Recommendations on fractional influenza vaccine dosing
Preamble
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization. 
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels. 
The additional factors to be considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI Statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select Statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest. 
On this page
Summary of the Information Contained in this NACI Supplemental Statement
The following highlights key information for immunization providers. Please refer to the remainder of this supplemental statement for details.

# 1. What
Influenza vaccination in Canada is provided annually through provincial and territorial seasonal influenza vaccine programs. Due to the rapid timelines required for vaccine production each year, any significant impact to the manufacturing process may cause delays in influenza vaccine delivery or decrease the overall number of doses produced, potentially resulting in vaccine shortages for a season. A significant and unexpected increase in demand for the influenza vaccine may also lead to insufficient supply, as the number of doses available is based on orders made primarily in the spring months. A strategy for the administration of fractional influenza vaccine doses (i.e., less than a full dose) might be considered in these situations, as the use of fractional doses would provide vaccine programs the ability to vaccinate a larger number of people with the amount of vaccine that is available. 

# 2. Who
This supplemental statement provides an evidence summary and recommendations on the topic of fractional influenza vaccine doses for consideration by public health programs during a significant influenza vaccine shortage.

# 3. How
In the event of a significant population-level shortage of the currently available influenza vaccine products, NACI recommends that full dose influenza vaccine should continue to be used and existing vaccine supply should be prioritized for those considered to be at high risk or capable of transmitting to those at high risk of influenza-related complications or hospitalizations. NACI recommends against the use of fractional doses of influenza vaccines in any population.

# 4. Why
There is some, but still insufficient, evidence that fractional doses of influenza vaccine provided via the intramuscular (IM) route are effective and immunogenic in healthy individuals. Although there is some evidence on the use of fractional intradermal (ID) doses in adults 65 years of age, including those with chronic health conditions, that demonstrates that lower doses may be immunogenic in this population, there is no evidence regarding the use of fractional dosing in other adult high-risk groups. Moreover, administering influenza vaccines through the ID route, while using regular syringes, has been determined to not be feasible.
Since many of those at high risk of influenza (e.g., adults 65 years of age and older, individuals with specific underlying chronic health conditions) may have a lower immune response to influenza vaccination already (due to immunosenescence in older adults or a condition that alters immune function), it is important to ensure that those at high risk continue to receive the full dose of influenza vaccine. 
There is fair evidence that fractional doses of influenza vaccine administered via the IM and ID routes do not result in a significant difference with regard to severe systemic adverse events (AEs)  post-influenza vaccination; however, ID administration of influenza vaccine will likely result in a higher proportion of individuals who experience local AEs.
There are feasibility issues when considering fractional dosing of current influenza immunizations or administration of ID doses of influenza vaccines. Pre-filled syringes cannot be used for fractional dosing. ID administration of vaccine requires a different gauge needle than IM administration, and training and skill in ID administration that not all vaccinators will have. The volume of vaccine to be administered is high, requiring two ID injections if regular needles and syringes are used.  The majority of studies of administration of influenza vaccine by the ID route used micro-needle injectors for administration. The use of fractional doses is not covered within influenza vaccine product monographs and would therefore require a novel communication and consent plan for any off-label dosing if it were adopted. Moreover, implementation of such an ID immunization program would require monitoring for any potential modification to a seasonal influenza vaccine program running low on vaccine supply and thus would be a challenge without significant advanced planning.   
I. Introduction
 Influenza is a viral infection that is estimated to cause approximately 12,200 hospitalizations and 3,500 deaths in Canada annually. All provinces and territories in Canada have implemented seasonal influenza vaccination programs, with the aim of reducing morbidity and mortality caused by influenza-associated illness. Although influenza programs vary across the country, all programs cover individuals who are at high risk of severe outcomes due to influenza and individuals that are capable of transmitting influenza to those at high risk (e.g., household members, healthcare workers). 
 Influenza vaccine for use in publicly funded programs in Canada is coordinated by the federal government's Public Services and Procurement Canada, and vaccine orders are completed in the spring in advance of the next influenza season. The schedule for finalizing influenza vaccine orders is generally consistent for all countries in the Northern Hemisphere, as vaccine manufacturers must follow strict timelines to produce influenza vaccine with the recommended strain composition for the next season. The strain composition for the upcoming Northern Hemisphere
 season is announced by the World Health Organization annually in February . Significant changes to the amount of influenza vaccine ordered are, therefore, difficult once the influenza season has begun. In addition, unforeseen influenza vaccine production issues or an unexpected increase in demand for influenza vaccine could result in a delay or decrease in vaccine available for Canadians. In the event that a significant shortage of influenza vaccine were to occur in Canada, guidance on appropriate strategies for fractional dosing, or dose sparing, would be needed. However, significant global influenza vaccine shortages are extremely rare, given the variety of influenza vaccine products available on the market, with any issues that do arise typically being isolated to only one vaccine product or manufacturer. 
 In Canada, influenza vaccines are currently authorized for IM administration only, apart from the live-attenuated influenza vaccine (LAIV), which is administered intranasally. The stated dose of an influenza vaccine is based on the hemagglutinin (HA) content within the vaccine. Standard dose influenza vaccines contain 15 mcg of HA per strain and are delivered in 0.5 mL volume. Therefore, the total amount of HA in standard dose trivalent vaccines is 45 mcg, and the total amount of HA in standard dose quadrivalent vaccines is 60 mcg. Fractional dosing strategies are those where less than the standard amount of HA antigen and thus less volume of vaccine is administered during influenza vaccination, increasing the overall number of doses available. For the purposes of these recommendations, NACI considered two different strategies: 
1. Fractional intramuscular (IM) administration of influenza vaccine
2. Fractional intradermal (ID) administration of influenza vaccine

#  Guidance Objective
 The objective of this advisory committee supplemental statement is to review the available evidence for efficacy, effectiveness, immunogenicity, and safety of fractional influenza vaccine dosing, and to provide guidance on potential fractional dosing strategies in the event of a significant influenza vaccine shortage in Canada. 
II. Methods
 In brief, the broad stages in the preparation of a NACI Advisory Committee Statement are: 
1. Knowledge synthesis - individual studies were retrieved and key data abstracted, and the level (i.e., study design) and quality of the evidence assessed. This information is summarized in Summary of Evidence Tables.
2. Synthesis of the body of evidence of benefits and harms, considering the quality of the evidence and magnitude of effects observed.
3. Translation of evidence into recommendations.
 Further information on NACI's evidence-based methods is available in: .
 In preparation for this Statement, two reviews were conducted to gather evidence to inform NACI's recommendations regarding the use of fractional dosing strategies. The review methodologies were developed in collaboration with the Methods and Applications Group for Indirect Comparisons (MAGIC) through the Drug Safety and Effectiveness Network (DSEN). The methods were specified *a priori- in a written protocol that included the research questions, search strategy, inclusion and exclusion criteria, and quality assessment. The reviews were completed by MAGIC, with additional data extraction (notably immunogenicity outcomes as indirect evidence for effectiveness for IM administration of fractional doses) completed by PHAC. 

