Public Health Agency of Canada
Symbol of the Government of Canada

Share this page

ARCHIVED - Canada Communicable Disease Report

Warning This page has been archived.

Archived Content

Information identified as archived on the Web is for reference, research or recordkeeping purposes. It has not been altered or updated after the date of archiving. Web pages that are archived on the Web are not subject to the Government of Canada Web Standards. As per the Communications Policy of the Government of CanadaExternal link, you can request alternate formats on the "Contact Us" page.

Volume 37 • ACS-7
November 2011

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

Recommendations on the use of live, attenuated influenza vaccine (FluMist®): Supplemental Statement on Seasonal Influenza Vaccine for 2011-2012

Preamble

The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific and public health advice relating to immunization. The Public Health Agency of Canada 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 the Public Health Agency of Canada's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

Table of Contents

I. Introduction

I.1 Overview of Statement

This supplement to the National Advisory Committee on Immunization (NACI) Statement on Seasonal Influenza Vaccine for 2011-2012 will:

  • Provide information on the authorized live attenuated influenza vaccine (LAIV) product (FluMist®), which is administered by intranasal spray.
  • Provide recommendations for the use of LAIV
NACI Recommendations
Children

Healthy Children 2-17 years of age

  • Based on effectiveness, efficacy and immunogenicity data, NACI recommends LAIV for use in healthy children and adolescents 2-17 years of age. Available data indicates that LAIV would be preferred over TIV in this population, although NACI recognizes that other programmatic considerations will impact the implementation of this recommendation in publicly-funded programs. (NACI Recommendation Grade A)

Children with Immune Compromising Conditions

  • NACI recommends against LAIV for individuals with immune compromising conditions. (NACI Recommendation Grade D)

Live vaccines have generally been contraindicated in people with immune compromising conditions, with some exceptions. NACI concludes that there is insufficient evidence supporting the use of LAIV in those with immune compromising conditions in terms of both safety and effectiveness. Based on expert opinion, NACI concludes that the use of LAIV in this population is contraindicated.

Children with Asthma

  • NACI recommends that LAIV can be used in children 24 months and older with stable, non-severe asthma. (NACI Recommendation Grade B)
  • LAIV should not be used in those with severe asthma (as defined as currently on oral or high dose inhaled glucocorticosteriods or active wheezing) and those with medically attended wheezing in the seven days prior to vaccination.

Children with other chronic health conditions

  • NACI recommends that LAIV can be used in children with chronic health conditions (excluding those with immune compromising conditions and severe asthma, as defined above). (NACI Recommendation Grade B)
    • A limited number of immunogenicity and efficacy studies have been conducted in these populations. Based on expert review, it is expected that LAIV should be as safe, immunogenic and efficacious in immune competent children with chronic health conditions as it is in healthy children. At this time there is insufficient evidence to recommend LAIV preferentially over TIV in children with chronic health conditions.
ADULTS

Healthy Adults 18 to 59 years of age

  • NACI recommends that LAIV can be used for the prevention of influenza in healthy adults 18 to 59 years of age. (NACI Recommendation Grade A)
    • There is some evidence that TIV may provide better efficacy than LAIV in healthy adults, although this finding is not consistent across available studies.

Adults with Immune Compromising Conditions

  • NACI recommends against LAIV for individuals with immune compromising conditions. (NACI Recommendation Grade D)

Live vaccines have generally been contraindicated in people with immune compromising conditions, with some exceptions. NACI concludes that there is insufficient evidence supporting the use of LAIV in those with immune compromising conditions in terms of both safety and effectiveness. Based on expert opinion, NACI concludes that the use of LAIV in this population is contraindicated.

Adults with other chronic health conditions

  • At this time NACI concludes that there is insufficient evidence to recommend LAIV in adults with chronic health conditions. (NACI Recommendation Grade I)
  • The potentially better immune response following TIV compared to LAIV in healthy adults in some studies should be considered when selecting an influenza vaccine for adults at high risk for influenza complications.

Health Care Workers providing care to individuals with immune compromising conditions

  • NACI recommends that TIV, instead of LAIV, should be used for health care workers providing care to those with immune compromising conditions, unless the individual will only accept LAIV. (NACI Recommendation Grade B)
  • NACI recommends that if a health care worker, or another caregiver, receives LAIV and is providing care to individuals with severe immune compromising conditions (defined as hospitalized and requiring care in a protected environment), they should wait two weeks following receipt of LAIV before continuing to provide care to such individuals. (NACI Recommendation Grade D)

Egg Allergy/hypersensitivity

  • Given the lack of data around egg allergy and the intranasal vaccine FluMist®, TIV is the currently recommended product for egg-allergic individuals. Ovalbumin concentrations in FluMist® are documented to be very low and a study is currently underway to assess the use of FluMist® in egg-allergic individuals. The use of FluMist® in egg-allergic individuals will be reevaluated when further data becomes available. If FluMist® is the only option that will be considered by an egg-allergic individual, consultation with a specialist with expertise in allergies should be sought.

I.2 Background

In June 2010, an intranasal, live, attenuated, trivalent influenza vaccine (FluMist® AstraZeneca Canada)1 was authorized in Canada. FluMist® is indicated for active immunization of individuals 2 to 59 years of age against influenza caused by specific influenza virus strains contained in the vaccine. It was first approved for use in the United States in 2003 for individuals 5 to 49 years of age, and was extended to those 2 to 49 years of age in 2007.

Two formulations of FluMist® a have been studied worldwide: first a frozen formulation (0.5 mL/dose) and later a refrigerated formulation (0.2 mL/dose). Both formulations were derived from the same attenuated, cold-adapted master donor virus and are designed to have comparable potency per dose and have demonstrated comparable clinical efficacy. The 0.2 mL/dose is the formulation authorized for use in Canada.

Most influenza vaccines are administered by injection and stimulate the production of immunoglobulin G (IgG) antibodies. The intranasal administration route directly stimulates local immunity [mucosal response including production of IgA and cell-mediated immune response (CMI)] and induces a systemic immune response (production of IgG and CMI).2

I.3 Overview of 2011-2012 seasonal influenza recommendations

For further detail on the epidemiology of influenza and recommended recipients of influenza vaccine for the 2011-2012 season, refer to NACI's Statement on Seasonal Influenza Vaccine for 2011-2012.


a FluMist® has been described in clinical studies using various terminology and acronyms such as CAIV-T, LAIV, and LAIV-T.  In this document, FluMist will be referred to as LAIV (live, attenuated, influenza vaccine), except in the evidence tables, where the terminology will be consistent with the study citation.

Ii. Methods

Details regarding NACI's evidence-based process for developing a statement are outlined in Evidence-Based Recommendations for Immunization: Methods of the NACI, January 2009, CCDR, available at:
http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/09vol35/acs-1/index-eng.php.

NACI reviewed the key questions for the literature review as proposed by the Influenza Working Group, including such considerations as the burden of illness of the disease to be prevented and the target population(s), safety, immunogenicity, efficacy, effectiveness of the vaccine, vaccine schedules, and other aspects of the overall immunization strategy. The knowledge synthesis was performed by PHAC and supervised by the Working Group. This supplement reflects published literature up to April 2011. Following critical appraisal of individual studies, summary tables with ratings of the quality of the evidence using NACI's methodological hierarchy were prepared (Table 9), and proposed recommendations for vaccine use developed. The Working Group chair (Dr. Nadine Sicard) presented the evidence and proposed recommendations to NACI on June 1 and 2, 2011. Following thorough review of the evidence and consultation at the NACI meeting on June 1 and 2, 2011, the committee voted on specific recommendations. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the text.

Iii. Epidemiology

Review of the epidemiology of influenza is available in NACI's Statement on Seasonal Influenza Vaccine for 2011-2012.

Iv. Vaccine

IV.1. Preparation(s) authorized for use in Canada

FluMist® [influenza vaccine (live, attenuated)] is a colourless to pale yellow liquid and is clear to slightly cloudy. It is a live, trivalent vaccine for administration by intranasal spray by a healthcare professional. Each 0.2 mL dose contains 106.5-7.5 FFUb (fluorescent focus units) of live attenuated influenza virus reassortants of each of three strains of virus: influenza virus type A (H1N1); influenza virus type A (H3N2); and influenza virus type B.

LAIV is indicated for the active immunization of individuals 2 to 59 years of age against two strains of influenza A and one strain of influenza B contained in the vaccine for that influenza season. The types of viral antigens contained in LAIV conform to the current requirements for the northern hemisphere as per the World Health Organization (WHO). Annual revaccination with an influenza vaccine is recommended because immunity declines over time and because circulating strains of influenza virus can change from year to year.

Non-medicinal ingredients contained in each 0.2 mL dose include sucrose, dibasic potassium phosphate, monobasic potassium phosphate, gelatin hydrolysate (porcine Type A), arginine hydrochloride, monosodium glutamate, and gentamicin (a trace residual). See package insert for specific amounts of each ingredient. FluMist® contains no preservatives (e.g. thimerosal). The intranasal sprayer does not contain latex.

LAIVs are produced in specific pathogen-free (SPF) embryonated eggs. When the WHO recommends a new strain for the annual influenza vaccine, a new master seed (used to inoculate the SPF eggs) is created by reverse genetics. In this process, the haemagglutinin (HA) and neuraminidase (NA) genes of the new strain are reassorted with an appropriate master donor strain. These master donor strains have been previously cold adapted by serial passages in tissue culture cells in sequentially lower temperatures. During this process, the viruses acquire multiple mutations in internal protein gene segments yielding viruses that are (a) cold-adapted (ca) - they replicate efficiently at 25ºC, a temperature that is restrictive for replication of many wild-type influenza viruses; (b) temperature-sensitive (ts) – they are restricted in replication at 37ºC (Type B strains) or 39ºC (Type A strains), temperatures at which many wild-type influenza viruses grow efficiently; (c) attenuated (att) – they do not produce classic influenza-like illness. The cumulative effect of the mutations associated to the ca, ts, and att phenotypes ensure that the attenuated vaccine viruses replicate in the ciliated epithelial cells of the nasopharyngeal mucosa with no or restricted replication in the lungs due to the higher temperature in the lower respiratory airways. These biological properties enable the vaccine to elicit a protective immune response (via mucosal immunoglobulin IgA, serum IgG antibodies, and cellular immunity) without causing clinical disease.


b The strength may change with the selection of the contained influenza strains for the specific season but will always be within the specification of 106.5-7.5 FFU.

IV.2. Stability of live attenuated viruses

Viruses isolated from vaccine recipients have demonstrated genetic stability by retaining attenuated phenotypes. In one study, nasal and throat swab specimens were collected from 17 study participants for two weeks after vaccine receipt.3 Virus isolates were analyzed by multiple genetic techniques. All isolates retained the LAIV genotype after replication in the human host, and all retained the cold-adapted and temperature-sensitive phenotypes. A study conducted in a child-care setting demonstrated that limited genetic change occurred in the LAIV strains following replication in vaccine recipients.4

IV.3 Efficacy

Live attenuated influenza vaccine has been administered to over 30,000 people in controlled clinical studies over multiple years, in various regions, using different vaccine strains. Many clinical studies evaluated the primary efficacy endpoint of the incidence of culture-confirmed influenza compared to placebo or an injectable influenza vaccine (commonly referred to as TIV or trivalent inactivated vaccine) against strains that match or do not match the circulating influenza virus that season. The term “absolute efficacy” refers to comparisons of LAIV to placebo. The term “relative efficacy” is used when comparing LAIV to TIV. Since the evidence shows variability in efficacy with children and adults, this section addresses them separately.

IV.3.1 Absolute efficacy in children 2 to 17 years of age (placebo comparison)

Several placebo controlled (LAIV versus placebo) and TIV controlled studies (LAIV versus TIV) have been conducted in over 20,000 healthy and asthmatic children over seven influenza seasons to determine absolute and relative efficacy against influenza illness and complications. The first section below describes six placebo controlled randomized studies and three community-based non-randomized studies analyzed for absolute vaccine efficacy. The following section on relative vaccine efficacy describes three TIV controlled studies measuring the relative efficacy of LAIV when compared to TIV.

Belshe et al, in the two year (1996 & 1997) pivotal randomized placebo controlled trial, demonstrated that LAIV was highly efficacious against well-matched circulating strains in healthy young children 15 to 71 months of age5 and also against mismatched strains in children who returned for a booster dose in the subsequent season.6 Overall, the vaccine was 92% efficacious in preventing culture-confirmed influenza (95% CI: 88,94) and exhibited some cross-protection properties against a variant strain in year two. In year one of the study and after two doses of LAIV, there was 96% (95% CI: 90,99) efficacy against A/H3N2 and 91% (95% CI: 78,96) efficacy against influenza B viruses. Even after a single dose, efficacy was demonstrated (89%, CI: 65,96) against antigenically matched A/H3N2 and B viruses, although protection increased when two doses were administered (94%, 95% CI: 88,97). Efficacy was also demonstrated against a mismatched strain during year two when the influenza epidemic consisted largely of influenza A/Sydney/5/97, a variant not contained in the vaccine. This variant strain caused 66/71 total influenza cases in the study population, with the remaining cases associated with A/Wuhan/359/95-like strain or influenza B strain (both strains were contained in the vaccine). In that year, the vaccine was 100% efficacious against matched strains (A/H3N2: 95% CI: 54,100) (B: 95% CI: 79,100) and 86% efficacious against the mismatched strain (95% CI: 77,93).

Two other randomized, multi-year, placebo controlled studies by Tam et al and Vesikari et al conducted in two seasons (2000 to 2002) also found that LAIV is efficacious in preventing culture-confirmed influenza caused by antigenically matched strains in vaccinated and revaccinated children. The first study by Tam et al was conducted in eight Asian countries with healthy children 12 to 35 months of age (first year overall vaccine efficacy 73%, 95% CI: 62,80; second year overall efficacy 84%, 95% CI: 70,92)7. The second study by Vesikari et al involved healthy children 6 to 35 months of age attending daycare in five European countries (first year overall vaccine efficacy 85%, 95% CI: 74,92; second year overall efficacy 89%, 95% CI: 82,93).8 In Tam et al, there were insufficient cases of A/H1N1 or B strains to determine statistical significance, but efficacy against those strains was later determined by assessing reductions in medically attended acute respiratory illness (MAARI) against a drifted A/H1N1 and B strain by Gaglani et al and Halloran et al.9,10 In Vesikari et al, when there was a good match between vaccine and circulating strains, efficacy against A/H1N1 strains was 91.8% (95% CI: 80.8,97.1) in year one, and 90.0% (95% CI: 56.3, 98.9) in year two. Efficacy against influenza B strains was 72.6% (95% CI: 38.6,88.9) in year one and 81.7% (95% CI: 53.7,91.9) in year two. Efficacy against A/H3N2 was not assessed in the first year, but in the second year when it was the predominantly circulating strain, efficacy was 90.3% (95% CI: 82.9,94.9).

Similarly, a study by Bracco Neto et al was conducted with healthy vaccine-naïve children 6 to <36 months of age during the 2001 and 2002 influenza seasons in South Africa, Brazil and Argentina and found a reduction in culture-confirmed influenza caused by matched and mismatched strains.11 In year one, vaccine efficacy versus placebo in children vaccinated with one or two doses of LAIV was 57.7% (95% CI: 44.7,67.9) and 73.5% (95% CI: 63.6,81.0) respectively, against matched strains. In year two, absolute efficacy of a single dose of LAIV was 65.2% (95% CI: 31.2,82.8) and 73.6% (95% CI: 33.3,91.2) respectively, in recipients of one or two doses of LAIV in year one. Year two efficacy in recipients who received two doses of LAIV in year one and placebo in year two was 57% (95% CI: 6.1,81.7) against antigenically similar strains compared to those who received placebo in both years. Efficacy was 35.3% (95% CI: -0.3,58.7) and 20.4% against any community acquired strain and antigenically dissimilar influenza B strains, respectively. In addition, when the groups who received placebo in year one and either one dose of LAIV or placebo in year two were compared, efficacy of a single dose of LAIV was 60.3% against matched strains and 59.4% (95% CI: 32.3,76.4) against any community strain and 54.9% (95% CI:16.6,76.6) against mismatched B strains.

Lum et al, in 2002-2003 examined the safety and efficacy of LAIV when co-administered with measles, mumps and rubella (MMR) vaccine in 1,150 healthy children 11-24 months in Europe/Asia.12 The safety profile of this study is discussed in the Adverse Events section of this statement. Overall vaccine efficacy against a similar subtype was 78.4% (95% CI: 50.9,91.3) and 63.8% (95% CI: 36.2, 79.8) against any subtype. LAIV efficacy was not adversely affected by the concomitant administration with another live vaccine (MMR).

The absolute efficacy of LAIV in young children outlined above has been further documented by a 2009 meta-analysis by Rhorer et al examining efficacy against culture-confirmed influenza as compared to placebo in randomized clinical trials in 25,000 children 6 to 71 months of age.13 In this analysis, combined year one vaccine efficacy (relative to placebo) for two doses in vaccine-naïve young children was 77% (p<.001) against matched strains and 72% (p<.001) against strains regardless of antigenic match in the per protocol population. It was noted that efficacy varied by strain, showing that vaccine efficacy versus placebo after two doses was 85% (95% CI: 78,90), 76% (95% CI: 70,81), and 73% (95% CI: 63,80) against antigenically similar A/H1N1, A/H3N2, and B respectively. In summary, LAIV shows high vaccine efficacy in children across all age groups when compared with placebo regardless of circulating subtype.

Rhorer et al also examined four multi-year placebo controlled studies to determine the combined efficacy of second-season revaccination. Considering combined results from all four trials [Belshe5, 6, Tam7, Vesikari8, and Bracco Neto et al11], the efficacy of LAIV following second season re-vaccination ranged from 74 to 100% for matched strains and from 47 to 87% for all strains regardless of antigenic match. Efficacy against matched strains after re-vaccination in the second year was either the same as, or higher than, efficacy after the primary (first season) vaccination. In two studies, two doses of LAIV in the first year were associated with some protection persisting through a second season without revaccination. The effectiveness rates in year two ranged from 44.8% (95% CI: 18.2,62.9) when the vaccine was mismatched on one of the circulating strains in both seasons7 to 57.0% (95% CI: 6.1,81.7) when the vaccine was well matched to the circulating strains in both seasons.11 Regardless, annual vaccination is recommended because protection is lower in the second year following vaccination, and because circulating strains of influenza can change from year to year.

The above studies measure the frequency of culture-confirmed influenza to assess vaccine efficacy in children. In non-randomized, community-based studies, other measures of vaccine effectiveness have been evaluated. Gaglani et al9 studied healthy children aged 18 months to 18 years across three influenza seasons (1998 to 2001) in Texas, USA. The study measured the direct effectiveness of LAIV against influenza A/H1N1 and B infections by comparing rates of medically attended acute respiratory illness (MAARI) in LAIV recipients and age-eligible non-recipients in the intervention communities. A single dose of LAIV was received by 9,765/19,700 children aged 1.5 to 18 years during the study. It also measured the total effectiveness of LAIV by comparing MAARI for LAIV recipients with that of non-recipients in comparison communities where LAIV was not offered. Individuals who had received LAIV for three consecutive years up to and including 2000-2001 demonstrated overall direct effectiveness of 20% (95% CI, 14,25) on decreasing MAARI during the weeks in the 2000-2001 influenza season with an identified influenza A and B epidemic, and 17% (95% CI: 9,27) during the weeks where only influenza A (H1N1) was predominant. The estimated total effectiveness was 18% (95% CI 13, 24) and 26% (95% CI: 18,33) in the same respective periods.

In a subsequent paper, Halloran et al examined one of the Texan regions studied in Gagani et al during the 2003-2004 influenza season to determine the effect of LAIV against drift variant influenza strain in children aged 5 to 18 years.10 Vaccine effectiveness against MAARI was similar among children 5 to 9 years (0.31, 95% CI: 0.11,0.47) and older children 10 to 18 years (0.24, 95% CI: 0.03,0.40). The overall vaccine effectiveness of LAIV compared to non-vaccinated children against MAARI was 0.26 (95% CI: 0.11,0.39). When comparing surveillance data for culture confirmed influenza for children who received LAIV and non-vaccinated children, the overall vaccine effectiveness was 0.56 (95% CI: 0.24,0.84) using data from children with a health plan only, and 0.56 (95% CI: 0.32,0.75) in all children. Although some children in this study received TIV because LAIV was contraindicated, the direct comparison of LAIV and TIV should be interpreted with caution as the LAIV and TIV groups differed in their baseline characteristics (i.e. higher percentage of individuals in the TIV group with chronic obstructive pulmonary disease (COPD) and other chronic or congenital conditions).

The Texas trial evolved into a largely school-based program for children 4 to <18 years of age, and was evaluated by Glezen et al for the 2007-2008 season.14 The intervention sites (schools with LAIV administration) were compared to the comparison sites (schools without LAIV administration) during four periods in the influenza season: before the start of the vaccine program, after the start of the vaccine program but prior to the start of the influenza epidemic as determined by regional surveillance data, during the epidemic, and after the epidemic. The risk ratios for MAARI were 0.97 (95%CI: 0.95, 1.00), 0.89 (95%CI: 0.86, 0.91), 0.90 (95%CI: 0.88, 0.92), and 0.91 (95%CI: 0.88, 0.93) for each time period respectively. A total 2,500 medical encounters were estimated to have been prevented at the intervention sites.

Other studies using LAIV in a school-based immunization program also saw reductions in outcomes related to medically-attended influenza infection15, MAARI 16,17 and ILI18.

IV.3.2 Relative efficacy of LAIV in children 2 to 17 years of age (TIV comparison)

Three randomized TIV-comparison studies conducted in over 12,000 children from 6 months to 18 years of age consistently demonstrated statistically significant superior efficacy of LAIV relative to an injectable, trivalent inactivated influenza vaccine, against culture-confirmed influenza19-21 and MAARI10 caused by wild-type virus strains antigenically matched to those in the vaccine, as well as against all strains regardless of match.

The relative protection provided by LAIV and TIV was first studied in two trials by Ashkenazi et al and Fleming et al in Europe and Israel during the 2002-2003 influenza season.20,21 Ashkenazi et al randomized 2,187 children 6 to 71 months of age with a history of recurrent respiratory tract infections (RTIs), including, but not limited to, common colds, acute otitis media, bronchitis, pneumonia, and bronchiolitis. From this population, 2,085 children were evaluated for efficacy in the per protocol population. Treatment groups were well matched with respect to baseline characteristics, including the proportion of children with a history of wheezing in the prior 12 months (34–36%) or asthma (23%). Active surveillance for influenza was conducted during the influenza season and viral cultures were obtained to determine culture-confirmed influenza. They found that there were 53% (95% CI: 22,72) fewer cases of culture-confirmed influenza caused by vaccine-matched strains among recipients of LAIV compared with recipients of TIV (24/1,050 versus 50/1,035, respectively). Although not powered to look at efficacy across age groups, higher culture-confirmed rates of influenza in children who received TIV compared to LAIV were found in 7 of 11 age groups assessed. In the study's evaluation of health outcomes related to all-cause respiratory illness (i.e. influenza and non-influenza), LAIV recipients reported 9% (95% CI: 2,16) fewer health care provider visit days and 16% (95% CI: 10,22) fewer missed days from school or child care, compared with TIV recipients. There was no impact noted on medication or antibiotic treatment for respiratory tract infections, overnight hospitalizations or wheezing associated with influenza-like illness. In a post hoc analysis22, LAIV was found to decrease the severity of influenza illness that occurred despite vaccination (breakthrough influenza) compared to TIV.

Concurrently, Fleming et al evaluated the relative efficacy of a single dose of LAIV or TIV in a randomized, open-label trial in Europe in 2,220 children 6 to 17 years of age who had a prior clinical diagnosis of asthma.21 Subjects were excluded if they had serious chronic disease, altered immune function, and were currently receiving immunosuppressive therapy, including high-dose systemic corticosteroids (≥2 mg/kg per days or ≥20 mg/days of prednisolone or its equivalent). Of note, in spite of these exclusion criteria, in each treatment group, 69% of participants reported current inhaled steroid use and 43% had a history of systemic steroid treatment. LAIV recipients experienced 35% (95% CI: 4,56) fewer cases of influenza caused by matched strains than TIV recipients (46/1,109 versus 70/1102, respectively). In this study, the relative efficacy of LAIV versus TIV was similar for children 6 to 11 and 12 to 17 years of age. Unlike the observations by Ashkenazi et al, Fleming et al found no significant differences for any other outcome measures (e.g. health care provider visits, medication use, and days missed from school or work). As well, no difference in illness severity was noted between LAIV and TIV recipients who developed breakthrough influenza.22

In 2004–2005, Belshe et al compared the efficacy of LAIV and TIV in a multinational, randomized, double-blind study in 7,852 children 6 to 59 months of age.19 Vaccine-naïve children were given two doses of vaccine while previously vaccinated received one dose. Study groups were well matched with regard to history of prior influenza vaccination (22–23%), history of wheezing (21–22%), recurrent wheezing (6–7%), and asthma (4%). The primary endpoint was the incidence of culture-confirmed influenza, with illness being investigated upon report of fever plus ≥1 other symptom of cough, sore throat, or runny nose/nasal congestion. There were 45% (95% CI: 22,61) fewer cases of influenza caused by matched strains in LAIV recipients than TIV recipients (53/3,916 versus 93/3,936, respectively), and 58% (95% CI: 47,67) fewer cases caused by mismatched strains (102/3916 versus 245/3936, respectively). Comparing LAIV to TIV, this study also noted a reduction in otitis media of 51% (95% CI:22-70%) and lower respiratory tract illness of 46% (95%CI: 4-70%) for all strains combined regardless of match to the vaccine23. In a post-hoc analysis of the relative efficacy of LAIV versus TIV across age groups, the efficacy for all strains combined regardless of antigenic match to the vaccine was found to be similar across age groups and ranged from 42% to 57% across the four age groupings assessed.24

In their meta-analysis of the above studies, Rhorer et al also examined relative efficacy when two doses of LAIV were compared to two doses of TIV which showed vaccine-naïve children who received LAIV experienced 46% fewer cases of ILI caused by matched strains.13 Similarly, for studies including older children who had been previously vaccinated, those receiving one LAIV dose experienced 35% fewer cases of ILI than those receiving one TIV dose. Ambrose et al, in 2011, also reviewed comparative studies in children 6 months to 18 years of age and concluded that each of the four comparative studies reviewed (including the three reviewed above) demonstrated that LAIV was more protective than TIV.22

IV.3.3 Protection from Acute Otitis Media

Since influenza is known to be associated with acute otitis media (AOM) in children, many of the abovementioned studies examined the impact of LAIV on the incidence of AOM. Block et al pooled and analyzed data from six placebo controlled and two TIV controlled studies with children 6 to 83 months of age.25 The pre-specified secondary endpoint was efficacy against AOM. Of 24,046 children, 47% were younger than 24 months of age, 84% were healthy, 11% had a history of wheezing, 11% attended daycare ≥12 hours per week and 9% reported a history of two or more respiratory tract infections (e.g. common colds, AOM, bronchitis, pneumonia, and bronchiolitis) in the previous 12 months.

For the pooled analysis of the six placebo controlled studies, a total of 36 cases of AOM associated with culture-confirmed influenza due to any strain were found in 8,353 (0.4%) LAIV recipients and 165 cases were found in 5,756 (2.9%) placebo recipients. Therefore, the overall efficacy of LAIV against influenza-associated AOM was 85% (95% CI: 78.3,89.8). When analyzed by age at the time of vaccination, the incidence of AOM in influenza-positive subjects was similar in placebo-recipient children ≥24 months of age (18%) when compared with placebo-recipient children 6 to 23 months of age (16%). The incidence of AOM in influenza-positive subjects in LAIV recipients ≥24 months of age was 8%, and 12% in children 6-23 months of age. In LAIV recipients, there was higher overall efficacy against developing AOM in influenza-positive children ≥24 months of age (91%) versus 6 to 23 months (78%) of age.

In the two TIV controlled studies examined by Block et al (Belshe et al19 and Ashkenazi et al20 referred to above), 28 cases of AOM associated with culture-confirmed influenza due to any influenza strain, were found in 4,966 (0.6%) LAIV recipients and 61 cases were found in 4,971 (1.2%) TIV recipients. The relative efficacy of LAIV compared with TIV for influenza-associated AOM was 54.0% (95% CI: 27.0,71.7). As with the placebo controlled studies, the relative efficacy of LAIV compared with TIV was higher in children ≥24 months of age versus 6 to 23 months of age (61.7% versus 47.5%).

Block et al also examined whether LAIV had any effect on the incidence of AOM beyond simply preventing influenza illness, and analyzed the rates of AOM among placebo, LAIV and TIV recipients who developed culture-confirmed influenza. In placebo controlled trials, among children who acquired influenza despite vaccination, AOM was diagnosed in 10.3% of LAIV recipients and 16.8% of placebo recipients, representing a 38.2% (95% CI: 11.0,58.2) relative reduction in the development of AOM. The difference was statistically significant in children ≥24 months of age but not among those 6 to 23 months of age. In TIV controlled studies, among children with breakthrough influenza illness, the proportions of LAIV and TIV recipients who developed AOM were similar and not statistically significant.

IV.4. Absolute efficacy in adults 18 to 59 years of age (placebo comparison)

Clinical trial data provide evidence of efficacy and effectiveness of LAIV in adults. Over 10,000 adults were included in four randomized trials, which included one placebo controlled trial26 and four TIV controlled studies27-30, one of which was a wild-type challenge study30.

Nichol et al conducted a large randomized, double-blind, placebo controlled trial of LAIV effectiveness during the 1997-98 influenza season in 4,561 healthy working adults 18 to 64 years of age across thirteen centres in the US.26 There was no laboratory confirmation of influenza during this study, and the season experienced a drifted variant of the A/Wuhan/359/95 vaccine strain (A/Sydney/05/97 was the predominant circulating strain). An observed reduction of 9.7% in any febrile illness in LAIV recipients compared to placebo recipients was not statistically significant (95% CI: -2.1,20.7); however, there were significant reductions in the incidence of severe febrile illness (18% reduction; 95% CI: 7.4,28.8), and febrile upper respiratory illnesses (23.6% reduction; 95% CI: 12.7,33.2). Vaccination also led to substantial reductions in days of illness, days of work lost, days with health-care provider visits, and use of prescription antibiotics and over-the-counter medications among LAIV recipients. This study also demonstrated that LAIV provided cross-protection against the variant strain but since it did not compare LAIV with TIV, it is not known how the degree of cross-protection compared with that offered by the TIV vaccine.

IV.4.1 Relative efficacy in adults 18 to 59 years of age (TIV comparison)

In contrast to children, most comparative studies in individuals 18 to 59 years of age have found LAIV and TIV were similarly efficacious27,30-32 or that TIV was more efficacious.28 One study found LAIV to be somewhat more efficacious in a cohort of vaccine-naïve adults (no previous influenza vaccination).29 A possible reason for this difference between children and adults may be that adults generally have pre-existing immunity which may interfere with response to a live virus vaccine; by comparison, children, who are generally naïve to influenza, will mount a more robust immune response.

The primary limitation of the current analysis in adults 18 to 59 years of age is that a small number of prospective randomized studies have been conducted in this age group, therefore fewer data are available and results are more variable when compared to studies in children.

One of the first randomized placebo controlled studies to determine relative protection was by Edwards et al over five years (1985 to 1989) in 5,201 people (n=809 under 15 years of age) in seven sites in the US.27 For A/H1N1 disease, there were no statistically significant differences in efficacy between LAIV and TIV (85% versus 76%, respectively) regardless of illness definition. In general, relative efficacy rates were higher when there was a better vaccine match to the circulating strains than when there was poor match. For A/H3N2 disease, no significant differences were found between LAIV and TIV for preventing culture-confirmed influenza, but TIV was more efficacious than LAIV (73% versus 32%, respectively) in preventing H3N2 seroconversion. Efficacy rates for A/H3N2 disease did not differ from year to year.

