin use in adult populations could have implications for influenza VE and how this use is assessed in the measurement of VE. NACI will continue to monitor the literature related to this issue.

Guidance on reporting adverse events following immunization

To ensure the ongoing safety of influenza vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical, and in most jurisdictions, reporting is mandatory under the law.

An AEFI is any untoward medical occurrence that follows vaccination and that does not necessarily have a causal relationship with the usage of a vaccine. The AEFI may be any unfavourable or unintended sign, abnormal laboratory finding, symptom, or disease. In general, any AEFI felt to be temporally related to vaccination and for which there is no other clear cause at the time of reporting should be reported. Of particular interest are those AEFIs which are considered serious or unexpected. A serious AEFI is an adverse event that is life threatening or results in death, requires hospitalization or prolongation of an existing hospitalization, results in residual disability or causes congenital malformationFootnote 26. An unexpected AEFI is an event that is not listed in the approved product monograph but may be due to the vaccination, or one whose nature, severity, specificity, or outcome is not consistent with the term or description used in the product monographFootnote 26. Vaccine providers are asked to report AEFIs through local public health officials and to check for specific AEFI reporting requirements in their province or territory. If there is any doubt as to whether or not an event should be reported, a conservative approach should be taken and the event should be reported.

For influenza vaccines, the following AEFIs are of particular interest:

Refer to Reporting Adverse Events Following Immunization (AEFI) in Canada for additional information about AEFI reporting and to Vaccine Safety in Part 2 of the CIG for general vaccine safety information.

II.8 Travellers

Influenza occurs year-round in the tropics. In temperate northern and southern countries, influenza activity generally peaks during the winter season (November to March in the Northern Hemisphere and April to October in the Southern Hemisphere).

Vaccines prepared specifically for use in the Southern Hemisphere are not available in Canada, and the extent to which recommended vaccine components for the Southern Hemisphere may overlap with those in available Canadian formulations will vary. A decision for or against revaccination (i.e., boosting) of travellers to the Southern Hemisphere between April and October, if they had already been vaccinated in the preceding fall or winter with the Northern Hemisphere's vaccine, depends on individual risk assessment, the similarity between the Northern and Southern Hemisphere vaccines, the similarity between the Northern Hemisphere vaccine strains and currently circulating strains in the Southern Hemisphere, and the availability of a reliable and safe vaccine at the traveller's destination. Refer to Immunization of Travellers in Part 3 of the CIG for additional general information.

This concludes the summary of relevant influenza vaccine information typically found in the Canadian Immunization Guide. Additional technical information related to seasonal influenza vaccine can be found in the remainder of this statement.

III. Particularly Recommended Vaccine Recipients: Additional Information

The groups for whom influenza vaccination is particularly recommended are presented in List 1 of Section II. Additional information regarding these particularly recommended recipients is provided below.

III.1 People at High Risk of Influenza-Related Complications or Hospitalization

All children 6–59 months of age

On the basis of existing data, NACI recommends the inclusion of all children 6–59 months of age among those for whom influenza vaccine is particularly recommended.

Refer to the Statement on Seasonal Influenza Vaccine for 2011–2012 for additional details on children 6–23 months of age and to the Statement on Seasonal Influenza Vaccine for 2012–2013 for children 24–59 months of age.

Adults and children with chronic health conditions

A number of chronic health conditions, as noted in List 1, are associated with increased risk of influenza-related complications, and influenza can lead to exacerbation of the chronic disease. Influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune compromising conditions, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV-infected people. Vaccine effectiveness may be lower in people with immune compromising conditions than in healthy adults.

Neurologic or neurodevelopment conditions

Neurologic or neurodevelopment conditions (NNCs) that pose increased risk for severe disease or complications from influenza include neuromuscular, neurovascular, neurodegenerative, neurodevelopment conditions, and seizure disorders (and, for children, include febrile seizures and isolated developmental delay), but exclude migraines and psychiatric conditions without neurological conditions. Based on reviews of evidence and expert opinion, NACI includes adults and children with NNCs among the groups for whom influenza vaccination is particularly recommended. Refer to the NACI Statement on Seasonal Influenza Vaccine for 2018–2019 for a summary of the rationale supporting this decision and the Literature Review on Individuals with Neurologic or Neurodevelopment Conditions and Risk of Serious Influenza-Related Complications for additional details of the evidence reviews.

All pregnant individuals

NACI recommends the inclusion of all pregnant individuals, at any stage of pregnancy, among those who are particularly recommended to receive IIV. This is due to the risk of influenza-associated morbidity amongst those who are pregnant,Footnote 27Footnote 28Footnote 29Footnote 30Footnote 31 evidence of adverse neonatal outcomes associated with respiratory hospitalization during pregnancy or influenza during pregnancyFootnote 32Footnote 33Footnote 34Footnote 35, evidence that vaccination of pregnant individuals protects their newborns from influenza and influenza-related hospitalizationFootnote 36Footnote 37Footnote 38Footnote 39 and evidence that infants born during influenza season to vaccinated individuals are less likely to be premature, small for gestational age, and of low birth weight than if born to individuals that had not received an influenza vaccineFootnote 40Footnote 41Footnote 42Footnote 43. The risk of influenza-related hospitalization increases with length of gestation (i.e., it is higher in the third trimester than in the second).

The safety of IIV during pregnancy has been reviewedFootnote 42. Active studies of influenza vaccination during pregnancy have not shown evidence of harm to the pregnant individual or fetus associated with influenza vaccinationFootnote 44. Although the cumulative sample size of active studies of influenza vaccination in pregnant individuals is relatively small, particularly in the first trimester, passive surveillance has not raised any safety concerns despite widespread use of IIV during pregnancy over several decadesFootnote 29Footnote 30Footnote 45Footnote 46. Surveillance following the use of both adjuvanted and unadjuvanted 2009 pandemic influenza A(H1N1) vaccines in more than 100,000 pregnant persons in Canada and more than 488,000 pregnant persons in EuropeFootnote 47 has not revealed any safety concerns.

Very limited peer-reviewed, published data pertaining to safety of vaccination with RIV4 during pregnancy is currently available to inform vaccine-associated risks. Refer to the Supplemental Statement on Recombinant Influenza Vaccines, which will be forthcoming, for more information.

Refer to the Statement on Seasonal Influenza Vaccine for 2011–2012 and the Statement on Seasonal Influenza Vaccine for 2012–2013 for further details on influenza vaccination during pregnancy.

People of any age who are residents of nursing homes and other chronic care facilities

Residents of nursing homes and other chronic care facilities often have one or more chronic health conditions and live in institutional environments that may facilitate the spread of influenza.

Adults 65 years of age and older

Hospitalization attributable to influenza in this age group is estimated at 125–228 per 100,000 healthy peopleFootnote 48, and influenza-attributed mortality rates increase with increased ageFootnote 49.

Indigenous peoples

Based on a body of evidence indicating a higher rate of influenza-associated hospitalization and death among Indigenous peoples, NACI recommends the inclusion of this population among those for whom the influenza vaccine is particularly recommended.

it has been proposed that the increased risk of severe influenza outcomes in the Indigenous populations is a consequence of many factors, including high prevalence of chronic health conditions (e.g., diabetes, chronic lung disease, end-stage kidney disease, cardiovascular disease, obesity)Footnote 50, delayed access to health care, and increased susceptibility to disease because of poor housing and overcrowdingFootnote 51Footnote 52Footnote 53. Refer to the Statement on Seasonal Influenza Vaccine for 2011–2012 for further details.

III.2 People Capable of Transmitting Influenza to Those at High Risk of Influenza-Related Complications or Hospitalization

People who are potentially capable of transmitting influenza to those at high risk should receive annual vaccination, regardless of whether the high-risk individual has been vaccinated. Vaccination of Health Care Workers (HCW) decreases their own risk of illnessFootnote 54Footnote 55, as well as the risk of death and other serious outcomes among the individuals for whom they provide careFootnote 56Footnote 57Footnote 58Footnote 59. Vaccination of HCWs and residents of nursing homes is associated with decreased risk of ILI outbreaksFootnote 60.

People who are more likely to transmit influenza to those at high risk of influenza-related complications or hospitalization include:

Health care workers and other care providers in facilities and community settings

Vaccination of health care workers and other care providers

For the purposes of this statement, HCWs and other care providers in facilities and community settings refers to HCWs, regular visitors, emergency response workers, those who work in continuing care or long-term care facilities or residences, those who provide home care for people at high risk, and students of related health care services. HCWs include any person, paid or unpaid, who provides services, works, volunteers, or trains in a hospital, clinic, or other health care facility.

Transmission of influenza to patients at high risk of influenza-associated complications results in significant morbidity and mortality. Four cluster randomized controlled trials (RCTs) conducted in geriatric long-term care settings have demonstrated that vaccination of HCWs is associated with substantial decreases in influenza-like illnessFootnote 57Footnote 58Footnote 59 and all-cause mortalityFootnote 56Footnote 57Footnote 58Footnote 59 in the residents. In addition, due to their occupation and close contact with people who may be infected with influenza, HCWs are themselves at increased risk of infectionFootnote 61.

As previously stated, children 0–59 months of age, adults and children with chronic health conditions, pregnant individuals, people of any age who are residents of nursing homes and other chronic care facilities, and adults 65 years of age and older are at greater risk of more severe complications from influenza or worsening of their underlying condition. Given the potential for HCWs and other care providers to transmit influenza to individuals at high risk and knowing that vaccination is the most effective way to prevent influenza, NACI recommends that, in the absence of contraindications, HCWs and other care providers in facilities and community settings should be vaccinated against influenza annually. NACI considers the receipt of influenza vaccination to be an essential component of the standard of care for all HCWs and other care providers for their own protection and that of their patients. This group should consider annual influenza vaccination as part of their responsibilities to provide the highest standard of care.

Although current influenza vaccine coverage for HCWs is higher than in the general publicFootnote 62Footnote 63, it remains below the national goal of 80% coverage for HCWs in CanadaFootnote 64. Comprehensive vaccination programs should be adopted that address HCWs' acceptance of the vaccine and facilitate the process of vaccinating HCWs to improve uptake of the influenza vaccine beyond the current level. HCW influenza vaccination programs that have successfully increased vaccine coverage of HCWs have included a combination of education, increased awareness, accessible on-site vaccination delivery options for all HCWs, visible support from senior staff and other leaders, and regular review and improvement of vaccination strategiesFootnote 65Footnote 66Footnote 67Footnote 68Footnote 69Footnote 70.

Outbreak management in health care facilities

As noted in PHAC's Guidance: Infection Prevention and Control Measures for Healthcare Workers in Acute Care and Long-term Care Settings for seasonal influenza, all health care organizations should have a written plan for managing an influenza outbreak in their facilities. Inherent in such plans should be policies and programs to optimize HCW's influenza vaccinationFootnote 71. As part of outbreak management, the above-mentioned PHAC guidance suggests consideration of chemoprophylaxis for all unvaccinated HCWs, unless contraindications exist. Refer to the Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada) website for guidelines regarding the use of antiviral medications for prophylaxis.

Contacts of individuals at high risk of influenza complications

Vaccination is recommended for contacts, both adults and children, of individuals at high risk of influenza-related complications or hospitalization (see List 1), whether or not the individual at high risk has been vaccinated. These contacts include: household contacts and care providers of individuals at high risk, household contacts and care providers of infants less than 6 months of age (as these infants are at high risk of complications from influenza but cannot receive influenza vaccine), members of a household expecting a newborn during the influenza season, household contacts and care providers (whether in or out of the home) of children 0–59 months of age, and providers of services within closed or relatively closed settings with people at high risk of influenza-related complications (e.g., crew on a ship).

III.3 Others

People who provide essential community services

Vaccination for these individuals should be encouraged to minimize the disruption of services and routine activities during annual influenza epidemics. People who provide essential community services, including healthy working adults, should consider annual influenza vaccination, as this intervention has been shown to decrease work absenteeism due to respiratory and related illnessesFootnote 54Footnote 55Footnote 72Footnote 73Footnote 74.

People in direct contact with poultry infected with avian influenza during culling operations

Poultry workers

Although seasonal influenza vaccination will not prevent avian influenza infection, some countriesFootnote 75and provinces have recommended influenza vaccination on a yearly basis for poultry workers, based on the rationale that preventing infection with human influenza strains may reduce the theoretical potential for human-avian reassortment of genes, should such workers become co-infected with human and avian influenza virusesFootnote 76.

NACI recommends seasonal influenza vaccination for people who may be in direct contact with poultry infected with avian influenza during culling operations, as these individuals may be at increased risk of avian influenza infection because of exposure during the culling operationFootnote 77Footnote 78Footnote 79Footnote 80. Refer to the Statement on Seasonal Influenza Vaccine for 2013–2014 for further information supporting this recommendation.

Direct contact may be defined as sufficient contact with infected poultry to allow transmission of an avian virus to the exposed person. The relevant individuals include those performing the cull, as well as others who may be directly exposed to the avian virus, such as supervising veterinarians and inspectors. It is recommended that biosecurity measures such as personal protective equipment and antivirals be used. Refer to Human Health Issues Related to Avian Influenza in Canada for PHAC recommendations on the management of domestic avian influenza outbreaks.

Swine workers

NACI has concluded that there is insufficient evidence at this time to recommend routine influenza vaccination specifically for swine workers; however, NACI recommends that influenza vaccination should be offered to anyone 6 months of age and older who does not have contraindications to the vaccine.

Refer to the Statement on Seasonal Influenza Vaccine for 2013–2014 for further information supporting this recommendation.

IV. Vaccine Preparations Authorized for Use in Canada: Additional Information

The following sections describe information on the efficacy and effectiveness, immunogenicity, and safety of influenza vaccines that are authorized for use in Canada by type: IIV, RIV and LAIV. Refer to Appendix A for a summary of the characteristics of specific influenza vaccine products available in Canada for the 2022–2023 season.

NACI acknowledges that evidence related to influenza vaccine performance, particularly with respect to vaccine efficacy and effectiveness, is constantly evolving with advances in research methodology and accumulation of data over many influenza seasons. Therefore, the evidence summarized in this section may not include the latest studies. However, in accordance with usual practice, NACI continues to closely monitor the emerging evidence on the efficacy and effectiveness, immunogenicity, and safety of influenza vaccines to update and to make recommendations when warranted.

IV.1 Inactivated Influenza Vaccine (IIV)

IIVs contain standardized amounts of the HA protein from representative seed strains of the two human influenza A subtypes (H3N2 and H1N1) and either one (for trivalent vaccines) or both (for quadrivalent vaccines) of the two influenza B lineages (Yamagata or Victoria). IIVs currently authorized for use in Canada are a mix of split virus and subunit vaccines, both consisting of disrupted virus particles. Split virus vaccines contain whole inactivated viruses split with detergent, ether, or both, while subunit vaccines are made of purified HA and NA. The amount of NA in the vaccines is not standardized. HA-based serum antibody produced to one influenza A subtype is anticipated to provide little or no protection against strains belonging to the other subtype. The potential for trivalent vaccine to stimulate antibody protection across B lineages requires further evaluation and may be dependent upon factors such as age and prior antigenic experience with the two B lineagesFootnote 81Footnote 82Footnote 83Footnote 84Footnote 85Footnote 86.

Because of potential changes in the circulating influenza virus from year to year and waning immunity in vaccine recipients, annual influenza vaccination is recommended. Although NACI is aware of some recent studies that suggest that vaccine induced protection may be greater in individuals who have no recent vaccine history, optimal protection against influenza, season after season, is best achieved through annual influenza vaccinationFootnote 87Footnote 88. NACI will continue to monitor this issue.

Immunological considerations related to children

Young children have a high burden of illness and their vaccine-induced immune response is not as robust as older children. However, some studies suggest moderate improvement in antibody response in young children, without an increase in reactogenicity, with the use of a full vaccine dose (0.5 mL) for IIV-SDsFootnote 10Footnote 11Footnote 89. On the basis of this moderate improvement in antibody response without an increase in reactogenicity, NACI recommends the use of a 0.5 mL dose for all recipients of IIV-SDs, including young children.

