Summary of the National Advisory Committee on Immunization (NACI) Seasonal Influenza Vaccine Statement for 2021–2022

Background: Several influenza vaccines are authorized in Canada and the evidence on influenza immunization is continually evolving. The National Advisory Committee on Immunization (NACI) provides recommendations regarding the use of seasonal influenza vaccines annually to the Public Health Agency of Canada (PHAC). Objective: To summarize NACI recommendations regarding the use of seasonal influenza vaccines for 2021–2022 and to highlight new recommendations. Methods: Annual influenza vaccine recommendations are developed by NACI’s Influenza Working Group for consideration and approval by NACI. The development of the recommendations is based on the NACI evidence-based process. Results: The following new recommendations were made: 1) Influvac ® Tetra may be considered as an option among the standard dose quadrivalent inactivated influenza vaccines (IIV4-SD) offered to adults and children three years of age and older; 2) Fluzone High Dose Quadrivalent (IIV4-HD) may be considered an option for individuals 65 years of age and older who are currently recommended to receive Fluzone ® High Dose (trivalent); and 3) Flucelvax ® Quad may be considered amongst the quadrivalent influenza vaccines offered to adults and children nine years of age and older for annual influenza immunization. Guidance for use of influenza immunizations during the coronavirus disease 2019 pandemic is also highlighted. Conclusion: NACI continues to recommend that an age-appropriate influenza vaccine should be offered annually to anyone six months of age and older who does not have contraindications to the vaccine. Vaccination should be offered as a priority to people at high risk of influenza-related complications or hospitalization, people capable of transmitting influenza to those at high risk of complications, and others as indicated.


Introduction
Seasonal influenza is an infectious viral illness that occurs globally with an annual attack rate estimated at 5%-10% in adults and 20%-30% in children (1). Epidemics of seasonal influenza occur annually in Canada, generally in the late fall and winter months; however, the burden of influenza illness can vary from year to year. Current information on influenza activity globally can be found on the World Health Organization's FluNet website (2) and nationally on the Public Health Agency of Canada's (PHAC) FluWatch website (3).
The National Advisory Committee on Immunization (NACI) provides PHAC with annual recommendations regarding the use of seasonal influenza vaccines, which reflect identified changes in influenza epidemiology, immunization practices and influenza vaccine products authorized and available for use in Canada. The development of the annual influenza vaccine recommendations, which is led by the NACI Influenza Working Group (IWG), involves a thorough review and evaluation of the literature as well as discussion and debate at the scientific and clinical practice levels on a variety of issues, which can include the following: 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. Issues related to ethics, equity, feasibility and acceptability are also systematically examined by NACI for comprehensive development of vaccine guidance (4).
The objective of this article is to provide a concise summary of NACI's recommendations and supporting information for the 2021-2022 influenza season, including conclusions from reviews of evidence on 1) a new, biosimilar, egg-based, quadrivalent inactivated influenza vaccine (Influvac ® Tetra; IIV4-SD), 2) a new quadrivalent, egg-based high dose inactivated influenza vaccine (Fluzone ® High Dose Quadrivalent; IIV4-HD), and 3) a mammalian cell culture-based influenza vaccine (Flucelvax ® Quad; IIV4-cc). Complete details can be found on the PHAC website in the NACI Advisory Committee Statement: Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2021-2022 (the Statement) (5) and related publications.

Influenza vaccine abbreviations
Updated abbreviations used by NACI to describe the defining features of various types of influenza vaccines are presented in Table 1.