Treanor et al conducted a TIV-comparison study during the 1995-1996 influenza season which included a wild-type influenza challenge in 103 adult volunteers 18 to 45 years of age.30 The study evaluated protection against documented influenza, defined as viral shedding (evaluated daily for seven days after challenge) and/or ≥4-fold increase in hemagglutination-inhibition (HAI) titre (28 days after challenge) in the presence of respiratory symptoms. Subjects with baseline serum HAI antibody titers of ≤1:8 to the vaccine strains were randomized to receive LAIV, TIV, or placebo and challenged intranasally with one vaccine-like wild-type virus (A/H1N1, A/H3N2, or B) approximately 28 days later. Culture confirmed influenza occurred in 45% (14/31) of placebo recipients following wild-type virus challenge, compared with 6.9% (2/29) and 12.5% (4/32) of those given LAIV and TIV, respectively (p=.001 for LAIV versus placebo; p=.006 for TIV versus placebo; p=.67 for LAIV versus TIV). Protective efficacy was 85% (95% CI: 28,100) for LAIV and 71% (95% CI: 2,97) for TIV. There were trends toward less severe illness among LAIV recipients compared with TIV recipients and less severe illness in both vaccinated groups compared with placebo recipients. Both LAIV and TIV demonstrated statistically significant efficacy against laboratory-documented influenza compared to placebo.

A randomized, culture-confirmed field trial with healthy adults 18 to 49 years of age during three influenza seasons was evaluated by Monto et al and Ohmit et al (2004-2008). Monto et al reported on the 2007-2008 season and demonstrated that TIV was more efficacious than LAIV with a statistically significant difference.28 The absolute efficacy of LAIV was estimated to be 36-51% compared to 68-73% for TIV. TIV recipients experienced a 50% (95% CI: 20,69) reduction in culture-confirmed or PCR-identified influenza compared to the LAIV cohort. Ohmit et al studied vaccine efficacy in the same trial for two influenza seasons. In 2004-2005, depending on whether culture, PCR or both were used to detect influenza, the observed efficacies were 48-57% for LAIV and 74-77% for TIV; the difference between TIV and LAIV were not statistically significant.31 In 2005-2006, Ohmit et al noted the influenza attack rate observed in the placebo group was much lower than in the previous year (1.8% versus 7.8% respectively), rendering the study underpowered to detect vaccine efficacy.32 Absolute efficacies ranged from 8% (95% CI: -194,67) to 61% (95% CI: -48,89) for LAIV and 16% (95% CI: -171,70) to 23% (95% CI: -153,73) for TIV and were statistically similar. No analysis of illness severity among breakthrough cases was reported for any study season.

Wang et al conducted a large multi-year retrospective cohort study in the United States with over three million healthy, active duty military service members 17 to 49 years of age who received LAIV or TIV during 2004-2005, 2005-2006, or 2006-2007.29 Pregnant women were excluded from the study. The primary outcome was the first medical encounter with a diagnosis code (ICD-9 code) associated with pneumonia or influenza. The incidence rate for health care encounters, pneumonia/hospitalization were highest for the unimmunized groups and lower in the TIV cohort versus the LAIV cohort, during each season. In all three seasons, immunization with TIV was associated with lower incidence rates of health care encounters for pneumonia and influenza when compared with LAIV: 8.6 versus 18.3 (2004-2005), 7.8 versus 10.6 (2005-2006) and 8.0 versus 11.1 (2006-2007) per 1,000 person-years (all p<.001). Vaccine-naive (no history of influenza vaccination in previous one or two seasons) and unimmunized cohorts (no documented influenza vaccination during the season of interest) were matched by propensity scoring determined by age, sex, service branch, medical encounter history, and immunization history. The incidence rates of hospitalization for pneumonia and influenza were similar between the previously unimmunized and vaccine-naïve cohorts in both LAIV recipients (9.5 and 9.3/1,000 person-years) and the TIV recipients (7.4 and 8.2/1,000 person-years). In contrast to the general trend that TIV was more efficacious than LAIV, this study found LAIV had an effect similar to TIV in the vaccine-naïve cohort (new recruits), which further supports previous studies demonstrating that children and adults who were seropositive at baseline were less likely to have a serologic response to LAIV compared with those who were seronegative.33-35

The 2005-2006 and 2006-2007 seasons in the study by Wang et al, were subsequently analyzed by Eick et al.36 A slightly greater protection from ILI was found in both seasons for non-recruits who received TIV compared to LAIV (adjusted incidence rate ratio, 1.17 [95% CI, 1.14-1.20] and 1.33 [95% CI: 1.30-1.36], 2005-2006 and 2006-2007 influenza seasons, respectively). However, for recruits (who were less likely to have received prior influenza vaccine, as most were 20 years of age or younger), LAIV was found to provide significantly greater protection from ILI compared to TIV, with adjusted incidence rates of ILI 22-51% and 18-47% lower among LAIV compared to TIV recipients for the 2005-2006 and 2006-2007 seasons respectively. This suggests that pre-existing immunity may play a role in determining effectiveness of LAIV, in that it may be more effective when there has been minimal lifetime exposure to the influenza virus or vaccine.

In the same meta-analysis referenced in relative efficacy for children, Ambrose et al concluded that in individuals 17 to 49 years of age, most comparative studies have demonstrated that LAIV and TIV were similarly efficacious or that TIV was more efficacious and that the relative efficacy of LAIV and TIV among young adults may vary depending on the specific population and the antigenic match between the vaccines and circulating strains.22

IV.5. Immunogenicity

LAIV administered by the intranasal route results in an immune response that is thought to mimic the immune response induced by natural infection with wild-type viruses. Resistance to influenza infection and disease results from both mucosal and systemic immunity. The biological properties of LAIV (cold-adapted; temperature-sensitive; attenuated) enable a protective immune response without causing clinical disease.

Although serum antibodies are primarily responsible for lower respiratory tract protection and are the most commonly measured correlates of protection from illness, local mucosal antibodies are critical for protection of the upper respiratory tract and may be more important to overall protection against influenza.37 Local mucosal antibodies may also be a better indicator of immunogenicity for LAIV than serum antibody.38 Studies have demonstrated that presence of an HAI antibody response after the administration of LAIV is predictive of protection (see Table 1). However, the absence of an antibody response after the administration of LAIV does not reflect the absence of protection, as clinical efficacy studies have shown protection in the absence of a significant antibody response.27 30

The immunogenicity of LAIV has been assessed in multiple studies conducted among children and adults33 34 38-48 including studies where LAIV was co-administered with other live vaccines.12 49 50 Immunogenicity was measured based on immune responses elicited by the vaccine as measured by the serum level of antibodies against the HA envelope protein of the influenza viruses (as detected by the HAI assay). LAIV has predominately been shown to be equally if not more immunogenic than TIV in children, whereas TIV was typically more immunogenic in adults. Greater rates of seroconversion to LAIV occur in baseline seronegative individuals compared to baseline seropositive individuals in both child and adult populations. As well, the duration of TIV-induced immunity has been found to be more durable in adult compared with pediatric populations, and although the decline of TIV-induced serum antibody titres in adults occurs, it is less substantial than with children.51

Table 1 Comparison of the serum hemagglutination-inhibition antibody responses and vaccine efficacy
in children receiving LAIV against three influenza outbreaks
Season Vaccine virus Circulating Virus Percent of seronegative children who seroconverted VE% (95% CI)
A/Wuhan/359/95 A/Sydney
1996-1997 (Belshe) A/Wuhan/359/95 (H3N2) Closely matched 96 - 95 (88,97)
1996-1997 (Belshe) B/Harbin/7/94 Closely matched 96 - 91 (78, 96)
1997-1998 (Belshe) A/Wuhan/359/95 (H3N2) A/Sydney/5/97 (H3N2) 100 98 86 (77, 93) vs. Sydney
100 (54, 100) vs. A/Wuhan

Naturally acquired immunity against influenza is typically longer-lived and broader than that induced by inactivated vaccines, providing protection to both antigenically similar and drifted influenza strains. LAIV has demonstrated efficacy during seasons where there was a mismatch between vaccine and circulating strains. It is suggested that LAIV may trigger immunogenic activity similar to natural infection resulting from exposure to more antigens presented by a live vaccine virus compared to an inactivated vaccine.52 LAIV may stimulate a mucosal IgA and/or T-cell-mediated immune response, and the production of more broadly cross-reactive humoral antibodies that can confer cross-protection in circumstances where there is a suboptimal match of the vaccine and epidemic influenza strains.26

IV.6. Vaccine Administration and Schedule

IV.6.1 Schedule & dosage

The recommended vaccine dosage is 0.2 mL (0.1 mL per nostril) for individuals 2 to 59 years of age. For children 2 to 8 years of age inclusive who have not previously received a seasonal influenza vaccine, the recommended dosage schedule for nasal administration is one 0.2 mL dose (0.1 mL in each nostril) followed by a second 0.2 mL dose (0.1 mL in each nostril) administered at least 4 weeks later. For all other individuals, including children 2 to 8 years of age who have previously received a seasonal influenza vaccine, the recommended schedule is one 0.2 mL dose (0.1 mL in each nostril).