Immunological considerations related to older adults and those with immune compromising conditions

Although the initial antibody response in older adults may be lower to some influenza vaccine components when compared to those in other age groups, a literature review identified no evidence for a subsequent antibody decline that was any more rapid in older adults than in younger age groupsFootnote 90.

Influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune compromising conditions, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV-infected patientsFootnote 91Footnote 92Footnote 93Footnote 94.

Most studies have shown that administration of a second dose of influenza vaccine in the same season to older adults or other individuals who may have an altered immune response does not result in a clinically significant antibody boostFootnote 13Footnote 95Footnote 96Footnote 97.

Standard-dose, egg-based, trivalent inactivated influenza vaccine (IIV3-SD)

Vaccines currently authorized for use:

*Vaccine is not currently available in Canada.

Efficacy and effectiveness

The NACI Literature Review on Influenza Vaccination in Healthy 5–18 Year Olds found that vaccine efficacy or vaccine effectiveness (VE) of IIV3-SD against laboratory-confirmed influenza was variable but was most frequently between 65–85%Footnote 98Footnote 99Footnote 100Footnote 101Footnote 102Footnote 103Footnote 104Footnote 105Footnote 106Footnote 107Footnote 108Footnote 109Footnote 110Footnote 111Footnote 112Footnote 113Footnote 114Footnote 115Footnote 116. In the NACI literature review on Influenza Vaccine Effectiveness, Immunogenicity, and Safety in Healthy Adults 19–64 Years Old, efficacy against laboratory-confirmed influenza for IIV3-SD in healthy adults 18–64 years of age ranged widely from as low as 15% to as high as 75%, with the majority of studies estimating efficacy at 50–60%. Refer to the Statement on Seasonal Influenza Vaccine for 2018–2019 for a more detailed summary of efficacy and effectiveness evidence for IIV3-SD in healthy children 5–18 years of age and healthy adults 19–64 years of age.

In older adults, VE of IIV3-SD is about half of that in healthy adults and varies depending on the outcomes measured and the study populationFootnote 117Footnote 118. Systematic reviews have demonstrated that influenza vaccine decreases the incidence of pneumonia, hospital admissions, and deaths in older adultsFootnote 117 and reduces exacerbations in people with chronic obstructive pulmonary diseaseFootnote 119. The NACI Literature Review on the Comparative Effectiveness and Immunogenicity of Subunit and Split Virus Inactivated Influenza Vaccines in Adults 65 Years of Age and Older found no statistically significant differences in VE of subunit IIV3-SD compared with split virus IIV3-SD in adults 65 years of age and older against infection with any influenza virus strain, or against infection with influenza A(H1N1), A(H3N2), or B virus specifically.

In observational studies, influenza vaccination has been shown to reduce the number of physician visits, hospitalizations, and deaths in adults 18–64 years of age with high-risk medical conditionsFootnote 120, hospitalizations for cardiac disease and stroke in adults 65 years of age and olderFootnote 121, and hospitalization and deaths in adults 18 years of age and older with diabetes mellitusFootnote 122 during influenza epidemics. Observational studies that use non-specific clinical outcomes or that do not take into account differences in functional status or health-related behaviours should be interpreted with cautionFootnote 123Footnote 124Footnote 125Footnote 126Footnote 127.

Immunogenicity

Both humoral and cell-mediated immune responses are thought to play a role in immunity to influenza. While humoral immunity is thought to play a primary role in protection against infection, cell-mediated immunity, notably cytotoxic T lymphocyte responses to internal viral components, is increasingly invoked as important in protecting against severe outcomes of influenza, particularly those associated with subtype HA variations (shift and drift)Footnote 128. The IM administration of IIV3-SD results in the production of circulating immunoglobulin G (IgG) antibodies to the viral HA and NA proteins, as well as a more limited cytotoxic T lymphocyte response.

Safety

Studies evaluating the safety of IIV3-SDs in healthy children have found a good safety profile with no SAE of noteFootnote 129. The most common solicited local reactions are pain and redness at the injection site, while the most common solicited systemic reactions are irritability, malaise, and headache. Mild injection site reactions, primarily soreness at the vaccination site, have been found to occur in 7% or less of healthy children who are less than 3 years of ageFootnote 130Footnote 131Footnote 132. Post-vaccination fever may be observed in 12% or less of vaccinated children 1–5 years of ageFootnote 103Footnote 132.

For adults, IIV3-SDs have been demonstrated to have a good safety profile with acceptable reactogenicityFootnote 129. Common local reactions at injection site include redness, swelling, pain, and induration. These reactions last 2–3 days and rarely interfere with normal activities. Common systemic reactions include headache, malaise, myalgia, fatigue, arthralgia, and fever.

Standard-dose, egg-based, quadrivalent inactivated influenza vaccine (IIV4-SD)

Vaccines currently authorized for use:

Efficacy and effectiveness

In the NACI Literature Review on Quadrivalent Influenza Vaccines, only one study was identified that measured IIV4-SD efficacy. In that study, efficacy was estimated at 59% in children 3–8 years of age, in comparison to children who received hepatitis A vaccineFootnote 133. No literature was found in this review on efficacy or effectiveness directly comparing trivalent and quadrivalent formulations.

Immunogenicity

In the same review of the literature noted above, NACI reviewed the immunogenicity data for IIV4-SD produced by manufacturers who supplied influenza vaccine in Canada at the time of the literature review: AstraZeneca, GlaxoSmithKline, and Sanofi Pasteur. The results of phase II and III trials that compared trivalent formulations to quadrivalent formulations generally showed non-inferiority of the quadrivalent products for the A(H3N2), A(H1N1), and B strain contained in the trivalent formulations. As expected, these studies showed that the immune response to the B strain that was not in the trivalent formulation was better in subjects who received the quadrivalent vaccine, which contained the additional B strain. These findings were consistent across age groups. Refer to the Literature Review on Quadrivalent Influenza Vaccines for additional details.

In the phase III trials, recipients of the trivalent formulations showed, to a lesser degree, some immune response to the B strain not contained in the trivalent formulation. In one study of adults, both the trivalent and quadrivalent vaccines met all the European Medicines Agency Committee for Medicinal Products for Human Use and the United States Food and Drug Administration criteria for evaluation of influenza vaccine immunogenicity, including for the B strain not in the trivalent vaccine.

In all other studies, the trivalent vaccine failed at least one of the criteria for seroprotection or seroconversion for the missing B strain. It has been hypothesized that there is some level of cross-reactivity between B strains. The degree of cross protection against infection with one lineage provided by immunization against the other lineage is uncertainFootnote 134.

Safety

Pre-licensure clinical trials (refer to Literature Review on Quadrivalent Influenza Vaccines) and post-marketing surveillance showed that IIV4-SD had a similar safety profile to IIV3-SDFootnote 135.

Standard dose mammalian cell culture-based quadrivalent inactivated influenza vaccine (IIV-cc)

Vaccine currently authorized for use:

Methods

NACI reviewed the Health Canada assessment of a Phase 3/4 randomized clinical trial of Flucelvax Quad efficacy, immunogenicity and safety in children 2 years to less than18 years of age submitted by the manufacturer in support of an age extension for the use of the vaccine to adults and children 2 years of age and older. The clinical trial was conducted in 8 countries in Europe and South East Asia over three influenza seasons (Southern Hemisphere 2017 influenza season and the 2017–2018 and 2018–2019 Northern Hemisphere influenza seasons). Overall, the quality of the evidence was considered good.

In support of the original recommendation for use of the Flucelvax Quad in adults and children 9 years of age and older, NACI conducted a systematic review of the literature to examine vaccine efficacy, effectiveness, immunogenicity, and safety data for this age group.

Efficacy and effectiveness

Four observational studies, two peer-reviewed and two not peer-reviewed (conference abstracts and posters) were identified through the systematic review, which assessed the VE of IIV4-cc compared to egg-based IIV against laboratory-confirmed influenza infection during the 2017–2018 influenza season in the United StatesFootnote 136Footnote 137Footnote 138Footnote 139.Of these four studies, two were of good qualityFootnote 137138, while the quality of the other two studiesFootnote 136Footnote 139 could not be assessed because they were published as conference abstracts or posters. IIV4-cc may be more effective than egg-based IIV3 and IIV4 influenza vaccines against non-laboratory confirmed influenza-related outcomes, including influenza-related health care interactions and ILI. Although some data suggests that IIV4-cc may be more effective against laboratory-confirmed influenza A(H3N2) virus infection than egg-based IIV, there was no consistent and statistically significant difference in effectiveness identified for adults or children vaccinated with IIV4-cc compared to egg-based IIV. Evidence for the efficacy of IIV4-cc is based on the efficacy studies for the trivalent formulation, IIV3-cc.

Refer to the NACI Supplemental Statement on Mammalian Cell Culture-Based Influenza Vaccines for further details.

The Phase 3/4 RCT of Flucelvax Quad for children 2 years to 18 years met the pre-defined success criterion for efficacy against PCR- or culture-confirmed influenza due to any strain starting 14 days after the last dose in these children. The overall estimate of vaccine efficacy did not differ significantly when analyzed by subgroup (e.g., age, sex, race, influenza vaccination history, influenza season). When analyzed by influenza subtype/lineage in children 2 years to less than 18 years of age, the vaccine was found to be more efficacious against influenza A/H1N1 than against either A/H3N2 or influenza B during the three influenza seasons. Estimates of efficacy by influenza subtype/lineage in children 2 years to less than 4 years of age and children 2 years to less than 9 years of age were comparable to the estimates in children 2 years to less than 18 years of age, although with wider confidence intervals around the point estimates (which included zero for estimates of efficacy against influenza A/H3N2).

Immunogenicity

The immunogenicity for IIV4-cc is supported by evidence from the clinical development program for the IIV3-cc (authorization never sought in Canada), which has been licensed in the US and Europe and is produced using the same Madin-Darby Canine Kidney (MDCK) manufacturing platformFootnote 140Footnote 141Footnote 142Footnote 143. IIV3-cc has demonstrated non-inferiority to standard egg-based IIV3 comparators, for hemagglutinin inhibition antibody responses to A(H3N2), A(H1N1) and B strains in adults 18 years of age and older, and for A(H1N1) and B strains specifically, but not A(H3N2), in children, based on post-vaccination GMT ratios and seroconversion ratesFootnote 144Footnote 145Footnote 146Footnote 147. There is fair evidence that IIV4-cc has non-inferior immunogenicity to other inactivated influenza vaccines, based on direct and indirect evidence in adults and children 9 years of age and older.

Two studiesFootnote 148Footnote 149 that assessed the immunogenicity of IIV4-cc compared to different IIV3-cc formulations (produced by Seqirus using the same MDCK cell culture-based manufacturing process) were identified in this review; one study was conducted with adult participants18 years of age and older, while the other study focused on pediatric participants. In both studies, Flucelvax Quad demonstrated non-inferiority, based on geometric mean titre rise and seroconversion rates, and met the threshold for seroprotection for all influenza strains contained in the IIV3-cc vaccines, including superior immunogenicity for the B strain not contained in IIV3-cc.

In support of the use of the vaccine in adults and children 2 years of age and older, immunogenicity was assessed in a subset of the phase 3/4 RCT study participants 2 years to less than 9 years of age during the Northern Hemisphere influenza seasons (2017–2018 and 2018–2019), based on blood samples collected on the day of vaccination and 21 days after receipt of the last dose of vaccine. Participants experienced a substantial increase in antibody titres in response to vaccination, based on GMT ratios, seroconversion rates and seroprotection rates. The responses were generally highest against influenza A/H1N1 than for the other influenza subtypes/lineages. However, the immunogenicity results for influenza A/H3N2 were affected by differing hemagglutination abilities of the circulating strains and differences in the hemagglutination inhibition assays used in the two influenza seasons.

Safety

There is fair evidence that IIV4-cc is a safe and well-tolerated alternative to conventional egg-based influenza vaccines for children and adults. Two peer-reviewed randomized controlled trials assessed the safety of IIV4-cc; with one focused on healthy adultsFootnote 148 and the other on healthy childrenFootnote 149. Most systemic reactions were mild and resolved within 3 days. SAEs were rare and similar in frequency between cell culture-based and conventional egg-based influenza vaccines. Studies that assessed the safety of Flucelvax were considered to supplement the evidence base for safety. Overall, local and systemic solicited reactions as well as unsolicited AEs and SAE are comparable to those typically observed with other injectable egg-derived IIV3s. The evidence on safety was consistent across studies and showed that there was no significant difference in adults and children compared to comparator vaccines. Flucelvax, also has an established record of safety in other jurisdictions, and no new safety signals have been identified through routine pharmacovigilance in the US or Europe where the vaccine is licensedFootnote 144Footnote 145Footnote 150. The vaccine is safe to use during pregnancy, as no safety signals have been detected in this population. IIV4-cc is made using MDCK cells, which are developed from a canine source. An allergy to dogs is not considered a contraindication to the vaccine, based on a review of two in vitro allergenicity studiesFootnote 151Footnote 152.

The analysis of vaccine safety in a clinical trial in children 2 years to less than 18 years of age were consistent with the findings of the previous NACI systematic literature review summarized above. The majority of solicited (local and systemic) and unsolicited adverse events were mild to moderate in severity and resolved spontaneously within 1 to 3 days post-vaccination, with no significant differences in rates between the Flucelvax Quad and comparator vaccine recipients. There were low (less than or equal to 1.3%) and comparable proportions of serious adverse events identified in Flucelvax Quad and comparator vaccine recipients, with no serious adverse events determined to be related to receipt of the assigned vaccine.

Adjuvanted inactivated influenza vaccine (IIV-Adj)

Vaccines currently authorized for use:

Fluad (adults 65 years of age and older)

Efficacy and effectiveness

There is fair evidence that the MF59-adjuvanted Fluad (IIV3-Adj) may be effective at reducing the risk of hospitalization for influenza and influenza complications in older adults compared to unvaccinated individuals. However, there is insufficient evidence that IIV3-Adj is more effective at reducing the risk of hospitalization for influenza and influenza complications in older adults compared to those who received unadjuvanted subunit IIV3-SD. Refer to the NACI Literature Review Update on the Efficacy and Effectiveness of High-Dose and MF59-Adjuvanted Trivalent Inactivated Influenza Vaccines in Adults 65 Years of Age and Older for more information on the efficacy and effectiveness of IIV3-Adj in adults 65 years of age and older.

Immunogenicity

The mechanism of action of MF59 is not fully determined and has primarily been studied using in vitro and mouse models. From these studies, it appears that MF59 may act differently from aluminum-based adjuvants. These studies show that MF59 acts in the muscle fibres to create a local immune-stimulatory environment at the injection siteFootnote 153. MF59 allows for an increased influx of phagocytes (e.g., macrophages, monocytes) to the site of injection. The recruited phagocytes are further stimulated by MF59, thereby increasing the production of chemokines to attract more innate immune cells and inducing differentiation of monocytes into dendritic cellsFootnote 154Footnote 155. MF59 further facilitates the internalization of antigen by these dendritic cellsFootnote 154Footnote 156. The overall higher number of cells available locally increases the likelihood of interaction between an antigen presenting cell and the antigen, leading to more efficient transport of antigen to the lymph nodes, with resulting improved T cell primingFootnote 154.

There is evidence from RCTs that IIV3-Adj elicits non-inferior immune responses compared to the unadjuvanted subunit and split virus IIV3-SDs; however, superiority of IIV3-Adj to these vaccines by pre-defined criteria has not been consistently demonstrated. Refer to the Statement on Seasonal Influenza Vaccine for 2018–2019 for more information on the immunogenicity of IIV3-Adj in adults 65 years of age and older.

Safety

IIV3-Adj produces injection site reactions (pain, erythema, and induration) significantly more frequently than IIV3-SD, but they are classified as mild and transient. Systemic reactions (myalgia, headache, fatigue, and malaise) are comparable or more frequent with IIV3-Adj compared to IIV3-SD and are rated as mild to moderate and transient. SAEs were uncommon and were comparable to IIV3-SD. Refer to the Recommendations on the use of MF59-Adjuvanted Trivalent Influenza Vaccine (Fluad): Supplemental Statement of Seasonal Influenza Vaccine for 2011–2012 for additional information on the safety of IIV3-Adj in adults 65 years of age and older.

Fluad Pediatric (children 6–23 months of age)

Efficacy and effectiveness

A pre-licensure efficacy trial in children 6–71 months of age found a higher relative efficacy for IIV-Adj than the unadjuvanted IIV3-SDFootnote 157. However, the findings of this study should be interpreted with caution. The comparator unadjuvanted IIV3 used in this trial was shown, in an unrelated study, to induce a lower immune response compared to another unadjuvanted IIV3-SD. There were concerns raised by a European Medicines Agency inspection about the quality of diagnostic laboratory testing and validity of ascertainment of influenza cases. The study administered 0.25 mL doses of the comparator unadjuvanted IIV3-SD for children less than 36 months of age, which is lower than the dose of 0.5 mL of unadjuvanted IIV3-SD or IIV4-SD that is recommended for this age group in Canada. Refer to the NACI Literature Review on Pediatric Fluad Influenza Vaccine Use in Children 6–72 Months of Age for more information on the efficacy and effectiveness of IIV3-Adj in children.

Immunogenicity

In children, there is limited but consistent evidence that IIV3-Adj is more immunogenic than IIV3-SD against both influenza A and BFootnote 157Footnote 158Footnote 159Footnote 160Footnote 161Footnote 162. In particular, a single dose of IIV3-Adj is more immunogenic than a single dose of IIV3-SD, and has been shown in one study to produce greater GMTs than 2 doses of IIV3-SD against influenza AFootnote 162. However, similar to IIV3-SD, IIV3-Adj generally induced a weaker hemagglutination-inhibition antibody response against B strains compared to A strains and therefore 2 doses of IIV3-Adj are still necessary for first-time recipients to achieve a satisfactory immune response against influenza B.

Almost all of the pre-licensure pediatric studies used vaccine formulations of 0.25 mL in children 6–35 months of age, both for IIV3-Adj and the comparator unadjuvanted influenza vaccine (NACI recommends 0.5 mL dosage of IIV3-SD or IIV4-SD for all age groups). There is limited immunogenicity evidence comparing IIV3-Adj at 0.25 mL dose to IIV3-SD or IIV4-SD at 0.5 mL dose in the 6–23 month age group. Refer to the NACI Literature Review on Pediatric Fluad Influenza Vaccine Use in Children 6–72 Months of Age for more information on the immunogenicity of IIV3-Adj in children.

Safety

The safety data in children are consistent with what is known about IIV3-Adj’s safety profile in adults. In pediatric trials, IIV3-Adj was more reactogenic than IIV3-SD, with recipients experiencing 10–15% more solicited local and systemic reactions. However, most reactions were mild and resolved quickly. A dose-ranging study of MF59-adjuvanted and unadjuvanted IIV3 and IIV4 did not find an increased risk of AEs associated with increased MF59 dose, antigen dose, or the addition of a second B strain; however, the reactogenicity of 15 µg formulations were slightly higher for both adjuvanted and unadjuvanted vaccines compared to the corresponding 7.5 µg formulationsFootnote 160.

There are currently no data on the effects of long-term or repeated administration of adjuvanted influenza vaccines in children. The most significant experience with an adjuvanted influenza vaccine in children was the AS03-adjuvanted A(H1N1) pandemic vaccine that has been associated with an increased risk of narcolepsy. A study comparing two AS03-adjuvanted A(H1N1) vaccine products (Pandemrix and Arepanrix) has suggested that the underlying immune mediated mechanism associated with the increased narcolepsy risk may not be initiated by the adjuvant, but by the A(H1N1) nucleoprotein viral antigen, given that the study found significant antigenic differences between the two A(H1N1) pandemic vaccinesFootnote 163. However, the pandemic vaccine was a single strain adjuvanted vaccine administered only during one season, and it is unknown what effects a multi-strain adjuvanted vaccine or an adjuvanted vaccine administered for more than one season may have in young children.

Refer to the NACI Literature Review on Pediatric Fluad Influenza Vaccine Use in Children 6-72 Months of Age for additional information on the safety of IIV3-Adj in children.

High-dose inactivated influenza vaccine (IIV-HD)

Vaccines currently authorized for use:

Efficacy and effectiveness

There is good evidence that Fluzone High-Dose (IIV3-HD) provides better protection compared with IIV3-SD in adults 65 years of age and older. Two studies found that IIV3-HD may provide greater benefit in adults 75 years of age and older compared to adults 65–74 years of ageFootnote 164Footnote 165. The efficacy results for IIV3-HD are inferred to IIV4-HD based on the non-inferior immunogenicity, described in the next section.

Refer to the NACI Literature Review Update on the Efficacy and Effectiveness of High-Dose and MF59-Adjuvanted Trivalent Inactivated Influenza Vaccines in Adults 65 Years of Age and Older for more information on the efficacy and effectiveness of IIV3-HD in adults 65 years of age and older.

Immunogenicity

Five studies compared the rates of seroconversion for study participants receiving IIV3-HD and IIV3-SD among those 65 years of age and olderFootnote 166Footnote 167Footnote 168Footnote 169Footnote 170Footnote 171. Rates of seroconversion were found to be about 19% higher (ranging from 8–39% higher) for those receiving the higher dose vaccine across all three vaccine strains. Similarly, rates of seroconversion were higher for those receiving the high- compared to standard-dose vaccines for participants 75 years of age and older and for a cohort of participants with underlying cardiopulmonary disease.

Eight studies reported higher rates of seroprotection for older adults receiving IIV3-HD compared to those vaccinated with IIV3-SDFootnote 166Footnote 167Footnote 168Footnote 169Footnote 170Footnote 171Footnote 172Footnote 173. Seroprotection was significantly higher for all 3 strains in the vaccine in three of five studies assessing significance. There were different results in the remaining studies. In the study by Couch et al., seroprotection was higher only against A(H1N1), possibly attributed to the fact that 78% of participants were vaccinated against the same influenza strains within 6 months prior to the studyFootnote 167. In Nace et al., seroprotection was higher against A(H3N2) and B but not A(H1N1); the lack of higher seroprotection against A(H1N1) may be attributed to strain circulation during the study that made it difficult to assess seroprotection against this subtypeFootnote 152.

GMT ratios (GMTR) of participants’ responses to high- versus standard-dose influenza vaccines were reported in several studies and were calculated for those that provided group-specific, post-vaccination titres for each of the vaccinesFootnote 166Footnote 167Footnote 168Footnote 169Footnote 170Footnote 172Footnote 173. Seroresponse to the B strains in the vaccines was about 1.5 times greater (1.3–1.7) in the IIV3-HD recipients than the IIV3-SD recipients. The GMTR of the A strains was about 1.8 times higher for those receiving IIV3-HD compared to IIV3-SD, ranging from 1.6–2.3.

There is good evidence that the immunogenicity for Fluzone High Dose Quadrivalent (IIV4-HD) is non-inferior to IIV3-HDFootnote 174Footnote 175. In a pivotal RCT, IIV4-HD met all non-inferiority criteria set by the US Food and Drug Administration, based on GMTR and seroconversion rates when compared to IIV3-HDFootnote 175. Immunogenicity for IIV4-HD was superior for the influenza B strain not contained within the trivalent high dose vaccineFootnote 175.

Safety

IIV3-HD has been observed to produce a higher rate of some systemic and local reactions than IIV3-SD. Studies have reported higher rates of malaise, myalgia, and moderate to severe fever. Most systemic reactions were mild and resolved within 3 days. SAEs were rare and similar in frequency between standard-dose and high-dose vaccines. When comparing the two high dose vaccine products, IIV4-HD has been shown to produce a comparable rate of systemic and local reactions compared to IIV3-HD. A comparable proportion of study participants also experienced unsolicited and serious AEsFootnote 175.

Refer to NACI’s A Review of the Literature of High Dose Seasonal Influenza Vaccine for Adults 65 Years and Older for details on IIV3-HD.

IV.2 Recombinant quadrivalent influenza vaccine (RIV4)

Vaccines currently authorized for use:

Methods

For the review of evidence relating to RIV, NACI used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework to organize the information and develop recommendations for RIV. Further information on this framework can be found in the GRADE handbook.

Efficacy and effectiveness

One RCT was identified that assessed the relative vaccine efficacy (rVE) of RIV4 compared to egg-based IIV4 against laboratory confirmed influenza infection in adults 50 years of age and older during the 2014-2015 influenza season in the United StatesFootnote 176. The certainty of evidence for this outcome was rated as low and suggested that RIV4 may be more effective than egg-based IIV4 influenza vaccines against laboratory-confirmed influenza A virus infection, but not laboratory-confirmed influenza B virus infection in older adults.

Overall, there is fair evidence (of low certainty) that the efficacy of RIV4 is non-inferior to traditional egg-based comparators, based on data in adults aged 50 years and older. ​

Refer to the NACI Supplemental Statement on Recombinant Influenza Vaccines, which will be forthcoming, for further details.

Immunogenicity

Eight RCTsFootnote 176Footnote 177Footnote 178Footnote 179Footnote 180Footnote 181Footnote 182Footnote 183 were identified that assessed the immunogenicity of RIV4. Of these studies, two were conducted during the 2014-2015 influenza seasonFootnote 176Footnote 179, three were conducted over the 2017-2018 influenza seasonFootnote 177Footnote 181Footnote 182, and three were conducted over the 2018-2019 influenza seasonFootnote 178Footnote 180Footnote 183. The RCTs were of good quality overall. Non-inferiority was assessed using the criteria specified by the US FDAFootnote 139.

The eight RCTs compared rates of seroconversion for RIV4 recipients with IIV3-HD, IIV3-Adj, IIV4-SD, and IIV4-cc recipients aged 18 years of age or older. In fourFootnote 177Footnote 178Footnote 181Footnote 183 of the eight studies, rates of seroconversion were similar in those receiving RIV4 compared to those receiving IIV3-HD, IIV3-Adj, IIV4-SD, and IIV4-cc against influenza A/H1N1, A/H3N2, B/Yamagata lineage and B/Victoria lineage. There were different results in the remaining studies. The two studies by Dunkle et al.Footnote 176Footnote 179 demonstrated that, compared to IIV4-SD, RIV4 did not meet the non-inferiority threshold in HI antibody responses against B/Victoria lineage in adults 18 to 64 years of age. Additionally, rates of seroconversion following RIV4 did not meet the non-inferiority threshold compared to IIV4-SD against influenza A/H1N1 in adults 64 and olderFootnote 176. Non-inferiority could not be assessed for the remaining two RCTsFootnote 180Footnote 182 as these studies did not state confidence intervals for seroconversion estimates. Pooled seroconversion data from threeFootnote 176Footnote 178Footnote 181 of the eight RCTs identified in adult participants 50 years of age and older using a random-effects model revealed that RIV4 induced similar antibody responses compared to IIV4-SD, IIV3-HD, and IIV3-Adj.

Four RCTs reported comparable or greater rates of seroprotection for study participants receiving RIV4 compared to those receiving IIV3-HD, IIV3-Adj, IIV4-SD, and IIV4-cc among adults 18 years of age and olderFootnote 176Footnote 177Footnote 178Footnote 183. The four studies had varying findings. In two of the four studies, RIV4 met the non-inferiority criteria specified by the US FDA for all tested influenza strains including A/H1N1, A/H3N2, B/Yamagata lineage, and B/Victoria lineageFootnote 178Footnote 183. Across the four RCTs, RIV4 met non-inferiority criteria against five of seven tested strains of A/H3N2. In the study by Belongia et al.Footnote 177, RIV4 demonstrated lower rates of seroprotection for older adults 65 to 74 years of age against two of four tested strains of A/H3N2. However, one limitation was the small sample size of the study. In the study by Dunkle et al. (2017a)Footnote 176, RIV4 met the non-inferiority threshold for seroprotection against influenza A/H1N1, A/H3N2, and B/Yamagata lineage, but not against influenza B/Victoria lineage in adults aged 50 and older.

GMTR of participants’ responses to RIV4 versus IIV4-SD were reported in three RCTsFootnote 176Footnote 179Footnote 183Footnote 184. In one study, RIV4 met the non-inferiority criteria specified by the US FDA for all tested A/H1N1, A/H3N2, B/Yamagata lineage, and B/Victoria lineage influenza strainsFootnote 183. In two of the three studies, seroresponses to A/H1N1, A/H3N2, and B/Yamagata lineage in RIV4 recipients were comparable to seroresponses in IIV4-SD recipients based on the GMTRFootnote 176Footnote 179Footnote 184. However, the GMTR against B/Victoria lineage for IIV4-SD recipients compared to RIV4 recipients did not meet the non-inferiority criteria set by the US FDAFootnote 139.

Overall, there is fair evidence (of moderate certainty) that the immunogenicity for RIV4 is non-inferior to traditional egg-based comparators, based on data in adults aged 18 years and older.

Safety

Six studiesFootnote 176Footnote 178Footnote 179Footnote 181Footnote 185Footnote 186 were identified that assessed the safety of RIV4 in adults, including five RCTs and one review of post-marketing surveillance data from the United States. Of these studies, two were conducted during the 2014-2015 influenza seasonFootnote 176Footnote 179, two were conducted during the 2017-2018 influenza seasonFootnote 181Footnote 186, one was conducted during the 2018-2019 influenza seasonFootnote 178, and one study reported data from the Vaccine Adverse Event Reporting System (VAERS) from July 1, 2017 through June 30, 2020Footnote 185. Most systemic reactions reported by the clinical trials were mild to moderate in severity and were transient in nature. Adverse events were similar in frequency between recombinant and conventional egg-based influenza vaccines. Although serious AEs were reported across clinical trials, none were considered by the authors to be related to the trial vaccines. RIV4 also has an established record of safety in other jurisdictions, and no safety signals have been identified through routine pharmacovigilance in the US, where the vaccine is licensedFootnote 185. Most AE reported to VAERS following RIV4 administration were non-serious. When data from two RCTsFootnote 176Footnote 178 conducted among adult participants 50 years of age and older were combined and weighted using a random-effects model, there was no difference in the odds of experiencing a SAE following administration of RIV4 and traditional egg-based IIV3-HD and IIV4-SD vaccine comparators. No published clinical data pertaining to safety of vaccination with RIV4 during pregnancy is currently available to inform vaccine-associated risks.

Overall, there is evidence of moderate certainty that RIV4 is a safe and well-tolerated alternative to conventional egg-based influenza vaccines for adults.

IV.3 Live Attenuated Influenza Vaccine (LAIV)

LAIV contains standardized quantities of FFU of live attenuated influenza virus reassortants. The virus strains in LAIV are cold-adapted and temperature sensitive, so they replicate in the nasal mucosa rather than the lower respiratory tract, and they are attenuated, so they do not produce ILI. There have been no reported or documented cases, and no theoretical or scientific basis to suggest transmission of vaccine virus would occur to the individual administering LAIV. As a live replicating whole virus formulation administered intranasally, it elicits mucosal immunity, which may more closely mimic natural infection.

Vaccine currently authorized for use:

Efficacy and effectiveness

After careful review of the available Canadian and international LAIV VE data over many influenza seasons, NACI concluded that the current evidence is consistent with LAIV providing comparable protection against influenza to that afforded by IIV and does not support a recommendation for the preferential use of LAIV in children 2–17 years of age.