#  Research question #1
 What is the safety and effectiveness of using fractional dosing strategies to deliver IM seasonal influenza vaccines? 

#  Research question #2
 What is the safety and effectiveness of using fractional dosing strategies to deliver seasonal influenza vaccine by ID administration? 
 The search strategies were developed based on the research questions and pre-defined PICOST, in conjunction with an experienced librarian. For both reviews, EMBASE and MEDLINE electronic databases were searched for research articles, with the review of IM studies looking at publications in the last 20 years and the review of ID studies looking at publications in the last 10 years. The Cochrane library, the Cochrane Central Register of Controlled Trials, and international clinical trial registries were also searched for additional studies. Searches were restricted to articles published in English. Additionally, hand-searching of the reference lists of included articles and relevant systematic reviews were performed. 
 Screening of citations and full-text articles were completed using a standard form based on study eligibility criteria. The forms were pilot-tested between two reviewers until 70% or greater agreement was reached, after which screening was completed by one reviewer. 
 One reviewer extracted data from the studies included for review into an evidence table using a piloted data abstraction template designed to capture information on study design, vaccine characteristics, population and outcomes of interest. A second reviewer independently validated the abstracted data. 
 For the review of ID administration of fractional influenza vaccine, the DSEN MAGIC team conducted all data extraction and performed a meta-analysis for effectiveness, immunogenicity, and safety outcomes. The risk of bias for the studies included as part of the ID review was assessed using the Cochrane Tool for Risk of Bias in Randomized Controlled Studies. 
 For the IM fractional dose review, the DSEN MAGIC team extracted and narratively summarized the data for effectiveness and safety, and provided PHAC with a list of studies that assessed immunogenicity outcomes. PHAC then extracted the immunogenicity data from the studies provided, and summarized the evidence narratively. The level of evidence (i.e., study design) and methodological quality of studies included in the IM review were assessed independently by two reviewers with PHAC using the design-specific criteria outlined by Harris et al.(2001), which has been adopted by NACI for rating the internal validity of individual studies. 

#  Development of Recommendations
 Following critical appraisal of individual studies, summary tables (Tables 9, 10, and 11) were prepared with ratings of the quality of the evidence using NACI's methodological hierarchy, and proposed recommendations for vaccine use were developed. The evidence and proposed recommendations were discussed by the NACI Influenza Working Group (IWG) and considered the
 Ethics, Equity, Feasibility, and Acceptability (EEFA) framework . Following a thorough review of the evidence, NACI approved the recommendation contained in this statement on November 2, 2020. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the following sections. 
III. Fractional Influenza Vaccine doses

# Intramuscular fractional dosing
 Thirteen studies were identified through the DSEN MAGIC team review on IM fractional dosing, including 5 related reports or trial protocols. Twelve of the studies were randomized controlled trials (RCT), and were assessed as being of good quality, according to the criteria defined by Harris et al. One trial was considered as having a high risk of bias due to significant issues with the randomization process and concerns
 with missing outcome data and selection of the reported outcomes  This trial was later excluded from the PHAC analysis because it did not have any peer-reviewed published results. 

#  Intradermal fractional dosing
 The DSEN MAGIC team rapid review on fractional ID influenza vaccination identified 29 studies. Most of the 29 RCTs were rated as having some
 concerns with bias (n=17), based on the Cochrane Risk of Bias tool for RCTs , and two studies (Chuaychoo, 2010 and Han 2013) had a high risk of bias. Issues were most often noted for the randomization process, deviations from the intended intervention, and bias in the selection of reported results. 
 Evidence from the DSEN MAGIC team reviews and additional analyses by PHAC technical staff are presented in Tables 9, 10, and 11. 

# III.1 Vaccine Efficacy and Effectiveness

##  III.1.1 Fractional intramuscular dosing
 There were no studies included in the rapid review that assessed the efficacy of fractional IM administration of influenza vaccine. Two studies were identified that assessed the effectiveness of fractional IM administration of influenza vaccine. Both studies were RCTs that assessed the efficacy of a 7.5 mcg of HA per strain dose of a quadrivalent influenza vaccine versus a 15 mcg of HA per strain dose in adults. 
 The first study was conducted by Kramer et al. (2006), in a population of adult healthcare workers 18 years of age and older. The study reported on clinical diagnoses of influenza-like illness (ILI) and laboratory-confirmed influenza (type of test not specified). Laboratory testing was only completed for individuals who had a clinical diagnosis of influenza. This RCT study found that 6.8% (n=15 of 222) of individuals who received the half-dose received a clinical diagnosis of ILI compared to 3.6% (n=8 of 222) of those that received the standard 15 mcg of HA per strain dose; however, only one participant in the study (an individual that received the 15 mcg of HA per strain dose) had laboratory-confirmed influenza infection and this difference for the laboratory-confirmed outcome was not statistically significant (relative risk . The second study by Engler et al. (2008) assessed the efficacy of a half dose compared to a full dose of influenza vaccine against medical visits for ILI involving the upper and lower respiratory tract, but with no laboratory confirmation, in adults 18 to 49 (n=558) and 50 to 64 years of age (n=556), and there was no statistically significant difference in the relative risk between vaccine groups, before and after adjusting for confounders (18-49 year olds: adjusted RR: 1.01, 95% CI: 0.70-1.46; 50-64 year olds: adjusted RR: 1.07, 95% CI: 0.53-2.18). 

##  III.1.2 Fractional intradermal dosing
 Two studies assessed the efficacy of fractional ID administration of influenza vaccine against laboratory-confirmed influenza infection or ILI in adults using trivalent influenza vaccine. A meta-analysis of these two studies indicated no significant difference in the risk of influenza infection/ILI from the ID administration of a 9 mcg of HA per strain dose of influenza vaccine compared to 15 mcg of HA per strain IM dose (Figure 1). Note that the figure below also describes the comparison of 15 mcg of HA per strain ID and IM. These data were not used to inform this Statement, as it was not considered a fractional dose. 
Text description
The following information is depicted in this figure:
 Effect estimates from the single studies:
 Pooled results:

# III.2 Immunogenicity
 The serological assessments of antibody responses to vaccination are based on the geometric mean titres (GMT) assessed using a hemagglutinin inhibition assay (HI). The assessments used by regulators are: GMT ratio, seroprotection rate, and seroconversion rate. The United States (US) Food and Drug Administration (FDA) has published definitions for these serological assessments and define criteria for the immunogenicity data required for influenza vaccine licensure in the US (Table 5). Correlates of protection that are not based on HI antibody titres have not been well established. 

##  III.2.1 Fractional intramuscular dosing
 Ten published studies were identified that assessed immunogenicity outcomes
 for fractional doses of influenza vaccines administered intramuscularly. The 10 studies were all RCTs and were considered to be of good quality according to Harris et al. criteria. Of the 10 studies, two were conducted in adults within the range of ages of 18 and 64 and one was conducted in adults 65 years of age and older. The other seven studies
 were all conducted in children within the range of 6 to 35 months of age . Only one study in adults and four studies in children assessed the difference in immunogenicity between fractional and standard dose IM administration of influenza vaccine statistically. 
 One study statistically compared the immune response following the IM administration of a fractional dose (7.5 mcg of HA per strain) of influenza vaccine to the standard dose in adults. Engler et al. (2008) reported that the study groups that received a fractional dose of 7.5 mcg of HA per strain had statistically lower proportions of seroconversion and seroprotection post-vaccination when compared to the groups that had received the full dose for all strains. The exception to this was seroprotection against influenza B in the 18 to 49 years of age subgroup and seroconversion for influenza A(H1N1) in the 50 to 64 years of age subgroup, which showed no significant difference between 7.5 mcg of HA per strain and 15 mcg of HA per strain. 
 Four studies statistically assessed the difference in immunogenicity between a full dose and a half dose of influenza vaccine in children 6 to 35 months of age. Results from these studies were mixed. Langley et al. (2012) reported no significant difference based on GMT ratios (GMT of full dose/GMT of fractional dose) post-vaccination between the two study groups, and Halasa et al. (2015) found no significant difference in the absolute difference in GMTs. Robertson et al. (2019) reported better GMTs in groups that received the full dose compared to the half dose of influenza vaccine based on GMT ratios (lower limit of 95% CI was greater than 1 for all strains); however, they reported non-significant differences in seroconversion rates between the two study groups for all strains except for influenza A(H1N1) (difference in seroconversion for A(H1N1): 5.1, 95% CI: 0.189 to 10.0). Pavia-Ruz et al. (2013) reported contradictory results, with the group receiving a half dose experiencing higher GMTs and seroconversion rates compared to the group that received the full dose of vaccine, with the exception of influenza B (Yam) with regard to seroconversion rates, for which there was no statistically significant difference between the two groups. In a non-statistical
 comparison, the group that received 7.5 mcg of HA per strain of Fluarix  appeared to have similar immunogenicity to those that received 15 mcg of HA per strain Fluarix (i.e., 95% CI were widely overlapping). 
 Additional studies (one in adults and two in children) that assessed varying fractional doses of influenza vaccine (3 mcg, 6 mcg, 7.5 mcg, and 9 mcg of HA per strain) reported on GMT rise, seroprotection rates, and seroconversion rates for the different study groups, but did not compare them statistically. In general, as the dose of influenza vaccine decreased, the immunogenic response also decreased; however, most lower doses continued to meet criteria set for non-inferiority, despite the reduced response compared to full dose (according to current US FDA or previous European Medicines Agency criteria). 

##  III.2.2 Fractional intradermal dosing
Of the thirty studies identified in the rapid review, 16 studies assessed immunogenicity outcomes for fractional doses of influenza
 vaccine administered intradermally, all of which were RCTs. 
 A meta-analysis demonstrated no significant difference in the seroconversion rate for the study groups that had received fractionated doses (3 mcg, 6 mcg, 7.5 mcg or 9 mcg of HA per strain) by ID administration compared to 15 mcg of HA per strain dose given intramuscularly for influenza A(H1N1), A(H3N2), or B (Table 1). 
 A meta-analysis was also performed for seroprotection rates compared to a full 15 mcg of HA per strain per IM dose, and found no significant difference in seroprotection rates against influenza A(H1N1), A(H3N2), or B for groups that had received ID administration of influenza vaccine at doses of 3 mcg of HA per strain, 7.5 mcg of HA per strain, or 9 mcg of HA per strain (Table 1). However, rates of seroprotection were significantly lower for those that had received a dose of 6 mcg of HA per strain for influenza A(H1N1) (risk ratio : 0.93, 95% confidence interval : 0.88-0.99) and influenza B (RR: 0.92, 95% CI: 0.86-0.98) compared to the full IM dose. 
 A further sub-analysis was performed by the DSEN MAGIC team to assess immunogenicity in adults 60 years of age and older. The only fractional ID dose assessed by the studies that had sufficient data for inclusion in the sub-analysis was 9 mcg of HA per strain dose. Similar to the overall results, there was no significant difference in seroconversion or seroprotection rates between older adults that had received the fractional 9 mcg of HA per strain ID dose compared to those that received the full, 15 mcg of HA per strain IM dose (Table 2). 
Outcome significantly higher with ID administration
No significant difference in outcome between ID and IM administration
Outcome significantly lower with ID administration
No significant difference in outcome between ID and IM administration

# III.3 Safety

##  III.3.1 Adverse Events with IM administration
Children 
 The rapid review found 9 studies that assessed safety outcomes (local, systemic, and severe AEs) of fractional IM influenza vaccine (IIV3: 5 studies, IIV4: 3 studies, IIV3 and IIV4: 1 study) in infants or toddlers in the range of 6 to 36 months of age. Children that received one or two half doses (7.5 mcg of HA per strain) of influenza vaccine (dependent on whether they had ever received an influenza vaccine previously) generally reported similar levels of reactogenicity and AEs when compared to those that received one or two standard doses. In some instances, AEs appeared to be slightly more common with the full dose of influenza vaccine compared to the half dose, however there was no consistent trend. 
Adults 
 Three studies were identified in the rapid review that assessed safety of fractional IM influenza vaccination in adults: 2 of the studies involved
 adults between the ages of 18 to 64 (18 to 49 and 18 to 65) and one study included older adults >65 years of age. Belshe et al. (2008) reported no differences in the occurrence of AEs between any of the study groups (doses assessed: 3 mcg, 6 mcg, 9 mcg, and 15 mcg of HA per strain). The other study, by Engler et al. (2008), that assessed safety in adults less than 65 years of age also found no statistically significant difference in the occurrence of AEs after adjusting to only include clinically significant pain levels ( 3 out of 5 using a visual analog scale). The study conducted in older adults found no significant difference in the proportion of individuals that experienced AEs or in the severity of the AEs between the group that received the fractional dose (9 mcg of HA per strain) and the group that received the full standard dose. 

## III.3.2 Adverse events associated with ID administration
 Twenty-four studies were identified that assessed the safety of ID administration of influenza vaccine and were able to be included in a meta-analysis performed by the DSEN MAGIC team . The studies identified included various fractional doses (3 mcg, 6 mcg, 9 mcg of HA per strain), as well as a full non-fractional dose (i.e. 15 mcg of HA per strain) of ID administered influenza vaccine. Because ID administration of influenza vaccine is not authorized in Canada, there is a lack of data not only for ID administration of fractional doses, but of the full, non-fractional dose as well. Since the safety of ID administration of a full dose of influenza vaccine is likely comparable to that of fractional doses, evidence regarding safety for the full non-fractional dose was also considered to enhance the evidence base for this outcome. 
 Overall, the risk of ecchymosis, erythema, pruritus, and swelling occurring post-vaccination at the injection site was significantly higher with ID administration of influenza vaccine compared to IM administration. However, the risk of pain at the injection site was not significantly different for ID administration of 6 mcg, 9 mcg and 15 mcg of HA per strain compared to administration of 15 mcg per strain IM; whereas the risk of pain after the ID administration of a 3 mcg of HA per strain dose was significantly lower (Table 3). Unlike with local AEs, there was in general no significant difference in the risk of systemic events with ID influenza vaccine administration compared to IM administration, with the exception of chills and fever which were higher for ID administration but only at the 9 mcg per strain dose level and not at the lower or higher dose levels (Table 4). 
AE significantly lower with ID administration
No significant difference between ID and IM
AE significantly higher with ID administration
No significant difference between ID and IM
AE significantly higher with ID administration
IV. Feasibility
 An assessment of EEFA of influenza vaccine fractional dosing strategies was conducted according to established NACI methods. The assessment of feasibility in particular identified several significant issues that warrant further discussion within the Statement. 

#  Logistics for fractional dosing strategies
 Both fractional dosing strategies (IM and ID) assessed in this Statement would require using influenza vaccine that has been packaged in the format and of an antigen concentration authorized for use in Canada. Therefore, administering a fractional dose would require administering a lower volume of vaccine to achieve the desired lower dose, which is only possible when influenza immunizations have been packaged as multi-dose vials (MDV), and not as pre-filled syringes. A significant proportion of the influenza vaccine supply purchased for public programs is in MDV format; however, the distribution of MDV of influenza vaccine may not be equal across jurisdictions, and varies between provinces, based on provincial vaccine orders. When vaccine has already been ordered in a given season, there is not typically the opportunity to change the supply to MDV mid-season. 
 Using standard doses, MDVs contain 5 mL of vaccine solution, sufficient to vaccinate 10 individuals. The volume of vaccine for some fractional doses (e.g., 9 mcg of HA per strain is 0.3 mL), would not split evenly from 5 mL vials. Therefore, using fractional doses that do not divide evenly into 5 mL could result in unnecessary vaccine wastage, which would not allow for the full advantage of implementing fractional dosing as a dose sparing strategy. A half dose of influenza vaccine (7.5 mcg of HA per strain) is likely the most feasible fractional dose for influenza vaccine programs, regardless of route of administration, as this dose could allow the full use of the vial without wastage. 
 ID administration of vaccine requires a different needle gauge than IM administration. Most immunization venues providing influenza vaccines are unlikely to be equipped with a sufficient number of needles necessary for ID administration for the seasonal influenza vaccine program. Depending on the syringe used, different volumes may be more clearly marked (e.g., 0.5 mL, 0.25 mL). Therefore, fractional doses that require a vaccine volume that is not as clearly marked on the syringe may be more difficult to measure accurately in a vaccination setting, leading to variation in the amount of vaccine administered. 

#  Intradermal administration of influenza vaccine
 In addition to the logistical considerations above, the ID administration of fractional doses has further implementation issues. 
 ID administration requires skill to administer the vaccine correctly. Influenza vaccines in Canada are only authorized for IM administration or nasal spray in the case of LAIV. As such, many influenza vaccinators may be unfamiliar with the requisite technique for ID administration. Inexperience could lead to vaccine administration errors or wasted vaccine product. ID administration also requires creation of an ID wheal or "bleb" and it can be more difficult to perform in older adults, which may slow down the immunization process. As shown in Section III.4.2, ID administration is also associated with a significant increase in local adverse reactions across almost all fractionated dose levels, which could reduce uptake of the vaccine. ID administration by needle and syringe may also require 2 or more injections to administer the full dose, further exacerbating the issues with ID. A needle-free jet injector has been authorized for use in Canada for ID injections. NACI is actively reviewing the evidence on the use of this device to determine if it could potentially be used as an alternative method for administering ID vaccine. Novel technologies for ID injection, such as the needle-free jet injector, may be an option in the future that would facilitate delivery of ID dosing but are not yet widely available in Canadian settings. 
 Since fractional influenza vaccines doses are considered off-label for all ages, discussion with the patient and additional information in the vaccination consent form would be required. Finally, given that ID is not an authorized route of administration for influenza vaccine, many immunization registries/surveillance systems do not currently have the capacity to input ID as the route of administration, and would therefore require system-level changes before being able to effectively implement ID administration of influenza vaccine. This option would need to be added to these systems in advance of implementing ID administration to ensure the ability to evaluate the safety and effectiveness of ID administration of influenza vaccine. 
V. Recommendation
 The following section outlines recommendations made by NACI regarding potential fractional influenza vaccine dosing strategies. Additional information on the strength of NACI recommendations and the grading of evidence is available in Table 6. 
 The following recommendations are meant to be considered in situations of influenza vaccine shortage when it is not possible to procure additional vaccine doses. Policies regarding fractional dosing strategies should be implemented at a jurisdictional level, and vaccination should be consistent with the policy and not subject to individual preference. All recommendations should be considered in the context of a given shortage situation. The extent of the shortage and its potential impact will need to be assessed prior to deciding on the best course of action. 

# V.1 Public Health Program Decision-Making
1. NACI recommends that, in the event of a significant population-level shortage of influenza vaccine, a full dose influenza vaccine should continue to be used, and existing vaccine supply should be prioritized for those considered to be at high risk or capable of transmitting to those at high risk of influenza-related complications or hospitalizations (Strong NACI Recommendation).  
- NACI concludes that there is fair evidence to recommend the use of a full dose influenza vaccine (15 mcg or 60 mcg HA per strain, dependent on vaccine product) compared to a fractional dose for individuals at high risk or those capable of transmitting to those at high risk of influenza-related complications or hospitalizations (Grade B Evidence).
Summary of evidence and rationale  
- Influenza vaccine has previously been shown to be effective in the prevention of morbidity and mortality in individuals who are at high risk of influenza-related complications and hospitalizations.
- Since many of those at high risk of influenza (e.g., older adults, immunocompromised individuals) may have a lower response to influenza vaccination already (due to immunosenescence in older adults or other conditions that alter immune function), it is important to ensure this group continues to receive the full dose of influenza vaccine.
- Although there is some limited evidence on the use of fractional ID doses in adults 65 years of age, including those with chronic health conditions, there is no evidence of fractional dosing in other adult high risk-groups.
- There are some efficacy, effectiveness, and immunogenicity data regarding fractional dosing of current influenza vaccine products, but overall insufficient evidence that fractional doses of influenza vaccine provided via IM or ID are effective in healthy individuals. The majority of the evidence identified on fractional dosing is from studies conducted in healthy individuals, particularly in infants and young children, with no underlying chronic conditions.
2. NACI recommends against the use of fractional doses of influenza vaccine in any population (Discretionary NACI Recommendation)  
- NACI concludes that there is insufficient overall evidence at this time to recommend the use of fractional IM influenza vaccine doses (Grade I Evidence)
- NACI concludes that there is fair evidence that fractional ID influenza vaccine doses provide a sufficient immune response, but this route of administration is not feasible at this time (Grade B Evidence)
Summary of Evidence and Rationale 
- There are some efficacy, effectiveness, and immunogenicity data regarding fractional dosing of current influenza vaccine products, but overall, there is insufficient evidence that fractional doses of influenza vaccine provided via the IM route is effective in healthy individuals. The majority of the evidence identified on fractional dosing is from studies conducted in healthy individuals, mainly young children and infants, with no underlying chronic conditions.
- ID administration of influenza vaccine may be more effective at lower doses than IM and would be reasonable to recommend based on efficacy, effectiveness, immunogenicity, and safety data; however, significant system-level changes are needed to address the feasibility issues associated with this route of administration before it can be considered at a large scale.
- With regard to the safety of fractional doses of influenza vaccines, there is fair evidence that fractional doses of influenza vaccine administered via IM or ID routes do not result in significant differences compared to full dose with regard to severe AEs post-influenza vaccination; however, ID administration of influenza vaccine will likely result in a higher proportion of individuals who experience local AEs.
- Pre-filled syringes cannot be used for IM or ID fractional dosing.
- ID administration of vaccine by syringe and needle requires a different gauge needle than IM administration. Therefore, immunization venues providing influenza vaccines may not be equipped with a sufficient number of needles necessary for ID administration for a seasonal influenza vaccine program unless prepared in advance.
- Significant training would be required to ensure vaccinators are equipped to provide ID influenza vaccinations and feel comfortable doing so. Without training, it is possible that a greater number of vaccine administration errors could occur with ID administration.
- Not all vaccinators are authorized to provide ID administration. The number of vaccinators who are able to provide ID vaccination will vary by jurisdiction.
 Specified by the United States Food and Drug Administration
 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
- 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
 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
- 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
General design specific criteria are outlined in Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, Atkins D. Current methods of the US Preventive Services Task Force: A review of the process. Am J Prev Med. 2001;20(3):21-35.10
Doses:
 7.5 mcg
US 
 single site
20042005 influenza season
7.5 group: 
 n=222
15 group:
 (Fluzone)
Doses:
 7.5 mcg
US
 multi-center
2004-2005 influenza season
1849 year old subgroup:
 Mean age: 42.3
 44.3% female
7.5 mcg group: n=284
 15 mcg group: n= 274
5064 year old subgroup:
 Mean age: 55.6
 42.6% female
7.5 mcg group: n=276
Relative risk (95% CI) by age group:* 18-49 years:1.01 (0.70-1.46)
- 50-64 years:1.07 (0.53-2.18)
Random effects model
Included: RCTs, non-RCTs, observational studies
Number of participants (observational): 164,021
 Age range: all ages
 Meta-analysis included a total of 2 RCTs (no observational studies) on the effectiveness of a 9 mcg of HA per strain fractional dose of ID influenza vaccine.
CI: 
confidence interval
 IIV3: 
trivalent inactivated influenza vaccine
RCT: 
randomized controlled trial
Doses:- 3 mcg
- 6 mcg
- 9 mcg
- 15 mcg
US 
 single site
2006-2007 influenza season
mean age: 30
 68% female- 3mcg group: 
 n=29
- 6mcg group: 
 n=30
- 9mcg: 
 n=32
- 15mcg: 
 n=31
3 mcg:* A(H1N1): 62.1 (42.3-79.3)
- A(H3N2): 58.6 (38.9-76.5)
- Influenza B: 51.7 (32.5-70.6)
6 mcg:* A(H1N1): 60.0 (40.6-77.3)
- A(H3N2): 60.0 (40.6-77.3)
- Influenza B: 70.0 (50.6-85.3)
9 mcg:* A(H1N1): 66.7 (47.2-82.7)
- A(H3N2): 90.0 (73.5-97.9)
- Influenza B: 66.7 (47.2-82.7)
15 mcg:* A(H1N1): 67.7 (48.6-83.3)
- A(H3N2): 93.5 (78.6-99.2)
- Influenza B: 67.7 (48.6-83.3)
Proportion that achieved seroprotection (95% CI) 28 days post-vaccination:
3 mcg:* A(H1N1): 72.4 (52.8-87.3)
- A(H3N2): 79.3 (60.3-92.0)
- Influenza B: 89.7 (72.6-97.8)
6 mcg:* A(H1N1): 80 (61.4-92.3)
- A(H3N2): 80 (61.4-92.3)
- Influenza B: 86.7 (69.3-96.2)
9 mcg:* A(H1N1): 83.3 (65.3-94.4)
- A(H3N2): 93.3 (77.9-99.2)
- Influenza B: 93.3 (77.9-99.2)
15 mcg:* A(H1N1): 77.4 (58.9-90.4)
- A(H3N2): 100 (88.8-100)
- Influenza B: 90.3 (74.2-98.0)
 (Fluzone)
Doses:- 7.5 mcg
- 15 mcg
US
 multi-center
2004-2005 influenza season
1849 year old subgroup:
 Mean age: 42.3
 44.3% female- 7.5 mcg group: n=284
- 15 mcg group: n= 274
5064 year old subgroup:
 Mean age: 55.6
 42.6% female- 7.5 mcg group: n=276
- 15 mcg group: n= 280
- A(H3N2): 8.4 (0.5-16.2); p=0.04
- Influenza B: 1.27 (1.08-1.50); p=0.002
Difference in proportions that achieved seroconversion (95% CI) 21 days post-vaccination in 50-64 year old age group:* A(H1N1): 4.8 (-0.8-10.5); p=0.09
- A(H3N2): 12.9 (5.2-20.5); p=0.001
- Influenza B: 14.6 (6.8-22.5); p<0.001
Difference in proportions that achieved seroprotection (95% CI) 21 days post-vaccination in 18-49 year old age group:* A(H1N1): 11.8 (3.5-20.0); p=0.005
- A(H3N2): 8.3 (0.8-15.8); p=0.03
- Influenza B: 5.0 (-1.6-11.7); p=0.19
Difference in proportions that achieved seroprotection (95% CI) 21 days post-vaccination in 50-64 year old age group:* A(H1N1): 15.7 (8.1-23.4); p<0.001
- A(H3N2): 9.5 (1.7-17.2); p=0.02
- Influenza B: 8.8 (0.9-16.6); p=0.03
Doses:- 9 mcg
- 15 mcg
US
2007-2008 influenza season
 n=64
 17.2% female
 Mean age: 75.2
- 15 mcg group:
 n=65
 16.9% female
 Mean age: 75.6
Number that achieved seroprotection (%):
9 mcg:* A(H1N1): 37 (57.8%)
- A(H3N2): 48 (75%)
- Influenza B: 11 (17.2%)
15 mcg:* A(H1N1): 42 (65.5%)
- A(H3N2): 49 (76.6%)
- Influenza B: 17 (26.6%)
 (Vaxigrip)
Doses:- 7.5 mcg
- 15 mcg
Canada multi-center
2008-2009 influenza season 
 n=124
 50.8% female
 Mean age: 12.8 months
- 15 mcg group:
 n=128
 55.5% female
 Mean age: 13.2 months
7.5 mcg:* A(H1N1): 70.5 (61.6-78.4)
- A(H3N2): 67.2 (58.1-75.4)
- Influenza B: 66.4 (57.3-74.7)
15 mcg:* A(H1N1): 81.2 (72.9-87.8)
- A(H3N2): 83.8 (75.8-89.8)
- Influenza B: 80.3 (72-87.1)
Proportion that achieved seroconversion (95% CI) 27-45 days after the 2nd dose of influenza vaccine:
7.5 mcg:* A(H1N1): 70.5 (61.6-78.4)
- A(H3N2): 67.2 (58.1-75.4)
- Influenza B (Yam): 65.6 (56.4-73.9)
15 mcg:* A(H1N1): 80.3 (72-87.1)
- A(H3N2): 81.2 (72.9-87.8)
- Influenza B (Yam): 80.3 (72-87.1)
GMT rise (95% CI)  after the 2nd dose of influenza vaccine:
7.5 mcg:* A(H1N1): 10.2 (8.2-12.7)
- A(H3N2): 9.1 (7.5-11.0)
- Influenza B: 8.4 (6.7-10.6)
15 mcg:* A(H1N1): 12.2 (9.8-15.2)
- A(H3N2): 13.0 (10.9-15.7)
- Influenza B: 13.6 (10.8-17.1)
 (Flulaval or Vaxigrip)
Doses:- 7.5 mcg
- 15 mcg
Canada multi-center
2008-2009 influenza season
Funded by GlaxoSmith
 n=164
 42.7% female
 Mean age: 18.2 months
- Flulaval 15 mcg group:
 n=167
 49.3% female
 Mean age: 17.5 months
- Vaxigrip 7.5 mcg group:
 n=43
 60.5% female
 Mean age: 17.0 months
7.5 mcg (Vaxigrip):* A(H1N1): 80.6 (64.0-91.8)
- A(H3N2): 77.8 (60.8-89.9)
- Influenza B (Yam): 86.1 (70.5-95.3)
7.5 mcg (Flulaval):* A(H1N1): 51.1 (42.3-60)
- A(H3N2): 61.8 (52.9-70.2)
- Influenza B (Yam): 80.9 (73.1-87.3)
15 mcg (Flulaval):* A(H1N1): 62.1 (53.3-70.4)
- A(H3N2): 74.2 (65.9-81.5)
- Influenza B (Yam): 86.4 (79.3-91.7)
Proportion that achieved seroconversion (95% CI) 28 days post-vaccination:
7.5 mcg (Vaxigrip):* A (H1N1): 83.3 (67.2-93.6)
- A(H3N2): 83.3 (67.2-93.6)
- Influenza B (Yam): 91.7 (77.5-98.2)
7.5 mcg (Flulaval):* A(H1N1): 53.4 (44.5-62.2)
- A(H3N2): 62.6 (53.7-70.9)
- Influenza B (Yam): 84.7 (77.4-90.4)
15 mcg (Flulaval):* A(H1N1): 63.6 (54.8-71.8)
- A(H3N2): 75.0 (66.7-82.1)
- Influenza B (Yam): 92.4 (86.5-96.3)
GMT ratios (95% CI)  28 days post-vaccination (adjusted for prior influenza vaccination, baseline titre  pooled variance):* A(H1N1): 1.25 (0.9-1.75)
- A(H3N2): 1.11 (0.83-1.49)
- Influenza B (Yam): 1.27 (0.93-1.74)
 (Fluarix or Fluzone)
Doses:- 7.5 mcg
- 15 mcg
US, Hong Kong, Mexico, Thailand, and Taiwan 
Multi-centre
2008-2009 influenza season
Funded by GlaxoSmith
 n=1017
 50.7% female
 Mean age: 21.2 months
- Fluarix 15 mcg group:
 n=1013
 53.3% female
 Mean age: 21.2 months
- Fluzone 7.5 mcg group:
 n=1031
 49.1% female
 Mean age: 21.1 months
7.5 mcg (Fluzone):* A(H1N1): 95.6 (94.2-96.8)
- A(H3N2): 98.2 (97.1-98.9)
- Influenza B (Yam): 90.7 (88.7-92.4)
- Influenza B (Yam): 92.3 (90.5-93.9)
7.5 mcg (Fluarix):* A(H1N1): 68.7 (65.7-71.5)
- A(H3N2): 77.4 (74.7-79.9)
- Influenza B (Yam): 85.7 (83.4-87.8)
- Influenza B (Yam): 88 (85.9-89.9)
15 mcg (Fluarix):* A(H1N1): 74.2 (71.4-76.9)
- A(H3N2): 83.3 (80.8-85.5)
- Influenza B (Yam): 88.8 (86.7-90.7)
- Influenza B (Yam): 90.6 (88.6-92.3)
Proportion that achieved seroconversion (95% CI) 28 days (or 56 for unprimed children) post-vaccination:
7.5 mcg (Fluzone):* A(H1N1): 90.2 (88.2-91.9)
- A(H3N2): 95.9 (94.5-97)
- Influenza B (Yam): 87.8 (85.6-89.7)
- Influenza B (Yam): 89.3 (87.3-91.1)
7.5 mcg (Fluarix):* A(H1N1): 62.5 (59.5-65.5)
- A(H3N2): 73.5 (70.6-76.1)
- Influenza B (Yam): 79.8 (77.2-82.3)
- Influenza B (Yam): 82.6 (80.1-84.9)
15 mcg (Fluarix):* A(H1N1): 69 (66.1-71.8)
- A(H3N2): 79.8 (77.2-82.2)
- Influenza B (Yam): 85.3 (83-87.4)
- Influenza B (Yam): 87.1 (84.8-89.1)
GMT rise (95% CI)  post-vaccination:
7.5 mcg (Fluzone):* A(H1N1): 21.4 (19.9-23.1)
- A(H3N2): 24.1 (22.6-25.7)
- Influenza B (Yam): 21.4 (19.7-23.1)
- Influenza B (Yam): 23.1 (21.4-24.9)
7.5 mcg (Fluarix):* A(H1N1): 10.2 (9.2-11.4)
- A(H3N2): 10.4 (9.6-11.3)
- Influenza B (Yam): 13.4 (12.4-14.5)
- Influenza B (Yam): 14.9 (13.7-16.1)
15 mcg (Fluarix):* A(H1N1): 12.4 (11.2-13.7)
- A(H3N2): 14.2 (13.1-15.4)
- Influenza B (Yam): 18.4 (17-20)
- Influenza B (Yam): 19.7 (18.2-21.4)
Difference in immune response of 15 mcg Fluarix compared to 7.5 mcg Fluzone 28 days (or 56 for unprimed children) post-vaccination:
GMT ratio (95% CI):* A(H1N1) : 1.74 (1.54-1.98)
- A(H3N2): 1.72 (1.57-1.89)
- Influenza B (Yam): 1.13 (1.01-1.25)
- Influenza B (Yam): 1.13 (1.02-1.25)
Difference in seroconversion rate (95% CI) :* A(H1N1): 21.19 (17.82-24.58)
- A(H3N2): 16.16 (13.46-18.98)
 Influenza B (Yam): 2.48 (-0.49-5.45)
- Influenza B (Yam): 2.25 (-0.55-5.07)
 (Fluzone) 
Doses:- 7.5 mcg
- 15 mcg
US 
 Multi-center
October 5, 2010 and March 2, 2012; The studies were conducted before the 20102011 and 20112012 influenza seasons.
N=204
 52% female
 Mean age: 14.2 months
Primed subgroup:- 7.5 mcg group:
 n=9
 66.7% female
 Mean age: 23.4 months
- 15 mcg group:
 n=21
 45.4% female
 Mean age: 25.3 months
Influenza vaccine naive subgroup:- 7.5 mcg group:
 n=55
 50.7% female
- 15 mcg group:
 n=119
 52.9% female
7.5 mcg:* A(H1N1): 89 (0.52-1.00)
- A(H3N2): 89 (0.52-1.00)
- Influenza B (Yam): 33 (0.07-0.70)
15 mcg:* A(H1N1): 100 (0.84-1.00)
- A(H3N2): 90 (0.7-0.99)
- Influenza B (Yam): 14 (0.03-0.36)
Proportion of naive individuals that achieved seroprotection (95% CI) 28 days after the 2nd dose of influenza vaccine:
7.5 mcg:* A(H1N1): 85 (73-94)
- A(H3N2): 15 (6-27)
- Influenza B (Yam): 44 (30-58)
15 mcg:* A(H1N1): 89 (82-94)
- A(H3N2): 15 (9-23)
- Influenza B (Yam): 50 (40-59)
Proportion of primed individuals that achieved seroconversion (95% CI) 28 days post-vaccination:
7.5 mcg:* A(H1N1): 89 (52-100)
- A(H3N2): 78 (40-97)
- Influenza B (Yam): 22 (3-60)
15 mcg:* A(H1N1): 90 (70-99)
- A(H3N2): 86 (64-97)
- Influenza B (Yam): 10 (1-30)
Proportion of naive individuals that achieved seroconversion (95% CI) 28 days after the 2nd dose of influenza vaccine:
7.5 mcg: - A(H1N1): 78 (65-88)
- A(H3N2): 7 (2-18)
- Influenza B (Yam): 31 (19-45)
15 mcg:* A(H1N1): 85 (77-91)
- A(H3N2): 11 (6-18)
- Influenza B (Yam): 42 (33-51)
Difference in GMT (95% CI)  28 days after last vaccination:
Primed:* A(H1N1): -267.5 (-527.9 to -3.9)
- A(H3N2): -11.0 (-105.1 to 122.2)
- Influenza B (Yam): 3.0 (-7.5 to 14.8)
Naive:* A(H1N1): -5.7 (-94.9 to 90.2)
- A(H3N2): -1.9 (-2.0 to 5.2)
- Influenza B (Yam): -3.7 (-5.1 to 12.0)
 (Fluzone quadrivalent)
Doses:- 7.5 mcg
- 15 mcg
US and Mexico
Multi-centre
2014-2015 influenza season
Funded by GlaxoSmith
 n=1028
 48.2% female
 Mean age: 19.9 months
- 15 mcg group:
 n=1013
 45.6% female
 Mean age: 19.7 months
7.5 mcg:* A(H1N1): 75.4 (72.6-78)
- A(H3N2): 77.8 (75.2-80.3)
- Influenza B (Yam): 88.6 (86.5-90.5)
- Influenza B (Vic): 49.8 (46.7-52.9)
15 mcg:* A(H1N1): 80.4 (77.8-82.8)
- A(H3N2): 82.2 (79.7-84.5)
 Influenza B (Yam): 97 (95.8-98)
- Influenza B (Vic): 66 (63-69)
Proportion that achieved seroconversion (95% CI) 28 days (or 56 days for unprimed individuals) post-vaccination:
7.5 mcg:* A(H1N1): 67.3 (64.3-70.3)
- A(H3N2): 69.4 (66.4-72.3)
 Influenza B (Yam): 73.8 (70.9-76.5)
- Influenza B (Vic): 48.5 (45.3-51.6)
15 mcg:* A(H1N1): 73.7 (70.8-76.4)
- A(H3N2): 76.1 (73.3-78.8)
 Influenza B (Yam): 85.5 (83.2-87.7)
- Influenza B (Vic): 64.9 (61.8-67.9)
GMT rise (95% CI) 28 days (or 56 days for unprimed individuals) post-vaccination:
7.5 mcg:* A(H1N1): 7.7 (7.1-8.3)
- A(H3N2): 8.9 (8.2-9.7)
 Influenza B (Yam): 8.1 (7.5-8.8)
- Influenza B (Vic): 5.4 (5.0-5.8)
15 mcg:* A(H1N1): 9 (8.4-9.7)
- A(H3N2): 10.7 (10-11.6)
- Influenza B (Yam): 12.7 (11.7-13.7)
- Influenza B (Vic): 8.7 (8.1-9.4)
Doses:- 7.5 mcg
- 15 mcg
US 
 Multi-center
2016-2017 influenza season
 n=682
 49.4% female
 Mean age: 20.4 months
- 15 mcg group:
 n=682
 49.9% female
 Mean age: 20.5 months
- A(H3N2): 4.3 (-0.283 to 8.99)
 Influenza B (Yam): 3.4 (-2.78 to 5.56)
- Influenza B (Vic): 1.4 (-0.465 to 7.36)
GMT ratios (95% CI)  post-vaccination:* A(H1N1): 1.45 (1.19 to 1.77)
- A(H3N2): 1.50 (1.23 to 1.83)
 Influenza B (Yam): 1.44 (1.20 to 1.73)
- Influenza b (Vic): 1.33 (1.10 to 1.62)
Doses:- 7.5 mcg
- 15 mcg
Finland and Belgium
Multi-center
2008-2009 influenza season
(Note: only a subset of study groups relevant for this review are presented here. Authors combined the IIV3 and IIV4 groups for analysis in the publication)- IIV3 7.5 mcg group:
 n=25
 66% female
 Mean age: 20 months
- IIV3 15 mcg group:
 n=22
 27% female
 Mean age: 15 months
- IIV4 7.5 mcg group:
 n=25
 36% female
 Mean age: 18 months
- IIV4 15 mcg group:
 n=28
 46% female
 Mean age: 15.2 months
- IIV3 15 mcg group (Vaxigrip):
 n=26
 50% female
 Mean age: 16.1 months
- 7.5 mcg: 65% A(H1N1), 70% A(H3N2), 19% Influenza B (Yam) and 17% Influenza B (Vic).
- 15 mcg: 79% A(H1N1), 71% A(H3N2), 12% influenza B (Yam) and 14% influenza B (Vic).
Proportion (%) that achieved seroconversion on day 50:* 7.5 mcg (Vaxigrip): 96% A(H1N1), 92% A(H3N2) and 42% Influenza B (Yam). Data not reported for influenza B (Vic).
- 7.5 mcg: 62% A(H1N1), 62% A(H3N2), 19% influenza B (Yam) and 17% influenza B (Vic).
- 15 mcg: 79% A(H1N1), 71% A(H3N2), 21% influenza B (Yam) and 14% influenza B (Vic).
GMT rise (post-vaccination GMT / pre-vaccination GMT) on day 50:
7.5 mcg (Vaxigrip): - A(H1N1): 25
- A(H3N2): 27
- Influenza B (Yam): 4.06
7.5 mcg:* A(H1N1): 8.15
- A(H3N2): 8.7
- Influenza B (Yam): 2.39
- Influenza B (Vic): 2.16
15 mcg:* A(H1N1): 10
- A(H3N2): 9.91
- Influenza B (Yam): 2.07
- Influenza B (Vic): 1.94
Random effects model
Included: RCTs, non-RCTs, observational studies
Number of participants (observational): 164,021
 Age range: all ages
 Meta-analysis included a total of 16 RCTs (no observational studies) on the immunogenicity of fractional doses of IM influenza vaccine (includes 3 mcg, 6 mcg, 7.5 mcg, and 9 mcg).
CI:
confidence interval
 GMT: 
geometric mean titre
 IIV3: 
trivalent inactivated influenza vaccine
 IIV4: 
quadrivalent inactivated influenza vaccine
 mcg: 
microgram
 RCT: 
randomized controlled trial
 US: 
United States 
B/Florida/4/2006, which is a B/Florida/4/2006-like strain, as recommended by WHO for influenza season of this study
B/Brisbane/3/2007, which is a B/Florida/4/2006-like strain, as recommended by WHO for influenza season of this study
Calculated as post-vaccination GMT in 7.5 mcg Fluzone / 15 mcg Fluarix, adjusted for baseline titre  pooled variance)
Calculated as seroconversion rate in 7.5 mcg Fluzone  15 mcg Fluarix
Included: RCTs, non-RCTs, observational studies
 13 RCTs were included in the scoping review, including 10 RCTs that had safety data relevant for this Statement (3 in adults, 9 in children). 
All studies in children assessed the safety of 7.5 mcg of HA per strain fractional dose compared to standard dose (15 mcg of HA per strain). None of the studies identified in this review reported statistical differences in local or systemic AEs between study groups.
One study compared 3 fractional doses of Fluzone (3 mcg, 6 mcg, 9 mcg of HA per strain) to standard dose, and did not report any differences between the IM vaccination groups. A second in adults less than 65 years of age found no significant differences after adjusting for clinically significant pain levels (determined as 3 out of 5 on a visual analogue scale) between groups that had received a 7.5 mcg of HA per strain dose compared to standard dose.
Random effects model
Included: RCTs, non-RCTs, observational studies
Number of participants (observational): 164,021
 Age range: all ages
 Meta-analysis included a total of 24 RCTs (no observational studies) on the safety of fractional doses of IM influenza vaccine (includes 3 mcg, 6 mcg, 7.5 mcg, and 9 mcg).
AE:
 Adverse Event
 DSEN: 
Drug Safety Effectiveness Network
 HA: 
hemagglutinin
 mcg: 
microgram
 N/A:
not applicable
 RCT:
 randomized controlled trial