National Advisory Committee on Immunization (NACI) summary statement on seasonal influenza vaccine for 2022–2023

Abstract

Background: The National Advisory Committee on Immunization (NACI) reviews the evolving evidence on influenza immunization and provides annual recommendations regarding the use of authorized seasonal influenza vaccines to the Public Health Agency of Canada.

Objective: To summarize the NACI seasonal influenza vaccine recommendations for 2022–2023 and to highlight new recommendations and supporting evidence.

Methods: In the preparation of the Statement on Seasonal Influenza Vaccine for 2022–2023, NACI’s Influenza Working Group followed the NACI evidence-based process for developing recommendations. The recommendations were then considered and approved by NACI in light of the available evidence.

Results: The following key updates and new recommendations have been made for the 2022–2023 season: 1) updated information/guidance on influenza vaccination in the context of the coronavirus disease 2019 (COVID-19) has been incorporated; 2) Supemtek™ recombinant influenza vaccine may be considered for use among the quadrivalent influenza vaccines offered to adults 18 years of age and older for annual influenza immunization; and 3) Flucelvax^® Quad may be considered among the quadrivalent influenza vaccines offered to adults and children two years of age and older.

Conclusion: NACI continues to recommend that an age-appropriate influenza vaccine should be offered annually for all individuals aged six months of age and older who do not have contraindications to the vaccine, with particular focus on people at high risk of influenza-related complications or hospitalization, people capable of transmitting influenza to those at high risk, and other groups for whom influenza vaccination is particularly recommended.

Introduction

Seasonal influenza epidemics lead to significant morbidity and mortality in the Canadian population^{Footnote 1} and increase the demand on the healthcare system in the fall and winter months. Influenza circulation has been at a historical low since the onset of the coronavirus disease 2019 (COVID-19) pandemic, which has been associated with various reasons including the implementation of non-pharmaceutical public health measures (e.g. masking, social distancing) against COVID-19. Prior to the COVID-19 pandemic, the global annual attack rate was estimated to be 5%–10% in adults and 20%–30% in children^{Footnote 2}. Although the burden of influenza can vary from year to year, it is estimated that in Canada there are an average of 12,200 hospitalizations related to influenza and approximately 3,500 deaths attributable to influenza annually^{Footnote 3Footnote 4}. Current information on influenza activity internationally can be found on the World Health Organization’s Global Influenza Program website^{Footnote 5} and nationally on the Public Health Agency of Canada’s (PHAC) FluWatch website^{Footnote 6}.

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 annual update of the NACI Statement on Seasonal Influenza Vaccine 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.

This article provides a concise summary of NACI’s recommendations and supporting information for the 2022–2023 influenza season, including conclusions from evidence reviews on 1) a new, recombinant quadrivalent influenza vaccine (Supemtek™; RIV4) and 2) a mammalian cell-based influenza vaccine (Flucelvax^® Quad; IIV4-cc). Updated guidance for use of influenza vaccines during the COVID-19 pandemic is also highlighted. 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 2022–2023 (the Statement)^{Footnote 7} and related publications.

Influenza vaccine abbreviations

The current abbreviations used by NACI to describe the defining features of various types of influenza vaccines are presented in Table 1. For the 2022–2023 Statement, recombinant influenza vaccine (RIV) has been added as a new category of influenza vaccines authorized for use in Canada.

Methods

In the preparation of the Statement on Seasonal Influenza Vaccine for 2022–2023, the NACI 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 ^{Footnote 8}. More details regarding the strength of NACI recommendations and the grading of evidence is available in Table A1 in the Appendix. 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^{Footnote 9}.