Observational studies from the United States found low effectiveness of LAIV against circulating post-2009 pandemic A(H1N1) (A(H1N1)pdm09), in 2013–2014 and 2015–2016; however, reduced LAIV effectiveness was not observed in Canada or any other countries that have investigated the issue. Manufacturer investigation identified potential reduced replicative fitness of the A(H1N1)pdm09-like LAIV viruses in the nasal mucosa from the two affected A(H1N1)-dominant seasons compared to pre-2009 pandemic influenza A(H1N1) LAIV viruses as contributing to the poor LAIV effectiveness against circulating A(H1N1),Footnote 187. This finding led to the manufacturer replacing the A(H1N1)pdm09 component of LAIV with new strains, with the A/Slovenia/2903/2015 being the strain that has been used since the 2017–2018 season. In adults, studies have found IIV-SD to be similarly or more efficacious or effective compared with LAIV.

Refer to the Statement on Seasonal Influenza Vaccine for 2018–2019 for detailed information supporting this recommendation.

Immunogenicity

LAIV, which is administered by the intranasal route, is thought to result in an immune response that mimics that induced by natural infection with wild-type viruses, with the development of both mucosal and systemic immunity. Local mucosal antibodies protect the upper respiratory tract and may be more important for protection than serum antibody.

Studies have demonstrated that the presence of a hemagglutination-inhibition antibody response after the administration of LAIV3 is predictive of protection. However, efficacy studies have shown protection in the absence of a significant antibody response as wellFootnote 188. In these studies, LAIV3 has generally been shown to be equally, if not more, immunogenic compared to IIV3-SD for all 3 strains in children, whereas IIV3-SD was typically more immunogenic in adults than LAIV3. Greater rates of seroconversion to LAIV3 occurred in baseline seronegative individuals compared to baseline seropositive individuals in both pediatric and adult populations, because pre-existing immunity may interfere with response to a live vaccine. Refer to the NACI Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMist): Supplemental Statement on Seasonal Influenza Vaccine for 2011–2012 for further details regarding the immunogenicity of LAIV3.

LAIV4 has shown non-inferiority based on immunogenicity compared to LAIV3 in both children and adults. The immune response to the B strain found only in the quadrivalent formulation was better in children who received the quadrivalent vaccineFootnote 189Footnote 190Footnote 191.

Safety
The most common AEs experienced by recipients of LAIV3 are nasal congestion and runny nose, which are also reported for LAIV4. In a large efficacy trial, rates of wheezing were statistically higher among children 6–23 months of age for LAIV3 compared to IIV3-SD (188). This finding is expected to be the same for recipients of LAIV4; however, pre-licensure clinical studies for LAIV4 were conducted only in adults and children 2 years of age and older. LAIV4 is not authorized in children less than 2 years of age.

Studies on LAIV3 have shown that vaccine virus can be recovered by nasal swab in children and adults following vaccination (i.e., “shedding”). The frequency of shedding decreases with increasing age and time since vaccination. Shedding is generally below the levels needed to transmit infection, although in rare instances, shed vaccine viruses can be transmitted from vaccine recipients to unvaccinated people. Refer to the NACI Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMist): Supplemental Statement on Seasonal Influenza Vaccine for 2011–2012 for more information on LAIV and viral shedding.

Considerations related to individuals with HIV infection

Following a review of the literature regarding the use of LAIV in HIV-infected individuals, NACI concluded that LAIV is immunogenic in children with stable HIV infection on HAART and with adequate immune function. In addition, NACI concluded that LAIV appears to have a similar safety profile as IIV in children on HAART and with stable HIV infection with regard to frequency and severity of AEsFootnote 192. As expected, injection site reactions were seen only with IIV and nasal symptoms were more common with LAIV. However, the evidence base is too small to effectively detect uncommon, rare, and very rare AEs related to the use of LAIV in in this population. Nasal spray may be preferable to IM injection for some individuals who are averse to receiving the vaccine by injection. Therefore, NACI recommends that LAIV may be considered as an option for children 2–17 years of age with stable HIV infection on HAART and with adequate immune function. LAIV should be considered only in children with HIV who meet the following criteria:

IM influenza vaccination is still considered the standard for children living with HIV by NACI and the Canadian Pediatric and Perinatal HIV/AIDS Research Group, particularly for those without HIV viral load suppression (i.e., plasma HIV RNA >40 copies/mL). However, if IM vaccination is not accepted by the individual or substitute decision maker, LAIV would be a reasonable option for children meeting the criteria listed above.

Refer to the NACI Statement on the Use of LAIV in HIV-Infected Individuals for more information on the use of LAIV in this population.

IV.4 Schedule

The first time that children 6 months to less than 9 years of age receive seasonal influenza vaccination, a two-dose schedule is required to achieve protectionFootnote 193Footnote 194Footnote 195. Several studies have looked at whether these two initial doses need to be given in the same seasonFootnote 83Footnote 84Footnote 196. Englund et al. reported similar immunogenicity in children 6–23 months of age whether 2 doses were given in the same or separate seasons when there was no change, or only minor vaccine strain change, in vaccine formulation between seasonsFootnote 83Footnote 84. However, seroprotection rates to the B component were considerably reduced in the group that received only one dose in the subsequent season when there was a major B lineage change, suggesting that the major change in B virus lineage reduced the priming benefit of previous vaccinationFootnote 82Footnote 84. Issues related to effective prime-boost when there is a major change in influenza B lineage across sequential seasons require further evaluation Footnote 197. Because children 6–23 months of age are less likely to have had prior priming exposure to an influenza virus, special effort is warranted to ensure that a two-dose schedule is followed for previously unvaccinated children in this age group.

IV.5 Concomitant Administration with Other Vaccines

All seasonal influenza vaccines, including LAIV, may be given at the same time as, or at any time before or after administration of other vaccines, including COVID-19 vaccines for those aged 12 years and older as of September 2021.

NACI will continue to monitor the evidence base, including ongoing and anticipated trials investigating influenza vaccines administered at the same time as, or any time before or after, COVID-19 vaccines and update its recommendations as needed.

Refer to the NACI Statement on the Use of COVID-19 Vaccines and the CIG COVID-19 chapter for current recommendations concerning the use of COVID-19 vaccines and further information on concomitant administration of COVID-19 vaccines with other vaccines.

In general, NACI recommends that two live parenteral vaccines be administered either on the same day or at least 4 weeks apartFootnote 198. This recommendation is based largely on a single study from 1965 that demonstrated immune interference between smallpox vaccine and measles vaccine administered 9–15 days apart. Subsequent studies have revealed conflicting results on immune interference between live vaccinesFootnote 199Footnote 200Footnote 201Footnote 202. No studies were found on potential immune interference between LAIV and other live attenuated vaccines (oral or parenteral) administered within 4 weeks. A few studies on concomitant administration of LAIV3 with MMR, varicella, and oral polio vaccines did not find evidence of clinically significant immune interferenceFootnote 12Footnote 14Footnote 15. One study reported a statistically significant but not clinically meaningful decrease in seroresponse rates to rubella antigen when administered concomitantly with LAIV.

In theory, the administration of two live vaccines sequentially within less than 4 weeks could reduce the efficacy of the second vaccine. Possible immune mechanisms include: the inhibitory and immunomodulatory effects of systemic and locally produced cytokines on B- and T-cell response and viral replication; immunosuppression induced by certain viruses (such as measles); and direct viral interference as a result of competition for a common niche. Mucosal vaccines may have less impact on a parenteral vaccine and vice versa. The immune response with a mucosal vaccine may be compartmentalized to the mucosa while that to a parenteral vaccine is systemic. It is likely that there is some interaction between the systemic and mucosal compartments; however, the extent to which this interaction occurs is not known.

Given the lack of data for immune interference, and based on expert opinion, NACI recommends that LAIV can be given together with or at any time before or after the administration of any other live attenuated or inactivated vaccine. However, some vaccine providers may continue to choose to give LAIV and other live vaccines separated by at least 4 weeks, based on the theoretical possibility of immune interference, although NACI does not believe that this precaution is necessary for LAIV. The use of an inactivated influenza vaccine would avoid this theoretical concern.

IV.6 Additional Vaccine Safety Considerations

Influenza vaccine is safe and well tolerated. Contraindications, precautions, and common AEs are described in Section II. Additional information regarding egg-allergic individuals and GBS is provided below.

Egg-allergic individuals

After careful review of clinical and post-licensure safety data, NACI has concluded that egg-allergic individuals may be vaccinated against influenza using any influenza vaccine, including egg-based vaccines and LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg and without any particular consideration, including vaccination setting. The amount of trace ovalbumin allowed in influenza vaccines that are authorized for use in Canada is associated with a low risk of AE, and in addition, two of the authorized products do not contain any ovalbumin. The observation period post-vaccination is as recommended in Vaccine Safety in Part 2 of the CIG. As with all vaccine administration, vaccine providers should be prepared with the necessary equipment, knowledge, and skills to respond to a vaccine emergency at all times.

Refer to the Statement on Seasonal Influenza Vaccine for 2018–2019 for safety data supporting this recommendation for IIV and LAIV.

Guillain-Barré syndrome

In a review of studies conducted between 1976 and 2005, the United States Institute of Medicine concluded that the 1976 “swine flu” vaccine was associated with an elevated risk of GBS. However, evidence was inadequate to accept or to reject a causal relation between GBS in adults and seasonal influenza vaccinationFootnote 203. The attributable risk of GBS in the period following seasonal and monovalent 2009 pandemic influenza vaccination is about one excess case per million vaccinationsFootnote 20Footnote 21. In a self-controlled study that explored the risk of GBS after seasonal influenza vaccination and after influenza health care encounters (a proxy for influenza illness), the attributable risks were 1.03 GBS admissions per million vaccinations compared with 17.2 GBS admissions per million influenza-coded health care encountersFootnote 21. This finding shows that both influenza vaccination and influenza illness are associated with small attributable risks of GBS, but the risk of GBS associated with influenza illness is notably higher than with influenza vaccination. The self-controlled study also found that the risk of GBS after vaccination was highest during weeks 2–4, whereas for influenza illness, the risk was greatest within the first week after a health care encounter and decreased thereafter, but remained significantly elevated for up to 4 weeks. The risk of GBS associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and all the other benefits of influenza vaccinationFootnote 204Footnote 205Footnote 206Footnote 207.

V. Choice of Seasonal Influenza Vaccine: Additional Information

With the recent availability of a number of new influenza vaccines, some of which are designed to enhance immunogenicity in specific age groups, the choice of product is now more complex. Section II.5 summarizes NACI’s recommendations on the choice of currently authorized influenza vaccines. This section provides more details for these recommendations.

V.1 Children

Burden of disease in children

Canadian surveillance data from 2001–2002 to 2012–2013 has shown that influenza B strains accounted for 17% of laboratory-confirmed tests for influenza in children, which is a higher proportion of disease burden due to influenza B infection compared to other age groups.

Although children less than 24 months of age comprise approximately 2% of the Canadian populationFootnote 208, children 0–23 months of age averaged 10.8% of reported influenza B cases (range: 8.3–13.7%), using case-based laboratory data from 2001–2012 (excluding 2009). With respect to severe outcomes (e.g., hospitalization, intensive care unit admission, and death), influenza B was confirmed in 15.5–58.3% (median: 38.4%) of pediatric influenza-associated hospitalizations (children 16 years of age and younger) reported by the Canadian Immunization Monitoring Program Active (IMPACT) surveillance network between 2004–2005 and 2012–2013 (excluding the 2009–2010 pandemic season)Footnote 209.

The IMPACT study also found that the proportion of deaths attributable to influenza (any strain) was significantly greater for children admitted to hospital with influenza B (1.1%) than for those admitted with influenza A (0.4%). The proportion of hospitalizations due to influenza B relative to all influenza hospitalizations has been generally similar to the proportion of influenza B detections relative to all influenza infections in the general population during the same time period. Additional information can be found in the Statement on Seasonal Influenza Vaccine for 2014–2015.

In the NACI Literature Review on Quadrivalent Influenza Vaccines, a review of B lineage antigens included in the Canadian influenza vaccines and the circulating strains each season indicates a match in five of the 12 seasons from 2001–2002 through to 2012–2013, a moderate match (about 50% from each lineage) in 1 season, and a mismatch in remaining 6 influenza seasons (i.e., 70% or more of the characterized B strains were of the opposite lineage to the antigen in that season’s vaccine).

Children 6–23 months of age

Three types of influenza vaccine are authorized for use in children 6–23 months of age: IIV3-SD, IIV3-Adj, and IIV4-SD.

Given the burden of influenza B disease in children and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine, NACI recommends that a quadrivalent influenza vaccine should be used. If a quadrivalent vaccine is not available, any of the available age-appropriate trivalent vaccines should be used.

There is insufficient evidence to make comparative recommendations on the use of IIV3-Adj over IIV3-SD.

Children 2–17 years of age

Four types of influenza vaccine have been authorized for use in children 2–17 years of age (IIV3-SD, IIV4-SD, IIV4-cc, and LAIV4.

Given the burden of influenza B disease in children and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine, NACI recommends that an age appropriate quadrivalent vaccine should be used. If a quadrivalent vaccine is not available, an age-appropriate trivalent vaccine should be used.

The current evidence does not support a recommendation for the preferential use of LAIV in children and adolescents 2–17 years of age. Refer to the NACI Statement on Seasonal Influenza Vaccine for 2018–2019 for information supporting this recommendation.

Children 2–17 years of age with chronic health conditions

NACI recommends that any age-appropriate influenza vaccine (IIV or LAIV) may be considered for children 2–17 years of age with chronic health conditions; however, LAIV should not be used for children with severe asthma (as defined as currently on oral or high-dose inhaled glucocorticosteroids or with active wheezing), those with medically attended wheezing in the 7 days prior to vaccination, those currently receiving aspirin or aspirin-containing therapy, and those with immune compromising conditions, excluding those with stable HIV infection on HAART and with adequate immune function. LAIV is also contraindicated in pregnant adolescents. Children and adolescents for whom LAIV is contraindicated should receive IIV. If IIV is used, NACI recommends that a quadrivalent vaccine should be used. If a quadrivalent vaccine is not available, an age-appropriate trivalent vaccine should be used.

NACI recommends that LAIV may be given to children with stable, non-severe asthma, children with cystic fibrosis who are not treated with immunosuppressive drugs, such as prolonged systemic corticosteroids, and children with stable HIV infection on HAART and with adequate immune function.

Refer to the NACI Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMist): Supplemental Statement on Seasonal Influenza Vaccine for 2011–2012 for additional information supporting these recommendations.

Summary of vaccine characteristics for decision making

IIV3-SD, IIV4-SD, IIV4-cc, and LAIV4 are authorized for use in Canada for children 2–17 years of age. The comparison of the vaccine characteristics of IIV and LAIV, in Table 4 below, may be considered in making a decision on the preferred vaccine option(s) for use by an individual or a public health program. Note that although data comparing LAIV to IIV4-cc are not available, IIV-cc is comparable to egg-based IIV.

Table 4: Vaccine characteristics of live attenuated influenza vaccine (LAIV) compared with inactivated influenza vaccine (IIV) in children 2–17 years of age
ConsiderationsTable 4 Footnote a LAIVTable 4 Footnote b compared with IIVTable 4 Footnote c
Efficacy and effectiveness There was early evidence of superior efficacy of LAIV3 compared with IIV3-SD in children less than 6 years of age from randomized controlled trials, with weaker evidence of superior efficacy in older children. However, later post-marketing and surveillance studies across multiple influenza seasons found comparable protection against influenza for LAIV and IIV, with findings of reduced effectiveness for LAIV against A(H1N1) in some studies.
Like IIV4-SD, LAIV4 is expected to provide additional protection against the influenza B strain not contained in IIV3-SD.
Immunogenicity LAIV3 has been shown to be as immunogenic as IIV3-SD, depending on age, with LAIV4 being non-inferior to LAIV3.
Safety Rhinitis (runny nose) and nasal congestion are more common with LAIV. Clinical studies and post-marketing studies showed a similar safety profile to IIV.
Contraindications There are vaccine contraindications specific to LAIV. LAIV is contraindicated for children with severe asthma, medically attended wheezing in the 7 days prior to vaccination, and immune compromising conditions (with the exception of children with stable HIV infection on HAART and with adequate immune function), as well as those currently receiving aspirin or aspirin-containing therapy. LAIV is also contraindicated for pregnant adolescents.
Acceptability Delivery of LAIV as a nasal spray may be preferable for children who are averse to receiving the vaccine by needle injection.