Methods
In the preparation of the 2020-2021 seasonal influenza vaccine recommendations, NACI's IWG identified the need for evidence reviews for new topics, and then reviewed and analyzed the available evidence, and proposed new or updated recommendations according to the NACI evidence-based process for developing recommendations (6). For a more detailed explanation of the strength of NACI recommendations and the grading of evidence refer to Appendix Table A1. A published, peer-reviewed framework and evidence-informed tools (including the Ethics Integrated Filters, Equity Matrix, Feasibility Matrix, and Acceptability Matrix) was applied to ensure that issues related to ethics, equity, feasibility and acceptability were systematically assessed and integrated into guidance (4).
For the 2020-2021 influenza season, the IWG reviewed evidence regarding the use of two new vaccines: 1) Influvac Tetra, a new biosimilar, egg-based, quadrivalent inactivated influenza vaccine; and 2) Fluzone High Dose (HD) Quadrivalent an egg-based high dose quadrivalent inactivated influenza vaccine (IIV4). Influvac Tetra (IIV4-SD) was first authorized for use in Canada in adults in March 2019 and subsequently in children three years of age and older in February 2020. Fluzone High Dose (HD) Quadrivalent was first authorized for use in Canada in adults in June 2020. A trivalent formulation, Fluzone High-Dose, was previously authorized for use in adults 65 years of age and older in Canada, and recommended by NACI, but marketing of the vaccine was discontinued as of February 2021. Following the review and 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; NACI, National Advisory Committee on Immunization 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" is used when referring to IIV products that do not have an adjuvant, contain 15 µg HA per strain and are administered as a 0.5 mL dose by intramuscular injection; "-cc" refers to an IIV product that is made from influenza virus grown in cell cultures instead of chicken eggs (Flucelvax ® Quad); "-Adj" 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  and National Immunization Technical Advisory Groups were also considered. Additionally, hand-searching of the reference lists of included articles was performed by one reviewer to identify additional relevant publications. Two reviewers independently screened the titles and abstracts of records retrieved from the search and eligible full-text articles for inclusion. One reviewer extracted data from eligible studies and appraised the methodological quality of these studies using the criteria outlined by Harris et al. (8). A second reviewer independently validated the data extraction and quality assessment. A narrative synthesis of the extracted data was performed. NACI provided new recommendations based on assessment of the evidence.

Use of seasonal influenza vaccine in the presence of the novel coronavirus disease 2019 (COVID-19)
In light of the ongoing coronavirus disease 2019 (COVID-19) pandemic, PHAC, in consultation with NACI and the Canadian Immunization Committee, has developed the following additional guidance on the delivery of influenza vaccination programs and administration of seasonal influenza vaccine to support provincial and territorial vaccine programs and primary care providers during the COVID-19 pandemic for 2021-2022: • Guidance for Influenza Vaccine delivery in the presence of COVID-19 (9) • Guidance on the use of seasonal influenza vaccine in the presence of COVID-19 (10) This guidance is based on currently available scientific evidence and expert opinion. The content will be reviewed regularly, and updates will be made as necessary throughout the upcoming influenza season as the public health context evolves and new evidence and policy issues emerge.
New egg-based quadrivalent influenza vaccine NACI concluded that Influvac Tetra is safe and has non-inferior immunogenicity to the trivalent Influvac formulation. Therefore, NACI recommended that Influvac Tetra may be considered among the standard dose quadrivalent inactivated influenza vaccines (IIV4-SD) offered to adults and children three years of age and older (Discretionary NACI Recommendation).
New egg-based high dose quadrivalent influenza vaccine NACI concluded that Fluzone High Dose Quadrivalent is comparably safe and has non-inferior immunogenicity to the previously authorized trivalent Fluzone High Dose formulation. Therefore, NACI has issued the following discretionary individual-level recommendation on the use of Fluzone High Dose Quadrivalent (IIV4-HD): For individuals 65 years of age and older whom are currently recommended to receive Fluzone High Dose (trivalent), NACI recommends that Fluzone High Dose Quadrivalent (IIV4-HD) may be considered as an option (Discretionary NACI Recommendation).
Recommendations for public health programs remain unchanged at this time.