For the 2022–2023 influenza season, the NACI IWG reviewed evidence and developed new recommendations regarding the use of two vaccines: 1) Supemtek, a new, quadrivalent recombinant influenza vaccine (RIV4) and 2) Flucelvax Quad, a mammalian cell culture-based, inactivated seasonal influenza vaccine (IIV4-cc). Supemtek is the first and, to date, the only available recombinant influenza vaccine that was first authorized for use in Canada in adults 18 years of age and older on January 14, 2021. NACI has not previously made a recommendation on recombinant influenza vaccines in any population; therefore, the NACI IWG oversaw the completion of a systematic literature review and meta-analysis on the vaccine efficacy, effectiveness, immunogenicity and safety of RIV4 in adults 18 years of age and older to inform the development of guidance on its use among adults in Canada. The methodology was specified a priori in a written protocol that included the research questions, search strategy, inclusion and exclusion criteria and quality assessment. The search spanned publications from January 1, 2000, to January 12, 2021, with an update to August 8, 2021. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework^{Footnote 10} was used to organize and analyze the quality of the body of evidence across studies in developing recommendations. The strength and certainty of evidence included in syntheses were assessed by two independent reviewers using the GRADE system. NACI provided a new recommendation based on assessment of the available evidence.

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 nine years of age and older on November 22, 2019. In support of the original recommendation for use of the Flucelvax Quad in adults and children nine 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. The systematic review methodology was developed with the NACI IWG and specified a priori in a written protocol that included review questions, search strategy, inclusion and exclusion criteria and quality assessment. Further details, recommendations and supporting evidence on the use of Flucelvax Quad in adults and children nine years of age and older can be found in the NACI Supplemental Statement – Mammalian Cell Culture-Based Influenza Vaccines^{Footnote 11} and have also been 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 two years of age and older. Following the review and analysis of Health Canada’s assessments of clinical trial evidence submitted by the manufacturer in support of the age extension, the NACI IWG proposed new recommendations for vaccine use to NACI. NACI critically appraised the available evidence and approved the specific recommendations brought forward.

Results

Use of seasonal influenza vaccine in the presence of COVID-19

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 healthcare system to enhance the capacity to respond to ongoing COVID-19 activity. Public Health Agency of Canada guidance on seasonal influenza vaccination, developed in consultation with NACI and the Canadian Immunization Committee, to support provincial and territorial vaccine programs and primary care providers offering influenza vaccine during the COVID-19 pandemic, is available on the Guidance on the use of influenza vaccine in the presence of COVID-19 web page^{Footnote 12}. The web content will continue to be reviewed regularly and updates will be made as necessary to align with the currently available scientific evidence, expert opinion and public health context.

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 Canadian Immunization Guide COVID-19 chapter^{Footnote 13} for updated NACI guidance on the concomitant administration of influenza and COVID-19 vaccines as the number of authorized COVID-19 vaccines and the age groups eligible to receive them expand.

Inclusion of quadrivalent recombinant seasonal influenza vaccine (RIV4)

Recombinant protein technology is a novel, alternative platform for influenza vaccine manufacturing that differs considerably from existing egg-based and mammalian cell culture-based technologies. Although Supemtek is the first, and currently the only, recombinant seasonal influenza vaccine authorized in Canada, recombinant protein technology is a well-established vaccine-manufacturing platform that may allow for faster, more flexible production times, yields a highly pure product, and mitigates the risk of mismatch between the vaccine and circulating influenza virus strains. These advantages can help to overcome challenges associated with conventional egg-based influenza vaccine production and to improve the development process and quality of influenza vaccines for reducing and preventing future influenza epidemics and pandemics. However, they are also counterbalanced by barriers that may restrict feasibility, including limited RIV manufacturing infrastructure and higher cost of production^{Footnote 14}.

Ten eligible studies were included in the evidence synthesis. Two vaccine efficacy and effectiveness outcomes were ranked as critical to decision making during the outcome prioritization process: efficacy or effectiveness against laboratory-confirmed influenza (LCI)-related mortality and efficacy or effectiveness against LCI. The peer-reviewed published evidence on the efficacy of RIV4 against LCI illness was sparse. No studies reporting on the efficacy of RIV4 against LCI-related mortality were identified. One randomized controlled trial (RCT) that assessed the efficacy of RIV4 against LCI in adults aged 50 years and older provided evidence that RIV4 may potentially offer improved protection against laboratory-confirmed influenza A infection compared to standard egg-based influenza vaccines^{Footnote 15}. However, all the relative vaccine efficacy analyses were conducted using data only from the 2014–2015 influenza season in the United States (US), which was influenza A(H3N2)-dominant, and in adults aged 50 years and older. Peer-reviewed, published clinical data pertaining to the efficacy or effectiveness of vaccination with RIV4 during pregnancy or including breastfeeding were not available at the time of this review. 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.

Three vaccine immunogenicity outcomes were ranked as critical during the outcome prioritization process of this review: seroprotection rate; seroconversion rate; and geometric mean titre ratio. Eight RCTs that assessed the immunogenicity of RIV4 compared to different vaccines, including IIV3-HD, IIV3-Adj, IIV4-SD and IIV4-cc, were identified in this review. Of these studies, two were conducted during the 2014–2015 influenza season ^{Footnote 15Footnote 16}, three were conducted over the 2017–2018 influenza season^{Footnote 17Footnote 18Footnote 19} and three were conducted over the 2018–2019 influenza season^{Footnote 20Footnote 21Footnote 22}. The RCTs were of good quality overall. Non-inferiority was assessed using the criteria specified by the US Food and Drug Administration^{Footnote 23}. Across studies, RIV4 demonstrated non-inferiority compared to egg-based influenza vaccines against influenza A(H1N1), most strains of A(H3N2), and B/Yamagata lineage^{Footnote 15Footnote 16Footnote 17Footnote 18Footnote 19Footnote 20Footnote 21Footnote 22}. Findings differed across studies regarding the non-inferiority of RIV4 compared to egg-based influenza vaccines against influenza B/Victoria lineage based on seroconversion rates, seroprotection rates and geometric mean titre ratio^{Footnote 15Footnote 16}. 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.

Two vaccine safety outcomes were ranked as critical during the outcome prioritization process for this review: serious adverse events (SAEs) and solicited systemic adverse events (AEs). Six eligible studies were identified that assessed the safety of RIV4 in adults, including five RCTs and one review of post-marketing surveillance data from the US. Of these studies, two were conducted during the 2014–2015 influenza season^{Footnote 15Footnote 16}, two were conducted during the 2017–2018 influenza season^{Footnote 18Footnote 24}, one was conducted during the 2018–2019 influenza season^{Footnote 21} and one study^{Footnote 25} reported data from the Vaccine Adverse Event Reporting System (VAERS) from July 1, 2017, through June 30, 2020. The five RCTs found that Supemtek is a safe, well-tolerated and immunogenic alternative to conventional egg-based influenza vaccines for adults (noting that no published clinical data pertaining to the safety of vaccination with RIV4 during pregnancy were available at the time of this review to inform vaccine-associated risks)^{Footnote 15Footnote 16Footnote 18Footnote 21Footnote 24}. No elevated risk of severe allergic reactions compared to traditional egg-based influenza vaccines was identified; however, lack of egg proteins in RIV4 does not eliminate the risk of allergic reactions following vaccine administration, as allergic reactions can occur following exposure to any drug or vaccine ^{Footnote 26}. Overall, there is evidence of moderate certainty that RIV4 is a safe and well-tolerated alternative to conventional egg-based influenza vaccines for adults.

Based on the review of available pre-licensure and post-market clinical trial and surveillance data, NACI made the following recommendation, supplementing NACI’s overarching recommendation for influenza vaccination, which is available in the NACI Seasonal Influenza Vaccine Statement^{Footnote 7}:

NACI recommends that Supemtek may be considered among the seasonal influenza vaccines offered to adults 18 years of age and older (Discretionary NACI Recommendation).

• NACI concludes that there is fair evidence to recommend vaccination of adults 18 years of age and older with Supemtek (Grade B Evidence)

For complete details of this review, rationale, relevant considerations and additional information supporting this recommendation, refer to the NACI Supplemental Statement: Recombinant Influenza Vaccines^{Footnote 27}. NACI will continue to monitor the evidence related to recombinant influenza vaccines and will update this supplemental statement as needed and as data on Supemtek from several different influenza seasons accumulates.

Updated recommendations on mammalian cell culture-based quadrivalent influenza vaccine (IIV4-cc)

The age extension for the use of Flucelvax Quad in adults and children two years of age and older was based on a phase 3/4 randomized clinical trial of efficacy, immunogenicity and safety of the vaccine in children two years to less than 18 years of age. The clinical trial was conducted in eight countries in Europe and South East Asia over three influenza seasons (Southern Hemisphere 2017 influenza season and Northern Hemisphere 2017–2018 and 2018–2019 influenza seasons). Overall, the quality of the evidence was considered good. NACI concluded that Flucelvax Quad is effective and safe compared to comparable vaccines, and elicits a robust immune response based on direct evidence in children two years to less than nine years of age. The quantity of direct safety and immunogenicity evidence for Flucelvax Quad in children two years to less than nine years of age is limited; however, the currently reviewed and previous clinical trial evidence provided fair evidence of efficacy, immunogenicity, and safety in children. Therefore, NACI recommended that Flucelvax Quad may be considered among the IIV4 offered to adults and children two years of age and older (Discretionary NACI Recommendation).

Additional information supporting this recommendation can be found in Section IV.1 of the NACI Seasonal Influenza Vaccine Statement for 2022–2023^{Footnote 7}. Notably, Flucelvax Quad was recently authorized by Health Canada for use in adults and children six months of age and older. This updated authorized age indication supersedes the information for Flucelvax Quad found in relevant sections within the NACI Statement on Seasonal Influenza Vaccine for 2022–2023. Further details are available in the new product monograph for this vaccine^{Footnote 28}.

Summary of National Advisory Committee on Immunization recommendations for the use of influenza vaccines for the 2022–2023 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.

Conclusion

NACI continues to recommend annual influenza vaccination for all individuals aged six months and older (noting product-specific age indications and contraindications), with particular focus on people at high risk of influenza-related complications or hospitalization, people capable of transmitting influenza to those at high risk, people who provide essential community services and people in direct contact during culling operations with poultry infected with avian influenza. For the 2022–2023 influenza season, NACI newly recommend that Supemtek recombinant influenza vaccine may be considered for use among the quadrivalent influenza vaccines offered to adults 18 years of age and older. NACI also newly recommends that Flucelvax Quad may be considered among the quadrivalent influenza vaccines offered to adults and children two years of age and older.

Authors’ statement

• AS — Writing, original draft, review, editing
• JP — Review, editing

The NACI Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2022–2023 was prepared by A Sinilaite, R Stirling and R Harrison, on behalf of the NACI Influenza Working Group, and was approved by NACI.

Competing interests

J Papenburg reports grants to his institution from MedImmune, Sanofi Pasteur, Merck and AbbVie and personal fees from AbbVie, Astra-Zeneca and Merck; all of which were outside of the submitted work.

Acknowledgements

Influenza Working Group members: J Papenburg (Chair), P De Wals, D Fell, I Gemmill, R Harrison, J Langley, A McGeer, and D Moore

Former members: N Dayneka, K Klein, D Kumar, J McElhaney, S Smith, and B Warshawsky

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), J Comeau (Association of Medical Microbiology and Infectious Disease Control), L Dupuis (Canadian Nurses Association), E Adams (Indigenous Physicians Association of Canada), J Hu (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), 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), Public Health Agency of Canada [PHAC]), M Lacroix (Public Health Ethics Consultative Group, PHAC), C Lourenco (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada [HC]), D MacDonald (COVID-19 Epidemiology and Surveillance, PHAC), S Ogunnaike-Cooke (CIRID, PHAC), K Robinson (Marketed Health Products Directorate, HC), M Routledge (National Microbiology Laboratory, PHAC), and T Wong (First Nations and Inuit Health Branch, Indigenous Services Canada)

The NACI acknowledges and appreciates the contribution of A Gil, C Tremblay, M Tunis, M Xi, and K Young to this statement.

Funding

The work of the National Advisory Committee on Immunization is supported by the Public Health Agency of Canada.

Appendix