Abbreviations: HAART: highly active antiretroviral therapy; IIV: inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; LAIV: live attenuated influenza vaccine; LAIV3: trivalent live attenuated influenza vaccine; LAIV4: quadrivalent live attenuated influenza vaccine.

Table 4 Footnote a

NACI has not assessed the comparative cost-effectiveness of authorized influenza vaccine types for children 2–17 years of age.

Table 4 Return to footnote a referrer

Table 4 Footnote b

The trivalent formulation of LAIV (LAIV3) received a Notice of Compliance from Health Canada in June 2010 and was first used in publicly funded immunization programs in Canada for the 2012–2013 influenza season. The quadrivalent formulation (LAIV4) was approved for use in Canada for the 2014–2015 season and has been in use since that time. LAIV3 is no longer available in Canada.

Table 4 Return to footnote b referrer

Table 4 Footnote c

Both trivalent and quadrivalent IIV-SD (IIV3-SD and IIV4-SD) are authorized for use in Canada for the 2021–2022 influenza season. Data comparing LAIV to IIV4-cc are not available, however IIV-cc is comparable to egg-based IIV.

Table 4 Return to footnote c referrer

V.2 Adults

Burden of disease in adults

A study focusing on estimates of deaths associated with influenza in the United States has established that the average annual rate of influenza-associated deaths for adults aged 65 years of age and older was 17.0 deaths per 100,000 (range: 2.4–36.7)Footnote 210. The study also states that of deaths coded as being influenza- or pneumonia-related, persons 65 years of age and older accounted for 87.9% of the overall estimated annual average number of deaths. When influenza-related deaths among adults 65 years of age and older were estimated using codes for underlying respiratory and circulatory causes of death, these estimates increased to 66.1 deaths per 100,000 (range: 8.0–121.1) and 89.4%, respectively. This study described a wide variation in the estimated number of deaths from season to season, which was closely related to the particular influenza virus types and subtypes in circulation. Estimates presented in the study of yearly influenza-associated deaths with underlying pneumonia and influenza causes (1976–2007) reveal a large difference between influenza type A and B with a calculated median of greater than 6,000 deaths associated with influenza type A and half of that number for influenza type B (approximately 3,360) for persons 65 years of age and older. During the 22 seasons in which influenza A(H3N2) was the prominent strain, the average influenza-associated mortality rates were 2.7 times higher than for the nine seasons that it was not (all age groups combined), and on average, there were about 37% more annual influenza-associated deaths, regardless of the primary medical cause of death. A higher risk of hospitalization and death was also reported by Cromer et al. in adults 65 years of age and older, compared to younger adults in their assessment of the burden of influenza in England by age and clinical risk groupFootnote 211.

Canadian surveillance data show that hospitalization rates among adults 65 years of age and older were higher during the A(H3N2)-predominant 2014–2015 season compared to the previous five influenza seasons and also compared to the 2012–2013 season when A(H3N2) also predominated; 2014–2015 was a season in which there was a vaccine mismatch with the circulating A(H3N2) strain. Similar to the hospitalization rates, death rates among older adults were highest in the 2014–2015 season compared to the previous five seasons and compared to the previous A(H3N2) season in 2012–2013. Mortality rates among other age groups were similar to or lower than the previous five influenza seasons. Laboratory detections over this same time period showed that influenza seasons in which influenza subtype A(H3N2) predominated, disproportionally affected adults 65 years of age and older, while seasons with greater A(H1N1) detections resulted in a higher proportion of positive cases in younger age groups.

Adults 18–59 years of age

Five types of influenza vaccine are authorized for use in adults 18–59 years of age: IIV3-SD, IIV4-SD, IIV4-cc, RIV4, and LAIV4.

NACI recommends that any of the available influenza vaccines should be used in adults without contraindications. IIV or RIV should be used for adults with chronic health conditions identified in List 1, HCWs or pregnant persons (noting that no published clinical data pertaining to safety of vaccination with RIV4 during pregnancy is currently available to inform vaccine-associated risks for this population).

Adults 60–64 years of age

Four types of influenza vaccine are authorized for use in adults 60–64 years of age: IIV3-SD, IIV4-SD, IIV4-cc, and RIV4.

NACI recommends that any of the available age-appropriate influenza vaccines should be used.

Adults 65 years of age and older

Six types of influenza vaccine are authorized for use in adults 65 years of age and older: IIV3-SD, IIV3-Adj, IIV4-SD, IIV4-cc, IIV4-HD, and RIV4.

Recommendation for individual-level decision making

When available, IIV-HD should be used over IIV-SD, given the burden of influenza A(H3N2) disease and the good evidence of better protection of IIV3-HD compared to IIV3-SD in adults 65 years of age and older. Based on a review of pre-authorization trials, IIV4-HD is non-inferior to IIV3-HD and is therefore expected to provide the same enhanced protection against A(H3N2) compared to standard dose IIV, including IIV4-SD. Although IIV-HD is expected to provide better protection against influenza A(H3N2) for adults 65 years of age or older, the benefit of providing this vaccine to all adults 65+ as opposed to any other influenza vaccine is not clear (refer to the next section). NACI is currently conducting an updated review of influenza vaccines in this population.

Any of the available influenza vaccines would be preferable to remaining unvaccinated or requesting individuals to return for vaccine. Therefore, in the absence of a specific product, NACI recommends that any of the available influenza vaccines authorized for this age group should be used.

Recommendation for public health program-level decision making

IIV3-HD is expected to provide better protection compared to IIV3-SD. Similarly, IIV4-HD is expected to provide better protection compared to IIV4-SD. The previous assessment completed by NACI demonstrated insufficient evidence to make a comparative recommendation on the use of IIV3-HD over IIV3-SD at the programmatic level and a complete assessment that includes economic considerations has not yet been conducted for IIV4-HD. Therefore, NACI currently recommends that any of the available influenza vaccines should be used for public health programs. NACI is in the process of completing an updated assessment on influenza vaccines for adults 65 years of age and older.

Refer to the NACI Literature Review Update on the Efficacy and Effectiveness of High-Dose (Fluzone High-Dose) and MF59-Adjuvanted (Fluad) Trivalent Inactivated Influenza Vaccines in Adults 65 Years of Age and Older for additional information supporting these recommendations.

Summary of vaccine characteristics for decision making

There are six types of inactivated influenza vaccines (IIV3-SD, IIV3-Adj, IIV4-SD, IIV4-cc, and IIV4-HD) and one type of recombinant influenza vaccine (RIV4) authorized for use in Canada for adults 65 years of age and older. The comparison of vaccine characteristics across vaccine types, in Table 5 below, may be considered in making a decision on the preferred vaccine option(s) for use by an individual or a public health program. Due to the limited available data directly comparing the performance of IIV3-Adj, IIV-HD, IIV4-SD, IIV4-cc, or RIV4, considerations for these vaccines in Table 5 are compared to IIV3-SD for which comparative data on efficacy, effectiveness, and/or immunogenicity with each of IIV3-Adj and IIV4-SD are available. Data directly comparing IIV4-cc and IIV4-HD to IIV3-SD are not available. Comparative data on efficacy, effectiveness, and/or immunogenicity of IIV3-cc and IIV3-SD are available.

Table 5: Comparison of the vaccine characteristics of influenza vaccine types available for use in adults 65 years of age and older
ConsiderationsTable 5 Footnote a Influenza vaccine type
IIV3-Adj IIV4-HDTable 5 Footnote b IIV4-SD IIV4-ccTable 5 Footnote c RIV4
Burden of disease Although influenza-associated morbidity and mortality varies each season, in general there is an increased burden of severe disease in adults 65 years of age and older during influenza seasons when influenza A(H3N2) predominatesFootnote 210
Efficacy and effectiveness Overall, insufficient comparative evidence with IIV3-SD to draw conclusion.

ExpectedTable 5 Footnote b better protection compared with IIV3-SD, particularly against influenza A(H3N2).

Better protection against the influenza B strain not contained in IIV3-HD.

Better protection against the influenza B strain not contained in IIV3-SD. ExpectedTable 5 Footnote c better protection against the influenza B strain not contained in IIV3-SD. ExpectedTable 5 Footnote c better protection against the influenza B strain not contained in IIV3-SD.

PotentiallyTable 5 Footnote d better protection compared with IIV4 SD.

Immunogenicity Non-inferior immune response compared to IIV3-SD. Superiority to IIV3-SD has not been consistently demonstrated. ExpectedTable 5 Footnote b superior immune response to influenza A strains compared to IIV3-SD. Superior immune response to the additional B strain compared to IIV3-HD. Non-inferior immune response to the strains contained in IIV3-SD with superior immune response to the additional B strain. Non-inferior immune response to the strains contained in IIV3-cc. Superior immune response against the influenza B strain not contained in IIV3-SD. Non-inferior response expectedTable 5 Footnote c compared to IIV3-SD. ExpectedTable 5 Footnote e non-inferior immune response compared to IIV4-HD, IIV4-cc, IIV3-HD, IIV3-Adj.
Contraindications Same contraindications as IIV3-SD.
Safety Higher rate of injection site reactions than IIV3-SD. Higher or comparable systemic reactions compared to IIV3-SD; systemic reactions were mild to moderate and transient. SAEs were comparable to IIV3-SD and were uncommon. Higher rate of some systemic reactions than IIV4-SD and the same is expectedTable 5 Footnote b compared to IIV3-SD; most systemic reactions were mild and transient. SAEs were rare and similar in frequency to IIV4-SD and the same is expected compared to IIV3-SDTable 5 Footnote b. Pre-licensure clinical trials and post-marketing surveillance showed a similar safety profile to IIV3-SD. Pre-licensure clinical trials showed a similar safety profile to IIV3-cc. Similar safety profile to IIV3-SD is expectedTable 5 Footnote c. Pre-licensure clinical trials showed a similar safety profile to IIV4-SD, IIV3-HD and IIV-Adj. Similar safety profile to IIV3-SD is expected.

Abbreviations: IIV3-Adj: adjuvanted egg-based trivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-cc: standard-dose cell culture-based quadrivalent inactivated influenza vaccine; IIV4-HD: high-dose quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; RIV4: quadrivalent recombinant influenza vaccine; SAE: serious adverse event.

Table 5 Footnote a

NACI has not assessed the comparative cost-effectiveness of available influenza vaccine types for adults 65 years of age and older.

Table 5 Return to footnote a referrer

Table 5 Footnote b

Data directly comparing IIV4-HD to IIV3-SD are not available; however, IIV4-HD has been shown to be non-inferior to IIV3-HD and has a comparable rate of systemic and local reactions. Therefore, information presented here is expected to apply to IIV4-HD as well.

Table 5 Return to footnote b referrer

Table 5 Footnote c

Data directly comparing IIV4-cc to IIV3-SD are not available; however, IIV3-cc (licensure never sought in Canada) has been shown to be non-inferior to IIV3-SD. Therefore, information presented here is expected to apply to IIV4-cc as well.

Table 5 Return to footnote c referrer

Table 5 Footnote d

Data directly comparing RIV4 to IIV3-SD are not available; however, RIV4 has been shown to provide better protection than IIV4-SD based on one study conducted during a single influenza season (2014-2015).

Table 5 Return to footnote d referrer

Table 5 Footnote e

Data directly comparing RIV4 to IIV3-SD are not available; however, RIV4 has been shown to be non-inferior to IIV4-SD, IIV4-cc, IIV3-HD and IIV3-Adj against all tested influenza strains (A/H1N1, A/H3N2, B/Yamagata lineage, and B/Victoria lineage) and has a comparable rate of adverse events based on 3 influenza seasons (2014-2015, 2017-2018, 2018-2019). Therefore, information presented here is expected to apply to IIV3-SD as well.

Table 5 Return to footnote e referrer

Adults with chronic health conditions

NACI recommends that any age-appropriate IIV or RIV, but not LAIV, should be offered to adults with chronic health conditions identified in List 1, including those with immune compromising conditions.

Pregnant individuals

NACI recommends that any age-appropriate IIV or RIV, but not LAIV, should be offered to pregnant individuals (noting that no published clinical data pertaining to safety of vaccination with RIV4 during pregnancy is currently available to inform vaccine-associated risks).

Due to a lack of safety data at this time, LAIV should not be administered to pregnant individuals due to the theoretical risk to the fetus from administering a live virus vaccine. LAIV can be administered to breastfeeding individuals.

Health care workers

NACI recommends that any age-appropriate IIV or RIV, but not LAIV, should be offered to HCWs.

Comparative studies in healthy adults have found IIV to be similarly or more efficacious or effective compared with LAIVFootnote 187. In addition, as a precautionary measure, LAIV recipients should avoid close association with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection.

VI. List of Abbreviations

AE
Adverse event
AEFI
Adverse event following immunization
ART
Antiretroviral therapy
CAEFISS
Canadian Adverse Events Following Immunization Surveillance System
CI
Confidence interval
CIG
Canadian Immunization Guide
DIN
Drug Identification Number
FFU
Fluorescent focus units
GBS
Guillain-Barré syndrome
GMT
Geometric mean titre
GMTR
Geometric mean titre ratio
HA
Hemagglutinin
HAART
Highly active antiretroviral therapy
HCW
Health care worker
HIV
Human immunodeficiency virus
Ig
Immunoglobulin
IIV
Inactivated influenza vaccine
IIV3
Trivalent inactivated influenza vaccine
IIV3-Adj
Adjuvanted trivalent inactivated influenza vaccine (egg-based)
IIV3-HD
High-dose trivalent inactivated influenza vaccine (egg-based)
IIV3-SD
Standard-dose trivalent inactivated influenza vaccine (egg-based)
IIV4
Quadrivalent inactivated influenza vaccine
IIV4-cc
Mammalian cell culture-based quadrivalent inactivated influenza vaccine
IIV4-HD
High-dose quadrivalent inactivated influenza vaccine (egg-based)
IIV4-SD
Standard-dose quadrivalent inactivated influenza vaccine (egg-based)
ILI
Influenza-like illness
IM
Intramuscular
IMPACT
Immunization Monitoring Program Active
LAIV
Live attenuated influenza vaccine (egg based)
LAIV3
Trivalent live attenuated influenza vaccine (egg based)
LAIV4
Quadrivalent live attenuated influenza vaccine (egg based)
MDCK
Madin-Darby Canine Kidney
MMR
Measles, mumps and rubella
NA
Neuraminidase
NACI
National Advisory Committee on Immunization
ORS
Oculorespiratory syndrome
PHAC
Public Health Agency of Canada
RCT
Randomized controlled trial
RIV
Recombinant influenza vaccine
RIV4
Recombinant quadrivalent influenza vaccine
RNA
Ribonucleic acid
rVE
Relative vaccine efficacy
RZV
Recombinant zoster vaccine
SAE
Serious adverse event
VE
Vaccine effectiveness
WHO
World Health Organization

VII. Acknowledgments

This statement was prepared by: A Sinilaite, R Stirling, and R Harrison, on behalf of the NACI Influenza Working Group and was approved by NACI.

NACI gratefully acknowledges the contribution of: A Gil, C Tremblay, M Tunis, M Xi, and K Young

NACI Influenza Working Group

Members: J Papenburg (Chair), P De Wals, D Fell, I Gemmill, R Harrison, D Kumar, J Langley, A McGeer, and D Moore

Former members: N Dayneka, K Klein, J McElhaney, and S Smith

Liaison representatives: L Grohskopf (Centers for Disease Control and Prevention [CDC], United States)

Ex-officio representatives: C Bancej (Centre for Immunization and Respiratory Infectious Diseases [CIRID], PHAC), J Reiter (First Nations and Inuit Health Branch [FNIHB], Indigenous Services Canada [ISC]), B Warshawsky (Vice President’s Office, Infectious Disease Prevention and Control Branch [IDPCB]), and J Xiong (Biologics and Genetic Therapies Directorate [BGTD], Health Canada [HC]).

NACI

Members: S Deeks (Chair), R Harrison (Vice-Chair), J Bettinger, N Brousseau, P De Wals, E Dubé, V Dubey, K Hildebrand, K Klein, J Papenburg, A Pham-Huy, C Rotstein, B Sander, S Smith, and S Wilson.

Former member: C Quach (Chair)

Liaison representatives: L Bill (Canadian Indigenous Nurses Association), LM Bucci (Canadian Public Health Association), E Castillo (Society of Obstetricians and Gynaecologists of Canada), A Cohn (Centers for Disease Control and Prevention, United States), L Dupuis (Canadian Nurses Association), P Emberley (Canadian Pharmacists Association), J Emili (College of Family Physicians of Canada), D Fell (Canadian Association for Immunization Research and Evaluation), S Funnel (Indigenous Physicians Association of Canada), J Hu (College of Family Physicians of Canada), Noah Ivers (College of Family Physicians of Canada), M Lavoie (Council of Chief Medical Officers of Health), D Moore (Canadian Paediatric Society), M Naus (Canadian Immunization Committee), A Pham-Huy (Association of Medical Microbiology and Infectious Disease Canada), and A Ung (Canadian Pharmacists Association).

Ex-officio representatives: V Beswick-Escanlar (National Defence and the Canadian Armed Forces), E Henry (Centre for Immunization and Respiratory Infectious Diseases [CIRID], PHAC), M Lacroix (Public Health Ethics Consultative Group, PHAC), C Lourenco (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada),D MacDonald (CIRID, PHAC), S Ogunnaike-Cooke (CIRID, PHAC), G Poliquin (National Microbiology Laboratory, PHAC), K Robinson (Marketed Health Products Directorate, HC) and T Wong (First Nations and Inuit Health Branch, Indigenous Services Canada).

VIII. Appendix A: Characteristics of Influenza Vaccines Available for Use in Canada, 2022–2023Appendix A Footnote a

Product name (manufacturer) Vaccine Characteristic
Vaccine type Route of administration Authorized ages for use Antigen content for each vaccine strain Adjuvant Formats available Post-puncture shelf life for multi-dose vials Thimerosal Antibiotics (traces) Production medium
Quadrivalent
Flulaval Tetra
(GSK)
IIV4-SD
(split virus)
IM 6 months and older 15 µg HA
/0.5 mL dose
None 5 mL multi-dose vial 28 days Yes
(multi-dose vial only)
None Egg (Avian)
Fluzone Quadrivalent
(Sanofi Pasteur)
IIV4-SD
(split virus)
IM 6 months and older 15 µg HA
/0.5 mL dose
None 5 mL multi-dose vial

Single-dose pre-filled syringe without attached needle
Up to expiry date indicated on vial label Yes
(multi-dose vial only)
None Egg (Avian)
Afluria Tetra
(Seqirus)
IIV4-SD
(split virus)
IM 5 years and older 15 µg HA
/0.5 mL dose
None 5 mL multi-dose vial

Single dose pre-filled syringe without attached needle
Up to expiry date indicated on vial label Yes
(multi-dose vial only)
Neomycin and polymyxin B Egg (Avian)
Influvac Tetra
(BGP Pharma ULC, operating as Mylan, d.b.a. Viatris Canada)
IIV4-SD
(subunit)
IM or deep subcutaneous injection 6 months and older 15 µg HA
/0.5 mL dose
None Single dose pre-filled syringe with or without attached needle Not applicable No Gentamicin or neomycin and polymyxin BAppendix A Footnote b Egg (Avian)
Flucelvax Quad (Seqirus) IIV4-cc
(subunit)
IM 6 months and older 15 µg HA
/0.5 mL dose
None 5 mL multi-dose vial Single dose pre-filled syringe without attached needle 28 days Yes
(multi-dose vial only)
None Cell culture (Mammalian)
Fluzone High-Dose Quadrivalent
(Sanofi Pasteur)
IIV4-HD
(split virus)
IM 65 years and older 60 µg HA
/0.7 mL dose
None Single dose pre-filled syringe without attached needle Not applicable No None Egg (Avian)
Supemtek
(Sanofi Pasteur)
RIV4
(recombinant protein)
IM 18 years and older 45 µg HA
/0.5 mL dose
None Single dose pre-filled syringe without attached needle Not applicable No None Recombinant (Insect vector-expressed)
FluMist
Quadrivalent
(AstraZeneca)
LAIV4
(live attenuated)
Intranasal 2–59 years 106.5-7.5 FFU of live attenuated reassortants
/0.2 mL dose
(given as 0.1 mL in each nostril)
None Single use pre-filled glass sprayer Not applicable No Gentamicin Egg (Avian)
Trivalent
Fluad Pediatric
and Fluad
(Seqirus)
IIV3-Adj
(subunit)
IM Pediatric:
6–23 months

Adult:
65 years and older
Pediatric:
7.5 µg HA
/0.25 mL dose

Adult:
15 µg HA
/0.5 mL dose
MF59 Single dose pre-filled syringe without a needle Not applicable No Kanamycin and neomycin Egg (Avian)

Abbreviations: FFU: fluorescent focus units; HA: hemagglutinin; IIV3-Adj: adjuvanted egg-based trivalent inactivated influenza vaccine; inactivated influenza vaccine; IIV4-cc: standard-dose cell culture-based quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose egg-based quadrivalent inactivated influenza vaccine; IM: intramuscular; LAIV4: quadrivalent live attenuated influenza vaccine; NA: neuraminidase.

Appendix A Footnote a

Full details of the composition of each vaccine authorized for use in Canada, including other non-medicinal ingredients, and a brief description of its manufacturing process can be found in the product monograph.

Appendix A Return to footnote a referrer

Appendix A Footnote b

Neomycin and polymyxin B are only used if gentamicin cannot be used. No trace amounts of neomycin or polymyxin B are present if gentamicin was used.

Appendix A Return to footnote b referrer

IX. References

Footnote 1

World Health Organization. Influenza (Seasonal): Fact Sheet N°211. 2014. Accessed: 9 October 2018. Available from: http://www.who.int/mediacentre/factsheets/fs211/en/

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Footnote 2

Mamas MA, Fraser D, Neyses L. Cardiovascular Manifestations Associated with Influenza Virus Infection. Int J Cardiol. 2008 Nov ;130(3):304-9.

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Footnote 3

Moriarty LF, Omer SB. Infants and the seasonal influenza vaccine. A global perspective on safety, effectiveness, and alternate forms of protection. Hum Vaccin Immunother. 2014;10(9):2721-8.

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Footnote 4

Schwarz TF, Aggarwal N, Moeckesch B, Et Al. Immunogenicity and Safety of an Adjuvanted Herpes Zoster Subunit Vaccine Coadministered With Seasonal Influenza Vaccine in Adults Aged 50 Years or Older. J Infect Dis. 2017;216(11):1352-61.

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Footnote 5

Koutsakos M, Wheatley AK, Laurie K, Et Al. Influenza Lineage Extinction during the COVID-19 Pandemic? Nature Reviews Microbiology. 2021

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Footnote 6

Spencer JA, Shutt DP, Moser SK, Et Al. Epidemiological Parameter Review and Comparative Dynamics of Influenza, Respiratory Syncytial Virus, Rhinovirus, Human Coronavirus, and Adenovirus. Medrxiv. 2020:2020.02.04.20020404.

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Footnote 7

Statistics Canada. the 10 Leading Causes of Death, 2011. 2014. Accessed: 9 October 2018. Available from: http://www.statcan.gc.ca/pub/82-625-x/2014001/article/11896-eng.htm

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Footnote 8

Schanzer DL, Mcgeer A, Morris K. Statistical Estimates of Respiratory Admissions Attributable to Seasonal and Pandemic Influenza for Canada. Influenza Other Respir Viruses. 2013;7(5):799-808.

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Footnote 9

Schanzer DL, Sevenhuysen C, Winchester B, Et Al. Estimating Influenza Deaths in Canada, 1992-2009. Plos One. 2013;8(11):E80481.

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Footnote 10

Langley JM, Vanderkooi OG, Garfield HA, Et Al. Immunogenicity and Safety of 2 Dose Levels of a Thimersol-Free Trivalent Seasonal Influenza Vaccine in Children Aged 6-35 Months. J Ped Infect Dis. 2012;1(1):55-8.

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Footnote 11

Skowronski DM, Hottes TS, Chong M, Et Al. Randomized Controlled Trial of Dose Response to Influenza Vaccine in Children Aged 6 to 23 Months. Pediatrics. 2011;128(2):E276-89.

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Footnote 12

Mcelhaney JE, Hooton JW, Hooton N, Et Al. Comparison of Single versus Booster Dose of Influenza Vaccination on Humoral and Cellular Immune Responses in Older Adults. Vaccine. 2005;23(25):3294-300.

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Footnote 13

Breiman RF, Brooks WA, Goswami D, Et Al. A Multinational, Randomized, Placebo-Controlled Trial to Assess the Immunogenicity, Safety, and Tolerability of Live Attenuated Influenza Vaccine Coadministered with Oral Poliovirus Vaccine in Healthy Young Children. Vaccine. 2009;27(40):5472-9.

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Footnote 14

Lum LC, Borja-Tabora C, Breiman RF, Et Al. Influenza Vaccine Concurrently Administered with a Combination Measles, Mumps, and Rubella Vaccine to Young Children. Vaccine. 2010;28(6):1566-74.

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Footnote 15

Nolan T, Bernstein DI, Block SL, Et Al. Safety and Immunogenicity of Concurrent Administration of Live Attenuated Influenza Vaccine with Measles-Mumps-Rubella and Varicella Vaccines to Infants 12 to 15 Months of Age. Pediatrics. 2008;121(3):508-16.

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Footnote 16

National Advisory Committee on Immunization. Updated Recommendations on the Use of Herpes Zoster Vaccines. Ottawa: Public Health Agency of Canada. 2018; Available At: Https://Www.Canada.Ca/En/Services/Health/Publications/Healthy-Living/Updated-Recommendations-Use-Herpes-Zoster-Vaccines.html.

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Footnote 17

National Advisory Committee Oi. Statement on Thimerosal. Can Commun Dis Rep. 2003;29(-1):1-12.

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Footnote 18

National Advisory Committee on Immunization. Thimerosal: Updated Statement. an Advisory Committee Statement (ACS). Can Commun Dis Rep. 2007;33(ACS-6):1-13.

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Footnote 19

Gerber JS, Offit PA. Vaccines and Autism: A Tale of Shifting Hypotheses. Clin Infect Dis. 2009;48(4):456-61.

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Footnote 20

Centers for Disease Control, and Prevention. Preliminary Results: Surveillance for Guillain-Barré Syndrome after Receipt of Influenza A (H1N1) 2009 Monovalent Vaccine - United States, 2009-2010. MMWR Morb Mortal Wkly Rep. 2010;59(21):657-61.

Return to footnote 20

Footnote 21

Kwong JC, Vasa PP, Campitelli MA, 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 22

National Advisory Committee on Immunization. Supplementary Statement on Influenza Vaccination: Continued Use of Fluviral® Influenza Vaccine in the 2000-2001 Season. Can Commun Dis Rep. 2001;27(ACS-1):1-3.

Return to footnote 22

Footnote 23

Ahmadipour N, Watkins K, Fréchette M, Coulby C, Anyoti H, Johnson K. Vaccine Safety Surveillance in Canada: Reports to CAEFISS, 2013–2016. Can Commun Dis Rep. 2018;44((9)):206-14. https://doi.org/10.14745/ccdr.v44i09a04

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Footnote 24

Black S, Nicolay U, Del Giudice G, Et Al. Influence of Statins on Influenza Vaccine Response in Elderly Individuals. J Infect Dis. 2016;213(8):1224-8.

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Footnote 25

Omer SB, Phadke VK, Bednarczyk RA, Et Al. Impact of Statins on Influenza Vaccine Effectiveness against Medically Attended Acute Respiratory Illness. J Infect Dis. 2016;213(8):1216-23.

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Footnote 26

Public Health Agency of Canada. Reporting Adverse Events Following Immunization (AEFI) in Canada: User Guide to Completion and Submission of the AEFI Reports. Ottawa, PHAC. 2004; Available at: Https://Www.Canada.Ca/En/Public-Health/Services/Immunization/Reporting-Adverse-Events-Following-Immunization/User-Guide-Completion-Submission-Aefi-Reports.Html. Accessed 05/23, 2019.

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Footnote 27

Louie JK, Acosta M, Jamieson DJ, Et Al. Severe 2009 H1N1 Influenza in Pregnant and Postpartum Women in California. N Engl J Med. 2010;362(1):27-35.

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Footnote 28

Siston AM, Rasmussen SA, Honein MA, Et Al. Pandemic 2009 Influenza A(H1N1) Virus Illness among Pregnant Women in the United States. JAMA. 2010;303(15):1517-25.

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Footnote 29

Mak TK, Mangtani P, Leese J, Et Al. Influenza Vaccination in Pregnancy: Current Evidence and Selected National Policies. Lancet Infect Dis. 2008;8(1):44-52.

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Footnote 30

Mcneil S, Halperin B, Macdonald N. Influenza in Pregnancy: the Case for Prevention. Adv Exp Med Biol. 2009;634:161-83.

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Footnote 31

Rasmussen SA, Jamieson DJ, Bresee JS. Pandemic Influenza and Pregnant Women. Emerg Infect Dis. 2008;14(1):95-100.

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Footnote 32

Centers for Disease Control, and Prevention. Maternal and Infant Outcomes among Severely Ill Pregnant and Postpartum Women with 2009 Pandemic Influenza A (H1N1)--United States, April 2009-August 2010. MMWR Morb Mortal Wkly Rep. 2011;60(35):1193-6.

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Footnote 33

Pierce M, Kurinczuk J, Spark P, Et Al. Perinatal Outcomes After Maternal 2009/H1N1 Infection: National Cohort Study. BMJ. 2011;342:D3214-.

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Footnote 34

Goldenberg R, Culhane J, Iams J, Et Al. Epidemiology and Causes of Preterm Birth. Lancet. 2008;371(9606):75-84.

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Footnote 35

Mcneil SA, Dodds LA, Fell DB, Et Al. Effect of Respiratory Hospitalization during Pregnancy on Infant Outcomes. Am J Obstet Gynecol. 2011;204(6):S54-7.

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Footnote 36

Zaman K, Roy E, Arifeen SE, Et Al. Effectiveness of Maternal Influenza Immunization in Mothers and Infants. N Engl J Med. 2008;359(15):1555-64.

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Footnote 37

Poehling K, Szilagyi P, Staat M, Et Al. Impact of Maternal Immunization on Influenza Hospitalizations in Infants. Obstet Gynecol. 2011;204(6):S141-8.

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Footnote 38

Eick AA, Uyeki TM, Klimov A, Et Al. Maternal Influenza Vaccination and Effect on Influenza Virus Infection in Young Infants. Arch Pediatr Adolesc Med. 2011;165(2):104-11.

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Footnote 39

France EK, Mcclure D, Hambidge S, Et Al. Impact of Maternal Influenza Vaccination During Pregnancy on the Incidence of Acute Respiratory Illness Visits Among Infants. Arch Pediatr Adolesc Med. 2006;160(12):1277-83.

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Footnote 40

Steinhoff M, Omer S, Roy E, Et Al. Neonatal Outcomes after Influenza Immunization during Pregnancy: A Randomized Controlled Trial. CMAJ. 2012;184(6):645-53.

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Footnote 41

Fell DB, Sprague AE, Liu N, Et Al. H1N1 Influenza Vaccination During Pregnancy and Fetal and Neonatal Outcomes. Am J Public Health. 2012;102(6):E33-40.

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Footnote 42

Omer S, Goodman D, Steinhoff M, Et Al. Maternal Influenza Immunization and Reduced Likelihood of Prematurity and Small For Gestational Age Births: A Retrospective Cohort Study. Plos Med. 2011;8(5):E1000441.

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Footnote 43

Dodds L, Macdonald N, Scott J, Et Al. the Association between Influenza Vaccine in Pregnancy and Adverse Neonatal Outcomes. J Obstetr Gynecol Can. 2012;34(8):714-20.

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Footnote 44

Macdonald NE, Riley LE, Steinhoff MC. Influenza Immunization in Pregnancy. Obstet Gynecol. 2009;114(2):365-8.

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Footnote 45

Tamma PD, Ault KA, Del Rio C, Et Al. Safety of Influenza Vaccination during Pregnancy. Am J Obstet Gynecol. 2009;201(6):547-52.

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Footnote 46

Moro PL, Broder K, Zheteyeva Y, Et Al. Adverse Events in Pregnant Women Following Administration of Trivalent Inactivated Influenza Vaccine and Live Attenuated Influenza Vaccine in the Vaccine Adverse Event Reporting System, 1990-2009. Am J Obstet Gynecol. 2011;204(2):146e1-7.

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Footnote 47

European MA. Fifteenth Pandemic Pharmacovigilance Update. Http://Www.Ema.Europa.Eu/Pdfs/Influenza/21323810en.Pdf Ed. London: European Medicines Agency; 2010. Accessed: 9 October 2018. Available from: https://www.ema.europa.eu/documents/report/fifteenth-pandemic-pharmacovigilance-update_en.pdf

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Footnote 48

Simonsen L, Fukuda K, Schonberger LB, Et Al. the Impact of Influenza Epidemics on Hospitalizations. J Infect Dis. 2000;181(3):831-7.

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Footnote 49

Schanzer DL, Tam TW, Langley JM, Et Al. Influenza-Attributable Deaths, Canada 1990-1999. Epidemiol Infect. 2007;135(7):1109-16.

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Footnote 50

Centers for Disease Control, and Prevention. Deaths Related to 2009 Pandemic Influenza A (H1N1) Among American Indian/Alaska Natives - 12 States, 2009. MMWR Morb Mortal Wkly Rep. 2009;58(48):1341-4.

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Footnote 51

National Center for ES. Individuals, Families and Children in Poverty. Status and Trends in the Education of American Indians and Alaska Natives. Http://Nces.Ed.Gov/Pubs2008/Nativetrends/Ind_1_6.Asp Ed. Washington, DC: US Department of Education; 2008. Accessed: 9 October 2018. Available from: http://nces.ed.gov/pubs2008/nativetrends/ind_1_6.asp

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Footnote 52

Indigenous and Northern AC. Highlights from the Report of the Royal Commission on Aboriginal Peoples - People to People, Nation to Nation. 2010; 2016.

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Footnote 53

Clark M, Riben P, Nowgesic E. the Association of Housing Density, Isolation and Tuberculosis in Canadian First Nations Communities. Int J Epidemiol. 2002;31(5):940-5.

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Footnote 54

Saxen H, Virtanen M. Randomized, Placebo-Controlled Double Blind Study on the Efficacy of Influenza Immunization on Absenteeism of Health Care Workers. Pediatr Infect Dis J. 1999;18(9):779-83.

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Footnote 55

Wilde JA, Mcmillan JA, Serwint J, Et Al. Effectiveness of Influenza Vaccine in Health Care Professionals: A Randomized Trial. JAMA. 1999;281(10):908-13.

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Footnote 56

Carman WF, Elder AG, Wallace LA, Et Al. Effects of Influenza Vaccination of Health-Care Workers on Mortality of Elderly People in Long-Term Care: A Randomised Controlled Trial. Lancet. 2000;355(9198):93-7.

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Footnote 57

Hayward AC, Harling R, Wetten S, Et Al. Effectiveness of an Influenza Vaccine Programme For Care Home Staff to Prevent Death, Morbidity, and Health Service Use Among Residents: Cluster Randomised Controlled Trial. BMJ. 2006;333(7581):1241.

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Footnote 58

Potter J, Stott DJ, Roberts MA, Et Al. Influenza Vaccination of Health Care Workers in Long-Term-Care Hospitals Reduces the Mortality of Elderly Patients. J Infect Dis. 1997;175(1):1-6.

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Footnote 59

Lemaitre M, Meret T, Rothan-Tondeur M, Et Al. Effect of Influenza Vaccination of Nursing Home Staff on Mortality of Residents: A Cluster-Randomized Trial. J Am Geriatr Soc. 2009;57(9):1580-6.

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Footnote 60

Shugarman LR, Hales C, Setodji CM, Et Al. the Influence of Staff and Resident Immunization Rates on Influenza-Like Illness Outbreaks in Nursing Homes. J Am Med Dir Assoc. 2006;7(9):562-7.

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Footnote 61

Kuster SP, Shah PS, Coleman BL, Et Al. Incidence of Influenza in Healthy Adults and Healthcare Workers: A Systematic Review and Meta-Analysis. Plos One. 2011;6(10):E26239.

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Footnote 62

Buchan SA, Kwong JC. Influenza Immunization among Canadian Health Care Personnel: A Cross-Sectional Study. CMAJ Open. 2016;4(3):E479-88.

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Footnote 63

Hussain H, Mcgeer A, Mcneil S, Et Al. Factors Associated with Influenza Vaccination Among Healthcare Workers in Acute Care Hospitals in Canada. Influenza Other Respir Viruses. 2018;12(3):319-25.

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Footnote 64

Public Health Agency of Canada. Vaccination Coverage Goals and Vaccine Preventable Disease Reduction Targets by 2025. 2019; Available At: Https://Www.Canada.Ca/En/Public-Health/Services/Immunization-Vaccine-Priorities/National-Immunization-Strategy/Vaccination-Coverage-Goals-Vaccine-Preventable-Diseases-Reduction-Targets-2025.Html#Det22. Accessed 05/13, 2019.

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Footnote 65

Bish A, Yardley L, Nicoll A, Et Al. Factors Associated with Uptake of Vaccination against Pandemic Influenza: A Systematic Review. Vaccine. 2011;29(38):6472-84.

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Footnote 66

Dini G, Toletone A, Sticchi L, Et Al. Influenza Vaccination in Healthcare Workers: A Comprehensive Critical Appraisal of the Literature. Hum Vaccin Immunother. 2018;14(3):772-89.

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Footnote 67

Hakim H, Gaur AH, Mccullers JA. Motivating Factors for High Rates of Influenza Vaccination among Healthcare Workers. Vaccine. 2011;29(35):5963-9.

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68. Lytras T, Kopsachilis F, Mouratidou E, Et Al. Interventions to Increase Seasonal Influenza Vaccine Coverage in Healthcare Workers: A Systematic Review and Meta-Regression Analysis. Hum Vaccin Immunother. 2016;12(3):671-81.

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Footnote 69

69. Schmid P, Rauber D, Betsch C, Et Al. Barriers of Influenza Vaccination Intention and Behavior - A Systematic Review of Influenza Vaccine Hesitancy, 2005 - 2016. Plos One. 2017;12(1):E0170550.

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Footnote 70

70. Vasilevska M, Ku J, Fisman DN. Factors Associated with Healthcare Worker Acceptance of Vaccination: a Systematic Review and Meta-Analysis. Infect Control Hosp Epidemiol. 2014;35(6):699-708.

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Footnote 71

71. Accreditation Canada. Infection Prevention and Control Standards. 9th Ed. Ottawa: Accreditation Canada; 2013.

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Grotto I, Mandel Y, Green MS, Et Al. Influenza Vaccine Efficacy in Young, Healthy Adults. Clin Infect Dis. 1998;26(4):913-7.

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Leighton L, Williams M, Aubery D, Et Al. Sickness Absence Following a Campaign of Vaccination against Influenza in the Workplace. Occup Med (Lond). 1996;46(2):146-50.

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Nichol KL, Lind A, Margolis KL, Et Al. the Effectiveness of Vaccination against Influenza in Healthy, Working Adults. N Engl J Med. 1995;333(14):889-93.

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Footnote 75

Department of Health (UK). Flu Vaccination for Poultry Workers. London: Department of Health; 2007.

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Gray GC, Trampel DW, Roth JA. Pandemic Influenza Planning: Shouldn't Swine and Poultry Workers Be Included? Vaccine. 2007;25(22):4376-81.

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Bridges CB, Lim W, Hu-Primmer J, Et Al. Risk of Influenza A (H5N1) Infection among Poultry Workers, Hong Kong, 1997-1998. J Infect Dis. 2002;185(8):1005-10.

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Footnote 78

Puzelli S, Di Trani L, Fabiani C, Et Al. Serological Analysis of Serum Samples from Humans Exposed to Avian H7 Influenza Viruses in Italy between 1999 and 2003. J Infect Dis. 2005;192(8):1318-22.

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Footnote 79

Tweed SA, Skowronski DM, David ST, Et Al. Human Illness from Avian Influenza H7N3, British Columbia. Emerg Infect Dis. 2004;10(12):2196-9.

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Skowronski DM, Li Y, Tweed SA, Et Al. Protective Measures and Human Antibody Response during an Avian Influenza H7N3 Outbreak in Poultry in British Columbia, Canada. CMAJ. 2007;176(1):47-53.

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Footnote 81

Heckler R, Baillot A, Engelmann H, Et Al. Cross-Protection against Homologous Drift Variants of Influenza A and B after Vaccination with Split Vaccine. Intervirology. 2007;50(1):58-62.

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Footnote 82

Walter EB, Neuzil KM, Zhu Y, Et Al. Influenza Vaccine Immunogenicity in 6- to 23-Month-Old Children: Are Identical Antigens Necessary for Priming? Pediatrics. 2006;118(3):E570-8.

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Footnote 83

Englund JA, Walter EB, Fairchok MP, Et Al. A Comparison of 2 Influenza Vaccine Schedules in 6- to 23-Month-Old Children. Pediatrics. 2005;115(4):1039-47.

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Footnote 84

Englund JA, Walter EB, Gbadebo A, Et Al. Immunization with Trivalent Inactivated Influenza Vaccine in Partially Immunized Toddlers. Pediatrics. 2006;118(3):E579-85.

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Footnote 85

Levandowski RA, Gross PA, Weksler M, Et Al. Cross-Reactive Antibodies Induced by a Monovalent Influenza B Virus Vaccine. J Clin Microbiol. 1991;29(7):1530-2.

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Footnote 86

Levandowski RA, Regnery HL, Staton E, Et Al. Antibody Responses to Influenza B Viruses in Immunologically Unprimed Children. Pediatrics. 1991;88(5):1031-6.

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Footnote 87

Mclean HQ, Thompson MG, Sundaram ME, and Et Al. Influenza Vaccine Effectiveness in the United States during 2012-2013: Variable Protection by Age and Virus Type. J Infect Dis. 2015;211(10):1529-40.

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Footnote 88

88. Mclean HQ, Thompson MG, Sundaram ME, Et Al. Impact of Repeated Vaccination on Vaccine Effectiveness against Influenza A(H3N2) and B During 8 Seasons. Clin Infect Dis. 2014;59(10):1375-85.

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Footnote 89

Pavia-Ruz N, Angel Rodriguez Weber M, Lau YL, Et Al. A Randomized Controlled Study to Evaluate the Immunogenicity of a Trivalent Inactivated Seasonal Influenza Vaccine at Two Dosages in Children 6 to 35 Months of Age. Hum Vaccin Immunother. 2013;9(9):1978-88.

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Footnote 90

Skowronski DM, Tweed SA, De Serres G. Rapid Decline of Influenza Vaccine-Induced Antibody in the Elderly: Is it Real, or is it Relevant? J Infect Dis. 2008;197(4):490-502.

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Footnote 91

Anema A, Mills E, Montaner J, Et Al. Efficacy of Influenza Vaccination in HIV-Positive Patients: A Systematic Review and Meta-Analysis. HIV Med. 2008;9(1):57-61.

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Footnote 92

Cooper C, Hutton B, Fergusson D, Et Al. A Review of Influenza Vaccine Immunogenicity and Efficacy in HIV-Infected Adults. Can J Infect Dis Med Microbiol. 2008;19(6):419-23.

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Footnote 93

Scharpe J, Evenepoel P, Maes B, Et Al. Influenza Vaccination is Efficacious and Safe in Renal Transplant Recipients. Am J Transplant. 2008;8(2):332-7.

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Footnote 94

Manuel O, Humar A, Chen MH, Et Al. Immunogenicity and Safety of an Intradermal Boosting Strategy for Vaccination against Influenza in Lung Transplant Recipients. Am J Transplant. 2007;7(11):2567-72.

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Footnote 95

Buxton JA, Skowronski DM, Ng H, Et Al. Influenza Revaccination of Elderly Travelers: Antibody Response to Single Influenza Vaccination and Revaccination at 12 Weeks. J Infect Dis. 2001;184(2):188-91.

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100. Fujieda M, Maeda A, Kondo K, Et Al. Inactivated Influenza Vaccine Effectiveness in Children Under 6 Years of Age during the 2002-2003 Season. Vaccine. 2006;24(7):957-63.

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Nichol KL, Nordin J, Mullooly J, Et Al. Influenza Vaccination and Reduction in Hospitalizations for Cardiac Disease and Stroke among the Elderly. N Engl J Med. 2003;348(14):1322-32.

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Jackson LA, Jackson ML, Nelson JC, Et Al. Evidence of Bias in Estimates of Influenza Vaccine Effectiveness in Seniors. Int J Epidemiol. 2006;35(2):337-44.

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Jain VK, Rivera L, Zaman K, Et Al. Vaccine for Prevention of Mild and Moderate-to-Severe Influenza in Children. N Engl J Med. 2013;369(26):2481-91.

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US Food and Drug Administration. Guidance for Industry: Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines. 2007; Available At: Https://Www.Fda.Gov/Downloads/Biologicsbloodvaccines/Guidancecomplianceregulatoryinformation/Guidances/Vaccines/Ucm091990.Pdf. Accessed 06/05, 2021.

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Skowronski DM, Janjua NZ, De Serres G, Et Al. Low 2012-13 Influenza Vaccine Effectiveness Associated with Mutation in the Egg-Adapted H3N2 Vaccine Strain Not Antigenic Drift in Circulating Viruses. Plos ONE. 2014;9(3):E92153.

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Zost SJ, Parkhouse K, Gumina ME, Et Al. Contemporary H3N2 Influenza Viruses Have a Glycosylation Site That Alters Binding of Antibodies Elicited By Egg-Adapted Vaccine Strains. Proceedings of the National Academy of Sciences. 2017;114((47)):12578-83.

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Wu NC, Zost SJ, Thompson AJ, Et Al. A Structural Explanation for the Low Effectiveness of the Seasonal Influenza H3N2 Vaccine. Plos Pathogens. 2017;13((10)):E1006682.

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European Union European Medicines Agency. Optaflu European Public Assessment Report: Scientific Discussion. 2007; Available At: Https://Www.Ema.Europa.Eu/En/Documents/Scientific-Discussion/Optaflu-Epar-Scientific-Discussion_En.Pdf. Accessed 07/15, 2019.

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US Food and Drug Administration. Flucelvax Quadrivalent. 2019; Available At: Https://Www.Fda.Gov/Vaccines-Blood-Biologics/Vaccines/Flucelvax-Quadrivalent. Accessed 07/15, 2019.

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US Food and Drug Administration. FLUCELVAX - Seqirus, Inc. 1.14.1.3 US Package Insert. 2019; Available At: Https://Www.Fda.Gov/Media/85322/Download. Accessed 07/15, 2019.

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Bart S, Cannon K, Herrington D, Et Al. Immunogenicity and Safety of a Cell Culture-Based Quadrivalent Influenza Vaccine in Adults: A Phase III, Double-Blind, Multicenter, Randomized, Non-Inferiority Study. . Hum Vaccines Immunother. 2016;12((9)):2278-88.

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Footnote 149

Hartvickson R, Cruz M, Ervin J, Et Al. Non-Inferiority of Mammalian Cell-Derived Quadrivalent Subunit Influenza Virus Vaccines Compared to Trivalent Subunit Influenza Virus Vaccines in Healthy Children: A Phase III Randomized, Multicenter, Double-Blind Clinical Trial. Int J Infect Dis. 2015;41:65-72.

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Moro PL, Winiecki S, Lewis P, Et Al. Surveillance of Adverse Events After the First Trivalent Inactivated Influenza Vaccine Produced in Mammalian Cell Culture (Flucelvax) Reported to the Vaccine Adverse Event Reporting System (VAERS), United States, 2013-2015. Vaccine. 2015;33((45)):6684-6688.

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Footnote 151

Bencharitiwong R, Leonard S, Tsai T, Et Al. in Vitro Assessment of the Allergenicity of Novel MF59-Adjuvanted Pandemic H1N1 Influenza Vaccine Produced in Dog Kidney Cells. Hum Vaccin Immunother. 2012;8((7)):863-865.

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Wanich N, Bencharitiwong R, Tsai T, Et Al. in Vitro Assessment of the Allergenicity of a Novel Influenza Vaccine Produced in Dog Kidney Cells in Individuals with Dog Allergy. Ann Allergy Asthma Immunol. 2010;104(5):426-33.

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Mosca F, Tritto E, Muzzi A, Et Al. Molecular and Cellular Signatures of Human Vaccine Adjuvants. Proc Natl Acad Sci U S A. 2008;105(30):10501-6.

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Calabro S, Tortoli M, Baudner B, Et Al. Vaccine Adjuvants Alum and MF59 Induce Rapid Recruitment of Neutrophils and Monocytes that Participate in Antigen Transport to Draining Lymph Nodes. Vaccine. 2011;29(9):1812-23.

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Seubert A, Monaci E, Pizza M, Et Al. the Adjuvants Aluminum Hydroxide and MF59 Induce Monocyte and Granulocyte Chemoattractants and Enhance Monocyte Differentiation toward Dendritic Cells. J Immunol. 2008;180(8):5402-12.

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O'Hagan DT, Rappuoli R, De Gregorio E, Et Al. MF59 Adjuvant: the Best Insurance against Influenza Strain Diversity. Expert Rev Vaccines. 2011;10(4):447-62.

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Vesikari T, Knuf M, Wutzler P, Et Al. Oil-in-Water Emulsion Adjuvant with Influenza Vaccine in Young Children. N Engl J Med. 2011;365:1406-16.

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Vesikari T, Groth N, Karvonen A, Et Al. MF59 (R)-Adjuvanted Influenza Vaccine (FLUAD (R)) in Children: Safety and Immunogenicity Following a Second Year Seasonal Vaccination. Vaccine. 2009;27:6291-5.

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Vesikari T, Pellegrini M, Karvonen A, Et Al. Enhanced Immunogenicity of Seasonal Influenza Vaccines in Young Children using MF59 Adjuvant. Pediatr Infect Dis J. 2009;28:563-71.

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Della Cioppa G, Vesikari T, Sokal E, Lindert K, Nicolay U. Trivalent and Quadrivalent MF59 (R)-Adjuvanted Influenza Vaccine in Young Children: A Dose- and Schedule-Finding Study. Vaccine. 2011;29:8696-704.

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Zedda L, Forleo-Neto E, Vertruyen A, Et Al. Dissecting the Immune Response to MF59-Adjuvanted and Nonadjuvanted Seasonal Influenza Vaccines in Children Less than Three Years of Age. Pediatr Infect Dis J. 2015;34(1):73-8.

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Nolan T, Bravo L, Ceballos A, Et Al. Enhanced and Persistent Antibody Response against Homologous and Heterologous Strains Elicited By a MF59-Adjuvanted Influenza Vaccine in Infants and Young Children. Vaccine. 2014;32(46):6146-56.

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Vaarala O, Vuorela A, Partinen M, Et Al. Antigenic Differences between AS03 Adjuvanted Influenza A (H1N1) Pandemic Vaccines: Implications for Pandemrix-Associated Narcolepsy Risk. Plos One. 2014;9(12):E114361.

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Diaz Granados CA, Dunning AJ, Robertson CA, Et Al. Efficacy and Immunogenicity of High-Dose Influenza Vaccine in Older Adults by Age, Comorbidities, and Frailty. J Am Geriatr Soc. 2014;62:S37-8.

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Izurieta HS, Thadani N, Shay DK, Et Al. Comparative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccines in US Residents Aged 65 Years and Older from 2012 to 2013 Using Medicare Data: A Retrospective Cohort Analysis. Lancet Infect Dis. 2015;15(3):293-300.

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Footnote 166

Falsey AR, Treanor JJ, Tornieporth N, Et Al. Randomized, Double-Blind Controlled Phase 3 Trial Comparing the Immunogenicity of High-Dose and Standard-Dose Influenza Vaccine in Adults 65 Years of Age and Older. J Infect Dis. 2009;200(2):172-80.

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Couch RB, Winokur P, Brady R, Et Al. Safety and Immunogenicity of a High Dosage Trivalent Influenza Vaccine among Elderly Subjects. Vaccine. 2007;25(44):7656-63.

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Keitel WA, Atmar RL, Cate TR, Et Al. Safety of High Doses of Influenza Vaccine and Effect on Antibody Responses in Elderly Persons. Arch Intern Med. 2006;166(10):1121-7.

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Tsang P, Gorse GJ, Strout CB, Et Al. Immunogenicity and Safety of Fluzone Intradermal and High-Dose Influenza Vaccines in Older Adults >65 Years of Age: A Randomized, Controlled, Phase II Trial. Vaccine. 2014;32(21):2507-17.

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Nace DA, Lin CJ, Ross TM, Et Al. Randomized, Controlled Trial of High-Dose Influenza Vaccine among Frail Residents of Long-Term Care Facilities. J Infect Dis. 2015;211(12):1915-24.

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Diazgranados CA, Dunning AJ, Jordanov E, Et Al. High-Dose Trivalent Influenza Vaccine Compared to Standard Dose Vaccine in Elderly Adults: Safety, Immunogenicity and Relative Efficacy during the 2009-2010 Season. Vaccine. 2013;31(6):861-6.

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Diazgranados CA, Dunning AJ, Kimmel M, Et Al. Efficacy of High-Dose versus Standard-Dose Influenza Vaccine in Older Adults. N Engl J Med. 2014;371(7):635-45.

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Footnote 174

Sanofi Pasteur. Product Monograph: FLUZONE® High-Dose Quadrivalent. 2019; Available At: Https://Health-Products.Canada.Ca/Dpd-Bdpp/Info.Do?Lang=En&Code=99020. Accessed 09/15, 2020.

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Chang LJ, Meng Y, Janosczyk H, Et Al. Safety and Immunogenicity of High-Dose Quadrivalent Influenza Vaccine in Adults ≥65 Years of Age: A Phase 3 Randomized Clinical Trial. Vaccine. 2019;37(39):5825-34.

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Dunkle LM, Izikson R, Patriarca P, Et Al. Efficacy of Recombinant Influenza Vaccine in Adults 50 Years of Age or Older. N Engl J Med. 2017;376(25):2427-36.

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Footnote 177

Belongia EA, Levine MZ, Olaiya O, Et Al. Clinical Trial to Assess Immunogenicity of High-Dose, Adjuvanted, and Recombinant Influenza Vaccines against Cell-Grown A(H3N2) Viruses in Adults 65 to 74 Years, 2017–2018. Vaccine. 2020;38(15):3121-8.

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Footnote 178

Shinde V, Cai R, Plested J, Et Al. Induction of Cross-Reactive Hemagglutination Inhibiting Antibody and Polyfunctional CD4+ T-Cell Responses by a Recombinant Matrix-M–Adjuvanted Hemagglutinin Nanoparticle Influenza Vaccine. Clinical Infectious Diseases. 2020:Ciaa1673.

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Dunkle LM, Izikson R, Patriarca PA, Et Al. Randomized Comparison of Immunogenicity and Safety of Quadrivalent Recombinant Versus Inactivated Influenza Vaccine in Healthy Adults 18–49 Years of Age. J Infect Dis. 2017;216(10):1219-26.

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Footnote 180

Wang W, Alvarado-Facundo E, Vassell R, Et Al. Comparison of A(H3N2) Neutralizing Antibody Responses Elicited by 2018–2019 Season Quadrivalent Influenza Vaccines Derived from Eggs, Cells, and Recombinant Hemagglutinin. Clinical Infectious Diseases. 2020:Ciaa1352.

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Cowling BJ, Perera RAPM, Valkenburg SA, Et Al. Comparative Immunogenicity of Several Enhanced Influenza Vaccine Options for Older Adults: A Randomized, Controlled Trial. Clin Infect Dis. 2020;71(7):1704-14.

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Gouma S, Zost SJ, Parkhouse K, Et Al. Comparison of Human H3N2 Antibody Responses Elicited by Egg-Based, Cell-Based, and Recombinant Protein-Based Influenza Vaccines during the 2017-2018 Season. Clin Infect Dis. 2020;71(6):1447-53.

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Dawood FS, Naleway AL, Flannery B, Levine MZ, Murthy K, Sambhara S, Gangappa S, Edwards L, Ball S, Grant L, Belongia E, Et Al. Comparison of the Immunogenicity of Cell Culture-Based and Recombinant Quadrivalent Influenza Vaccines to Conventional Egg-Based Quadrivalent Influenza Vaccines Amongamong Healthcare Personnel Aged 18–64 Years: A Randomized Open-Label Trial. Clinical Infectious Diseases.Clin Infect Dis. 2021 Jul 10.

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Footnote 184

European Medicines Agency (EMA). Assessment Report: Supemtek. 2020; Available at: Https://Www.Ema.Europa.Eu/En/Documents/Assessment-Report/Supemtek-Epar-Public-Assessment-Report_En.Pdf. Accessed September 28, 2021.

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Footnote 185

Woo EJ, Moro PL. Postmarketing Safety Surveillance of Quadrivalent Recombinant Influenza Vaccine: Reports to the Vaccine Adverse Event Reporting System. Vaccine. 2021;39(13):1812-7.

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Cowling BJ, Thompson MG, Ng TWY, Et Al. Comparative Reactogenicity of Enhanced Influenza Vaccines in Older Adults. J Infect Dis. 2020;222(8):1383-91.

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Footnote 188

National Advisory Committee Oi. Recommendations on the Use of Live, Attenuated Influenza Vaccine (Flumist®): Supplemental Statement on Seasonal Influenza Vaccine 2011-2012. Can Commun Dis Rep. 2011;37(-7):1-77.

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Block SL, Falloon J, Hirschfield JA, Et Al. Immunogenicity and Safety of a Quadrivalent Live Attenuated Influenza Vaccine in Children. Pediatr Infect Dis J. 2012;31(7):745-51.

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Block SL, Yi T, Sheldon E, Et Al. A Randomized, Double-Blind Noninferiority Study of Quadrivalent Live Attenuated Influenza Vaccine in Adults. Vaccine. 2011;29(50):9391-7.

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Medimmune. A Randomized, Partially Blind Active Controlled Study to Evaluate the Immunogenicity of MEDI8662 in Adults 18-49 Years of Age. 2011; 2015.

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Public Health Agency of Canada. NACI Recommendation on the Use of Live Attenuated Influenza Vaccine (LAIV) in HIV-Infected Individuals. 2020; Available At: Https://Www.Canada.Ca/En/Public-Health/Services/Immunization/National-Advisory-Committee-on-Immunization-Naci/Live-Attenuated-Influenza-Vaccine-Hiv-Infected-Individuals.html.

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Neuzil KM, Jackson LA, Nelson J, Et Al. Immunogenicity and Reactogenicity of 1 versus 2 Doses of Trivalent Inactivated Influenza Vaccine in Vaccine-Naive 5-8-Year-Old Children. J Infect Dis. 2006;194(8):1032-9.

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Shuler CM, Iwamoto M, Bridges CB, Et Al. Vaccine Effectiveness against Medically Attended, Laboratory-Confirmed Influenza among Children Aged 6 to 59 Months, 2003-2004. Pediatrics. 2007;119(3):E587-95.

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Allison MA, Daley MF, Crane LA, Et Al. Influenza Vaccine Effectiveness in Healthy 6- o 21-Month-Old Children during the 2003-2004 Season. J Pediatr. 2006;149(6):755-62.

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Skowronski DM, Hottes TS, De Serres G, Et Al. Influenza B/Victoria Antigen Induces Strong Recall of B/Yamagata but Lower B/Victoria Response in Children Primed with Two Doses of B/Yamagata. Pediatr Infect Dis J. 2011;30(10):833-9.

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Public Health Agency of Canada. Canadian Immunization Guide: Part 1 - Key Immunization Information: Timing of Vaccine Administration. 2017; Available At: Https://Www.Canada.Ca/En/Public-Health/Services/Publications/Healthy-Living/Canadian-Immunization-Guide-Part-1-Key-Immunization-Information/Page-10-Timing-Vaccine-Administration.Html. Accessed 10/09, 2018.

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200. Stefano I, Sato HK, Pannuti CS, Et Al. Recent Immunization against Measles does not Interfere with the Sero-Response to Yellow Fever Vaccine. Vaccine. 1999;17(9-10):1042-6.

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Footnote 203

Institute of Medicine of the National Academies. Immunization Safety Review: Influenza Vaccines and Neurological Complications. Washington, DC: National Academy of Sciences; 2008.

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Footnote 205

Stowe J, Andrews N, Wise L, Et Al. Investigation of the Temporal Association of Guillain-Barre Syndrome with Influenza Vaccine and Influenza Like Illness using the United Kingdom General Practice Research Database. Am J Epidemiol. 2009;169(3):382-8.

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Footnote 206

Tam CC, O'Brien SJ, Petersen I, Et Al. Guillain-Barre Syndrome and Preceding Infection with Campylobacter, Influenza and Epstein-Barr Virus in the General Practice Research Database. Plos One. 2007;2(4):E344.

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Footnote 207

Andrews N, Stowe J, Al-Shahi Salman R, Et Al. Guillain-Barre Syndrome and H1N1 (2009) Pandemic Influenza Vaccination Using an AS03 Adjuvanted Vaccine in the United Kingdom: Self-Controlled Case Series. Vaccine. 2011;29(45):7878-82.

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Footnote 208

Statistics Canada. Table 051-0001 - Estimates of Population, by Age Group and Sex for July 1, Canada, Provinces and Territories, Annual (Persons Unless Otherwise Noted), CANSIM (Database). 2014; 2015.

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Footnote 209

Tran D, Vaudry W, Moore D, Et Al. Hospitalization for Influenza A versus B. Pediatrics. 2016;138(3):10.1542/Peds.2015,4643. Epub 2016 Aug 17.

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Footnote 210

Centers for Disease Control, and Prevention. Estimates of Deaths Associated with Seasonal Influenza --- United States, 1976-2007. MMWR Morb Mortal Wkly Rep. 2010;59(33):1057-62. https://www.fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/Guidance-for-Industry--Clinical-Data-Needed-to-Support-the-Licensure-of-Seasonal-Inactivated-Influenza-Vaccines.pdf

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Footnote 211

Assessment report: Supemtek [Internet]. Cromer D, Van Hoek AJ, Jit M, Et Al. the Burden of Influenza in England by Age and Clinical Risk Group: A Statistical Analysis to Inform Vaccine Policy. J Infect. 2014;68(4):363-712021. Available from: https://www.ema.europa.eu/en/documents/assessment-report/supemtek-epar-public-assessment-report_en.pdf

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