Inclusion of mammalian cell culture-based quadrivalent influenza vaccine
The peer-reviewed published evidence on the effectiveness, immunogenicity and safety of IIV4-cc manufactured using fully cell-derived viruses was sparse. The systematic review identified four observational studies (11)(12)(13)(14) investigating the vaccine effectiveness of IIV4-cc compared with egg-based IIV and two peer-reviewed randomized controlled trials that assessed the immunogenicity and safety of IIV4-cc compared with different IIV3-cc formulations (produced using the same Madin-Darby Canine Kidney [MDCK] cell culture-based manufacturing process). There was evidence indicating that 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 influenza-like-illness (ILI). Although some data suggest 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 with egg-based IIV. Two studies that assessed the immunogenicity and safety of IIV4-cc compared with different IIV3-cc formulations (produced by Seqirus using the same MDCK cell culture-based manufacturing process) were identified in this review (15,16). There was also evidence indicating that IIV4-cc has a comparable immunogenicity and safety profile to egg-based influenza vaccines already licensed in Canada and the trivalent formulation of this cell culture-based influenza vaccine that has been licensed in the United States and Europe, but for which licensure has never been sought in Canada (17)(18)(19)(20)(21)(22).
Based on assessment of the available pre-licensure and postmarket clinical trial and observational data, NACI concluded that IIV-cc is an effective, safe, well-tolerated and immunogenic alternative to conventional egg-based influenza vaccines for children and adults. Therefore, NACI has made the following recommendation, supplementing NACI's overarching recommendation for influenza vaccination, which is available in the NACI Seasonal Influenza Vaccine Statement (5): NACI recommends that Flucelvax Quad may be considered among the IIV4 offered to adults and children nine years of age and older (Discretionary NACI Recommendation).

Summary of National Advisory
Committee on Immunization recommendations for the use of influenza vaccines for the 2021-2022 influenza season NACI continues to recommend influenza vaccination to anyone six months and older who does not have contraindications to the vaccine. Vaccination should be offered as a priority to people at high risk of influenza-related complications or hospitalization, people capable of transmitting influenza to those at high risk of complications, and others as indicated in List 1.
Recommended influenza vaccine options by age group and by dosage and route of administration by age are summarized in Table 2 and Table 3, respectively.

IIV4-SD
• A quadrivalent influenza vaccine licensed 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. Other than a recommendation for using IIV-HD over IIV-SD formulations, NACI has not made comparative individuallevel 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.
• Any of the available influenza vaccines should be used. o 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: HAART, highly active antiretroviral therapy; IIV, inactivated influenza vaccine; IIV3-Adj, adjuvanted trivalent inactivated influenza vaccine; IIV3-HD, high-dose 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; LAIV, live attenuated influenza vaccine; LAIV4, quadrivalent live attenuated influenza vaccine; NACI, National Advisory Committee on Immunization a IIV3-SD formulations will not be available for use in Canada during the 2021-2022 influenza season b Refer to In addition, people capable of transmitting to high-risk individuals, people who provide essential community services and people in direct contact during culling operations with poultry infected with avian influenza are particularly recommended to receive the influenza vaccine. Abbreviations: IIV3-Adj, adjuvanted trivalent inactivated influenza vaccine; IIV3-HD, high-dose trivalent; 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; IM, intramuscular; LAIV4, quadrivalent live attenuated influenza vaccine; -, not applicable a IIV3-SD formulations (Agriflu ® [six months and older], Fluviral ® [six months and older] and Influvac ® [three years and older]) are authorized but will not be available for use in Canada during the 2021-2022 influenza season b Afluria ® Tetra (five years and older), Flulaval ® Tetra (six months and older), Fluzone ® Quadrivalent (six months and older), Influvac ® Tetra (three years and older) c Flucelvax ® Quad (nine years and older) d Fluad Pediatric ® (6-23 months) or Fluad ® (65 years and older) e Fluzone ® High-Dose (65 years and older) was previously authorized, but marketing of the vaccine has been discontinued as of February 2021 f Fluzone ® High-Dose Quadrivalent (65 years and older) g FluMist ® Quadrivalent (2-59 years) 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 vaccines (25,26). 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 (27) i Children six months to less than nine years of age receiving seasonal influenza vaccine for the first time in their life should be given two doses of influenza vaccine, with a minimum interval of four weeks between doses. Children six months to younger than nine years of age who have been properly vaccinated with one or more doses of seasonal influenza vaccine in the past should receive one dose of influenza vaccine per season thereafter Source: