Influvac^®use in children

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

Addendum - Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2017–2018

I. NACI recommendation
II. Background
III. Literature review methods
IV. Evidence summary
V. List of abbreviations
VI. Acknowledgments
VII. References
Appendix A: Characteristics of influenza vaccines available for use in Canada, 2017–2018*
Appendix B: NACI recommendations: Strength of recommendation and grade of evidence
Appendix C: Search strategy and results
Appendix D: Level of evidence based on research design and quality (internal validity) rating of evidence
Appendix E: Flow diagram of the study selection process for literature evidence on the efficacy and effectiveness, immunogenicity and safety of the Influvac^® trivalent inactivated influenza vaccine in children
Appendix F: Summary of literature evidence related to the efficacy and effectiveness of Influvac^® trivalent inactivated influenza vaccine in children
Appendix G: Summary of literature evidence related to the immunogenicity of Influvac^® trivalent inactivated influenza vaccine in children
Appendix H: Summary of literature evidence related to the safety of Influvac^® trivalent inactivated influenza vaccine in children

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. PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC’s Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

This addendum to the Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2017–2018 has been issued to address updated recommendations regarding the use of the Influvac^® trivalent inactivated influenza vaccine in children 3–17 years of age.

Organization: Public Health Agency of Canada

Published: December 2017
ISBN: 2371-5375

I. NACI recommendation

Use of Influvac^® trivalent inactivated influenza vaccine in children

The recent authorization by Health Canada, extending the indication for the use of Influvac^® (BGP Pharma ULC) to include children 3–17 years of age, provided the impetus for NACI to review the recommendation on the use of the vaccine. After careful review of available evidence, NACI has revised its recommendation on the use of Influvac^®, a trivalent inactivated influenza vaccine (TIV):

NACI recommends that Influvac^® should be considered among the TIVs offered to children 3–17 years of age when a quadrivalent influenza vaccine is not available (Strong NACI Recommendation).

NACI concludes that there is fair evidence of vaccine effectiveness, immunogenicity and safety to recommend the use of Influvac^® for children 3–17 years of age (Grade B Evidence). There is insufficient evidence, in quantity and quality, to recommend the use of Influvac^® for children younger than three years of age (Grade I Evidence). The recommendation on the use of Influvac^® in children is a change from previous NACI statements, as Influvac^® was not previously recommended by NACI for use in persons younger than 18 years of age.

Notwithstanding this new recommendation on the use of Influvac^® (a TIV), NACI continues to recommend that a quadrivalent formulation of influenza vaccine be used for children younger than 18 years of age. If a quadrivalent vaccine is not available, a TIV should be used (see Choice of Vaccine Product for Children below for more details).

An updated summary of the characteristics of influenza vaccines available in Canada for the 2017–2018 influenza season can be found in Appendix A. For complete prescribing information, readers should consult the product leaflets or information contained within the authorized product monographs available through Health Canada’s Drug Product Database.

Please refer to Appendix B for an explanation of NACI methodology for the grading of evidence.

Choice of Vaccine Product for Children

The current recommendations on the choice of influenza vaccine currently available for use in Canada are summarized below by pediatric age group. Additional details regarding the NACI recommendations on choice of vaccine product for children 6–23 months of age and 2–17 years of age can be found in the NACI Advisory Committee Statement: Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2017–2018.

Children 6–23 months of age

There are three types of vaccines authorized for use in this age group: quadrivalent inactivated influenza vaccine (QIV), TIV, and adjuvanted TIV.

NACI recommends that, given the burden of influenza B disease, QIV should be used. If QIV is not available, either unadjuvanted or adjuvanted TIV should be used.

Children 2–17 years of age

In children without contraindications to the influenza vaccine, any of the following vaccines can be used: quadrivalent live attenuated influenza vaccine (LAIV), QIV, or TIV. The current evidence does not support a recommendation for the preferential use of LAIV in children 2–17 years of age.

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 continues to recommend that a quadrivalent formulation of influenza vaccine be used in children 2–17 years of age. If a quadrivalent vaccine is not available, TIV should be used.

II. Background

Influvac^® Trivalent Inactivated Influenza Vaccine

Influvac^® is a surface antigen, subunit TIV that contains 15 µg of haemagglutinin (HA) per strain, administered as a 0.5 mL dose using a pre-filled syringe. First marketed in 1982^{Footnote 1}, Influvac^® is currently authorized for use in 85 countries^{Footnote 2}. The thimerosal-free formulation of Influvac^® was introduced for the 2004–2005 influenza season in the Northern Hemisphere and for the 2005 influenza season in the Southern Hemisphere.

Influvac^® has been approved for use in Canada since 2005 for persons 18 years of age and older. In May 2017, Health Canada authorized an indication extension for Influvac^® to include children 3–17 years of age, based on a review of published literature submitted by the manufacturer^{Footnote 3}. Although Influvac^® is indicated for persons six months and older in other jurisdictions, such as Australia^{Footnote 4} and the European Union^{Footnote 5}, the indication for the use of Influvac^® in children less than three years of age was not sought by the manufacturer for Canada, citing that the safety and efficacy of the vaccine have not been established for this younger age group^{Footnote 3}. Rationale supporting the regulatory decisions to authorize Influvac^® for use in children less than three years of age in other jurisdictions is unavailable. Full details of the composition of Influvac^® can be found in its product monograph^{Footnote 3}.

To inform NACI’s recommendation on the use of Influvac^® in persons less than 18 years of age, a systematic literature review of the current evidence on the efficacy and effectiveness, immunogenicity, and safety for the pediatric use of Influvac^® was conducted.

III. Literature review methods

Search Strategy

A search strategy was developed with Federal Science Librarians (Health Library) using parameters developed by the NACI Influenza Working Group. EMBASE (1974 to 21 June 2017), Global Health (1973 to 21 June 2017), International Pharmaceutical Abstracts (1970 to 29 June 2017), MEDLINE (1947 to 21 June 2017), ProQuest Public Health Database (1963 to 29 June 2017), and Scopus (1960 to 29 June 2017) electronic databases were searched from inception using the following keyword search string structure and, when applicable, controlled vocabulary: (Influvac [OR synonyms]) AND (children [OR synonyms]). These keywords were used to search the titles and abstracts of articles, as well as the full-text when available in the database, to increase the sensitivity (i.e., comprehensiveness) of the search. The searches were restricted to articles published in English and French. The full electronic search strategies are presented in Appendix C.

Identification of eligible studies

Studies retrieved from the database searches were loaded into RefWorks (ProQuest LLC, Ann Arbor, MI) with duplicate records removed. First, title and abstract information returned by the database searches were screened for potential eligibility. Second, the full-texts of studies deemed potentially eligible, or for which insufficient information was available to determine eligibility (e.g., no abstract), after title and abstract screening, were retrieved for further assessment. Both steps were performed independently by two reviewers.

Studies were included for review if they met the following criteria:

Study population is within the age range of interest (less than 18 years of age); or contains less than 10% of the study population outside the age range of interest; or a separate analysis was conducted for the age range of interest; and
Study investigated and reported Influvac^® vaccine efficacy or effectiveness, immunogenicity (seroprotection, seroconversion, or serological assessments of haemagglutination inhibition [HI] assay antibody titres), or safety (local and systemic reactogenicity or adverse events following immunization [AEFI]).

Studies were excluded if they met one or more of the following criteria:

Non-human study;
Non-English and non-French language publication;
Secondary research (e.g., literature review, systematic review, meta-analysis); or
Editorial, opinion or news report.

The reference lists of included studies were independently handsearched by two reviewers to identify additional relevant publications. The reference lists of relevant secondary research articles retrieved from the database searches and of the most recent version of the product monograph for Influvac^®^{Footnote 3} were also handsearched.

Data extraction

Two reviewers independently extracted data from the studies included for review and any disagreements or discrepancies were resolved by discussion and consensus. A data abstraction template was used to capture information on a study’s design, population, intervention, and outcome(s) of interest.

Several included publications have data sets that overlap either partially or completely. To avoid the extraction of repetitive, duplicate, or redundant data, these publications were condensed and described under a single primary reference in the evidence tables. The publication chosen for the primary reference in these cases was defined as the publication containing the analysis that is most relevant to the objectives of the present systematic review. Unique studies were considered primary references.

Qualitative synthesis

Information extracted from the included studies was synthesized narratively and the overall patterns in the data were described for the outcomes of interest.

Methodological quality assessment

The methodological quality of studies was independently assessed by two reviewers, based on study methodology. The design-specific parameters outlined by Harris et al. (2001)^{Footnote 6} were used for rating the internal validity of individual studies (Appendix D). Included studies with study designs that are not covered by Harris et al. criteria (e.g., pre-post, non-randomized controlled or surveillance studies) could not be rated using the criteria, but were still appraised for critical methodological limitations.

IV. Evidence summary

The study identification and selection process and study details are summarized in section IV.1. Evidence relating to efficacy and effectiveness is summarized in section IV.2. Studies of immunogenicity are presented in section IV.3. Vaccine safety findings are summarized in section IV.4.

IV.1 Study inclusion and characteristics

The process for study identification, screening and inclusion is summarized visually in Appendix E. Database searches and subsequent hand searches yielded a total of 199 unique records for title and abstract screening. Full-text screening of 92 records identified a total of 20 studies that were eligible for qualitative synthesis^{Footnote 7} ^{Footnote 8} ^{Footnote 9} ^{Footnote 10} ^{Footnote 11} ^{Footnote 12} ^{Footnote 13} ^{Footnote 14} ^{Footnote 15} ^{Footnote 16} ^{Footnote 17} ^{Footnote 18} ^{Footnote 19} ^{Footnote 20} ^{Footnote 21} ^{Footnote 22} ^{Footnote 23} ^{Footnote 24} ^{Footnote 25} ^{Footnote 26}. Of the 20 published studies included for review, three were identified by handsearching the reference lists of relevant review articles retrieved through the database searches^{Footnote 8} ^{Footnote 12} ^{Footnote 24}. Three included studies were funded^{Footnote 20} or conducted^{Footnote 16} ^{Footnote 25} by the manufacturer. All included studies were available as English language publications. Unpublished pharmacovigilance data for Influvac^® were also provided by the manufacturer to the NACI Influenza Working Group^{Footnote 2}. Therefore, a total of 21 studies were included in the synthesis.

Extracted study data are presented in the evidence table in Appendix F for efficacy and effectiveness, Appendix G for immunogenicity and Appendix H for safety findings (confidential unpublished safety data provided by the manufacturer^{Footnote 2} are not summarized in the evidence table). Of the 21 included studies, three pairs of related studies were identified^{Footnote 10} ^{Footnote 12} ^{Footnote 13} ^{Footnote 18} ^{Footnote 19} ^{Footnote 22}. One study from each of the three pairs of related studies was further identified as a primary reference for the present review^{Footnote 10} ^{Footnote 12} ^{Footnote 18}. Extracted data for these three primary references were supplemented with non-duplicative findings from their respective related studies as indicated in Appendices F through H.

After consolidation of studies with overlapping data sets, a total of 18 primary references were included in the present review, including 10 clinical trials^{Footnote 9} ^{Footnote 10} ^{Footnote 11} ^{Footnote 12} ^{Footnote 16} ^{Footnote 17} ^{Footnote 18} ^{Footnote 23} ^{Footnote 25} ^{Footnote 26}, seven vaccine safety surveillance studies (Level III Evidence)^{Footnote 7} ^{Footnote 8} ^{Footnote 14} ^{Footnote 15} ^{Footnote 20} ^{Footnote 21} ^{Footnote 24}, and one unpublished vaccine safety study by the manufacturer (Level III Evidence)^{Footnote 2}. Of the 10 clinical trials, two were double-blind randomized controlled trials (RCTs) (Level I Evidence)^{Footnote 12} ^{Footnote 18}, one was an endpoint-blind RCT (Level I Evidence)^{Footnote 25}, two were non-randomized controlled trials (Level II-1 Evidence)^{Footnote 23} ^{Footnote 26}, and five were pre-post studies (Level III Evidence)^{Footnote 9} ^{Footnote 10} ^{Footnote 11} ^{Footnote 16} ^{Footnote 17}.

Quality assessment was performed for the 17 published primary references included for review. Of these, three studies with study designs evaluable by Harris et al. received “fair” ratings^{Footnote 12} ^{Footnote 18} ^{Footnote 25}. For all other study designs that were not evaluable with the Harris et al. criteria, no critical flaws were noted besides the intrinsic limitations of those designs. However, of note, one pre-post immunogenicity study did not assess HI titres after the second vaccine dose in vaccine-naïve children^{Footnote 17}.

A few studies included in the present review were not among those submitted by the manufacturer to Health Canada for the purpose of obtaining licensure for the pediatric use of Influvac^®^{Footnote 7} ^{Footnote 15} ^{Footnote 19} ^{Footnote 21}. Conversely, several studies submitted by the manufacturer for the pediatric indication extension were excluded from the present review due to:

Publication in a language other than English or French^{Footnote 27} ^{Footnote 28} ^{Footnote 29};
Interim analysis being superseded by a later publication included for review^{Footnote 30};
A lack of specific reporting on Influvac^®^{Footnote 31};
Reporting only secondary research^{Footnote 32};
Reporting outcomes in aggregate (i.e., no separate reporting by vaccine brand)^{Footnote 33}; and
Inclusion of a substantial proportion of subjects outside the age range of interest^{Footnote 34}.

IV.2 Efficacy and effectiveness

Two studies assessed the effectiveness of Influvac^® in children^{Footnote 18} ^{Footnote 26}.

One study included for review assessed the effectiveness of Influvac^® to prevent laboratory-confirmed influenza infection as a secondary outcome. Jansen et al. (2008) conducted a double-blind RCT comparing Influvac^® plus heptavalent pneumococcal conjugate (PCV7) vaccination, Influvac^® plus placebo vaccination, and control hepatitis B plus placebo vaccination in children aged 18–72 months with a previously reported physician-diagnosed respiratory tract infection (RTI) (n=579)^{Footnote 18}. The study found that the receipt of Influvac^® plus PCV7 vaccine (relative risk [RR]: 0.48, 95% confidence interval [CI]: 0.25–0.93) and Influvac^® plus placebo (RR: 0.49, 95% CI: 0.25–0.97) were both statistically significantly associated with a lower risk of laboratory-confirmed influenza infection compared to immunization with a non-influenza vaccine (i.e., hepatitis B vaccine). The Influvac^® plus PCV7 vaccine group saw a statistically significant reduction in the incidence of febrile RTI by 24% (incidence rate ratio [IRR]: 0.76, 95% CI: 0.58–0.99) while a non-statistically different incidence rate was observed for the Influvac^® plus placebo group (IRR: 0.87, 95% CI: 0.68–1.12) compared with the control group. Statistically significant reductions in the incidence of acute otitis media were observed for the Influvac^® plus PCV7 (IRR: 0.43, 95% CI: 0.20–0.94) and Influvac^® plus placebo (IRR: 0.29, 95% CI: 0.12–0.70) groups compared with the control group.

The community-based, pragmatic, non-randomized controlled trial by Ghendon et al. (2006) investigated the effectiveness of influenza vaccination to protect against influenza-like illness (ILI; sudden onset of fever >38°C and cough or sore throat) in healthy children aged 3–17 years in kindergartens (3–6 years of age) and schools (7–17 years of age) of four communities of Moscow, Russia^{Footnote 26}. Children in two communities received the Influvac^® vaccine (coverage rate of 69.7% among 40,611 children) while children in two control communities were not routinely immunized (coverage rate of <1% among 60,946 children). Vaccine effectiveness against ILI was found to be 60.9% for children attending kindergartens, 68.8% for children attending schools, and 63.7% overall.

No efficacy studies for Influvac^® were identified.

IV.3 Immunogenicity

The HI assay is a commonly used laboratory test to quantify the level of serum antibodies produced in response to vaccine antigens. The concentration of observed serum HI antibodies is calculated as the geometric mean titre (GMT), which is the mean of the logarithmic values of serum antibody titres. Serological assessments of immune response, such as seroprotection, seroconversion and geometric mean fold rise (GMFR; also referred to as mean fold increase) after vaccination, derived from HI titres are accepted standards for the evaluation and licensing of new influenza vaccines^{Footnote 35}. Seroprotection rate is the proportion of subjects achieving an HI titre of ≥1:40 post-vaccination. An HI titre of 1:40 has been suggested to correlate with an efficacy of 50–70% against clinical symptoms of influenza in healthy adults, but may vary depending on individual characteristics, population, age and vaccine type^{Footnote 36}. A similar correlate for protection between antibody titre and vaccine efficacy has not been determined for children. Seroconversion rate is the proportion of subjects achieving significant increase from pre- to post-vaccination HI titres (≤1:10 to ≥1:40 or at least four-fold rise in HI titres). GMFR is the ratio of the post- and pre-vaccination HI titres. Correlates of protection against influenza have not been well established for other serological assessments, such as microneutralization assay^{Footnote 37} or neuraminidase inhibition assay^{Footnote 38}, and therefore findings for these assays were not included in the present literature review.

With regard to seasonal inactivated influenza vaccines, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has previously recommended specific protective thresholds for the three aforementioned serological assessments to be considered for each vaccine strain (e.g., H1N1, H3N2, B)^{Footnote 35}. Although CHMP has revised its guideline on influenza vaccines not to rely on serological assays with predefined protective thresholds to establish benefit^{Footnote 39}, the previously used thresholds are presented to aid in interpretation of immunogenicity study findings, as follows for adult subjects 18–60 years of age:

Seroprotection in over 70% of subjects
Seroconversion in over 40% of subjects

Mean fold increase of over 2.5

CHMP criteria were not established for children, but the adult criteria have been used by manufacturers to evaluate influenza vaccine immunogenicity in pediatric trials^{Footnote 40}.

The United States (US) Department of Health and Human Services (HHS) published the following criteria for clinical data necessary to support the licensure of seasonal inactivated influenza vaccines for adults younger than 65 years of age and for the pediatric population (criteria for adults 65 years of age and older are not presented):

Lower limit of the two-sided 95% CI for the percent of subjects achieving seroconversion for HI antibody should meet or exceed 40%
Lower limit of the two-sided 95% CI for the percent of subjects achieving seroprotection should meet or exceed 70%^{Footnote 41}.

For clinical trials comparing two influenza vaccines, the US HHS recommends the following criteria to assess the non-inferiority of a new vaccine compared to a licensed vaccine for all age groups: the upper limit of the two-sided 95% CI for the ratio of post-vaccination GMTs (established vaccine versus new vaccine) for all three vaccine strains should not exceed 1.5 and the upper limit of the two-sided 95% CI of the difference between seroconversion rates (established vaccine minus new vaccine) for all three vaccine strains should not exceed 10%^{Footnote 41}.

Health Canada has not published similar criteria for the assessment of influenza vaccine immunogenicity.

Healthy children

Two studies assessed the immunogenicity of Influvac^® in healthy children^{Footnote 17} ^{Footnote 25}.

Zhu et al. (2008) conducted an endpoint-blind RCT in 300 healthy children 3–12 years of age, 300 healthy adults 18–59 years of age and 240 healthy elderly persons 60 years of age and older to assess the immunogenicity of Influvac^® compared to another subunit TIV, Agrippal^® (Seqirus; marketed in Canada as Agriflu^®, in these age groups^{Footnote 25}. In per-protocol analysis, Influvac^® achieved seroprotection rates of 95–99%, seroconversion rates of 87–92%, and mean fold increases of 17.4–23.3 in healthy children for the three vaccine virus strains. The lower limits of the 95% CI of the ratio of post-vaccination GMTs comparing Influvac^® to Agrippal^® for children aged 3–12 years (1.42–1.63), 3–5 years (0.94–1.29) and 6–12 years (1.44–1.70) were above the study-defined non-inferiority margin of 0.35, indicating that the immunogenicity of Influvac^® was at least comparable to Agrippal^® in these age groups.

El-Madhun et al. (1998) conducted a pre-post study examining the effect of previous exposure to the influenza virus (i.e., natural priming) on immune response following vaccination with Influvac^®^{Footnote 17}. The study population consisted of a group of persons, including 18 children aged 2–3 years, who had not been previously vaccinated against influenza and were undergoing tonsillectomy. Study subjects did not have any serious health problems, with the exception of frequent tonsillar infections. Of the 18 children, based on the presence of pre-vaccination serum antibodies, 14 were determined to be primed by influenza A(H3N2), one was primed by influenza A(H1N1), and three were primed by influenza B. All children primed by an influenza virus strain achieved at least a four-fold increase from pre- to post-vaccination antibody titres for that strain 28–42 days after the first of two half doses of vaccine, whereas no substantial increase in HI titres was observed in children who were not primed by that strain. Serology was not assessed after the second dose of vaccine. A two-dose schedule is required to achieve protection in children less than nine years of age receiving seasonal influenza vaccine for the first time^{Footnote 42}.

Children with chronic health conditions

Six studies assessed the immunogenicity of Influvac^® in children with specific chronic health conditions: acute lymphoblastic leukemia (ALL)^{Footnote 9} ^{Footnote 10} ^{Footnote 23}, hemophilia^{Footnote 11}, asthma^{Footnote 12}, chronic lung disease, and congenital heart disease^{Footnote 16}.

In a multi-arm pre-post study, Brydak et al. (1998) assessed the immunogenicity of Influvac^® in children aged 7–16 years with ALL (n=45) compared by previous influenza vaccination status and with a control group of unvaccinated healthy children aged 8–15 years (n=23)^{Footnote 10}. A majority of the subjects with ALL completed chemotherapy treatment at least one month before immunization (n=43 of 45). Serological assessment was completed at three weeks and six months post-vaccination with Influvac^®. Children aged 7–16 years with ALL who were previously vaccinated (n=25) achieved seroprotection rates of 52.0–92.0% (>60% for two of three vaccine strains) and 68.0–100.0%, seroconversion rates of 52.0–92.0% and 68.0–100.0%, and mean fold increases of 17.2–26.7 and 22.1–38.2 for the three strains assessed at three weeks and at six months post-vaccination respectively. Among children aged 7–11 years with ALL who were not previously immunized with influenza vaccine (n=20), Influvac^® achieved similar seroprotection rates of 55.0–85.0% (>60% for two of three vaccine strains) and 90.0–100.0%, seroconversion rates of 55.0–80.0% and 90.0–100.0%, and mean fold increases of 15.7–22.6 and 30.3–39.3 for the three strains assessed at three weeks and at six months post-vaccination respectively. Post-vaccination HI titres were statistically significantly higher for vaccinated children with ALL compared to unvaccinated healthy children. In a follow-up study, Brydak et al. (2000) did not find statistically significant differences in post-vaccination immune response in ALL subjects by time since completion of chemotherapy treatment^{Footnote 9}.

In another multi-arm, pre-post study by Brydak et al. (1998), the immune response elicited by Influvac^® was assessed in a group of hemophiliac patients aged 10–19 years who have been previously vaccinated against influenza (n=38) and compared to healthy controls who did not receive influenza vaccination during this study or previously (n=23)^{Footnote 11}. For the vaccinated group of hemophiliac patients, the mean fold increase was observed to range from 3.9–10.9 and 8.4–28.6 for all three vaccine strains assessed at three weeks and at six months post-vaccination respectively. Seroprotection rates were found to be 52.6–60.5% (>60% for one of three vaccine strains) and 76.3–97.4% for the three vaccine strains assessed at three weeks and at six months post-vaccination respectively. The seroconversion rate was found to be 39.5–42.1% and 71.1–86.8% for all three vaccine strains assessed at three weeks and at six months post-vaccination respectively. These observed measures of immune response appear to be higher for vaccinated hemophiliac patients than unvaccinated controls. Post-vaccination HI titres in vaccinated hemophiliac patients were statistically significantly higher than pre-vaccination titres and titres observed for unvaccinated controls. In stratified analysis by severity of hemophilia, children suffering from severe and mild hemophilia had similar GMTs and mean fold increases for influenza A and B strains at 6 months post-vaccination with Influvac^®^{Footnote 22}. Seroprotection and seroconversion rates were similar for both severities of hemophiliacs for influenza A(H3N2) and B; however, patients with severe hemophilia had lower rates of seroprotection and seroconversion compared to patients with mild hemophilia for influenza A(H1N1) at 3 weeks and 6 months post-vaccination.

Shahgholi et al. (2010) conducted a non-randomized controlled trial assessing the immunogenicity of Influvac^® in children aged 1–18 years with ALL in first remission and receiving maintenance therapy (n=32) compared to healthy sibling controls (n=30)^{Footnote 23}. Compared to pre-vaccination HI titres, ALL patients showed statistically significantly elevated protective responses for the three vaccine strains assessed at four weeks post-vaccination. Post-vaccination GMTs were not statistically significantly different between ALL patients and healthy controls for influenza A(H1N1) and B, but was statistically significantly lower in ALL patients for influenza A(H3N2) (p=0.041). Seroprotection rates were lower in vaccinated ALL patients (26.0–63.3%) than vaccinated healthy controls (73.0–88.0%), with a statistically significantly lower seroprotection rate for the H1N1 (p=0.04) and B (p=0.001) antigens. Seroconversion rates ranged from 40.6–59.4% for vaccinated ALL patients and from 53.3–83.3% for controls. Seroconversion rates were statistically significantly lower for the H1N1 and B antigens (p=0.04 and 0.038 respectively), but not for the H3N2 antigen.

Bueving et al. (2004) conducted a double-blind RCT in children 6–18 years of age with asthma to assess the immunogenicity of Influvac^® (n=347) compared to placebo (n=349)^{Footnote 12}. Influvac^® achieved statistically significantly higher seroprotection rates (85.6–98.5%) and seroconversion rates (26.5–59.9%) compared to placebo for the three vaccine strains at 14–21 days after vaccination.

In a single-arm pre-post study in 52 children aged 6 months to 4 years with chronic lung disease and/or congenital heart disease, Daubeney et al. (1997) found that Influvac^® achieved seroprotection rates of 55–71% (>60% for two of three vaccine strains), seroconversion rates of 55–71% and mean fold increases of 5.8–10.8 for the three vaccine strains^{Footnote 16}.

IV.4 Safety

Fourteen published studies were identified that assessed the safety of Influvac^® in children^{Footnote 7} ^{Footnote 8} ^{Footnote 9} ^{Footnote 12} ^{Footnote 14} ^{Footnote 15} ^{Footnote 16} ^{Footnote 18} ^{Footnote 20} ^{Footnote 21} ^{Footnote 23} ^{Footnote 24} ^{Footnote 25} ^{Footnote 26}. The manufacturer also provided unpublished pharmacovigilance data for Influvac^®^{Footnote 2}.

All clinical trials included for review that assessed safety and tolerability found Influvac^® to be safe and well tolerated in healthy children^{Footnote 19} ^{Footnote 25} ^{Footnote 26} and in children with specific chronic health conditions^{Footnote 10} ^{Footnote 13} ^{Footnote 16} ^{Footnote 23}. A surveillance study recorded one child between 6 months and 4 years of age who had received Influvac^® that experienced a severe adverse event (SAE); the precise age of the child and nature of the SAE are not reported, but it was reported that the child improved within days^{Footnote 21}. Several other studies noted that no SAEs following vaccination were observed for Influvac^®^{Footnote 13} ^{Footnote 16} ^{Footnote 19} ^{Footnote 25} ^{Footnote 26}. Among the clinical trials included for review, reported local reactions include erythema^{Footnote 13} ^{Footnote 16} ^{Footnote 19} ^{Footnote 23}, interference with limb movement^{Footnote 19}, stiff or painful arm^{Footnote 13}, pain^{Footnote 13} ^{Footnote 23}, swelling^{Footnote 19} ^{Footnote 23}, and tenderness^{Footnote 19}. Reported systemic reactions include fever^{Footnote 16} ^{Footnote 19} ^{Footnote 23} ^{Footnote 25}, headache^{Footnote 19} ^{Footnote 25}, increased irritability^{Footnote 16}, insomnia^{Footnote 16}, malaise^{Footnote 19}, and myalgia^{Footnote 13} ^{Footnote 19}. Local and systemic reactions were noted to be mostly mild and transient, resolving within a few days^{Footnote 16} ^{Footnote 19} ^{Footnote 25}.

Several observational studies were identified that examined AEFI in children and reported product-specific findings, including for Influvac^®^{Footnote 7} ^{Footnote 8} ^{Footnote 14} ^{Footnote 15}, ^{Footnote 20} ^{Footnote 21} ^{Footnote 24}.

Between 1998 and 2007, four cases of AEFI related to Influvac^® were reported to the Danish Medicines Agency for children 2–3 years of age, three of which were classified as serious; however, details of the AEFI were not reported. AEFI were not reported for the other pediatric age groups (less than 18 years of age)^{Footnote 7}.

In Western Australia during the 2010 Southern Hemisphere influenza season, a split virion TIV (Fluvax^® and Fluvax Junior^®, CSL) was found to be associated with higher rates of febrile convulsions following vaccination in children less than 5 years of age compared to previous seasons^{Footnote 43}. As a comparator to Fluvax^® and Fluvax Junior^®, resulting safety surveillance investigations of febrile events following influenza vaccine administration found statistically significantly lower risk of febrile reactions in children 6 months to four and five years for Influvac^® in Australia^{Footnote 8} ^{Footnote 24} and New Zealand^{Footnote 20}.

A web-based active AEFI surveillance system (Vaxtracker) for the state of New South Wales in Australia found that pediatric recipients (<10 years of age) of Influvac^® reported lower frequencies of any AEFI (3.1%; n=32) compared to Fluarix^® (11.6%; n=43), Vaxigrip^® (21.7%; n=212) and all influenza vaccine brands (17.9%; n=290) for the 2012 and 2013 Southern Hemisphere influenza seasons^{Footnote 14}.

The Australian national vaccine safety surveillance system (AusVaxSafety) reported AEFI, including fever, by influenza vaccine brand for the 2015 Southern Hemisphere season. Influvac^®, however, was administered in insufficient numbers in children aged six months to four years (n=47) to allow for a reliable comparison of differences in reported fever rates with other vaccine brands^{Footnote 21}.

An Australian state-based passive surveillance system identified one pediatric case of anaphylaxis following vaccination with Influvac^® during the 2008 and 2009 Southern Hemisphere influenza seasons^{Footnote 15}. An anaphylaxis incidence rate for Influvac^® was not available.

The manufacturer’s enhanced passive surveillance system did not identify any unexpected reactogenicity in children and adults for Influvac^® over the 2015–2016 Northern Hemisphere influenza season^{Footnote 2}.

IV.5 Conclusion

The present literature review identified evidence on the effectiveness, immunogenicity and safety of the Influvac^® TIV for pediatric use, but few studies were of stronger methodological rigor (i.e., Level I Evidence)^{Footnote 12} ^{Footnote 18} ^{Footnote 25}. No efficacy studies were identified. Despite the limited quantity and quality of the body of evidence, the overall direction of findings from the identified studies is consistent across the outcomes of interest. Influvac^® was found to be effective, immunogenic and safe in healthy children and in children with specific chronic health conditions.

Only two studies were identified that examined the effectiveness of Influvac^®. These studies did not compare Influvac^® with other influenza vaccines. A double-blind RCT found Influvac^® to be effective in reducing the risk of laboratory-confirmed influenza infection, incidence of febrile RTI, and acute otitis media among children aged 18–72 months with a previously reported physician-diagnosed RTI^{Footnote 18}. Among children 3–17 years of age, a community-based, pragmatic non-randomized controlled trial found Influvac^® to be effective against ILI compared to no vaccination^{Footnote 26}.

Several clinical trials were identified that found that Influvac^® elicited a protective immune response in healthy children^{Footnote 17} ^{Footnote 25} as well as in children with specific chronic health conditions^{Footnote 9} ^{Footnote 10} ^{Footnote 11} ^{Footnote 12} ^{Footnote 16} ^{Footnote 23}. A double-blind RCT found that Influvac^® was no less immunogenic than another licensed subunit TIV (Agrippal^® in healthy children aged 3–12 years^{Footnote 25}. In children aged 6–18 years with asthma, recipients of Influvac^® achieved statistically significantly higher serological responses compared to placebo in a double-blind RCT^{Footnote 12}. Results from a few trials with comparatively weaker study designs (i.e., pre-post study, non-randomized controlled trial), mostly in older children (e.g., six years of age and older), found that Influvac^® is able to induce elevated serological immune responses in children with ALL^{Footnote 9} ^{Footnote 10}, hemophilia^{Footnote 11}, and chronic lung disease or congenital heart disease^{Footnote 16}. A small pre-post study of children who had frequent tonsillar infections but were otherwise healthy and were not previously vaccinated for influenza found that Influvac^® may elicit a stronger immune response in naturally primed children 2–3 years of age after the first of two half doses of vaccine compared to unprimed children^{Footnote 17}. However, it should be noted that a two-dose schedule is required to achieve protection in vaccine-naïve children less than nine years of age^{Footnote 42}.

Clinical trials that reported on adverse events and vaccine safety surveillance studies found Influvac^® to be safe and well tolerated in children^{Footnote 7} ^{Footnote 8} ^{Footnote 10} ^{Footnote 13} ^{Footnote 14} ^{Footnote 15} ^{Footnote 16} ^{Footnote 19} ^{Footnote 20} ^{Footnote 21}, ^{Footnote 23} ^{Footnote 24} ^{Footnote 25} ^{Footnote 26}. Among these vaccine safety studies, few SAEs were reported in children vaccinated with Influvac^®^{Footnote 7} ^{Footnote 21}.

Evidence gaps

There is a paucity of evidence for Influvac^® use in children younger than three years of age, particularly in children aged 6–23 months. Evidence on the effectiveness and immunogenicity of Influvac^® in children younger than three years of age is limited to a few clinical trials^{Footnote 16} ^{Footnote 17} ^{Footnote 18} ^{Footnote 23}, with only two pre-post immunogenicity studies having study subjects that are entirely or mostly within this age group^{Footnote 16} ^{Footnote 17}. Only a few studies reporting on the safety of Influvac^® included children younger than three years of age^{Footnote 2} ^{Footnote 14} ^{Footnote 16} ^{Footnote 19} ^{Footnote 23}.

Evidence on how Influvac^® compares with other TIVs in children is limited to a single clinical trial of immunogenicity and safety with another subunit TIV as comparator^{Footnote 25}. No information is available on how Influvac^® compares with split virion TIV, adjuvanted TIV, or QIV.

V. List of abbreviations

Abbreviation: Term
AE: Adverse event
AEFI: Adverse events following immunization
ALL: Acute lymphoblastic leukemia
CHMP: Committee for Medicinal Products for Human Use
CI: Confidence interval
CTAB: Cetyltrimethyl-ammonium bromide
ED: Emergency department
GMFR: Geometric mean fold rise
GMT: Geometric mean titre
HA: Haemagglutinin
HBV: Hepatitis B vaccine
HHS: Department of Health and Human Services (US)
HI: Haemagglutination inhibition
ICD: International Classification of Diseases
ILI: Influenza-like illness
IM: Intramuscular
IRR: Incidence rate ratio
LAIV: Live attenuated influenza vaccine
NA: Not applicable
NACI: National Advisory Committee on Immunization
NR: Not reported
OR: Odds ratio
PCR: Polymerase chain reaction
PCV7: Heptavalent pneumococcal conjugate
PHAC: Public Health Agency of Canada
QIV: Quadrivalent inactivated influenza vaccine
RCT: Randomized controlled trial
RR: Relative risk
RTI: Respiratory tract infection
SAE: Severe adverse event
TIV: Trivalent inactivated influenza vaccine
US: United States

VI. Acknowledgments

This statement was prepared by: Dr. L. Zhao, Ms. K. Young, Dr. R. Stirling, Ms. S. Chen, Dr. I. Gemmill and approved by NACI.

Influenza Working Group Members: Dr. C. Bancej, Ms. L. Cochrane, Dr. N. Dayneka, Dr. I. Gemmill (Chair), Dr. L. Grohskopf, Ms. E. Henry, Dr. D. Kumar, Dr. J. Langley, Dr. M. Lavoie, Dr. J. McElhaney, Dr. A. McGeer, Dr. D. Moore, Dr. B. Warshawsky, Dr. J. Xiong.

NACI Members: Dr. N. Dayneka, Dr. S. Deeks, Dr. P. DeWals, Dr. R. Harrison, Dr. M. Lavoie, Dr. C. Quach-Thanh (Chair), Ms. S. Marchant-Short, Dr. C. Rotstein, Dr. M. Salvadori, Dr. B. Sander, Dr. N. Sicard, Dr. W. Vaudry (Vice-Chair), Dr. R. Warrington.

Former NACI Members: Dr. I. Gemmill, Dr. B. Henry.

Liaison Representatives: Dr. J. Brophy (Canadian Association for Immunization Research and Evaluation), Dr. E. Castillo (Society of Obstetricians and Gynaecologists of Canada), Dr. A. Cohn (Centers for Disease Control and Prevention, United States), Ms. T. Cole (Canadian Immunization Committee), Dr. J. Emili (College of Family Physicians of Canada), Dr. C. Mah (Canadian Public Health Association), Dr. D. Moore (Canadian Paediatric Society), Dr. A. Pham-Huy (Association of Medical Microbiology and Infectious Disease Canada).

Former Liaison Representatives: Dr. J. Blake (Canadian Association for Immunization Research and Evaluation)

Ex-Officio Representatives: Dr. (LCdr) K. Barnes (National Defence and the Canadian Armed Forces), Ms. G. Charos (Centre for Immunization and Respiratory Infectious Diseases, Public Health Agency of Canada), Dr. G. Coleman (Biologics and Genetic Therapies Directorate, Health Canada), Dr. J. Gallivan (Marketed Health Products Directorate, Health Canada), Ms. J. Pennock (Centre for Immunization and Respiratory Infectious Diseases, Public Health Agency of Canada), Dr. T. Wong (First Nations and Inuit Health Branch, Health Canada).

NACI gratefully acknowledges the contribution of Ms. R. Hocking, Ms. A. House, Ms. K. Merucci and Ms. T. Museau.

VII. References

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van de Witte S, Nauta J, Giezeman-Smits K, de Voogd J. Trivalent inactivated subunit influenza vaccine Influvac^®: 30-year experience of safety and immunogenicity. Trials in Vaccinology. 2012;1:42-8.

Return to footnote 1 referrer

Reference 2

Abbott Laboratories. 26th Periodic Safety Update Report: Influenza vaccine (surface antigen, inactivated). 2017.

Return to footnote 2 referrer

Reference 3

BGP Pharma. Product monograph: INFLUVAC^®: influenza vaccine, surface antigen, inactivated [Internet]. 2017. Available from: http://www.mylan.ca/-/media/mylanca/documents/english/product%20pdf/influvac-pm-2017-05-30.pdf.

Return to footnote 3 referrer

Reference 4

Therapeutic Goods Administration (Australian Government). 2016 seasonal influenza vaccines [Internet]. 2016. Available from: https://www.tga.gov.au/media-release/2016-seasonal-influenza-vaccines.

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Reference 5

European Centre for Disease Prevention and Control. Influenza vaccination [Internet]. 2017. Available from: https://ecdc.europa.eu/en/seasonal-influenza/prevention-and-control/influenza-vaccination.

Return to footnote 5 referrer

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Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, et al. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med. 2001;20(3):21-35.

Return to footnote 6 referrer

Reference 7

Aagaard L, Hansen EW, Hansen EH. Adverse events following immunization in children: retrospective analysis of spontaneous reports over a decade. Eur J Clin Pharmacol. 2011;67(3):283-8.

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Reference 8

Armstrong PK, Dowse GK, Effler PV, Carcione D, Blyth CC, Richmond PC, et al. Epidemiological study of severe febrile reactions in young children in Western Australia caused by a 2010 trivalent inactivated influenza vaccine. BMJ Open. 2011;1(1):e000016.

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Reference 9

Brydak LB, Rokicka-Milewska R, Machala M, Jackowska T. Studies on the humoral immune response to hemagglutinin of influenza vaccine in children with acute lymphoblastic leukemia after chemotherapy treatment. Int J Pediatr Hematol Oncol. 2000;7(1):29-40.

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Reference 10

Brydak LB, Rokicka-Milewska R, MacHaLa M, Jackowska T, Sikorska-Fic B. Immunogenicity of subunit trivalent influenza vaccine in children with acute lymphoblastic leukemia. Pediatr Infect Dis J. 1998;17(2):125-9.

Return to footnote 10 referrer

Reference 11

Brydak LB, Rokicka-Milewska R, Machala M, Klukowska A, Laguna P, Sikorska-Fic B. Efficacy of subunit trivalent influenza vaccine in previously vaccinated children suffering from hemophilia. Clin Microbiol Infect. 1998;4(10):589-93.

Return to footnote 11 referrer

Reference 12

Bueving HJ, Bernsen RM, de Jongste JC, van Suijlekom-Smit LW, Rimmelzwaan GF, Osterhaus AD, et al. Influenza vaccination in children with asthma: randomized double-blind placebo-controlled trial. Am J Respir Crit Care Med. 2004;169(4):488-93.

Return to footnote 12 referrer

Reference 13

Bueving HJ, Bernsen RM, de Jongste JC, van Suijlekom-Smit LW, Rimmelzwaan GF, Osterhaus AD, et al. Does influenza vaccination exacerbate asthma in children? Vaccine. 2004;23(1):91-6.

Return to footnote 13 referrer

Reference 14

Cashman P, Moberley S, Dalton C, Stephenson J, Elvidge E, Butler M, et al. Vaxtracker: active on-line surveillance for adverse events following inactivated influenza vaccine in children. Vaccine. 2014;32(42):5503-8.

Return to footnote 14 referrer

Reference 15

Cheng DR, Perrett KP, Choo S, Danchin M, Buttery JP, Crawford NW. Pediatric anaphylactic adverse events following immunization in Victoria, Australia from 2007 to 2013. Vaccine. 2015;33(13):1602-7.

Return to footnote 15 referrer

Reference 16

Daubeney P, Taylor CJ, McGaw J, Brown EM, Ghosal S, Keeton BR, et al. Immunogenicity and tolerability of a trivalent influenza subunit vaccine (Influvac) in high-risk children aged 6 months to 4 years. Br J Clin Pract. 1997;51(2):87-90.

Return to footnote 16 referrer

Reference 17

El-Madhun AS, Cox RJ, Soreide A, Olofsson J, Haaheim LR. Systemic and mucosal immune responses in young children and adults after parenteral influenza vaccination. J Infect Dis. 1998;178(4):933-9.

Return to footnote 17 referrer

Reference 18

Jansen AG, Sanders EA, Hoes AW, van Loon AM, Hak E. Effects of influenza plus pneumococcal conjugate vaccination versus influenza vaccination alone in preventing respiratory tract infections in children: a randomized, double-blind, placebo-controlled trial. J Pediatr. 2008;153(6):764.

Return to footnote 18 referrer

Reference 19

Jansen AG, Sanders EA, Smulders S, Hoes AW, Hak E. Adverse reactions to simultaneous influenza and pneumococcal conjugate vaccinations in children: randomized double-blind controlled trial. Pediatr Allergy Immunol. 2008;19(6):552-8.

Return to footnote 19 referrer

Reference 20

Petousis-Harris H, Poole T, Turner N, Reynolds G. Febrile events including convulsions following the administration of four brands of 2010 and 2011 inactivated seasonal influenza vaccine in NZ infants and children: the importance of routine active safety surveillance. Vaccine. 2012;30(33):4945-52.

Return to footnote 20 referrer

Reference 21

Pillsbury A, Cashman P, Leeb A, Regan A, Westphal D, Snelling T, et al. Real-time safety surveillance of seasonal influenza vaccines in children, Australia, 2015. Euro Surveill. 2015;20(43).

Return to footnote 21 referrer

Reference 22

Rokicka-Milewska R, Brydak LB, Machala M, Klukowska A. Antibody response to influenza vaccine in children with severe and mild hemophilia. Int J Pediatr Hematol Oncol. 2000;7(1):21-7.

Return to footnote 22 referrer

Reference 23

Shahgholi E, Ehsani MA, Salamati P, Maysamie A, Sotoudeh K, Mokhtariazad T. Immunogenicity of trivalent influenza vaccine in children with acute lymphoblastic leukemia during maintenance therapy. Pediatr Blood Cancer. 2010;54(5):716-20.

Return to footnote 23 referrer

Reference 24

Wood N, Sheppeard V, Cashman P, Palasanthiran P, Casacelli M, Cannings K, et al. Influenza vaccine safety in children less than 5 years old: the 2010 and 2011 experience in Australia. Pediatr Infect Dis J. 2012;31(2)199-202.

Return to footnote 24 referrer

Reference 25

Zhu FC, Zhou W, Pan H, Lu L, Gerez L, Nauta J, et al. Safety and immunogenicity of two subunit influenza vaccines in healthy children, adults and the elderly: a randomized controlled trial in China. Vaccine. 2008;26(35):4579-84.

Return to footnote 25 referrer

Reference 26

Ghendon YZ, Kaira AN, Elshina GA. The effect of mass influenza immunization in children on the morbidity of the unvaccinated elderly. Epidemiol Infect. 2006;134(1):71-8.

Return to footnote 26 referrer

Reference 27

Eyubova A, Nasrullayeva GM. Combined use of the Influvac vaccine and immunomodulator IRS-19 in the prophylaxis and treatment of viral respiratory infections. Azerbaycan Metabolizm Jumali. 2001;27-30.

Return to footnote 27 referrer

Reference 28

Klukowska A, Brydak LB, Laguna P, Machala M, Sikorska-Fic B, Rokicka-Milewska R. Immunologcial response to influenza vaccination of hemophiliac children. Ac Hematol Pol. 1998;29(1):115-20.

Return to footnote 28 referrer

Reference 29

Uchaykin VF, Schamscheva OV, Novikova IN, Arzamasteva YY. Use of ribomunil as combination prophylaxis of influenza and acute respiratory diseases in children. Pediatriya. 2006;6.

Return to footnote 29 referrer

Reference 30

Kelly H, Carcione D, Dowse G, Effler P. Quantifying benefits and risks of vaccinating Australian children aged six months to four years with trivalent inactivated seasonal influenza vaccine in 2010. Euro Surv. 2010;15(37).

Return to footnote 30 referrer

Reference 31

Blyth CC, Currie AJ, Wiertsema SP, Conway N, Kirkham LA, Fuery A, et al. Trivalent influenza vaccine and febrile adverse events in Australia, 2010: clinical features and potential mechanisms. Vaccine. 2011;29(32):5107-13.

Return to footnote 31 referrer

Reference 32

Stokes B. Ministerial review into the public health response into the adverse events to the seasonal influenza vaccine. Final report to the Minister for Health [Internet]. 2010. Available from: http://www.health.wa.gov.au/publications/documents/Stokes_Report.pdf.

Return to footnote 32 referrer

Reference 33

Davies JR, Grilli EA. Natural or vaccine-induced antibody as a predictor of immunity in the face of natural challenge with influenza viruses. Epidemiol Infect. 1989;102(2):325-33.

Return to footnote 33 referrer

Reference 34

Schaad UB, Buhlmann U, Burger R, Ruedeberg A, Wilder-Smith A, Rutishauser M, et al. Comparison of immunogenicity and safety of a virosome influenza vaccine with those of a subunit influenza vaccine in pediatric patients with cystic fibrosis. Antimicrob Agents Chemother. 2000;44(5):1163-7.

Return to footnote 34 referrer

Reference 35

Committee for Proprietary Medicinal Products (CPMP). Note for guidance on harmonisation of requirements for influenza vaccines [Internet]. 1997. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003945.pdf.

Return to footnote 35 referrer

Reference 36

Committee for Medicinal Products for Human Use. Guideline on influenza vaccines: non-clinical and clinical module. 2016. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/07/WC500211324.pdf.

Return to footnote 36 referrer

Reference 37

Verschoor CP, Singh P, Russell ML, Bowdish DM, Brewer A, Cyr L, et al. Microneutralization assay titres correlate with protection against seasonal influenza H1N1 and H3N2 in children. PloS One. 2015;10(6):e0131531.

Return to footnote 37 referrer

Reference 38

Monto AS, Petrie JG, Cross RT, Johnson E, Liu M, Zhong W, et al. Antibody to influenza virus neuraminidase: an independent correlate of protection. J Infect Dis. 2015;212(8):1191-9.

Return to footnote 38 referrer

Reference 39

Wijnans L, Voordouw B. A review of the changes to the licensing of influenza vaccines in Europe. Influenza Other Respir Viruses. 2016;10(1):2-8.

Return to footnote 39 referrer

Reference 40

Granström M, Voordouw AC. Registration of influenza vaccines for children in Europe. Vaccine. 2011;29(43):7572-5.

Return to footnote 40 referrer

Reference 41

US Department of Health and Human Services. Guidance for industry: clinical data needed to support the licensure of seasonal inactivated influenza vaccines [Internet]. 2007. Available from: https://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/vaccines/ucm074794.htm.

Return to footnote 41 referrer

Reference 42

National Advisory Committee on Immunization (NACI). Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2017–2018 [Internet]. 2017. Available from: https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2017-2018.html.

Return to footnote 42 referrer

Reference 43

Therapeutic Goods Administration (Australian Government). Seasonal flu vaccine: investigation into febrile reactions in young children following 2010 seasonal trivalent influenza vaccination [Internet]. 2010. Available from: https://www.tga.gov.au/alert/seasonal-flu-vaccine-investigation-febrile-reactions-young-children-following-2010-seasonal-trivalent-influenza-vaccination.

Return to footnote 43 referrer

Appendix A: Characteristics of influenza vaccines available for use in Canada, 2017–2018^{Footnote *}

Manufacturer and Product name	BGP Pharma ULC (Mylan) Influvac^®	GSK Fluviral^®	Seqirus Agriflu^®	Seqirus Fluad Pediatric^® and Fluad^®	Sanofi Pasteur Vaxigrip^®	Sanofi Pasteur Fluzone^®	Sanofi Pasteur Fluzone^® High-Dose	AstraZeneca FluMist^® Quadrivalent	GSK Flulaval^® Tetra	Sanofi Pasteur Fluzone^® Quadrivalent
Vaccine preparations	TIV	TIV	TIV	TIV	TIV	TIV	TIV	LAIV	QIV	QIV
Vaccine type	Inactivated, surface antigen subunit	Inactivated, split virus	Inactivated, subunit	Inactivated, subunit	Inactivated, split virus	Inactivated, split virus	Inactivated, split virus	Live attenuated	Inactivated, split virus	Inactivated, split virus
Route of administration	IM^{Footnote **}	IM	IM	IM	IM	IM	IM	Intranasal spray	IM	IM
Authorized ages for use	≥3 years^{Footnote ***}	≥6 months	≥6 months	Pediatric: 6–23 months Adult: ≥65 years	≥6 months	≥6 months	≥65 years	2–59 years	≥6 months	≥6 months
Antigen content (each of strains)	15 µg HA per 0.5 mL dose	15 µg HA per 0.5 mL dose	15 µg HA per 0.5 mL dose	Pediatric: 7 µg HA per 0.25 mL dose Adult: 15 µg HA per 0.5 mL dose	15 µg HA per 0.5 mL dose	15 µg HA per 0.5 mL dose	60 µg HA per 0.5 mL dose	106.5-7.5 fluorescent focus units of live attenuated reassortants per 0.2 mL dose given as 0.1 mL in each nostril	15 µg HA per 0.5 mL dose	15 µg HA per 0.5 mL dose
Adjuvant	No	No	No	MF59 (oil-in-water emulsion)	No	No	No	No	No	No
Formats available	Single dose pre-filled syringes with Luer tip	5 mL multi-dose vial	5 mL multi-dose vial Single dose pre-filled syringes without a needle	Single dose pre-filled syringes without a needle	5 mL multi-dose vial Single dose ampoule Single-dose pre-filled syringes with or without a needle	5 mL multi-dose vial Single dose ampoule Single dose pre-filled syringes without a needle	Single dose pre-filled syringes	Prefilled single use glass sprayer	5 mL multi-dose vial	5 mL multi-dose vial Single dose vials Single dose pre-filled syringes without attached needle
Post puncture shelf life for multi-dose vials	NA	28 days	28 days	NA	7 days	28 days	NA	NA	28 days	Up to expiry date indicated on vial label
Thimerosal	No	Yes	Yes (multi-dose vials only)	No	Yes (multi-dose vials only)	Yes (multi-dose vials only)	No	No	Yes	Yes (multi-dose vials only)
Antibiotics (traces)	Gentamicin	None	Kanamycin Neomycin	Kanamycin Neomycin	Neomycin	None	None	Gentamicin	None	None
*Other clinically relevant non-medicinal ingredients^{Footnote }**	Egg protein, Chicken protein, Formalde-hyde, CTAB, Polysorbate 80	Egg protein, α-tocopheryl hydrogen succinate, Polysorbate 80, Formalde-hyde, Ethanol, Sodium deoxy-cholate, Sucrose	Egg protein, Formalde-hyde, Polysorbate 80, CTAB	Egg protein, Formalde-hyde, Polysorbate 80, CTAB	Egg protein, Formalde-hyde, Triton X-100	Egg protein, Formalde-hyde, Triton X-100, Gelatin, Sucrose	Formalde-hyde, Egg protein, Triton X-100	Egg protein, Gelatin hydrosylate, Sucrose, Arginine, Monosodium glutamate	Egg protein, α-tocopheryl hydrogen succinate, Polysorbate 80, Formalde-hyde, Ethanol, Sodium deoxy-cholate, Sucrose	Egg protein, Formaldehyde, Triton X-100, Sucrose
Abbreviations: CTAB, cetyltrimethyl-ammonium bromide; HA, haemagglutinin; IM, intramuscular; LAIV, live attenuated influenza vaccine; NA, not applicable; QIV, quadrivalent inactivated influenza vaccine; TIV, trivalent inactivated influenza vaccine. Table 1 - Footnote * Full details of the composition of each vaccine authorized for use in Canada and a brief description of its manufacturing process can be found in the product monograph. Return to Table 1 - Footnote * referrer Table 1 - Footnote Refer to product monograph for alternate route(s) of administration. Return to Table 1 - Footnote referrer Table 1 - Footnote * Change in authorized age indication for the 2017–2018 influenza season. Return to Table 1 - Footnote * referrer

Appendix B: NACI recommendations: Strength of recommendation and grade of evidence

Strength of NACI recommendation	Grade of evidence
Based on factors not isolated to strength of evidence (e.g. public health need)	Based on assessment of the body of evidence
Strong “should/should not be offered” Known/Anticipated advantages outweigh known/anticipated disadvantages (“should”), OR Known/Anticipated disadvantages outweigh known/anticipated advantages (“should not”) Implication: A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present	A - good evidence to recommend
	B - fair evidence to recommend
	C - conflicting evidence, however other factors may influence decision-making
	D - fair evidence to recommend against
	E - good evidence to recommend against
	I - insufficient evidence (in quality or quantity), however other factors may influence decision-making
Discretionary “may be considered” Known/Anticipated advantages closely balanced with known/anticipated disadvantages, OR uncertainty in the evidence of advantages and disadvantages exists Implication: A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.	A - good evidence to recommend
	B - fair evidence to recommend
	C - conflicting evidence, however other factors may influence decision-making
	D - fair evidence to recommend against
	E - good evidence to recommend against
	I - insufficient evidence (in quality or quantity), however other factors may influence decision-making

Appendix C: Search strategy and results

Set #	Searches	Results
EMBASE (1974 to 20 June 2017), Global Health (1973 to 20 June 2017) and MEDLINE (1947 to 20 June 2017)
1	influenza vaccine/ or influenza vaccination/	55633
2	exp influenza/pc or exp Influenza virus/pc	36160
3	(exp influenza/ or exp Influenza virus/) and (vaccine/ or virus vaccine/ or inactivated virus vaccine/ or vaccination/)	37518
4	((flu or influenza* or H?N? or (trivalent or inactiv* subunit)) and (vaccin or immuni?ation*)).tw,kw.	104418
5	or/1-4 [Flu Vaccine]	128519
6	(abbott or solvay or BGP Pharma or Mylan).mf,ad,tn,ti,ab.	51292
7	5 and 6 [Flu Vaccine by Abbott or Solvay]	389
8	influvac*.af.	349
9	7 or 8 [Influvac or suspected Influvac]	576
10	limit 9 to (infant <to one year> or child <unspecified age> or preschool child <1 to 6 years> or school child <7 to 12 years> or adolescent <13 to 17 years>) [Limit not valid in Global Health,Ovid MEDLINE(R),Ovid MEDLINE(R) Daily Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; records were retained]	112
11	juvenile/ or exp child/ or exp adolescent/	5959007
12	(baby or babies or infan* or child* or youth* or juvenile* or adolescen* or p?ediatric*).tw,kw.	4505804
13	9 and (11 or 12)	120
14	10 or 13 [Influvac + Children]	162
15	limit 14 to (english or french)	137
16	(baby or babies or infan* or child* or youth* or juvenile* or adolescen* or p?ediatric*).mp.	7812184
17	11 or 16	8047584
18	9 and (11 or 16)	128
19	10 or 18	170
20	limit 19 to (english or french) [Expanding Pediatric Limit]	144
21	20 use oemezd	92
22	Influenza Vaccines/	44253
23	Influenza, Human/pc [Prevention & Control]	18537
24	(Influenza, Human/ or exp influenzavirus a/ or exp influenzavirus b/) and exp vaccines/	23917
25	((flu or influenza* or H?N? or (trivalent or inactiv* subunit)) and (vaccin or immuni?ation*)).tw,kf.	103905
26	or/22-25 [Flu Vaccine]	120373
27	(abbott or solvay or BGP Pharma or Mylan).af.	90837
28	26 and 27 [Flu Vaccine by Abbott or Solvay or BGP Pharma]	497
29	influvac*.af.	349
30	28 or 29 [Influvac or suspected Influvac]	683
31	limit 30 to "all child (0 to 18 years)" [Limit not valid in Embase,Global Health; records were retained]	615
32	exp Pediatrics/ or exp Infant/ or exp Child/ or Adolescent/	6510773
33	(baby or babies or infan* or child* or youth* or juvenile* or adolescen* or p?ediatric*).tw,kw.	4505804
34	30 and (32 or 33)	144
35	31 or 34 [Influvac + Children]	618
36	(baby or babies or infan* or child* or youth* or juvenile* or adolescen* or p?ediatric*).mp.	7812184
37	30 and (32 or 36)	151
38	31 or 37	618
39	limit 38 to (english or french)	560
40	39 use ppezv	17
41	exp influenza viruses/ or influenzavirus a/ or influenzavirus b/	103893
42	exp vaccination/ or exp vaccines/ or exp immunization/	780965
43	((flu or influenza* or H?N? or (trivalent or inactiv* subunit)) and (vaccin or immuni?ation*)).mp.	134380
44	(41 and 42) or 43	134619
45	(abbott or solvay or BGP Pharma or Mylan).af.	90837
46	44 and 45	576
47	influvac*.af.	349
48	46 or 47	757
49	exp children/ or exp adolescents/ or exp infants/ or exp paediatrics/	6030218
50	(baby or babies or infan* or child* or youth* or juvenile* or adolescen* or p?ediatric*).mp.	7812184
51	48 and (49 or 50)	166
52	limit 51 to (english or french)	148
53	52 use cagf	13
54	21 or 40 or 53	122
55	remove duplicates from 54	106
International Pharmaceutical Abstracts (1970 to 29 June 2017)
1	("influenza vaccines" or (influenza and vaccines)).sh,hw.	1695
2	((flu or influenza* or H?N? or (trivalent or inactiv* subunit)) and (vaccin or immuni?ation*)).mp.	2482
3	1 or 2	2482
4	(abbott or solvay or BGP Pharma or Mylan).mp.	241
5	3 and 4	1
6	Influvac*.mp.	14
7	5 or 6	15
8	(baby or babies or infan* or child* or youth* or juvenile* or adolescen* or p?ediatric*).mp.	35612
9	7 and 8	0
1	("influenza vaccines" or (influenza and vaccines)).sh,hw.	1695
2	((flu or influenza* or H?N? or (trivalent or inactiv* subunit)) and (vaccin or immuni?ation*)).mp.	2482
3	1 or 2	2482
4	(abbott or solvay or BGP Pharma or Mylan).mp.	241
5	3 and 4	1
ProQuest Public Health Database (1963 to 29 June 2017)
-	(((((ti,ab,ft(flu OR influenza* OR H?N? OR (trivalent OR inactiv* subunit)) AND (vaccin OR immuni?ation)) OR mesh.Exact("Influenza Vaccines")) OR ((mesh.Exact("Influenza, Human" OR "influenzas a" OR "influenzas b") OR SU.EXACT("Influenza")) AND (SU.EXACT("Immunization") OR SU.EXACT("Vaccines") OR mesh.Exact("vaccines")))) AND ti,ab,ft((abbott OR solvay OR "BGP Pharma" OR Mylan) NEAR/5 vaccin)) OR ti,ab,ft(influvac)) AND (SU.EXACT("Children & youth") OR SU.EXACT("Newborn babies") OR SU.EXACT("Babies") OR SU.EXACT("Teenagers") OR mesh.Exact("Pediatrics" OR "Infant" OR "Child" OR "Adolescent") OR ti,ab(baby OR babies OR infan OR child* OR youth* OR juvenile* OR adolescen* OR p?ediatric*)) AND stype.exact("Scholarly Journals") AND la.exact("English" OR "French")	43
Scopus (1960 to 29 June 2017)
-	((TITLE-ABS-KEY(((flu OR influenza* OR h?n? OR (trivalent OR inactiv* AND subunit)) AND (vaccin OR immunisation* OR immunization))) AND TITLE-ABS-KEY((abbott OR solvay OR "bgp pharma" OR mylan) W/3 vaccin)) OR ALL(influvac)) AND TITLE-ABS-KEY(baby OR babies OR infan OR child* OR youth* OR juvenile* OR adolescen* OR pediatric* OR paediatric*) AND LANGUAGE(English OR French)	117

Appendix D: Level of evidence based on research design and quality (internal validity) rating of evidence

Table D1: Ranking individual studies: levels of evidence based on research design
Level	Description
I	Evidence from randomized controlled trial(s).
II-1	Evidence from controlled trial(s) without randomization.
II-2	Evidence from cohort or case-control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy.
II-3	Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence.
III	Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees.

Table D2: Ranking individual studies: quality (internal validity) rating of evidence
Level	Quality Rating
Good	A study (including meta-analyses or systematic reviews) that meets all design-specific criteria^{Footnote *} well.
Fair	A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion^{Footnote *} but has no known "fatal flaw".
Poor	A study (including meta-analyses or systematic reviews) that has at least one design-specific^{Footnote *} "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.
Table D2 - Footnote * General design-specific criteria are outlined in Harris et al. (2001)^{Footnote 6}. Return to Table D2 - Footnote * referrer

Appendix E: Flow diagram of the study selection process for literature evidence on the efficacy and effectiveness, immunogenicity and safety of the Influvac^® trivalent inactivated influenza vaccine in children

Figure 1 - Text Equivalent

The attrition flow diagram describes the process by which articles were selected for the literature review. The process is broken down into four stages: Identification, Screening, Eligibility and Included.

Stage 1: Identification

171 records were identified through the database search. 30 records were identified through additional sources.

199 records remained after the duplicates were removed from the 201 records.

Stage 2: Screening

199 records were screened.

Of these 199 records, 107 records were excluded.

Stage 3: Eligibility

92 full-text articles were assessed for eligibility.

Of these 92 full-text articles, 72 full-text articles were excluded. The exclusion breakdown is as follows:

51 non-relevant
13 secondary research
3 not in English or French
3 other (2 superseded by an included study and 1 in vitro analysis)
2 no full text available

Stage 4: Included

Of the 92 full-text articles assessed for eligibility, 21 studies were included in the synthesis. There were 18 primary references (1 unpublished data) and 3 supplementary analyses.

Appendix F: Summary of literature evidence related to the efficacy and effectiveness of Influvac^® trivalent inactivated influenza vaccine in children

Study Details					Summary
Study	Study design	Influenza vaccine	Participants	Summary of key findings	Level of evidence	Quality
Ghendon et al. (2006)^{Footnote 26}	Design Non-randomized controlled trial Influenza season 2001–2002 Location Russia Follow-up Morbidity: 4 months post-vaccination (December 2001–March 2002) Adverse events: 3–5 days post-vaccination	Influenza vaccine Influvac^® TIV Dose and administration 1 dose (15 µg per strain) Strains 2001–2002 formulation: A/New Caledonia/20/99 (H1N1) A/Moscow/10/99 (H3N2) B/Sichuan/379/99	Population definition Healthy children without contraindications Study groups Intervention: Mass immunization campaign (coverage rate 69.7%) Control: No immunization campaign (coverage rate <1.0%) Sample size Intervention: n=40,611 Control: n=60,946 Age 3–17 years Sex NR	Incidence rate of ILI defined as sudden onset of fever >38°C and cough or sore throat Morbidity 3–6 years of age Intervention: 14.8% Control: 37.9% 7–17 years of age Intervention: 6.4% Control: 20.5% Total Intervention: 7.7% Control: 23.6% Vaccine effectiveness Definition: Difference in attack rate of ILI between non-immunized and immunized children divided by attack rate of ILI in non-immunized children only 3–6 years of age: 60.9% (p<0.001) 7–17 years of age: 68.8% (p<0.001) Total: 63.7% (p<0.001)	Level II-1	NA
Jansen et al. (2008a)^{Footnote 18} Supplemented with additional details from Jansen et al. (2008b)^{Footnote 19} on AEFI.	Design Double-blind RCT (placebo-controlled) Influenza seasons 2003–2004 2004–2005 2005–2006 Location The Netherlands Follow-up 2003–2004 and 2004–2005 seasons: 18 months post-vaccination 2005–2006 season: 6 months post-vaccination Adverse events: 7 days post-vaccination	Influenza vaccine Influvac^® TIV Dose and administration 2 doses, 4–8 weeks apart 2003–2004 and 2004–2005 cohorts received an additional vaccination in the following year Strains 2003–2004 formulation: A/New Caledonia/20/99 (H1N1) A/Moscow/10/99 (H3N2) B/Hong Kong/330/01 2004–2005 formulation: A/New Caledonia/20/99 (H1N1) A/Fuijan/411/2002 (H3N2) B/Shanghai/361/2002 2005–2006 formulation: A/New Caledonia/20/99 (H1N1) A/California/7/2004 (H3N2) B/Shanghai/361/2002	Population definition Unvaccinated children aged 18–72 months with previously diagnosed RTI Study groups TIV plus PCV7 TIV plus placebo HBV plus placebo (control) Sample size TIV plus PCV7: n=197 TIV plus placebo: n=187 HBV plus placebo (control): n=195 Age (mean) TIV plus PCV7: 3.0 years TIV plus placebo: 3.1 years HBV plus placebo (control): 3.1 years Sex TIV plus PCV7: 41.4% female TIV plus placebo: 44.4% female HBV plus placebo: 49.7% female The study groups were similar with regard to age, sex and medical history.	Primary outcome Febrile RTI defined as having fever ≥38.0°C for at least two consecutive days accompanied by at least two signs of RTI (general weakness/malaise, rhinitis, sore throat, ear-ache, coughing, wheezing/shortness of breath, shivering/muscle aches) with a moderate or severe severity score. Incidence rate (per 1000 days) (95% CI) TIV plus PCV7: 5.2 (4.2–6.5) TIV plus placebo: 6.0 (5.0–7.2) HBV plus placebo (control): 6.9 (5.9–8.2) Incidence rate ratio (95% CI) TIV plus PCV7 vs. HBV plus placebo (control): 0.76 (0.58–0.99) TIV plus placebo vs. HBV plus placebo (control): 0.87 (0.68–1.12) Secondary outcomes Laboratory-confirmed influenza defined by the presence of influenza A or B as determined by real-time PCR of a nasopharyngeal swab. A swab was only taken if a child’s parent reported febrile RTI. Of the children who received Influvac^® plus PCV7, 4% had confirmed influenza, while 9% of children in the control group (HBV plus placebo) had laboratory-confirmed influenza. The relative risk for patients who received Influvac^® plus PCV7 compared to those who received HBV plus placebo was 0.48 (95% CI: 0.25–0.93). Of the children who received Influvac^® plus placebo, 5% had confirmed influenza, while 9% of children in the control group (HBV plus placebo) had laboratory-confirmed influenza. The relative risk for patients who received Influvac^® compared to those who received HBV plus placebo was 0.49 (95% CI: 0.25–0.97). Findings by influenza virus type were not reported. Primary care visit defined as a visit to a general practitioner’s office. Incidence rate (per 1000 days) (95% CI) TIV plus PCV7: 2.2 (1.6–3.0) TIV plus placebo: 2.0 (1.4–2.7) HBV plus placebo (control): 2.9 (2.3–3.7) Incidence rate ratio (95% CI) TIV plus PCV7 vs. HBV plus placebo (control): 0.75 (0.50–1.12) TIV plus placebo vs. HBV plus placebo (control): 0.67 (0.45–1.02) Antibiotic prescription defined as the prescription of an antibiotic resulting from febrile RTI episode Incidence rate (per 1000 days) (95% CI) TIV plus PCV7: 1.0 (0.6–1.6) TIV plus placebo: 1.2 (0.8–1.9) HBV plus placebo (control): 1.4 (0.9–2.1) Incidence rate ratio (95% CI) TIV plus PCV7 vs. HBV plus placebo (control): 0.73 (0.40–1.32) TIV plus placebo vs. HBV plus placebo (control): 0.89 (0.50–1.61) Acute otitis media defined as a physician-diagnosed episode of acute otitis media Incidence rate (per 1000 days) (95% CI) TIV plus PCV7: 0.5 (0.3–1.0) TIV plus placebo: 0.4 (0.2–0.8) HBV plus placebo (control): 1.2 (0.8–1.9) Incidence rate ratio (95% CI) TIV plus PCV7 vs. HBV plus placebo (control): 0.43 (0.20–0.94) TIV plus placebo vs. HBV plus placebo (control): 0.29 (0.12–0.70) Notes Effects of influenza vaccination outside of the influenza seasons are not presented.	Level I	Fair 14–20% loss to follow up.
Abbreviations: Refer to section V. List of abbreviations.

Appendix G: Summary of literature evidence related to the immunogenicity of Influvac^® trivalent inactivated influenza vaccine in children

Study Details	Summary
Brydak et al. (2000)^{Footnote 9}	Design Pre-post study Location Poland Follow-up 3 weeks and 6 weeks post-vaccination	Influenza vaccine Influvac^® TIV Dose and administration 1 dose (15 µg per strain) Strains 1996–1997 formulation: A/Singapore/6/86 (H1N1) A/Wuhan/359/95 (H3N2) B/Beijing/184/93	Population definition Children with ALL (groups A and B) Study groups A: Chemotherapy completed before 1991 B: Chemotherapy completed after 1991 Unvaccinated controls (healthy children) Sample size Group A: n=10 Group B: n=12 Controls: n=22 Age 6–13 years Sex NR	3 week post-vaccination: GMT Group A H1N1: 37.3 H3N2: 52.8 B: 80.0 Group B H1N1: 33.6 H3N2: 40.0 B: 75.5 Controls H1N1: 3.1–3.3 H3N2: 1.3–1.8 B: 1.2–2.7 GMFR Group A H1N1: 18.7 H3N2: 11.5 B: 20.5 Group B H1N1: 18.7 H3N2: 25.0 B: 37.8 Controls H1N1: 2.4–2.8 H3N2: <1.0 B: <1.0–2.0 Seroprotection rate Group A H1N1: 60.0% H3N2: 80.0% B: 100.0% Group B H1N1: 41.7% H3N2: 50.0% B: 83.3% Controls H1N1: 0.0–8.3% H3N2: 0.0% B: 0.0% Seroconversion rate Group A H1N1: 60.0% H3N2: 80.0% B: 100.0% Group B H1N1: 41.7% H3N2: 50.0% B: 83.3% Controls H1N1: 0.0–10.0% H3N2: 0.0% B: 0.0–8.3% 6 month post-vaccination: GMT Group A H1N1: 65.0 H3N2: 91.9 B: 113.1 Group B H1N1: 26.2 H3N2: 100.8 B: 134.5 Controls H1N1: 3.7–4.8 H3N2: 7.1–7.9 B: 33.6–34.8 GMFR Group A H1N1: 32.5 H3N2: 20.0 B: 29.0 Group B H1N1: 14.6 H3N2: 63.0 B: 67.3 Controls H1N1: 3.1–3.7 H3N2: 2.3–2.6 B: 17.7–26.7 Seroprotection rate Group A H1N1: 90.0% H3N2: 100.0% B: 100.0% Group B H1N1: 41.7% H3N2: 100.0% B: 83.3% Controls H1N1: 8.3–10.0% H3N2: 8.3–10.0% B: 50.0% Seroconversion rate Group A H1N1: 90.0% H3N2: 100.0% B: 100.0% Group B H1N1: 41.7% H3N2: 100.0% B: 83.3% Controls H1N1: 8.3–10.0% H3N2: 0.0–10.0% B: 16.7–50.0% Notes Subjects were vaccinated with FluShield^® (Wyeth) in the 1993–1994 influenza season and with Influvac^® in the 1996–1997 influenza season. Data for the 1996–1997 influenza season is presented. Results are also available for subjects vaccinated for the first time in the 1996–1997 influenza season, but are not presented. Though not stated explicitly in the article, the study subjects likely overlap with Brydak et al. (1998a)^{Footnote 10}	Level III	NA
Brydak et al. (1998a)^{Footnote 10}	Design Pre-post study Location Poland Follow-up 3 weeks and 6 weeks post-vaccination	Influenza vaccine Influvac^® TIV Dose and administration 1 dose (15 µg per strain) Strains 1996–1997 formulation: A/Singapore/6/86 (H1N1) A/Wuhan/359/95 (H3N2) B/Beijing/184/93	Population definition Children with ALL (groups A and B) Study groups A: Vaccinated in the 1993–1994 influenza season B: Unvaccinated prior to the 1996–1997 influenza season Unvaccinated controls (healthy children) Sample size Group A: n=25 Group B: n=20 Controls: n=23 Age Group A: 7–16 years Group B: 7–11 years Controls: 8–15 years Sex NR	3 week post-vaccination: GMT Group A H1N1: 35.8 H3N2: 44.7 B: 80.0 Group B H1N1: 42.9 H3N2: 62.8 B: 77.3 Controls H1N1: 3.0 H3N2: 1.8 B: 2.8 GMFR Group A H1N1: 18.8 H3N2: 17.2 B: 26.7 Group B H1N1: 22.6 H3N2: 15.7 B: 15.8 Controls H1N1: 2.1 H3N2: NA B: 1.5 Seroprotection rate Group A H1N1: 52.0% H3N2: 64.0% B: 92.0% Group B H1N1: 55.0% H3N2: 85.0% B: 75.0% Controls H1N1: 4.3% H3N2: 0.0% B: 0.0% Seroconversion rate Group A H1N1: 52.0% H3N2: 60.0% B: 92.0% Group B H1N1: 55.0% H3N2: 80.0% B: 70.0% Controls H1N1: 4.3% H3N2: 0.0% B: 0.0% 6 month post-vaccination: GMT Group A H1N1: 41.9 H3N2: 91.9 B: 114.7 Group B H1N1: 74.6 H3N2: 121.3 B: 149.3 Controls H1N1: 4.5 H3N2: 6.7 B: 23.0 GMFR Group A H1N1: 22.1 H3N2: 35.3 B: 38.2 Group B H1N1: 39.3 H3N2: 30.3 B: 30.5 Controls H1N1: 3.2 H3N2: 2.3 B: 12.1 Seroprotection rate Group A H1N1: 68.0% H3N2: 100.0% B: 92.0% Group B H1N1: 90.0% H3N2: 100.0% B: 100.0% Controls H1N1: 8.7% H3N2: 4.3% B: 30.4% Seroconversion rate Group A H1N1: 68.0% H3N2: 100.0% B: 92.0% Group B H1N1: 90.0% H3N2: 100.0% B: 95.0% Controls H1N1: 8.7% H3N2: 4.3% B: 30.4% Notes Though not stated explicitly in the article, the study subjects likely overlap with Brydak et al. (2000)^{Footnote 9}. The controls included in this study are the same subjects as the controls in Brydak et al. (1998b)^{Footnote 11}.	Level III	NA
Brydak et al. (1998b)^{Footnote 11} Supplemented with additional details from Rokicka-Milewska et al. (1999)^{Footnote 22} on the stratified analysis by severity of hemophilia (mild vs. severe).	Design Pre-post study Location Poland Follow-up 3 weeks and 6 weeks post-vaccination	Influenza vaccine Influvac^® TIV Dose and administration 1 dose (15 µg per strain) Strains 1996–1997 formulation: A/Singapore/6/86 (H1N1) A/Wuhan/359/95 (H3N2) B/Beijing/184/93	Population definition Children with hemophilia who have previously been vaccinated for influenza in the 1993–1994 season Study groups Hemophiliac patients Unvaccinated controls (healthy children) Sample size Hemophiliac patients: n=38 (n=26 severe and 12 mild) Controls: n=23 Age Hemophiliac patients: 10–19 years Controls: 8–15 years Sex NR	3 week post-vaccination: GMT Hemophiliac patients H1N1: 28.3 H3N2: 29.3 B: 35.2 Controls H1N1: 3.0 H3N2: 1.8 B: 2.8 GMFR Hemophiliac patients H1N1: 6.7 H3N2: 10.9 B: 3.9 Controls H1N1: 2.1 H3N2: <1.0 B: 1.5 Seroprotection rate Hemophiliac patients H1N1: 57.9% H3N2: 52.6% B: 60.5% Controls H1N1: 4.3% H3N2: 0.0% B: 0.0% Seroconversion rate Hemophiliac patients H1N1: 42.1% H3N2: 42.1% B: 39.5% Controls H1N1: 4.3% H3N2: 0.0% B: 0.0% 6 month post-vaccination: GMT Hemophiliac patients H1N1: 45.7 H3N2: 77.1 B: 75.3 Controls H1N1: 4.5 H3N2: 6.7 B: 23.0 GMFR Hemophiliac patients H1N1: 10.9 H3N2: 28.6 B: 8.4 Controls H1N1: 3.2 H3N2: 2.3 B: 12.1 Seroprotection rate Hemophiliac patients H1N1: 76.3% H3N2: 92.1% B: 97.4% Controls H1N1: 8.7% H3N2: 4.3% B: 30.4% Seroconversion rate Hemophiliac patients H1N1: 71.1% H3N2: 84.2% B: 86.8% Controls H1N1: 8.7% H3N2: 4.3% B: 30.4% Stratified analysis by severity of hemophilia Patients with mild and severe hemophilia had similar GMTs and GMFRs for influenza A and B strains at 6 months post-vaccination. Seroprotection and seroconversion rates were similar for both groups for influenza A(H3N2) and B; however, patients with severe hemophilia had a lower rate of seroprotection compared to patients with mild hemophilia for influenza A(H1N1) at 3 weeks and 6 months post-vaccination (61.5–65.4% vs. 83.3%). Patients with severe hemophilia also had lower rates of seroconversion for influenza A(H1N1) compared to patients with mild hemophilia at 3 weeks and 6 months post-vaccination (46.2–53.8% vs. 66.7%). Notes The controls included in this study are the same subjects as the controls in Brydak et al. (1998a)^{Footnote 10}.	Level III	NA
Bueving (2004a)^{Footnote 12} Supplemented with additional details from Bueving et al. (2004b)^{Footnote 13} on AEFI and asthma exacerbation following vaccination.	Design Double-blind RCT (placebo-controlled) Location The Netherlands Follow-up 14–21 days and 4–5 months post-vaccination Adverse events: 7 days post-vaccination (findings presented in Appendix H)	Influenza vaccine Influvac^® TIV (reported as a Solvay TIV) Dose and administration 1 dose (15 µg per strain) Strains 1999–2000 formulation: A/Beijing/262/95-like (H1N1) A/Sydney/5/97-like (H3N2) B/Beijing/184/93-like 2000–2001 formulation: A/New Caledonia/20/99 (H1N1) A/Moscow/10/99-like (H3N2) B/Beijing/184/93-like Children could only participate in one of the two seasons	Population definition Children 6–18 years of age with asthma, without other chronic diseases Sample size Vaccine: n=347 Placebo: n=349 Age (mean) Vaccine: 10.5 years Placebo: 10.6 years Sex Vaccine: 48.1% female Placebo: 43.6% female	14–21 days post-vaccination: GMT Vaccine H1N1: 200.7 H3N2: 227.1 B: 358.4 Placebo H1N1: 23.0 H3N2: 79.4 B: 157.6 Vaccine vs. placebo (p-value) H1N1: <0.001 H3N2: <0.001 B: <0.001 Seroprotection rate Vaccine H1N1: 85.6% H3N2: 98.5% B: 95.3% Placebo H1N1: 38.9% H3N2: 79.2% B: 87.7% Vaccine vs. placebo (p-value) H1N1: <0.001 H3N2: <0.001 B: <0.001 Seroconversion rate Vaccine H1N1: 59.9% H3N2: 27.1% B: 26.5% Placebo H1N1: 0.9% H3N2: 1.2% B: 0.0% Vaccine vs. placebo (p-value) H1N1: <0.001 H3N2: <0.001 B: <0.001 4–5 months post-vaccination: GMT Vaccine H1N1: 188.0 H3N2: 186.3 B: 1.8 Placebo H1N1: 38.0 H3N2: 88.3 B: 0.9 Vaccine vs. placebo (p-value) H1N1: <0.001 H3N2: <0.001 B: <0.001 Seroconversion rate* Vaccine H1N1: 7.0% H3N2: 1.2% B: 1.8% Placebo H1N1: 17.5% H3N2: 4.0% B: 0.9% Vaccine vs. placebo (p-value) H1N1: <0.001 H3N2: 0.03 B: 0.26 * Seroconversion at 4–5 months post-vaccination was calculated by comparing the sample taken at 4–5 months post-vaccination to the sample taken at 14–21 days post-vaccination.	Level I	Fair Conducted per-protocol analyses.
Daubeney et al. (1997)^{Footnote 16}	Design Pre-post study Location United Kingdom Follow-up Up to 72 hours post-vaccination	Influenza vaccine Influvac^® TIV Dose and administration 2 doses (7.5 µg per strain), 4 weeks apart Strains A/Singapore/6/86 (H1N1) A/Shangdong/9/93 (H3N2) B/Panama/45/90	Population definition Children with chronic respiratory disease, congenital heart disease, or both. Sample size n=52 Age Mean (range): 19.5 months (6 months–4 years) Sex NR	GMT GMT pre-vaccination (95% CI) H1N1: 5.2 (4.8–5.6) H3N2: 13.1 (8.7–19.6) B: 6.2 (5.1–7.6) GMT post-vaccination (95% CI) H1N1: 56.0 (38.1–82.3) H3N2: 76.2 (40.9–142.2) B: 65.3 (44.3–96.4) GMFR GMFR (95% CI) H1N1: 10.8 (7.5–15.4) H3N2: 5.8 (4.3–7.9) B: 10.5 (7.4–14.8) Seroprotection rate Seroprotection rate (95% CI) H1N1: 71% (56–83%) H3N2: 55% (40–69%) B: 71% (56–83%) Seroconversion rate Seroconversion rate (95% CI) H1N1: 71% (56–81%) H3N2: 55% (40–69%) B: 69% (54–81%)	Level III	NA
El-Madhun et al. (1998)^{Footnote 17}	Design Pre-post study Location Norway Follow-up 6–8, 12–20 and 28–42 days post-vaccination after the first dose of the vaccine	Influenza vaccine Influvac^® TIV (reported as a Solvay subunit TIV) Dose and administration 2 doses (7.5 µg per strain), 28–42 days apart Strains A/Texas/36/91 (H1N1) A/Johannesburg/33/94 (H3N2) B/Harbin/7/94	Population definition Children with a history of frequent tonsillar infections scheduled for tonsillectomy, without any other serious health problem and without previous vaccination against influenza. Study groups Primed and unprimed, based on presence of pre-vaccination antibodies to each vaccine strain Sample size n=18, with n=14 primed by influenza A(H3N2), 1 by influenza A(H1N1) and 3 by influenza B Age 2–3 years Sex 27.8% female	6–8 days post-vaccination (after first dose): GMT Primed H1N1: Not available H3N2: 640 B: 101 Unprimed H1N1: 10 H3N2: 10 B: 10 Seroprotection rate Primed H1N1: Not available H3N2: 100% B: 100% Unprimed H1N1: 0% H3N2: 0% B: 0% 12–20 days post-vaccination (after first dose): GMT Primed H1N1: Not available H3N2: 1581 B: 160 Unprimed H1N1: 18 H3N2: 14 B: 10 Seroprotection rate Primed H1N1: Not available H3N2: 100% B: 100% Unprimed H1N1: 16.7% H3N2: 0% B: 0% 28–42 days post-vaccination (after first dose): GMT Primed H1N1: Not available H3N2: 1634 B: 640 Unprimed H1N1: 15 H3N2: 12 B: 14 Seroprotection rate Primed H1N1: Not available H3N2: 100% B: 100% Unprimed H1N1: 15.4% H3N2: 0% B: 27.3% Seroconversion rate Significant increase in antibody (four-fold or higher) occurred at 6–8 or 12–20 days post-vaccination after the first dose in the primed group. No significant increase was observed after the first dose for the unprimed children. Notes The study also included eight adults. However, analysis was done separately for children and adults. Only the findings in children are presented. Serology was not assessed after the second dose in vaccine-naïve children.	Level III	NA
Shahgholi et al. (2010)^{Footnote 23}	Design Non-randomized controlled trial Location Iran Follow-up 4 weeks post-vaccination Adverse events: 5 days post-vaccination (findings presented in Appendix H)	Influenza vaccine Influvac^® TIV Dose and administration <36 months of age: 2 doses (0.25mL), 3–4 weeks apart 36 months–13 years of age: 2 doses (0.5mL), 3–4 weeks apart >13 years of age: 1 dose (0.5mL) Strains 2007–2008 formulation: A/Solomon Islands/3/2006 (H1N1) A/Wisconsin/67/2005 (H3N2) B/Malaysia/2506/2004-like	Population definition Children 1–18 years of age diagnosed with ALL in first remission and receiving maintenance therapy and healthy children (siblings) as controls. Sample size ALL: n=32 Controls: n=30 Age (mean) ALL: 10.65 years Controls: 10.8 years Sex ALL: 34.4% female Controls: 46.7% female No significant differences were found for the gender and age distributions of the two groups.	4 weeks post-vaccination: GMT ALL, pre-vaccine GMT (95% CI) H1N1: 32.5 (24.8–42.6) H3N2: 54.0 (40.0–77.0) B: 12.8 (10.6–15.2) Controls, pre-vaccine GMT (95% CI) H1N1: 31.5 (23.0–44.0) H3N2: 54.0 (35.2–83.0) B: 17.0 (12.3–23.4) ALL vs. controls, pre-vaccine GMT (p-value) H1N1: 0.873 H3N2: 0.946 B: 0.136 ALL, post-vaccine GMT (95% CI) H1N1: 52.9 (37.7–73.8) H3N2: 81.9 (55.8–120.0) B: 25.5 (18.5–35.0) Controls, post-vaccine GMT (95% CI) H1N1: 76.4 (55.0–106.4) H3N2: 145.4 (100.0–212.5) B: 38.1 (26.6–54.3) ALL vs. controls, post-vaccine GMT (p-value) H1N1: 0.130 H3N2: 0.041 B: 0.106 Seroprotection rate ALL, seroprotection rate H1N1: 43.4% H3N2: 63.3% B: 26.0% Controls, seroprotection rate H1N1: 88.0% H3N2: 80.0% B: 73.0% The protective response between the ALL and control groups for influenza A(H3N2) antigen did not differ significantly. However, the response rate for influenza A(H1N1) and B antigens in ALL patients was significantly lower than healthy controls (p=0.04 and 0.001, respectively). Seroconversion rate ALL, post-vaccination (95% CI) H1N1: 56.2% (26.9–73.1%) H3N2: 40.6% (11.6–55.1%) B: 59.4% (38.6–83.6%) Controls, post-vaccination (95% CI) H1N1: 80% (81.9–105.6%) H3N2: 53.3% (53.8–96.2%) B: 83.3% (81.9–105.6%) ALL vs. controls, odds ratio (95% CI) H1N1: 3.1 (1.1–9.7) H3N2: NR B: 3.4 (1.1–11.3) The seroconversion rates for influenza A(H1N1) and B were significantly lower in ALL patients than healthy controls (p=0.04 and 0.038, respectively), not for influenza A(H3N2).	Level II-1	NA Siblings were used as controls, but similarities in important confounders were not assessed.
Zhu et al. (2008)^{Footnote 25}	Design Endpoint-blind RCT Location China Follow-up 4 weeks post-vaccination Adverse events: 29 days post-vaccination (findings presented in Appendix H)	Influenza vaccine Influvac^® TIV Agrippal^® TIV Dose and administration 1 dose (15 µg per strain) Strains 2005–2006 formulation: A/New Caledonia/20/99 (H1N1) A/New York/55/2004 (H3N2) B/Jiangsu/10/2003	Population definition Healthy children 3–12 years of age Study groups Vaccination with Influvac^® Vaccination with Agrippal^® Sample size n=300 randomized 2:1 to receive either Influvac^® or Agrippal^®. Age (mean) Influvac^®: 8.2 years Agrippal^®: 8.1 years Sex Influvac^®: 50.0% female Agrippal^®: 50.0% female	29 days post-vaccination: GMT Influvac^®, pre-vaccine GMT (95% CI) H1N1: 69.5 (60.3–80.1) H3N2: 34.1 (28.2–41.2) B: 34.5 (28.8–41.3) Agrippal^®, pre-vaccine GMT (95% CI) H1N1: 63.3 (51.6–77.7) H3N2: 40.3 (31.2–52.1) B: 31.7 (24.8–40.4) Influvac^®, post-vaccine GMT (95% CI) H1N1: 1212.1 (982–1495) H3N2: 670.6 (558–806) B: 802.2 (647–994) Agrippal^®, post-vaccine GMT (95% CI) H1N1: 814.2 (616–1076) H3N2: 471.1 (364–609) B: 492.2 (369–657) GMFR Influvac^®, GMFR (95% CI) H1N1: 17.4 (14.3–21.2) H3N2: 19.7 (15.7–24.7) B: 23.3 (18.7–28.9) Agrippal^®, GMFR (95% CI) H1N1: 12.9 (9.9–16.7) H3N2: 11.7 (8.7–15.7) B: 15.5 (12.1–19.9) GMFR for Influvac^® by age subgroup Children aged 3–5 years (95% CI) H1N1: 9.1 (6.2–13.5) H3N2: 19.4 (11.1–34.1) B: 18.6 (10.5–33.1) Children aged 6–12 years (95% CI) H1N1: 20.1 (16.2–24.9) H3N2: 19.7 (15.4–25.2) B: 24.4 (19.4–30.8) Seroprotection rate Influvac^®, seroprotection rate (95% CI) H1N1: 99% (97–100%) H3N2: 98% (95–100%) B: 95% (91–98%) Agrippal ^®, seroprotection rate (95% CI) H1N1: 99% (94–100%) H3N2: 99% (94–100%) B: 93% (85–97%) Seroprotection rate for Influvac^® by age subgroup Children aged 3–5 years (95% CI) H1N1: 97% (84–100%) H3N2: 91% (75–98%) B: 72% (53–86%) Children aged 6–12 years (95% CI) H1N1: 96% (79–100%) H3N2: 96% (79–100%) B: 71% (49–87%) Seroconversion rate Influvac^®, seroconversion rate (95% CI) H1N1: 87% (81–91%) H3N2: 87% (81–92%) B: 92% (87–96%) Agrippal^®, seroconversion rate (95% CI) H1N1: 82% (73–89%) H3N2: 80% (71–88%) B: 86% (78–93%) Seroconversion rate for Influvac^® by age subgroup Children aged 3–5 years (95% CI) H1N1: 81% (64–93%) H3N2: 81% (64–93%) B: 66% (47–81%) Children aged 6–12 years (95% CI) H1N1: 88% (81–93%) H3N2: 88% (82–93%) B: 98% (94–98%) GMT ratios for Influvac^®:Agrippal^® The lower limits of the 95% CI of the ratio of post-vaccination GMTs for children aged 3–12 years (1.42–1.63), 3–5 years (0.94–1.29) and 6–12 years (1.44–1.70) were above the study-defined non-inferiority margin of 0.35.	Level I	Fair Conducted per-protocol analyses. Study was endpoint-blind (not double-blind).
Abbreviations: Refer to section V. List of abbreviations.

Study Details

Summary

Study

Study design

Influenza vaccine

Participants

Summary of key findings

Level of evidence

Quality

Brydak et al. (2000)^{Footnote 9}

Design
Pre-post study

Location
Poland

Follow-up
3 weeks and 6 weeks post-vaccination

Influenza vaccine
Influvac^® TIV

Dose and administration
1 dose (15 µg per strain)

Strains
1996–1997 formulation:
A/Singapore/6/86
(H1N1)
A/Wuhan/359/95
(H3N2)
B/Beijing/184/93

Population definition
Children with ALL (groups A and B)

Study groups
A: Chemotherapy completed before 1991

B: Chemotherapy completed after 1991

Unvaccinated controls (healthy children)

Sample size
Group A: n=10
Group B: n=12
Controls: n=22

Age
6–13 years

Sex
NR

3 week post-vaccination:

GMT
Group A
H1N1: 37.3
H3N2: 52.8
B: 80.0

Group B
H1N1: 33.6
H3N2: 40.0
B: 75.5

Controls
H1N1: 3.1–3.3
H3N2: 1.3–1.8
B: 1.2–2.7

GMFR
Group A
H1N1: 18.7
H3N2: 11.5
B: 20.5

Group B
H1N1: 18.7
H3N2: 25.0
B: 37.8

Controls
H1N1: 2.4–2.8
H3N2: <1.0
B: <1.0–2.0

Seroprotection rate
Group A
H1N1: 60.0%
H3N2: 80.0%
B: 100.0%

Group B
H1N1: 41.7%
H3N2: 50.0%
B: 83.3%

Controls
H1N1: 0.0–8.3%
H3N2: 0.0%
B: 0.0%

Seroconversion rate
Group A
H1N1: 60.0%
H3N2: 80.0%
B: 100.0%

Group B
H1N1: 41.7%
H3N2: 50.0%
B: 83.3%

Controls
H1N1: 0.0–10.0%
H3N2: 0.0%
B: 0.0–8.3%

6 month post-vaccination:

GMT
Group A
H1N1: 65.0
H3N2: 91.9
B: 113.1

Group B
H1N1: 26.2
H3N2: 100.8
B: 134.5

Controls
H1N1: 3.7–4.8
H3N2: 7.1–7.9
B: 33.6–34.8

GMFR
Group A
H1N1: 32.5
H3N2: 20.0
B: 29.0

Group B
H1N1: 14.6
H3N2: 63.0
B: 67.3

Controls
H1N1: 3.1–3.7
H3N2: 2.3–2.6
B: 17.7–26.7

Seroprotection rate
Group A
H1N1: 90.0%
H3N2: 100.0%
B: 100.0%

Group B
H1N1: 41.7%
H3N2: 100.0%
B: 83.3%

Controls
H1N1: 8.3–10.0%
H3N2: 8.3–10.0%
B: 50.0%

Seroconversion rate
Group A
H1N1: 90.0%
H3N2: 100.0%
B: 100.0%

Group B
H1N1: 41.7%
H3N2: 100.0%
B: 83.3%

Controls
H1N1: 8.3–10.0%
H3N2: 0.0–10.0%
B: 16.7–50.0%

Notes

Subjects were vaccinated with FluShield^® (Wyeth) in the 1993–1994 influenza season and with Influvac^® in the 1996–1997 influenza season. Data for the 1996–1997 influenza season is presented.
Results are also available for subjects vaccinated for the first time in the 1996–1997 influenza season, but are not presented.
Though not stated explicitly in the article, the study subjects likely overlap with Brydak et al. (1998a)^{Footnote 10}

Level III

Brydak et al. (1998a)^{Footnote 10}

Design
Pre-post study

Location
Poland

Follow-up
3 weeks and 6 weeks post-vaccination

Influenza vaccine
Influvac^® TIV

Dose and administration
1 dose (15 µg per strain)

Strains
1996–1997 formulation:
A/Singapore/6/86
(H1N1)
A/Wuhan/359/95
(H3N2)
B/Beijing/184/93

Population definition
Children with ALL (groups A and B)

Study groups
A: Vaccinated in the 1993–1994 influenza season

B: Unvaccinated prior to the 1996–1997 influenza season

Unvaccinated controls (healthy children)

Sample size
Group A: n=25
Group B: n=20
Controls: n=23

Age
Group A: 7–16 years
Group B: 7–11 years
Controls: 8–15 years

Sex
NR

3 week post-vaccination:

GMT
Group A
H1N1: 35.8
H3N2: 44.7
B: 80.0

Group B
H1N1: 42.9
H3N2: 62.8
B: 77.3

Controls
H1N1: 3.0
H3N2: 1.8
B: 2.8

GMFR
Group A
H1N1: 18.8
H3N2: 17.2
B: 26.7

Group B
H1N1: 22.6
H3N2: 15.7
B: 15.8

Controls
H1N1: 2.1
H3N2: NA
B: 1.5

Seroprotection rate
Group A
H1N1: 52.0%
H3N2: 64.0%
B: 92.0%

Group B
H1N1: 55.0%
H3N2: 85.0%
B: 75.0%

Controls
H1N1: 4.3%
H3N2: 0.0%
B: 0.0%

Seroconversion rate
Group A
H1N1: 52.0%
H3N2: 60.0%
B: 92.0%

Group B
H1N1: 55.0%
H3N2: 80.0%
B: 70.0%

Controls
H1N1: 4.3%
H3N2: 0.0%
B: 0.0%

6 month post-vaccination:

GMT
Group A
H1N1: 41.9
H3N2: 91.9
B: 114.7

Group B
H1N1: 74.6
H3N2: 121.3
B: 149.3

Controls
H1N1: 4.5
H3N2: 6.7
B: 23.0

GMFR
Group A
H1N1: 22.1
H3N2: 35.3
B: 38.2

Group B
H1N1: 39.3
H3N2: 30.3
B: 30.5

Controls
H1N1: 3.2
H3N2: 2.3
B: 12.1

Seroprotection rate
Group A
H1N1: 68.0%
H3N2: 100.0%
B: 92.0%

Group B
H1N1: 90.0%
H3N2: 100.0%
B: 100.0%

Controls
H1N1: 8.7%
H3N2: 4.3%
B: 30.4%

Seroconversion rate
Group A
H1N1: 68.0%
H3N2: 100.0%
B: 92.0%

Group B
H1N1: 90.0%
H3N2: 100.0%
B: 95.0%

Controls
H1N1: 8.7%
H3N2: 4.3%
B: 30.4%

Notes

Though not stated explicitly in the article, the study subjects likely overlap with Brydak et al. (2000)^{Footnote 9}.
The controls included in this study are the same subjects as the controls in Brydak et al. (1998b)^{Footnote 11}.

Level III

Brydak et al. (1998b)^{Footnote 11}

Supplemented with additional details from Rokicka-Milewska et al. (1999)^{Footnote 22} on the stratified analysis by severity of hemophilia (mild vs. severe).

Design
Pre-post study

Location
Poland

Follow-up
3 weeks and 6 weeks post-vaccination

Influenza vaccine
Influvac^® TIV

Dose and administration
1 dose (15 µg per strain)

Strains
1996–1997 formulation:
A/Singapore/6/86
(H1N1)
A/Wuhan/359/95
(H3N2)
B/Beijing/184/93

Population definition
Children with hemophilia who have previously been vaccinated for influenza in the 1993–1994 season

Study groups
Hemophiliac patients

Unvaccinated controls (healthy children)

Sample size
Hemophiliac patients: n=38 (n=26 severe and 12 mild)
Controls: n=23

Age
Hemophiliac patients: 10–19 years
Controls: 8–15 years

Sex
NR

3 week post-vaccination:

GMT
Hemophiliac patients
H1N1: 28.3
H3N2: 29.3
B: 35.2

Controls
H1N1: 3.0
H3N2: 1.8
B: 2.8

GMFR
Hemophiliac patients
H1N1: 6.7
H3N2: 10.9
B: 3.9

Controls
H1N1: 2.1
H3N2: <1.0
B: 1.5

Seroprotection rate
Hemophiliac patients
H1N1: 57.9%
H3N2: 52.6%
B: 60.5%

Controls
H1N1: 4.3%
H3N2: 0.0%
B: 0.0%

Seroconversion rate
Hemophiliac patients
H1N1: 42.1%
H3N2: 42.1%
B: 39.5%

Controls
H1N1: 4.3%
H3N2: 0.0%
B: 0.0%

6 month post-vaccination:

GMT
Hemophiliac patients
H1N1: 45.7
H3N2: 77.1
B: 75.3

Controls
H1N1: 4.5
H3N2: 6.7
B: 23.0

GMFR
Hemophiliac patients
H1N1: 10.9
H3N2: 28.6
B: 8.4

Controls
H1N1: 3.2
H3N2: 2.3
B: 12.1

Seroprotection rate
Hemophiliac patients
H1N1: 76.3%
H3N2: 92.1%
B: 97.4%

Controls
H1N1: 8.7%
H3N2: 4.3%
B: 30.4%

Seroconversion rate
Hemophiliac patients
H1N1: 71.1%
H3N2: 84.2%
B: 86.8%

Controls
H1N1: 8.7%
H3N2: 4.3%
B: 30.4%

Stratified analysis by severity of hemophilia
Patients with mild and severe hemophilia had similar GMTs and GMFRs for influenza A and B strains at 6 months post-vaccination. Seroprotection and seroconversion rates were similar for both groups for influenza A(H3N2) and B; however, patients with severe hemophilia had a lower rate of seroprotection compared to patients with mild hemophilia for influenza A(H1N1) at 3 weeks and 6 months post-vaccination (61.5–65.4% vs. 83.3%). Patients with severe hemophilia also had lower rates of seroconversion for influenza A(H1N1) compared to patients with mild hemophilia at 3 weeks and 6 months post-vaccination (46.2–53.8% vs. 66.7%).

Notes
The controls included in this study are the same subjects as the controls in Brydak et al. (1998a)^{Footnote 10}.

Level III

Bueving (2004a)^{Footnote 12}

Supplemented with additional details from Bueving et al. (2004b)^{Footnote 13} on AEFI and asthma exacerbation following vaccination.

Design
Double-blind RCT
(placebo-controlled)

Location
The Netherlands

Follow-up
14–21 days and 4–5 months post-vaccination

Adverse events: 7 days post-vaccination (findings presented in Appendix H)

Influenza vaccine
Influvac^® TIV (reported as a Solvay TIV)

Dose and administration
1 dose (15 µg per strain)

Strains
1999–2000 formulation:
A/Beijing/262/95-like
(H1N1)
A/Sydney/5/97-like
(H3N2)
B/Beijing/184/93-like

2000–2001 formulation:
A/New Caledonia/20/99
(H1N1)
A/Moscow/10/99-like
(H3N2)
B/Beijing/184/93-like

Children could only participate in one of the two seasons

Population definition
Children 6–18 years of age with asthma, without other chronic diseases

Sample size
Vaccine: n=347
Placebo: n=349

Age (mean)
Vaccine: 10.5 years
Placebo: 10.6 years

Sex
Vaccine: 48.1% female
Placebo: 43.6% female

14–21 days post-vaccination:

GMT
Vaccine
H1N1: 200.7
H3N2: 227.1
B: 358.4

Placebo
H1N1: 23.0
H3N2: 79.4
B: 157.6

Vaccine vs. placebo (p-value)
H1N1: <0.001
H3N2: <0.001
B: <0.001

Seroprotection rate
Vaccine
H1N1: 85.6%
H3N2: 98.5%
B: 95.3%

Placebo
H1N1: 38.9%
H3N2: 79.2%
B: 87.7%

Vaccine vs. placebo (p-value)
H1N1: <0.001
H3N2: <0.001
B: <0.001

Seroconversion rate
Vaccine
H1N1: 59.9%
H3N2: 27.1%
B: 26.5%

Placebo
H1N1: 0.9%
H3N2: 1.2%
B: 0.0%

Vaccine vs. placebo (p-value)
H1N1: <0.001
H3N2: <0.001
B: <0.001

4–5 months post-vaccination:

GMT
Vaccine
H1N1: 188.0
H3N2: 186.3
B: 1.8

Placebo
H1N1: 38.0
H3N2: 88.3
B: 0.9

Vaccine vs. placebo (p-value)
H1N1: <0.001
H3N2: <0.001
B: <0.001

Seroconversion rate*
Vaccine
H1N1: 7.0%
H3N2: 1.2%
B: 1.8%

Placebo
H1N1: 17.5%
H3N2: 4.0%
B: 0.9%

Vaccine vs. placebo (p-value)
H1N1: <0.001
H3N2: 0.03
B: 0.26

* Seroconversion at 4–5 months post-vaccination was calculated by comparing the sample taken at 4–5 months post-vaccination to the sample taken at 14–21 days post-vaccination.

Level I

Fair

Conducted per-protocol analyses.

Daubeney et al. (1997)^{Footnote 16}

Design
Pre-post study

Location
United Kingdom

Follow-up
Up to 72 hours post-vaccination

Influenza vaccine
Influvac^® TIV

Dose and administration
2 doses (7.5 µg per strain), 4 weeks apart

Strains
A/Singapore/6/86
(H1N1)
A/Shangdong/9/93
(H3N2)
B/Panama/45/90

Population definition
Children with chronic respiratory disease, congenital heart disease, or both.

Sample size
n=52

Age
Mean (range): 19.5 months (6 months–4 years)

Sex
NR

GMT
GMT pre-vaccination (95% CI)
H1N1: 5.2 (4.8–5.6)
H3N2: 13.1 (8.7–19.6)
B: 6.2 (5.1–7.6)

GMT post-vaccination (95% CI)
H1N1: 56.0 (38.1–82.3)
H3N2: 76.2 (40.9–142.2)
B: 65.3 (44.3–96.4)

GMFR
GMFR (95% CI)
H1N1: 10.8 (7.5–15.4)
H3N2: 5.8 (4.3–7.9)
B: 10.5 (7.4–14.8)

Seroprotection rate
Seroprotection rate (95% CI)
H1N1: 71% (56–83%)
H3N2: 55% (40–69%)
B: 71% (56–83%)

Seroconversion rate
Seroconversion rate (95% CI)
H1N1: 71% (56–81%)
H3N2: 55% (40–69%)
B: 69% (54–81%)

Level III

El-Madhun et al. (1998)^{Footnote 17}

Design
Pre-post study

Location
Norway

Follow-up
6–8, 12–20 and 28–42 days post-vaccination after the first dose of the vaccine

Influenza vaccine
Influvac^® TIV (reported as a Solvay subunit TIV)

Dose and administration
2 doses (7.5 µg per strain), 28–42 days apart

Strains
A/Texas/36/91
(H1N1)
A/Johannesburg/33/94
(H3N2)
B/Harbin/7/94

Population definition
Children with a history of frequent tonsillar infections scheduled for tonsillectomy, without any other serious health problem and without previous vaccination against influenza.

Study groups
Primed and unprimed, based on presence of pre-vaccination antibodies to each vaccine strain

Sample size
n=18, with n=14 primed by influenza A(H3N2), 1 by influenza A(H1N1) and 3 by influenza B

Age
2–3 years

Sex
27.8% female

6–8 days post-vaccination (after first dose):

GMT
Primed
H1N1: Not available
H3N2: 640
B: 101

Unprimed
H1N1: 10
H3N2: 10
B: 10

Seroprotection rate
Primed
H1N1: Not available
H3N2: 100%
B: 100%

Unprimed
H1N1: 0%
H3N2: 0%
B: 0%

12–20 days post-vaccination (after first dose):

GMT
Primed
H1N1: Not available
H3N2: 1581
B: 160

Unprimed
H1N1: 18
H3N2: 14
B: 10

Seroprotection rate
Primed
H1N1: Not available
H3N2: 100%
B: 100%

Unprimed
H1N1: 16.7%
H3N2: 0%
B: 0%

28–42 days post-vaccination (after first dose):

GMT
Primed
H1N1: Not available
H3N2: 1634
B: 640

Unprimed
H1N1: 15
H3N2: 12
B: 14

Seroprotection rate
Primed
H1N1: Not available
H3N2: 100%
B: 100%

Unprimed
H1N1: 15.4%
H3N2: 0%
B: 27.3%

Seroconversion rate
Significant increase in antibody (four-fold or higher) occurred at 6–8 or 12–20 days post-vaccination after the first dose in the primed group. No significant increase was observed after the first dose for the unprimed children.

Notes

The study also included eight adults. However, analysis was done separately for children and adults. Only the findings in children are presented.
Serology was not assessed after the second dose in vaccine-naïve children.

Level III

Shahgholi et al. (2010)^{Footnote 23}

Design
Non-randomized controlled trial

Location
Iran

Follow-up
4 weeks post-vaccination

Adverse events: 5 days post-vaccination (findings presented in Appendix H)

Influenza vaccine
Influvac^® TIV

Dose and administration
<36 months of age: 2 doses (0.25mL), 3–4 weeks apart

36 months–13 years of age: 2 doses (0.5mL), 3–4 weeks apart

>13 years of age: 1 dose (0.5mL)

Strains
2007–2008 formulation:
A/Solomon Islands/3/2006
(H1N1)
A/Wisconsin/67/2005
(H3N2)
B/Malaysia/2506/2004-like

Population definition
Children 1–18 years of age diagnosed with ALL in first remission and receiving maintenance therapy and healthy children (siblings) as controls.

Sample size
ALL: n=32
Controls: n=30

Age (mean)
ALL: 10.65 years
Controls: 10.8 years

Sex
ALL: 34.4% female
Controls: 46.7% female

No significant differences were found for the gender and age distributions of the two groups.

4 weeks post-vaccination:

GMT
ALL, pre-vaccine GMT (95% CI)
H1N1: 32.5 (24.8–42.6)
H3N2: 54.0 (40.0–77.0)
B: 12.8 (10.6–15.2)

Controls, pre-vaccine GMT (95% CI)
H1N1: 31.5 (23.0–44.0)
H3N2: 54.0 (35.2–83.0)
B: 17.0 (12.3–23.4)

ALL vs. controls, pre-vaccine GMT (p-value)
H1N1: 0.873
H3N2: 0.946
B: 0.136

ALL, post-vaccine GMT (95% CI)
H1N1: 52.9 (37.7–73.8)
H3N2: 81.9 (55.8–120.0)
B: 25.5 (18.5–35.0)

Controls, post-vaccine GMT (95% CI)
H1N1: 76.4 (55.0–106.4)
H3N2: 145.4 (100.0–212.5)
B: 38.1 (26.6–54.3)

ALL vs. controls, post-vaccine GMT (p-value)
H1N1: 0.130
H3N2: 0.041
B: 0.106

Seroprotection rate
ALL, seroprotection rate
H1N1: 43.4%
H3N2: 63.3%
B: 26.0%

Controls, seroprotection rate
H1N1: 88.0%
H3N2: 80.0%
B: 73.0%

The protective response between the ALL and control groups for influenza A(H3N2) antigen did not differ significantly. However, the response rate for influenza A(H1N1) and B antigens in ALL patients was significantly lower than healthy controls (p=0.04 and 0.001, respectively).

Seroconversion rate
ALL, post-vaccination (95% CI)
H1N1: 56.2% (26.9–73.1%)
H3N2: 40.6% (11.6–55.1%)
B: 59.4% (38.6–83.6%)

Controls, post-vaccination (95% CI)
H1N1: 80% (81.9–105.6%)
H3N2: 53.3% (53.8–96.2%)
B: 83.3% (81.9–105.6%)

ALL vs. controls, odds ratio (95% CI)
H1N1: 3.1 (1.1–9.7)
H3N2: NR
B: 3.4 (1.1–11.3)

The seroconversion rates for influenza A(H1N1) and B were significantly lower in ALL patients than healthy controls (p=0.04 and 0.038, respectively), not for influenza A(H3N2).

Level II-1

Siblings were used as controls, but similarities in important confounders were not assessed.

Zhu et al. (2008)^{Footnote 25}

Design
Endpoint-blind RCT

Location
China

Follow-up
4 weeks post-vaccination

Adverse events: 29 days post-vaccination (findings presented in Appendix H)

Influenza vaccine
Influvac^® TIV
Agrippal^® TIV

Dose and administration
1 dose (15 µg per strain)

Strains
2005–2006 formulation:
A/New Caledonia/20/99
(H1N1)
A/New York/55/2004
(H3N2)
B/Jiangsu/10/2003

Population definition
Healthy children 3–12 years of age

Study groups
Vaccination with Influvac^®

Vaccination with Agrippal^®

Sample size
n=300 randomized 2:1 to receive either Influvac^® or Agrippal^®.

Age (mean)
Influvac^®: 8.2 years
Agrippal^®: 8.1 years

Sex
Influvac^®: 50.0% female
Agrippal^®: 50.0% female

29 days post-vaccination:

GMT
Influvac^®, pre-vaccine GMT (95% CI)
H1N1: 69.5 (60.3–80.1)
H3N2: 34.1 (28.2–41.2)
B: 34.5 (28.8–41.3)

Agrippal^®, pre-vaccine GMT (95% CI)
H1N1: 63.3 (51.6–77.7)
H3N2: 40.3 (31.2–52.1)
B: 31.7 (24.8–40.4)

Influvac^®, post-vaccine GMT (95% CI)
H1N1: 1212.1 (982–1495)
H3N2: 670.6 (558–806)
B: 802.2 (647–994)

Agrippal^®, post-vaccine GMT (95% CI)
H1N1: 814.2 (616–1076)
H3N2: 471.1 (364–609)
B: 492.2 (369–657)

GMFR
Influvac^®, GMFR (95% CI)
H1N1: 17.4 (14.3–21.2)
H3N2: 19.7 (15.7–24.7)
B: 23.3 (18.7–28.9)

Agrippal^®, GMFR (95% CI)
H1N1: 12.9 (9.9–16.7)
H3N2: 11.7 (8.7–15.7)
B: 15.5 (12.1–19.9)

GMFR for Influvac^® by age subgroup
Children aged 3–5 years (95% CI)
H1N1: 9.1 (6.2–13.5)
H3N2: 19.4 (11.1–34.1)
B: 18.6 (10.5–33.1)

Children aged 6–12 years (95% CI)
H1N1: 20.1 (16.2–24.9)
H3N2: 19.7 (15.4–25.2)
B: 24.4 (19.4–30.8)

Seroprotection rate
Influvac^®, seroprotection rate (95% CI)
H1N1: 99% (97–100%)
H3N2: 98% (95–100%)
B: 95% (91–98%)

Agrippal ^®, seroprotection rate (95% CI)
H1N1: 99% (94–100%)
H3N2: 99% (94–100%)
B: 93% (85–97%)

Seroprotection rate for Influvac^® by age subgroup
Children aged 3–5 years (95% CI)
H1N1: 97% (84–100%)
H3N2: 91% (75–98%)
B: 72% (53–86%)

Children aged 6–12 years (95% CI)
H1N1: 96% (79–100%)
H3N2: 96% (79–100%)
B: 71% (49–87%)

Seroconversion rate
Influvac^®, seroconversion rate (95% CI)
H1N1: 87% (81–91%)
H3N2: 87% (81–92%)
B: 92% (87–96%)

Agrippal^®, seroconversion rate (95% CI)
H1N1: 82% (73–89%)
H3N2: 80% (71–88%)
B: 86% (78–93%)

Seroconversion rate for Influvac^® by age subgroup
Children aged 3–5 years (95% CI)
H1N1: 81% (64–93%)
H3N2: 81% (64–93%)
B: 66% (47–81%)

Children aged 6–12 years (95% CI)
H1N1: 88% (81–93%)
H3N2: 88% (82–93%)
B: 98% (94–98%)

GMT ratios for Influvac^®:Agrippal^®
The lower limits of the 95% CI of the ratio of post-vaccination GMTs for children aged 3–12 years (1.42–1.63), 3–5 years (0.94–1.29) and 6–12 years (1.44–1.70) were above the study-defined non-inferiority margin of 0.35.

Level I

Fair

Conducted per-protocol analyses. Study was endpoint-blind (not double-blind).

Appendix H: Summary of literature evidence related to the safety of Influvac^® trivalent inactivated influenza vaccine in children

Study Details	Summary
Aagaard et al. (2011)^{Footnote 7}	Design Passive surveillance Influenza seasons 1998–2007 Location Denmark	Influenza vaccine Influvac^® TIV Other non-influenza vaccines	Population definition Children <18 years of age Age NR Sex NR	AEFI defined as any noxious and unintended response to a drug that occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy of disease. 4 AEFI were reported for children in the 2–3 year old age group, 3 of which were serious AEFI. Details about the AEFI were not provided. No AEFI were reported in any other age groups.	Level III	NA
Armstrong et al. (2011)^{Footnote 8}	Design Passive surveillance Retrospective cohort study Influenza season 2010 Location Australia	Influenza vaccine Influvac^® TIV Fluvax^® TIV Fluvax Junior^® TIV Dose and administration 6–36 months: 2 doses (7.5 µg per strain) 4 years of age: 2 doses (15 µg per strain) Strains 2010 formulation: A/California/7/2009-like (H1N1) A/Perth/16/2009-like (H3N2) B/Brisbane/60/2008-like	Surveillance: Population definition Children 6 months–4 years of age Case definition: Child assigned ICD-10 code R56.0 (febrile convulsion) at ED within 72 hours of receipt of TIV or TIV-associated febrile convulsion cases that were reported by ED clinicians, primary care givers or vaccine providers. Sample size Cases: n=63 Age (mean) 1.85 years Sex 39.7% female Cohort: Population definition Children less than five years of age who were vaccinated with TIV in 2010. Sample size n=360 Age NR Sex NR	Surveillance: Febrile convulsions ≤2 years of age, rate/1000 TIV doses (95% CI) Influvac^®: 0.0 (0.0–1.8) Fluvax^®: 4.9 (3.4–7.1) Fluvax Junior^®: 7.9 (5.3–11.8) Fluvax^® and Fluvax Junior^®: 5.9 (4.5–7.7) 3–4 years of age, rate/1000 TIV doses (95% CI) Influvac^®: 0.0 (0.0–1.5) Fluvax^®: 1.4 (0.7–2.9) Fluvax Junior^®: 9.7 (3.8–24.7) Fluvax^® and Fluvax Junior^®: 2.0 (1.1–3.6) Febrile reactions (non-convulsive)* ≤2 years of age, rate/1000 TIV doses (95% CI) Influvac^®: 4.2 (2.2–8.0) Fluvax^®: 49.0 (43.7–54.9) Fluvax Junior^®: 47.3 (40.2–55.6) Fluvax^® and Fluvax Junior^®: 48.4 (44.1–53.1) 3–4 years of age, rate/1000 TIV doses (95% CI) Influvac^®: 0.8 (0.2–2.9) Fluvax^®: 25.3 (21.3–30.0) Fluvax Junior^®: 26.6 (14.9–47.0) Fluvax^® and Fluvax Junior^®: 25.4 (21.5–29.9) * Consists of passive reports made to the AEFI reporting system as opposed to active The RR of febrile reactions for combined Fluvax^® & Fluvax Junior^® compared to Influvac^® was 11.4 (95% CI: 5.9–22.1) for children ≤2 years of age and 33.0 (95% CI: 8.2–133.2) in children 3–4 years of age. Cohort: Percentage of children with symptom Influvac^® Fever: 17.3% Fatigue: 10.9% Vomiting: 2.7% Rigors: 0.9% Swelling: 10.9% Diarrhoea: 0.9% Rash: 0.9% Headache: 0.9% Convulsions: 0.0% Significant febrile adverse event: 4.5% Fluvax^® Fever: 52.3% Fatigue: 29.4% Vomiting: 14.7% Rigors: 11.9% Swelling: 12.8% Diarrhoea: 6.4% Rash: 5.5% Headache: 3.7% Convulsions: 2.8% Significant febrile adverse event: 22.9% Fluvax Junior^® Fever: 61.0% Fatigue: 37.0% Vomiting: 20.0% Rigors: 19.0% Swelling: 13.0% Diarrhoea: 4.0% Rash: 2.0% Headache: 3.0% Convulsions: 0.0% Significant febrile adverse event: 36.0% Fluvax^® and Fluvax Junior^® Fever: 56.5% Fatigue: 33.0% Vomiting: 17.2% Rigors: 15.3% Swelling: 12.9% Diarrhoea: 5.3% Rash: 3.8% Headache: 3.4% Convulsions: 1.4% Significant febrile adverse event: 29.2% Fever (OR=5.1), fatigue (OR=3.5), vomiting (OR=6.0), and significant febrile adverse events (OR=7.0) were significantly more common in children who received one of the two Fluvax^® vaccines than children who received the Influvac^® vaccine.	Level III	NA
Brydak et al. (2000)^{Footnote 9}	Design Pre-post study Location Poland Follow-up 3 weeks and 6 weeks post-vaccination	Influenza vaccine Influvac^® TIV Dose and administration 1 dose (15 µg per strain) Strains 1996–1997 formulation: A/Singapore/6/86 (H1N1) A/Wuhan/359/95 (H3N2) B/Beijing/184/93	Population definition Children with ALL (groups A and B) Study groups A: Chemotherapy completed before 1991 B: Chemotherapy completed after 1991 Unvaccinated controls (healthy children) Sample size Group A: n=10 Group B: n=12 Controls: n=22 Age 6–13 years Sex NR	None of the vaccinated children showed symptoms of influenza virus inflections. Vaccines were well tolerated and did not cause any severe adverse reactions. Notes Subjects were vaccinated with FluShield^® (Wyeth) in the 1993–1994 influenza season and with Influvac^® in the 1996–1997 influenza season. Data for the 1996–1997 influenza season is presented. Results are also available for subjects vaccinated for the first time in the 1996–1997 influenza season, but are not presented. Though not stated explicitly in the article, the study subjects likely overlap with Brydak et al. (1998a)^{Footnote 10}.	Level III	NA
Bueving (2004a)^{Footnote 12} Supplemented with additional details from Bueving et al. (2004b)^{Footnote 13} on AEFI and asthma exacerbation following vaccination.	Design Double-blind RCT (placebo-controlled) Location The Netherlands Follow-up 14–21 days and 4–5 months post-vaccination Adverse events: 7 days post-vaccination	Influenza vaccine Influvac^® TIV (reported as a Solvay TIV) Administration 1 dose (15 µg per strain) Strains 1999–2000 formulation: A/Beijing/262/95-like (H1N1) A/Sydney/5/97-like (H3N2) B/Beijing/184/93-like 2000–2001 formulation: A/New Caledonia/20/99 (H1N1) A/Moscow/10/99-like (H3N2) B/Beijing/184/93-like Children could only participate in one of the two seasons	Population definition Children 6–18 years of age with asthma, without other chronic diseases Sample size Vaccine: n=347 Placebo: n=349 Age (mean) Vaccine: 10.5 years Placebo: 10.6 years Sex Vaccine: 48.1% female Placebo: 43.6% female	Adverse events There was a significant difference in the proportion of local adverse events experienced in the vaccinated group compared to the placebo group. Local adverse events included erythema at the vaccination site and a stiff or painful arm. There was a 23% absolute difference between the two groups for erythema at the vaccination site and a 48% absolute difference for stiff or painful arm. In the 1999–2000 season, there was a significant difference in fever/shivers (8%), headaches (10%), and myalgia (18%) after injection between the vaccine group and the placebo group. In 2000–2001, only episodes of hoarseness (5%) were significantly different between the two groups. There were no other significant differences in systemic reactions between the two groups in either season (sickness, vomiting, diarrhoea, tiredness, sweating, sneezing, runny or stuffed-up nose, burning or watery eyes, sore throat). Of recorded asthma symptoms, the only significant difference occurred in the 1999–2000 season for episodes of cough (8%). There were no SAEs reported in either group. Asthma exacerbation The number of asthma exacerbations was not significantly different between asthmatic patients who were vaccinated with Influvac^® and those who received the placebo.	Level I	Fair Conducted per-protocol analyses.
Cashman et al. (2014)^{Footnote 14}	Design Active surveillance Influenza seasons 2012 2013 Location Australia Follow-up 3 days and 42 days post-vaccination	Influenza vaccine Influvac^® TIV Other TIVs	Population definition Children aged less than 10 years receiving influenza vaccine Sample size Total: n=290 Total vaccinated with Influvac^®: n=32 Survey response rate: 61% (n=290 of 477) Age NR Sex 47% female	Adverse events following the first dose Influvac^® Any adverse event following the first dose: 1 SAE: 0 Sought medical attention: 0 Reaction at injection site: 1 Fever: 1 Headaches: 0 Fatigue: 0 Joint pain: 0 ILI: 1 Lymph node swelling: 0 Seizures: 0 Muscle aches: 0 Weakness: 0 Other symptoms: 0 Total Any adverse event following the first dose: 52 SAE: 0 Sought medical attention: 4 Reaction at injection site: 23 Fever: 8 Headaches: 9 Fatigue: 15 Joint pain: 6 ILI: 12 Lymph node swelling: 3 Seizures: 0 Muscle aches: 14 Weakness: 2 Other symptoms: 9 Recipients of Influvac^® reported lower frequencies of any AEFI (3.1%; n=32) compared to Fluarix^® (11.6%; n=43), Vaxigrip^® (21.7%; n=212) and all influenza vaccine brands (17.9%; n=290) for the 2012 and 2013 Southern Hemisphere influenza seasons.	Level III	NA
Cheng et al. (2015)^{Footnote 15}	Design Passive surveillance Influenza seasons 2007–2013 (Influvac^® in schedule for 2008–2009 only) Location Australia Follow-up Within 24 hours of initial report	Influenza vaccine Influvac^® TIV Other non-influenza vaccines Dose and administration 1 dose	Population definition Children less than 18 years of age with suspected anaphylaxis following immunization. Case definition: The Brighton Collaboration Case Definition was used to define the level of certainty for an anaphylaxis event. Sample size Cases: n=1 Age (mean) 9.4 years Sex Female	Anaphylaxis following immunization One anaphylaxis AEFI was reported for Influvac^®. The level of certainty of an anaphylaxis event was 2, which indicates that symptoms included ≥1 major cardiovascular/respiratory and ≥1 minor symptoms involving ≥1 different systems, or ≥1 major dermatological and ≥1 minor cardiovascular/respiratory. Notes Influvac^® was only in schedule in Australia for 2008–2009. Therefore, report of anaphylaxis following immunization for Influvac^® only reflects this period and not the full study period.	Level III	NA
Daubeney et al. (1997)^{Footnote 16}	Design Pre-post study Location United Kingdom Follow-up Up to 72 hours post-vaccination	Influenza vaccine Influvac^® TIV Dose and administration 2 doses (7.5 µg per strain), 4 weeks apart Strains A/Singapore/6/86 (H1N1) A/Shangdong/9/93 (H3N2) B/Panama/45/90	Population definition Children with chronic respiratory disease, congenital heart disease, or both. Sample size n=52 Age Mean (range): 19.5 months (6 months–4 years) Sex NR	Adverse events AEs were recorded 24, 48 and 72 hours post-vaccination: n=15 AEs in total n=2 of 15 AEs were related to vaccination (2 cases of febrile episodes associated with cough) n=4 of 15 AEs were arranged hospital admissions for cardiac catheterisation or jejunal biopsy All hospitalizations were associated with underlying cardiac or respiratory conditions n=12 of 52 (23%) subjects had local reactions, with the most commonly reported reaction being redness at injection site (n=6) n=25 of 52 (48%) subjects had systemic reactions, with the most commonly reported reaction being fever (n=14), insomnia (n=13) and increased irritability (n=13) All systemic and local reactions were noted to be minor and resolved within a few days	Level III	NA
Ghendon et al. (2006)^{Footnote 26}	Design Non-randomized controlled trial Influenza season 2001–2002 Location Russia Follow-up Morbidity: 4 months post-vaccination (December 2001–March 2002) Adverse events: 3–5 days post-vaccination	Influenza vaccine Influvac^® TIV Dose and administration 1 dose (15 µg per strain) Strains 2001–2002 formulation: A/New Caledonia/20/99 (H1N1) A/Moscow/10/99 (H3N2) B/Sichuan/379/99	Population definition Healthy children without contraindications Study groups Intervention: Mass immunization campaign (coverage rate 69.7%) Control: No immunization campaign (coverage rate <1.0%) Sample size Intervention: n=40,611 Control: n=60,946 Age 3–17 years Sex NR	Adverse events No SAEs were observed immediately after vaccination or 3–5 days post-vaccination.	Level II-1	NA
Jansen et al. (2008a)^{Footnote 18} Supplemented with additional details from Jansen et al. (2008b)^{Footnote 19} on AEFI.	Design Double-blind RCT (placebo-controlled) Influenza seasons 2003–2004 2004–2005 2005–2006 Location The Netherlands Follow-up 2003–2004 and 2004–2005 seasons: 18 months post-vaccination 2005–2006 season: 6 months post-vaccination Adverse events: 7 days post-vaccination	Influenza vaccine Influvac^® TIV Other non-influenza vaccines Dose and administration 2 doses, 4–8 weeks apart 2003–2004 and 2004–2005 cohorts received an additional vaccination in the following year Strains 2003–2004 formulation: A/New Caledonia/20/99 (H1N1) A/Moscow/10/99 (H3N2) B/Hong Kong/330/01 2004–2005 formulation: A/New Caledonia/20/99 (H1N1) A/Fuijan/411/2002 (H3N2) B/Shanghai/361/2002 2005–2006 formulation: A/New Caledonia/20/99 (H1N1) A/California/7/2004 (H3N2) B/Shanghai/361/2002	Population definition Unvaccinated children aged 18–72 months with previously diagnosed respiratory tract infection Study groups TIV plus PCV7 TIV plus placebo HBV plus placebo (control) Sample size TIV plus PCV7: n=197 TIV plus placebo: n=187 HBV plus placebo (control): n=195 Age (mean) TIV plus PCV7: 3.0 years TIV plus placebo: 3.1 years HBV plus placebo (control): 3.1 years Sex TIV plus PCV7: 41.4% female TIV plus placebo: 44.4% female HBV plus placebo: 49.7% female The study groups were similar with regard to age, sex and medical history.	Adverse events TIV plus PCV7, proportion with adverse event Local: 66.8% (127/190) Systemic: 63.9% (117/183) TIV plus placebo, proportion with adverse event Local: 37.8% (68/180) Systemic: 52.3% (90/172) HBV plus placebo (control), proportion with adverse event Local: 36.0% (67/186) Systemic: 50.9% (88/173) No immediate adverse events were recorded following vaccination. The local adverse reactions recorded for TIV plus placebo, in descending order of incidence, were tenderness, swelling, erythema, and interference with limb movement. The systemic adverse reactions recorded for TIV plus placebo, in descending order of incidence, were malaise, fever, headaches, and myalgia. No severe reactions were recorded for all groups.	Level I	Fair 14–20% loss to follow up.
Petousis-Harris et al. (2012)^{Footnote 20}	Design Retrospective survey (multi-centre) Influenza seasons 2010 2011 Location New Zealand	Influenza vaccine Influvac^® TIV Fluvax^® TIV Other TIVs and a monovalent H1N1 vaccine Strains 2010 and 2011 formulations: A/California/7/2009 (H1N1) A/Perth/16/2009 (H3N2) B/Brisbane/60/2008	Population definition Child aged 6 months–5 years vaccinated for influenza Sample size Influvac^®: n=204 Fluvax^®: n=865 Age (mean) Influvac^®: 35 months Fluvax^®: 36 months Sex Influvac^®: 46% female Fluvax^®: 47% female	Febrile adverse events Influvac^® Convulsive seizures level 1–3: 0.0% Febrile with rigor: 0.0% Febrile and floppy/delirium: 0.0% Febrile with vomiting: 2.0% Febrile with malaise/lethargy/irritability/headache: 9.0% Any fever recalled occurring post-vaccination: 19.0% Any fever recalled occurring within 24 hours of vaccination: 17.0% Sought medical advice for fever: 5.0% Hospital/emergency: 0.0% Fever ≥38°C: 5.0% Fluvax^® Convulsive seizures level 1–3: 0.3% Febrile with rigor: 1.0% Febrile and floppy/delirium: 0.5% Febrile with vomiting: 6.5% Febrile with malaise/lethargy/irritability/headache: 12.0% Any fever recalled occurring post-vaccination: 28.0% Any fever recalled occurring within 24 hours of vaccination: 25.0% Sought medical advice for fever: 8.0% Hospital/emergency: 3.0% Fever ≥38°C: 13.0% Influvac^® vs. Fluvax^®, odds ratio (95% CI) Convulsive seizures level 1–3: NA Febrile with rigor: NA Febrile and floppy/delirium: NA Febrile with vomiting: 0.29 (0.10–0.81) Febrile with malaise/lethargy/irritability/headache: 0.70 (0.41–1.18) Any fever recalled occurring post-vaccination: 0.61 (0.42–0.89) Any fever recalled occurring within 24 hours of vaccination: 0.59 (0.40–0.88) Sought medical advice for fever: 1.07 (0.5–2.30) Hospital/emergency: NA Fever ≥38°C: 0.51 (0.24–1.07) Notes Influvac^® was only assessed in the 2010 season. Data for other vaccine brands not presented.	Level III	NA
Pillsbury et al. (2015)^{Footnote 21}	Design Active surveillance Influenza season 2015 Location Australia	Influenza vaccine Influvac^® TIV Other TIVs	Population definition Children aged 6 months–4 years receiving influenza vaccine Sample size Total: n=3340 Vaccinated with Influvac^®: n=47 Age (mean) 23.0 months Sex 46.3% female	Five of 47 participants who received Influvac^® had a fever and 2 of the 47 participants sought medical advice/attendance. One of the participants vaccinated with Influvac^® experienced a SAE, defined as any untoward medical event that resulted in death, was life-threatening or required hospitalization, and reported improvement within days (precise age of the child and nature of the SAE are not reported). Influvac^® was administered in insufficient numbers in children aged six months to four years (n=47) to allow for a reliable comparison of differences in reported fever rates with other vaccine brands.	Level III	NA
Shahgholi et al. (2010)^{Footnote 23}	Design Non-randomized controlled trial Location Iran Follow-up 4 weeks post-vaccination Adverse events: 5 days post-vaccination	Influenza vaccine Influvac^® TIV Dose and administration <36 months of age: 2 doses (0.25mL), 3–4 weeks apart 36 months–13 years of age: 2 doses (0.5mL), 3–4 weeks apart >13 years of age: 1 dose (0.5mL) Strains 2007–2008 formulation: A/Solomon Islands/3/2006 (H1N1) A/Wisconsin/67/2005 (H3N2) B/Malaysia/2506/2004-like	Population definition Children 1–18 years of age diagnosed with ALL in first remission and receiving maintenance therapy and healthy children (siblings) as controls. Sample size ALL: n=32 Controls: n=30 Age (mean) ALL: 10.65 years Controls: 10.8 years Sex ALL: 34.4% female Controls: 46.7% female No significant differences were found for the gender and age distributions of the two groups.	Adverse events ALL, proportion of participants who experienced event Mild to moderate pain: 0% Swelling: 1% Redness at injection site: 1% Controls, proportion of participants who experienced event Mild to moderate pain: 0% Swelling: 0% Redness at injection site: 1% Complete reactogenicity data was available for 56% of participants. No SAEs were reported. Axillary temperature >37.8°C during 5 days after vaccination was reported in two ALL patients and one healthy control. Rates of adverse reaction did not differ by dose or number of vaccine. No relapse was observed during the study period and at least 3 months after completion of vaccination.	Level II-1	NA Siblings were used as controls, but similarities in important confounders were not assessed.
Wood et al. (2012)^{Footnote 24}	Design Active surveillance Influenza seasons 2010 2011 Location Australia	Influenza vaccine Influvac^® TIV (reported as a Solvay TIV) Fluvax^® TIV (reported as a CSL TIV) Strains 2010 and 2011 formulations: A/California/7/2009 (H1N1) A/Perth/16/2009 (H3N2) B/Brisbane/60/2008	Population definition Children aged 6 months–5 years vaccinated for seasonal influenza in 2010 or 2011 at study site Sample size Influvac^®: n=99 Fluvax^®: n=73 Age (mean) Influvac^®: 2.7 years Fluvax^®: 3.3 years Sex NR	Febrile adverse events Influvac^® Parental reported fever: 7.1% Parental reported fever (>38.5°C): 3.0% Parental report of medical attendance within 48hrs: 2.0% Fluvax^® Parental reported fever: 45.2% Parental reported fever (>38.5°C): 31.5% Parental report of medical attendance within 48hrs: 16.4% Influvac^® vs. Fluvax^®, relative risk (95% CI) Parental reported fever: 6.5 (3.1–13.9) Parental reported fever (>38.5°C): Not available Parental report of medical attendance within 48hrs: 8.2 (1.9–35.4) There were no reports of febrile seizure for any of the vaccines. No participants vaccinated with Influvac^® had a fever ≥40°C.	Level III	NA
Zhu et al. (2008)^{Footnote 25}	Design Endpoint-blind RCT Location China Follow-up 4 weeks post-vaccination Adverse events: 29 days post-vaccination	Influenza vaccine Influvac^® TIV Agrippal^® TIV Dose and administration 1 dose (15 µg per strain) Strains 2005–2006 formulation: A/New Caledonia/20/99 (H1N1) A/New York/55/2004 (H3N2) B/Jiangsu/10/2003	Adverse events were recorded for both parts of the study, but a separate, open safety study was conducted prior to the RCT (see below for details on the open safety study and the entry in Appendix G for details on the RCT) Population definition Healthy children 3–12 years of age Sample size n=30 Age (mean) 7.6 years Sex 50.0% female	Adverse events Three children experienced local pain after vaccination with Influvac^® during the safety trial, while nine children experienced mild pain or itching/pruritus during the RCT. No local reactions were reported in children vaccinated with Agrippal^®. In the RCT, one child had a headache and nine experienced fever after vaccination with Influvac^®. There were reports of 2 children with headaches and 4 with fever after vaccination with Agrippal^®. Two children who were vaccinated with Influvac^® experienced mild inconvenience compared to one child vaccinated with Agrippal^®. No systemic reactions were reported during the safety trial. Episodes of acute tonsillitis (n=1), dizziness (n=1), and cough (n=1) were reported during the RCT in children vaccinated with Influvac^®. No AEs were reported during the safety study or in children who were vaccinated with Agrippal^®. No SAEs were reported during the safety trial or the RCT.	Level I	Fair Conducted per-protocol analyses. Study was endpoint-blind (not double-blind).
Abbreviations: Refer to section V. List of abbreviations.

Study Details

Summary

Study

Study design

Influenza vaccine

Participants

Summary of key findings

Level of evidence

Quality

Aagaard et al. (2011)^{Footnote 7}

Design
Passive surveillance

Influenza seasons
1998–2007

Location
Denmark

Influenza vaccine
Influvac^® TIV

Other non-influenza vaccines

Population definition
Children <18 years of age

Age
NR

Sex
NR

AEFI defined as any noxious and unintended response to a drug that occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy of disease.

4 AEFI were reported for children in the 2–3 year old age group, 3 of which were serious AEFI. Details about the AEFI were not provided.

No AEFI were reported in any other age groups.

Level III

Armstrong et al. (2011)^{Footnote 8}

Design
Passive surveillance

Retrospective cohort study

Influenza season
2010

Location
Australia

Influenza vaccine
Influvac^® TIV
Fluvax^® TIV
Fluvax Junior^® TIV

Dose and administration
6–36 months: 2 doses (7.5 µg per strain)

4 years of age: 2 doses (15 µg per strain)

Strains
2010 formulation:
A/California/7/2009-like
(H1N1)
A/Perth/16/2009-like
(H3N2)
B/Brisbane/60/2008-like

Surveillance:

Population definition
Children 6 months–4 years of age

Case definition: Child assigned ICD-10 code R56.0 (febrile convulsion) at ED within 72 hours of receipt of TIV or TIV-associated febrile convulsion cases that were reported by ED clinicians, primary care givers or vaccine providers.

Sample size
Cases: n=63

Age (mean)
1.85 years

Sex
39.7% female

Cohort:

Population definition
Children less than five years of age who were vaccinated with TIV in 2010.

Sample size
n=360

Age
NR

Sex
NR

Surveillance:

Febrile convulsions
≤2 years of age, rate/1000 TIV doses (95% CI)
Influvac^®: 0.0 (0.0–1.8)
Fluvax^®: 4.9 (3.4–7.1)
Fluvax Junior^®: 7.9 (5.3–11.8)
Fluvax^® and Fluvax Junior^®: 5.9 (4.5–7.7)

3–4 years of age, rate/1000 TIV doses (95% CI)
Influvac^®: 0.0 (0.0–1.5)
Fluvax^®: 1.4 (0.7–2.9)
Fluvax Junior^®: 9.7 (3.8–24.7)
Fluvax^® and Fluvax Junior^®: 2.0 (1.1–3.6)

Febrile reactions (non-convulsive)*
≤2 years of age, rate/1000 TIV doses (95% CI)
Influvac^®: 4.2 (2.2–8.0)
Fluvax^®: 49.0 (43.7–54.9)
Fluvax Junior^®: 47.3 (40.2–55.6)
Fluvax^® and Fluvax Junior^®: 48.4 (44.1–53.1)

3–4 years of age, rate/1000 TIV doses (95% CI)
Influvac^®: 0.8 (0.2–2.9)
Fluvax^®: 25.3 (21.3–30.0)
Fluvax Junior^®: 26.6 (14.9–47.0)
Fluvax^® and Fluvax Junior^®: 25.4 (21.5–29.9)

* Consists of passive reports made to the AEFI reporting system as opposed to active

The RR of febrile reactions for combined Fluvax^® & Fluvax Junior^® compared to Influvac^® was 11.4 (95% CI: 5.9–22.1) for children ≤2 years of age and 33.0 (95% CI: 8.2–133.2) in children 3–4 years of age.

Cohort:

Percentage of children with symptom
Influvac^®
Fever: 17.3%
Fatigue: 10.9%
Vomiting: 2.7%
Rigors: 0.9%
Swelling: 10.9%
Diarrhoea: 0.9%
Rash: 0.9%
Headache: 0.9%
Convulsions: 0.0%
Significant febrile adverse event: 4.5%

Fluvax^®
Fever: 52.3%
Fatigue: 29.4%
Vomiting: 14.7%
Rigors: 11.9%
Swelling: 12.8%
Diarrhoea: 6.4%
Rash: 5.5%
Headache: 3.7%
Convulsions: 2.8%
Significant febrile adverse event: 22.9%

Fluvax Junior^®
Fever: 61.0%
Fatigue: 37.0%
Vomiting: 20.0%
Rigors: 19.0%
Swelling: 13.0%
Diarrhoea: 4.0%
Rash: 2.0%
Headache: 3.0%
Convulsions: 0.0%
Significant febrile adverse event: 36.0%

Fluvax^® and Fluvax Junior^®
Fever: 56.5%
Fatigue: 33.0%
Vomiting: 17.2%
Rigors: 15.3%
Swelling: 12.9%
Diarrhoea: 5.3%
Rash: 3.8%
Headache: 3.4%
Convulsions: 1.4%
Significant febrile adverse event: 29.2%

Fever (OR=5.1), fatigue (OR=3.5), vomiting (OR=6.0), and significant febrile adverse events (OR=7.0) were significantly more common in children who received one of the two Fluvax^® vaccines than children who received the Influvac^® vaccine.

Level III

Brydak et al. (2000)^{Footnote 9}

Design
Pre-post study

Location
Poland

Follow-up
3 weeks and 6 weeks post-vaccination

Influenza vaccine
Influvac^® TIV

Dose and administration
1 dose (15 µg per strain)

Strains
1996–1997 formulation:
A/Singapore/6/86
(H1N1)
A/Wuhan/359/95
(H3N2)
B/Beijing/184/93

Population definition
Children with ALL (groups A and B)

Study groups
A: Chemotherapy completed before 1991

B: Chemotherapy completed after 1991

Unvaccinated controls (healthy children)

Sample size
Group A: n=10
Group B: n=12
Controls: n=22

Age
6–13 years

Sex
NR

None of the vaccinated children showed symptoms of influenza virus inflections.

Vaccines were well tolerated and did not cause any severe adverse reactions.

Notes

Subjects were vaccinated with FluShield^® (Wyeth) in the 1993–1994 influenza season and with Influvac^® in the 1996–1997 influenza season. Data for the 1996–1997 influenza season is presented.
Results are also available for subjects vaccinated for the first time in the 1996–1997 influenza season, but are not presented.
Though not stated explicitly in the article, the study subjects likely overlap with Brydak et al. (1998a)^{Footnote 10}.

Level III

Bueving (2004a)^{Footnote 12}

Supplemented with additional details from Bueving et al. (2004b)^{Footnote 13} on AEFI and asthma exacerbation following vaccination.

Design
Double-blind RCT
(placebo-controlled)

Location
The Netherlands

Follow-up
14–21 days and 4–5 months post-vaccination

Adverse events: 7 days post-vaccination

Influenza vaccine
Influvac^® TIV (reported as a Solvay TIV)

Administration
1 dose (15 µg per strain)

Strains
1999–2000 formulation:
A/Beijing/262/95-like
(H1N1)
A/Sydney/5/97-like
(H3N2)
B/Beijing/184/93-like

2000–2001 formulation:
A/New Caledonia/20/99
(H1N1)
A/Moscow/10/99-like
(H3N2)
B/Beijing/184/93-like

Children could only participate in one of the two seasons

Population definition
Children 6–18 years of age with asthma, without other chronic diseases

Sample size
Vaccine: n=347
Placebo: n=349

Age (mean)
Vaccine: 10.5 years
Placebo: 10.6 years

Sex
Vaccine: 48.1% female
Placebo: 43.6% female

Adverse events
There was a significant difference in the proportion of local adverse events experienced in the vaccinated group compared to the placebo group. Local adverse events included erythema at the vaccination site and a stiff or painful arm. There was a 23% absolute difference between the two groups for erythema at the vaccination site and a 48% absolute difference for stiff or painful arm.

In the 1999–2000 season, there was a significant difference in fever/shivers (8%), headaches (10%), and myalgia (18%) after injection between the vaccine group and the placebo group. In 2000–2001, only episodes of hoarseness (5%) were significantly different between the two groups. There were no other significant differences in systemic reactions between the two groups in either season (sickness, vomiting, diarrhoea, tiredness, sweating, sneezing, runny or stuffed-up nose, burning or watery eyes, sore throat).

Of recorded asthma symptoms, the only significant difference occurred in the 1999–2000 season for episodes of cough (8%). There were no SAEs reported in either group.

Asthma exacerbation
The number of asthma exacerbations was not significantly different between asthmatic patients who were vaccinated with Influvac^® and those who received the placebo.

Level I

Fair

Conducted per-protocol analyses.

Cashman et al. (2014)^{Footnote 14}

Design
Active surveillance

Influenza seasons
2012
2013

Location
Australia

Follow-up
3 days and 42 days post-vaccination

Influenza vaccine
Influvac^® TIV

Other TIVs

Population definition
Children aged less than 10 years receiving influenza vaccine

Sample size
Total: n=290
Total vaccinated with Influvac^®: n=32

Survey response rate: 61% (n=290 of 477)

Age
NR

Sex
47% female

Adverse events following the first dose
Influvac^®
Any adverse event following the first dose: 1
SAE: 0
Sought medical attention: 0
Reaction at injection site: 1
Fever: 1
Headaches: 0
Fatigue: 0
Joint pain: 0
ILI: 1
Lymph node swelling: 0
Seizures: 0
Muscle aches: 0
Weakness: 0
Other symptoms: 0

Total
Any adverse event following the first dose: 52
SAE: 0
Sought medical attention: 4
Reaction at injection site: 23
Fever: 8
Headaches: 9
Fatigue: 15
Joint pain: 6
ILI: 12
Lymph node swelling: 3
Seizures: 0
Muscle aches: 14
Weakness: 2
Other symptoms: 9

Recipients of Influvac^® reported lower frequencies of any AEFI (3.1%; n=32) compared to Fluarix^® (11.6%; n=43), Vaxigrip^® (21.7%; n=212) and all influenza vaccine brands (17.9%; n=290) for the 2012 and 2013 Southern Hemisphere influenza seasons.

Level III

Cheng et al. (2015)^{Footnote 15}

Design
Passive surveillance

Influenza seasons
2007–2013
(Influvac^® in schedule for 2008–2009 only)

Location
Australia

Follow-up
Within 24 hours of initial report

Influenza vaccine
Influvac^® TIV

Other non-influenza vaccines

Dose and administration
1 dose

Population definition
Children less than 18 years of age with suspected anaphylaxis following immunization.

Case definition: The Brighton Collaboration Case Definition was used to define the level of certainty for an anaphylaxis event.

Sample size
Cases: n=1

Age (mean)
9.4 years

Sex
Female

Anaphylaxis following immunization
One anaphylaxis AEFI was reported for Influvac^®. The level of certainty of an anaphylaxis event was 2, which indicates that symptoms included ≥1 major cardiovascular/respiratory and ≥1 minor symptoms involving ≥1 different systems, or ≥1 major dermatological and ≥1 minor cardiovascular/respiratory.

Notes
Influvac^® was only in schedule in Australia for 2008–2009. Therefore, report of anaphylaxis following immunization for Influvac^® only reflects this period and not the full study period.

Level III

Daubeney et al. (1997)^{Footnote 16}

Design
Pre-post study

Location
United Kingdom

Follow-up
Up to 72 hours post-vaccination

Influenza vaccine
Influvac^® TIV

Dose and administration
2 doses (7.5 µg per strain), 4 weeks apart

Strains
A/Singapore/6/86
(H1N1)
A/Shangdong/9/93
(H3N2)
B/Panama/45/90

Population definition
Children with chronic respiratory disease, congenital heart disease, or both.

Sample size
n=52

Age
Mean (range): 19.5 months (6 months–4 years)

Sex
NR

Adverse events
AEs were recorded 24, 48 and 72 hours post-vaccination:

n=15 AEs in total
n=2 of 15 AEs were related to vaccination (2 cases of febrile episodes associated with cough)
n=4 of 15 AEs were arranged hospital admissions for cardiac catheterisation or jejunal biopsy
All hospitalizations were associated with underlying cardiac or respiratory conditions
n=12 of 52 (23%) subjects had local reactions, with the most commonly reported reaction being redness at injection site (n=6)
n=25 of 52 (48%) subjects had systemic reactions, with the most commonly reported reaction being fever (n=14), insomnia (n=13) and increased irritability (n=13)
All systemic and local reactions were noted to be minor and resolved within a few days

Level III

Ghendon et al. (2006)^{Footnote 26}

Design
Non-randomized controlled trial

Influenza season
2001–2002

Location
Russia

Follow-up
Morbidity: 4 months post-vaccination (December 2001–March 2002)

Adverse events: 3–5 days post-vaccination

Influenza vaccine
Influvac^® TIV

Dose and administration
1 dose (15 µg per strain)

Strains
2001–2002 formulation:
A/New Caledonia/20/99
(H1N1)
A/Moscow/10/99
(H3N2)
B/Sichuan/379/99

Population definition
Healthy children without contraindications

Study groups
Intervention: Mass immunization campaign (coverage rate 69.7%)

Control: No immunization campaign (coverage rate <1.0%)

Sample size
Intervention: n=40,611
Control: n=60,946

Age
3–17 years
Sex
NR

Adverse events
No SAEs were observed immediately after vaccination or 3–5 days post-vaccination.

Level II-1

Jansen et al. (2008a)^{Footnote 18}

Supplemented with additional details from Jansen et al. (2008b)^{Footnote 19} on AEFI.

Design
Double-blind RCT
(placebo-controlled)

Influenza seasons
2003–2004
2004–2005
2005–2006

Location
The Netherlands

Follow-up
2003–2004 and 2004–2005 seasons: 18 months post-vaccination

2005–2006 season: 6 months post-vaccination

Adverse events: 7 days post-vaccination

Influenza vaccine
Influvac^® TIV

Other non-influenza vaccines

Dose and administration
2 doses, 4–8 weeks apart

2003–2004 and 2004–2005 cohorts received an additional vaccination in the following year

Strains
2003–2004 formulation:
A/New Caledonia/20/99
(H1N1)
A/Moscow/10/99
(H3N2)
B/Hong Kong/330/01

2004–2005 formulation:
A/New Caledonia/20/99
(H1N1)
A/Fuijan/411/2002
(H3N2)
B/Shanghai/361/2002

2005–2006 formulation:
A/New Caledonia/20/99
(H1N1)
A/California/7/2004
(H3N2)
B/Shanghai/361/2002

Population definition
Unvaccinated children aged 18–72 months with previously diagnosed respiratory tract infection

Study groups
TIV plus PCV7

TIV plus placebo

HBV plus placebo (control)

Sample size
TIV plus PCV7: n=197
TIV plus placebo: n=187
HBV plus placebo (control): n=195

Age (mean)
TIV plus PCV7: 3.0 years
TIV plus placebo: 3.1 years
HBV plus placebo (control): 3.1 years

Sex
TIV plus PCV7: 41.4% female
TIV plus placebo: 44.4% female
HBV plus placebo: 49.7% female

The study groups were similar with regard to age, sex and medical history.

Adverse events
TIV plus PCV7, proportion with adverse event
Local: 66.8% (127/190)
Systemic: 63.9% (117/183)

TIV plus placebo, proportion with adverse event
Local: 37.8% (68/180)
Systemic: 52.3% (90/172)

HBV plus placebo (control), proportion with adverse event
Local: 36.0% (67/186)
Systemic: 50.9% (88/173)

No immediate adverse events were recorded following vaccination.

The local adverse reactions recorded for TIV plus placebo, in descending order of incidence, were tenderness, swelling, erythema, and interference with limb movement.

The systemic adverse reactions recorded for TIV plus placebo, in descending order of incidence, were malaise, fever, headaches, and myalgia.

No severe reactions were recorded for all groups.

Level I

Fair

14–20% loss to follow up.

Petousis-Harris et al. (2012)^{Footnote 20}

Design
Retrospective survey
(multi-centre)

Influenza seasons
2010
2011

Location
New Zealand

Influenza vaccine
Influvac^® TIV
Fluvax^® TIV

Other TIVs and a monovalent H1N1 vaccine

Strains
2010 and 2011 formulations:
A/California/7/2009
(H1N1)
A/Perth/16/2009
(H3N2)
B/Brisbane/60/2008

Population definition
Child aged 6 months–5 years vaccinated for influenza

Sample size
Influvac^®: n=204
Fluvax^®: n=865

Age (mean)
Influvac^®: 35 months
Fluvax^®: 36 months

Sex
Influvac^®: 46% female
Fluvax^®: 47% female

Febrile adverse events
Influvac^®
Convulsive seizures level 1–3: 0.0%
Febrile with rigor: 0.0%
Febrile and floppy/delirium: 0.0%
Febrile with vomiting: 2.0%
Febrile with malaise/lethargy/irritability/headache: 9.0%
Any fever recalled occurring post-vaccination: 19.0%
Any fever recalled occurring within 24 hours of vaccination: 17.0%
Sought medical advice for fever: 5.0%
Hospital/emergency: 0.0%
Fever ≥38°C: 5.0%

Fluvax^®
Convulsive seizures level 1–3: 0.3%
Febrile with rigor: 1.0%
Febrile and floppy/delirium: 0.5%
Febrile with vomiting: 6.5%
Febrile with malaise/lethargy/irritability/headache: 12.0%
Any fever recalled occurring post-vaccination: 28.0%
Any fever recalled occurring within 24 hours of vaccination: 25.0%
Sought medical advice for fever: 8.0%
Hospital/emergency: 3.0%
Fever ≥38°C: 13.0%

Influvac^® vs. Fluvax^®, odds ratio (95% CI)
Convulsive seizures level 1–3: NA
Febrile with rigor: NA
Febrile and floppy/delirium: NA
Febrile with vomiting: 0.29 (0.10–0.81)
Febrile with malaise/lethargy/irritability/headache: 0.70 (0.41–1.18)
Any fever recalled occurring post-vaccination: 0.61 (0.42–0.89)
Any fever recalled occurring within 24 hours of vaccination: 0.59 (0.40–0.88)
Sought medical advice for fever: 1.07 (0.5–2.30)
Hospital/emergency: NA
Fever ≥38°C: 0.51 (0.24–1.07)

Notes
Influvac^® was only assessed in the 2010 season. Data for other vaccine brands not presented.

Level III

Pillsbury et al. (2015)^{Footnote 21}

Design
Active surveillance

Influenza season
2015
Location
Australia

Influenza vaccine
Influvac^® TIV

Other TIVs

Population definition
Children aged 6 months–4 years receiving influenza vaccine

Sample size
Total: n=3340
Vaccinated with Influvac^®: n=47

Age (mean)
23.0 months

Sex
46.3% female

Five of 47 participants who received Influvac^® had a fever and 2 of the 47 participants sought medical advice/attendance.

One of the participants vaccinated with Influvac^® experienced a SAE, defined as any untoward medical event that resulted in death, was life-threatening or required hospitalization, and reported improvement within days (precise age of the child and nature of the SAE are not reported).

Influvac^® was administered in insufficient numbers in children aged six months to four years (n=47) to allow for a reliable comparison of differences in reported fever rates with other vaccine brands.

Level III

Shahgholi et al. (2010)^{Footnote 23}

Design
Non-randomized controlled trial

Location
Iran

Follow-up
4 weeks post-vaccination

Adverse events: 5 days post-vaccination

Influenza vaccine
Influvac^® TIV

Dose and administration
<36 months of age: 2 doses (0.25mL), 3–4 weeks apart

36 months–13 years of age: 2 doses (0.5mL), 3–4 weeks apart

>13 years of age: 1 dose (0.5mL)

Strains
2007–2008 formulation:
A/Solomon Islands/3/2006
(H1N1)
A/Wisconsin/67/2005
(H3N2)
B/Malaysia/2506/2004-like

Population definition
Children 1–18 years of age diagnosed with ALL in first remission and receiving maintenance therapy and healthy children (siblings) as controls.

Sample size
ALL: n=32
Controls: n=30

Age (mean)
ALL: 10.65 years
Controls: 10.8 years

Sex
ALL: 34.4% female
Controls: 46.7% female

No significant differences were found for the gender and age distributions of the two groups.

Adverse events
ALL, proportion of participants who experienced event
Mild to moderate pain: 0%
Swelling: 1%
Redness at injection site: 1%

Controls, proportion of participants who experienced event
Mild to moderate pain: 0%
Swelling: 0%
Redness at injection site: 1%

Complete reactogenicity data was available for 56% of participants. No SAEs were reported.

Axillary temperature >37.8°C during 5 days after vaccination was reported in two ALL patients and one healthy control.
Rates of adverse reaction did not differ by dose or number of vaccine.
No relapse was observed during the study period and at least 3 months after completion of vaccination.

Level II-1

Siblings were used as controls, but similarities in important confounders were not assessed.

Wood et al. (2012)^{Footnote 24}

Design
Active surveillance

Influenza seasons
2010
2011

Location
Australia

Influenza vaccine
Influvac^® TIV (reported as a Solvay TIV)
Fluvax^® TIV (reported as a CSL TIV)

Strains
2010 and 2011 formulations:
A/California/7/2009
(H1N1)
A/Perth/16/2009
(H3N2)
B/Brisbane/60/2008

Population definition
Children aged 6 months–5 years vaccinated for seasonal influenza in 2010 or 2011 at study site

Sample size
Influvac^®: n=99
Fluvax^®: n=73

Age (mean)
Influvac^®: 2.7 years
Fluvax^®: 3.3 years

Sex
NR

Febrile adverse events
Influvac^®
Parental reported fever: 7.1%
Parental reported fever (>38.5°C): 3.0%
Parental report of medical attendance within 48hrs: 2.0%

Fluvax^®
Parental reported fever: 45.2%
Parental reported fever (>38.5°C): 31.5%
Parental report of medical attendance within 48hrs: 16.4%

Influvac^® vs. Fluvax^®, relative risk (95% CI)
Parental reported fever: 6.5 (3.1–13.9)
Parental reported fever (>38.5°C): Not available
Parental report of medical attendance within 48hrs: 8.2 (1.9–35.4)

There were no reports of febrile seizure for any of the vaccines. No participants vaccinated with Influvac^® had a fever ≥40°C.

Level III

Zhu et al. (2008)^{Footnote 25}

Design
Endpoint-blind RCT
Location
China

Follow-up
4 weeks post-vaccination

Adverse events: 29 days post-vaccination

Influenza vaccine
Influvac^® TIV
Agrippal^® TIV

Dose and administration
1 dose (15 µg per strain)

Strains
2005–2006 formulation:
A/New Caledonia/20/99
(H1N1)
A/New York/55/2004
(H3N2)
B/Jiangsu/10/2003

Adverse events were recorded for both parts of the study, but a separate, open safety study was conducted prior to the RCT (see below for details on the open safety study and the entry in Appendix G for details on the RCT)

Population definition
Healthy children 3–12 years of age

Sample size
n=30

Age (mean)
7.6 years

Sex
50.0% female

Adverse events
Three children experienced local pain after vaccination with Influvac^® during the safety trial, while nine children experienced mild pain or itching/pruritus during the RCT. No local reactions were reported in children vaccinated with Agrippal^®.

In the RCT, one child had a headache and nine experienced fever after vaccination with Influvac^®. There were reports of 2 children with headaches and 4 with fever after vaccination with Agrippal^®. Two children who were vaccinated with Influvac^® experienced mild inconvenience compared to one child vaccinated with Agrippal^®. No systemic reactions were reported during the safety trial.

Episodes of acute tonsillitis (n=1), dizziness (n=1), and cough (n=1) were reported during the RCT in children vaccinated with Influvac^®. No AEs were reported during the safety study or in children who were vaccinated with Agrippal^®. No SAEs were reported during the safety trial or the RCT.

Level I

Fair

Conducted per-protocol analyses. Study was endpoint-blind (not double-blind).

Abbreviations: Refer to section V. List of abbreviations.

Page details

Date modified:: 2021-07-05

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Influvac^®use in children

Addendum - Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2017–2018

Table of contents

Preamble

Related Topics

I. NACI recommendation

II. Background

III. Literature review methods

IV. Evidence summary

V. List of abbreviations

VI. Acknowledgments

Appendix A: Characteristics of influenza vaccines available for use in Canada, 2017–2018^{Footnote *}

Appendix B: NACI recommendations: Strength of recommendation and grade of evidence

Appendix C: Search strategy and results

Appendix D: Level of evidence based on research design and quality (internal validity) rating of evidence

Appendix E: Flow diagram of the study selection process for literature evidence on the efficacy and effectiveness, immunogenicity and safety of the Influvac^® trivalent inactivated influenza vaccine in children

Appendix F: Summary of literature evidence related to the efficacy and effectiveness of Influvac^® trivalent inactivated influenza vaccine in children

Appendix G: Summary of literature evidence related to the immunogenicity of Influvac^® trivalent inactivated influenza vaccine in children

Appendix H: Summary of literature evidence related to the safety of Influvac^® trivalent inactivated influenza vaccine in children

Page details

Influvac® use in children

Addendum - Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2017–2018

Table of contents

Preamble

I. NACI recommendation

II. Background

III. Literature review methods

IV. Evidence summary

V. List of abbreviations

VI. Acknowledgments

Appendix A: Characteristics of influenza vaccines available for use in Canada, 2017–2018Footnote *

Appendix B: NACI recommendations: Strength of recommendation and grade of evidence

Appendix C: Search strategy and results

Appendix D: Level of evidence based on research design and quality (internal validity) rating of evidence

Appendix E: Flow diagram of the study selection process for literature evidence on the efficacy and effectiveness, immunogenicity and safety of the Influvac® trivalent inactivated influenza vaccine in children

Appendix F: Summary of literature evidence related to the efficacy and effectiveness of Influvac® trivalent inactivated influenza vaccine in children

Appendix G: Summary of literature evidence related to the immunogenicity of Influvac® trivalent inactivated influenza vaccine in children

Appendix H: Summary of literature evidence related to the safety of Influvac® trivalent inactivated influenza vaccine in children

Page details

Influvac^®use in children

Appendix A: Characteristics of influenza vaccines available for use in Canada, 2017–2018^{Footnote *}

Appendix E: Flow diagram of the study selection process for literature evidence on the efficacy and effectiveness, immunogenicity and safety of the Influvac^® trivalent inactivated influenza vaccine in children

Appendix F: Summary of literature evidence related to the efficacy and effectiveness of Influvac^® trivalent inactivated influenza vaccine in children

Appendix G: Summary of literature evidence related to the immunogenicity of Influvac^® trivalent inactivated influenza vaccine in children

Appendix H: Summary of literature evidence related to the safety of Influvac^® trivalent inactivated influenza vaccine in children