If the vaccine recipient sneezes immediately after administration, the dose should not be repeated.

LAIV should be administered according to the following schedule:
a Administer as 0.1 mL per nostril
* LAIV is not recommended in persons <2 years of age due to increased risk of wheezing (See Adverse Events).
Age Group Vaccination Status Dosage Schedule
Children*
(2 to 8 years of age)
Not previously vaccinated with seasonal influenza vaccine Two doses (0.2 mLa each, at least 4 weeks apart)
Previously vaccinated with seasonal influenza vaccine Single dose (0.2 mLa)
Children, adolescents and adults
9 to 59 years of age
Not applicable Single dose (0.2 mLa)

IV.6.2 Route of administration

LAIV is administered by the intranasal route by a healthcare provider. Each pre-filled glass sprayer contains a single dose of LAIV; approximately one-half of the contents should be administered into each nostril. There is a dose divider clip in the plunger to ensure that 0.1 mL is administered in each nostril. Refer to the product monograph for administration instructions. Once LAIV has been administered; the sprayer should be disposed of according to the standard procedures for medical waste.

IV.7. Storage Requirements

LAIV should be stored in a refrigerator between 2° to 8°C upon receipt and until use. The product must be used before the expiration date on the sprayer label. Do not freeze.1

IV.8 Simultaneous Administration with Other Vaccines

Three studies evaluated the immune response and safety after concomitant administration of LAIV with MMR,12 49varicella,49 and the oral polio virus (OPV).50 Seroresponse rates and GMT titres for MMR (≥96%) and varicella (≥82%) vaccines were found to be similar with concurrent administration of LAIV or placebo. The results of these studies demonstrated that LAIV can be safely administered concurrently with MMR and varicella vaccines to young children in routine clinical practice without reducing the immunogenicity or safety of any of the vaccines. If not administered during the same visit as other live virus vaccines (e.g. MMR or varicella), administration of the two live vaccines should be separated by at least four weeks.

IV.9 Adverse Events

In clinical studies, the safety of LAIV was evaluated in over 28,500 children and adolescents 2 to 17 years of age and over 4,350 adults 18 to 59 years of age. The most common adverse reaction observed in clinical studies in all ages was nasal congestion/rhinorrhea.1 Adverse events have been identified in different age groups and time periods post-vaccination.

IV.9.1 Post-Market Adverse Drug Reactions

Since the authorization of FluMist® in June 2010, only a small number of post-marketing adverse events have been reported by the manufacturer, mostly involving non-serious events such as nasal symptoms with or without subsequent complaints of a “cold”. Due to the limited Canadian data at this point in time, post-market adverse drug reactions observed in the US will be detailed here for information purposes as it has been licensed there since 2003.

The US Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system, conducted an analysis of reported adverse events from 2003-200553 representing over 2.5 million persons who received LAIV during this timeframe. Table 2 provides the reactions identified during this post-marketing evaluation. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to estimate their incidence or establish a causal relationship to vaccine exposure.

Table 2: Summary of reported adverse events in VAERS, 2003-2005, following administration of LAIV54
Main condition All reports: No.
(% of all LAIV -associated reports)
N = 460
All serious reports: No.
(% of all serious LAIV-associated reports)
N = 40
Respiratory
(influenza-like illness, vaccine failure, rhinitis, pharyngitis, tracheitis, secondary transmission, sinusitis, asthma, pneumonia, other)
217 (47.2) 15 (37.5)
Constitutional
(weakness/tiredness, fever, headache, dizziness, arthritis)
67 (14.6) 4 (10.0)
Allergic
(possible anaphylaxis, other)
54 (11.7) 6 (15.0)
Abdominal symptoms
(vomiting, nausea)
33 (7.2) 1 (2.5)
Ear-nose-throat
(epistaxis, nose ulcer, redness, ear infection, oral herpes simplex)
18 (3.9) 0 (0.0)
Ocular
(edema, retinal hemorrhage, eye pain)
7 (1.5) 1 (2.5)
Neurological
(Guillain-Barré syndrome, Bell's palsy, febrile seizures, encephalomyelitis, encephalitis, other)
10 (2.2) 7 (17.5)
Cardiovascular
(pericarditis, myocardial infarction, chest pain/discomfort)
10 (2.2) 3 (7.5)
Other
(vaccine administration error, other)
44 (9.6) 3 (7.5)

A follow-up analysis on data from the VAERS for the period October 2007-April 2009 was conducted looking specifically into adverse event reports in children 24 to 59 months of age.55 After over 10 million doses distributed to people of all ages, there were 222 relevant reports in children and the most frequently reported adverse event was fever (47%), vomiting (28%) and rhinitis (21%). Six reports identified asthma exacerbation in children with a history of asthma, and eight reports identified wheezing in children without a history of asthma. No serious adverse events, such as death, anaphylaxis, Guillain-Barré Syndrome, or encephalitis were reported.

A post-licensure evaluation of LAIV by MedImmune is nearing completion.56 The evaluation assesses . outcomes in children and adults age 5 to 49 years from October 2003 to March 2008. It compares 63,061 unique subjects who received LAIV to 62,492 subjects receiving TIV and 71,949 unvaccinated subjects. Preliminary results have identified 114 serious adverse events in 107 individuals within 42 days post-vaccination, including one death. Five serious adverse events were considered potentially related to LAIV, including three cases of Bell's Palsy, one case of nonspecific paroxysmal spell, and one case of migraine/sinusitis. Nine deaths occurred within 180 days of LAIV vaccination, but were considered unrelated to LAIV (three deaths in subjects 9 to 17 years, six deaths in subjects 18 to 49 years). The rate of death was not considered statistically significant when compared to four deaths each occurring in the TIV and unvaccinated cohorts. Asthma and wheezing events were not statistically increased in the LAIV cohort, and no anaphylactic events were reported within 36 hours post-vaccination.

IV.9.2 Adverse Events in Children and Adolescents 2 to 17 years of age in Clinical Trials

Several placebo controlled studies(7,8,11,50,57-59) and TIV controlled studies19-21 were pooled to evaluate solicited events occurring in children and adolescents 2 to 17 years of age. Table 3 presents the solicited events that occurred within ten days of administering the first dose of LAIV in at least 1% of recipients, and compares rates from placebo and TIV-controlled studies. A total of 7,336 children and adolescents 2 to 17 years of age received at least one dose of LAIV in year one of dosing in controlled studies and provided data for the pooled safety analysis. In these studies, solicited events were documented within 10 days post vaccination. Solicited events after the second dose of LAIV were similar to those after the first dose, and were generally observed at a lower frequency. Similar findings were noted by Ambrose et al after their analysis of LAIV reactogenicity during second season revaccination, which is that side effects were lessened in year two.22 The most common solicited adverse events, observed during days 0-10 after the first dose, included runny/stuffy nose, cough, decreased appetite, irritability, abdominal pain, decreased activity, headache, vomiting, sore throat, muscle ache, chills, and fever. There were no observed differences in adverse events following LAIV administration between age groups in the 2 to 17 year age bracket.

Table 3: Summary of solicited events observed during days 0 to 10 after first dose for LAIV and either placebo or TIV control recipients; children and adolescents 2 to 17 years of age.1
Solicited Event Placebo Controlled Studies TIV Controlled Studies
LAIV
N=258-3,245a
%
Placebo
N=191-1,994a
%
LAIV
N=3,931-4,108a
%
Injectable Influenza Vaccine
N=3,982-4,118a
%
Any solicited event 74.2 69.5 70.4 64.8
Runny/stuffy nose 63.7 56.9 56.7 45
Cough 39.9 41.6 33.6 35.6
Decreased Appetite 24.1 21.7 15.9 15.2
Irritability 21.2 19a.7 13.8 12.5
Abdominal Pain 14.1 12.3 12.3 11.5
Decreased Activityb 13.8 11.7 13.1 11.8
Headache 13.4 6.5 13.8 12.3
Vomiting 12.3 13.7 6.8 6.9
Sore Throat 10.1 8.2 11.6 11.2
Muscle Aches 8.1 5.2 5.7 6.9
Chills 6.2 7.8 5.8 5.1
Fever
≥38.0°C 11.2 9.7 9.3 8.6
≥38.5°C 6.0 5.6 5.1 5.1
≥39.0°C 2.5 2.5 2.3 2.4
≥39.5°C 1.1 1.0 0.8 0.9
a Number of subjects evaluated for the specific solicited event. Range reflects differences in data collection between the pooled studies , which have different sample sizes.
b Collected as decreased activity/tiredness/weakness/malaise

IV.9.2.1 Serious Adverse Events (children/adolescents)

Days 0-42
In the same pooled safety analysis for children and adolescents, 0.45% (129/28,873) of those who received LAIV reported at least one serious adverse event (SAE) during days 0 to 42 post-dose in the first year of dosing. The majority of these were either infectious (0.23%) or respiratory (0.05%) events, including gastroenteritis, pneumonia, otitis media, and asthma. During days 0 to 42 post dosing in TIV controlled studies, 0.75% (32/4,245) of individuals who received LAIV and 1.01% (43/4,278) individuals who received injectable influenza vaccine reported at least 1 SAE, and in placebo controlled studies, 0.49% (52/10,693) of individuals who received LAIV and 0.55% (31/5,677) of individuals who received placebo reported at least one SAE.

Days 0-180
Of the 2.22% (182/8,202) individuals who received LAIV and reported at least one SAE during days 0 to 180 post-dose in the first year of dosing, the majority reported infectious (1.52%), respiratory (0.28%) or gastrointestinal (0.23%) events, including pneumonia, gastroenteritis, asthma, and otitis media. During days 0-180 post dosing in TIV controlled studies, 2.28% (94/4,130) of individuals who received injectable influenza vaccine reported at least one SAE, and in placebo controlled studies, 2.91% (70/2,408) of individuals who received LAIV and 2.72% (42/1,546) of individuals who received placebo reported at least one SAE.

IV.9.3 Wheezing

Earlier studies60 have suggested an association with wheezing in young children after receipt of LAIV while others have not. 20,61 A pivotal multi-centre efficacy trial19 was conducted in over 7,800 children 6 to 59 months of age in 2004-2005 by Belshe et al and showed the percentage of all subjects reporting medically significant wheezing (MSW)c through 42 days post-vaccination was similar between groups (3.9% for LAIV versus 3.1% for TIV recipients). Upon analysis by subgroup, however, the rates of wheezing were statistically higher among children 6 to 23 months of age (5.9% LAIV versus 3.8% TIV) during weeks 2, 3, and 4 after vaccination. The rate of wheezing was not increased in LAIV recipients 24 months of age and older (2.1% LAIV versus 2.5% TIV).

Among vaccine-naïve children in this study, wheezing after the first dose was more common with LAIV than with TIV, primarily among children 6 to 11 months of age; in this age group, 12 additional episodes of wheezing were noted within 42 days after receipt of dose one in recipients of LAIV (3.8%) than among recipients of TIV (2.1%, p=.076).

A total of 18 children were hospitalized (11/4,179 [0.3%] LAIV versus 7/4173 [0.2%] TIV) in association with an adverse event that met the protocol definition of MSW within 42 days of dosing. Two-thirds (12/18) of the children were 6 to 23 months of age, of whom nine [0.5%] were in the LAIV group and three [0.2%] were in the TIV group. Of the nine children in the LAIV group, two had a past history of wheezing or asthma, one had Respiratory Syncytial Virus (RSV) infection, and two children had both a past history of wheezing or asthma and RSV infection. Of the three children in the TIV group, one had RSV infection, one had a past history of wheezing or asthma and RSV infection, and one had a past history of wheezing or asthma and Mycoplasma infection. No deaths resulted from these events and none of the hospitalized children required mechanical ventilation or admission to an intensive care unit. There was no difference in severity of outcomes between LAIV and TIV groups. The rate of hospitalizations was not increased in LAIV recipients ≥12 months of age.

Table 4 Comparison of LAIV and TIV on hospitalizations and medically significant wheezing19
Adverse Reaction Age Group LAIV TIV Controli
All cause hospitalizationsii 6-23 months (n=3967) 4.2% 3.2%
24-59 months (n=4385) 2.1% 2.5%
Wheezingiii 6-23 months (n=3967) 5.9% 3.8%iv
24-59 months (n=4385) 2.1% 2.5%
i Injectable influenza vaccine made by Sanofi Pasteur inc
ii from randomization through 180 days post last vaccination
iii wheezing requiring bronchodilator therapy or with significant respiratory symptoms evaluation from randomization through 42 days post last vaccination
iv statistically significant difference, (95% CI: 7.2-3.38)


c MSW defined as the presence of wheezing on a physical examination conducted by a health care provider, accompanied by at least one of the following:  sign of respiratory distress: tachypnea, retractions, or dyspnea; hypoxemia (O2 saturation <95%); or a new prescription for a daily bronchodilator.

IV.9.4 Children with Asthma

In 1976, a small study by Storms et al with 20 asthmatics and 9 controls 18 to 57 years of age examined safety and immunogenicity of LAIV.62 This vaccine was derived from the strains A/England/42/72 and A/PR8/34. In subjects with a low influenza type A antibody titer, there was a 4-fold rise in titer to the vaccine, whereas those subjects with a high baseline titer showed no rise. There were no significant changes in pulmonary function and no significant adverse reactions reported. Redding et al also examined LAIV safety in 1997 with 48 moderate to severely (but stable) asthmatic children and adolescents 9 to 17 years of age.63 The percent change in forced expiratory volume at one second (FEV1) scores and on days two to five thereafter were similar in vaccine and placebo groups (0.2 versus 0.4%, p=.78). The groups were similar in terms of post-vaccination symptoms (night-time awakenings, daily use of rescue medication) within 10 days and there were no serious adverse events in either group though two individuals in the LAIV group had a recurrence of asthma post-vaccination which could not be definitively associated with the vaccine due to small sample size. In a large multi-year trial (1998-2002) with over 12,000 healthy children 1.5 to 18 years of age, a cohort each year (range 11-18%) with a history of intermittent wheezing were examined to assess safety and effectiveness of LAIV in this population.64 This study assessed rates of medically-attended acute respiratory illness (MAARI), including asthma exacerbation, at several reference points (days 0-14 and 0-42 days post LAIV) and found no increased risk for MAARI, including asthma exacerbation. This did not differ between single dose recipients and those receiving two to four consecutive annual doses.

Subsequently, Fleming et al compared LAIV to TIV in over 2,000 children and adolescents with a clinical diagnosis of asthma.21 In this 2002-2003 study, not only was LAIV well tolerated, but it was shown to have higher relative efficacy versus TIV with matched strains (34.7%) as well as any strain (31.9%). Similar to Redding's findings, there was no significant difference between LAIV and TIV groups in the incidence of asthma exacerbations post-vaccination.

IV.10 Adverse Events in Adults 18 to 59 years of age

Twelve placebo controlled studies and three TIV controlled studies including over 3,300 adults ≥18 to 59 years of age were pooled to evaluate solicited events.1 Table 5 summarizes solicited events and rates occurring in at least 1% of LAIV recipients. In these studies, solicited events were documented for six days post vaccination. The solicited AEs observed during days 0-6 post-dose were runny/stuffy nose, headache, sore throat (note, the incidence of sore throat was higher in adults than in children), malaise, muscle ache, cough, chills, fever, decreased appetite, abdominal pain/stomach ache, and vomiting.

Table 5: Summary of solicited events observed during days 0 to 6 after dose for LAIV and either placebo or TIV control recipients; Adults 18 to 59 years of age.1
Solicited Event Placebo Controlled Studies TIV Controlled Studies
LAIV
N=64 - 3,265a %
Placebo
N=65 - 1,711a %
LAIV
N=10 - 80a %
Injectable Influenza Vaccine
N=11 - 77a %
Any solicited event 69.1 58.9 62.5 58.4
Runny/stuffy nose 43.6 26.2 40.0 33.8
Headache 37.5 34.5 25.0 36.4
Sore throat 24.7 15.2 15.0 11.7
Malaiseb 23.8 19.3 11.4 20.5
Muscle ache 15.4 13.7 16.3 18.2
Cough 13.1 10.2 18.8 14.3
Chills 7.7 5.6 6.3 6.5
Decreased appetite 5.8 8.9 2.3 9.1
Abdominal pain/stomach ache 4.7 6.2 0.0 9.1
Vomiting 3.5 3.8 2.3 2.3
Fever
≥38.0°C 0.9 1.2 2.5 0.0
≥38.5°C 0.2 0.4 1.3 0.0
≥39.0°C 0.1 0.0 1.3 0.0
a Number of subjects evaluated for the specific solicited event. Range reflects differences in data collection between the pooled studies, which have different sample sizes.
b Collected as decreased activity/tiredness/weakness/malaise

IV.10.1 Serious Adverse Events (Adults 18 to 59 years of age)

In the pooled safety analysis for individuals 18 to 59 years of age, 0.18% (8/4,376) of individuals exposed to LAIV reported at least one SAE during days 0-28 post-dose. Two gastroenteritis events were reported; all other events occurred in one individual each. In placebo controlled studies, 0.18% (6/3,315) of individuals who received LAIV and 0.29% (5/1,740) of individuals who received placebo reported at least one SAE during days 0-28 post-dose.1

There were two deaths reported within 180 days of receipt of LAIV: one due to homicide and one due to drowning. In addition, four subjects died within 180 days of receipt of concurrent LAIV and injectable influenza vaccine in a study that enrolled subjects with stable COPD65; two due to COPD; one due to a gastrointestinal hemorrhage; and one due to an acute myocardial infarction. None of these deaths were considered to be related to LAIV.

IV.11 Special populations

IV.11.1 Adults ≥60 years of age

The use of LAIV in adults ≥60 years of age does not have regulatory approval in Canada; however data on use of LAIV in this population is published and are included in this statement because they provide some information regarding adults with chronic conditions.

Forrest et al directly compared the safety and efficacy of LAIV versus TIV in over 3,000 adults ≥60 years of age in South Africa in 2002. Over 90% of participants reported underlying medical conditions, including cardiovascular disease (64%), endocrine/metabolic disease (36%), and respiratory conditions (18%). The relative efficacy for LAIV versus TIV was -49% (95% CI: -259,35).66 Results for this study should be interpreted with caution since there was low incidence of influenza during that season in South Africa, however individuals with breakthrough illness showed less feverishness and less fever in LAIV recipients than in TIV recipients.

An earlier (2001) placebo controlled randomized study by De Villiers et al, also conducted in South Africa, investigated the absolute efficacy, safety and immunogenicity of LAIV in 3,242 adults ≥60 years of age.67 Many of the participants had chronic underlying conditions (hypertension, cardiac disease, diabetes, hypothyroidism, asthma and COPD). Reactogenicity events were higher in LAIV than placebo recipients during 11 days post-vaccination (p=.042), including runny nose/nasal congestion, cough, sore throat, headache, muscle aches, tiredness, and decreased appetite. However, this was the first study in this age group to demonstrate efficacy of LAIV against culture-confirmed influenza. Overall efficacy against well matched strains was 42.3% (95% CI: 21.6,57.8). Post-hoc analysis in subjects 60 to <70 years of age was 41.8% and -22.7% against A/H3N2 and B, respectively and 65.7% and 9.9% respectively for subjects ≥70 years.

In 2008-2009, Gorse et al 65 studied 2,215 veterans ≥50 years of age with COPD and found the relative efficacy of TIV + LAIV compared with TIV + placebo in the prevention of laboratory-documented influenza illness was 16%, with confidence intervals overlapping zero (95% CI: −22,43) for any influenza strain. Although this study did not show efficacy of LAIV against laboratory-confirmed influenza, recipients who were administered both TIV and LAIV had improved chronic lung disease severity index scores.

The efficacy of LAIV administered simultaneously with TIV has also been studied in older adults.68 Treanor et al randomized 523 residents of a nursing home to receive TIV + intranasal placebo versus TIV + monovalent A/H3N2 LAIV over three years (1987-1989). Relative protective efficacy of TIV + LAIV versus TIV+placebo recipients against laboratory-confirmed influenza A was 61% (95% CI: 18,82). In 1997, Jackson et al also conducted a study involving co-administration of TIV with either LAIV or placebo to 200 individuals aged 65 years and older to assess the safety and tolerability of LAIV in individuals with at least one additional risk factor for influenza morbidity (chronic cardiovascular or pulmonary conditions or diabetes mellitus). The safety and tolerability of LAIV plus TIV following vaccination was similar to that of placebo plus TIV with the exception of a higher incidence of sore throat, which is a similar finding in studies with younger adults.69 No other reactogenicity symptom was statistically associated with receipt of LAIV. These studies demonstrate that there may be additional protective benefits against influenza A when LAIV is combined with TIV in the elderly. These findings, though relatively small sample size, demonstrate the need for further research with LAIV in this age group.

IV.11.2 Individuals with chronic health conditions

There are very limited data available on the use of LAIV in children and young adults with underlying chronic medical conditions. Although safety in children two years of age and older with mild to moderate asthma has been established, data in children with other pulmonary diseases or with chronic cardiovascular, metabolic or renal diseases are limited.

A post-marketing evaluation was conducted by Tennis et al 70 on the frequency of use and safety of LAIV in children for whom the vaccine was not recommended, as defined by the Advisory Committee on Immunization Practices in children under 24 months of age, or children with asthma, recurrent wheezing or altered immune competence. Data was obtained from a health insurance database on vaccinations between 2007 to 2009. Reports of LAIV vaccination in children <24 months of age or children 24-59 months with asthma or immune compromising conditions were infrequent. However, LAIV immunization in children aged 24-59 months with wheezing occurred at a similar frequency as in the populations of children recommended for the vaccine. No safety signals were identified. The number of children vaccinated was insufficient to detect rare events.

In the studies outlined above in adults with chronic underlying medical conditions, the safety profile of LAIV was similar to the safety profile in individuals without these conditions. The absolute or relative efficacy of LAIV in older adults with chronic conditions, as in the healthy adult population, remains questionable.

IV.12 Contraindications and Precautions

IV.12.1 Contraindications

Children <2 years of age
Do not administer LAIV to children <24 months of age due to increased risk of wheezing (see Section IV.9.3).

Hypersensitivity
LAIV should not be administered to anyone with a history of anaphylaxis to a previous dose of the vaccine or have a history of hypersensitivity (especially anaphylactic reactions) to any of the non-medicinal ingredients contained in the vaccine (see Section IV.1)

Use of Aspirin with LAIV
LAIV is also contraindicated in children and adolescents (2 to 17 years of age) currently receiving aspirin therapy or aspirin-containing therapy because of the association of Reye's syndrome with aspirin and wild-type influenza infection.

Pregnancy
LAIV should not be administered to pregnant women because of the lack of safety data at this time. However, no unexpected patterns of pregnancy complications or fetal outcomes have been identified after the inadvertent administration of LAIV to pregnant women. A 19-year (1990-2009) review of the US Vaccine Adverse Event Reporting System (VAERS) was completed by Moro et al examining the reported incidence of adverse events after receipt of TIV and LAIV in pregnant women.71 From July 1, 2003 through June 30, 2009 VAERS received 27 reports of pregnant women who inadvertently received LAIV. No AEs were noted in 16 of the 27 reports. Seven reports were systemic/generalized reactions, three were spontaneous abortions, and one was a serious event with a threatened abortion. Since causality cannot be determined in passive surveillance systems such as VAERS, data should be interpreted with caution. The effect of LAIV on embryo-fetal and pre-weaning development was evaluated in developmental toxicity studies of pregnant rats and pregnant ferrets showing no observed adverse effects on pregnancy, parturition, lactation or embryo-fetal development.2 No adverse effects on pre-weaning development were observed in the rat study and no fetal malformations or other evidence of teratogenesis were observed. Until additional safety data on the use of LAIV in pregnant women become available it should not be administered to these individuals.

It is not known whether LAIV is excreted in human milk; however LAIV is not contraindicated in breastfeeding women.

Asthma
LAIV should not be administered to individuals with severe asthma (as defined as currently on oral or high dose inhaled glucocorticosteriods or active wheezing) and those with medically attended wheezing in the seven days prior to vaccination. Based on the trial results, LAIV can be considered safe and efficacious in stable asthmatics.

Immune Compromising Conditions
Live vaccines have generally been contraindicated in people with immune compromising conditions, with some exceptions. LAIV is not recommended for individuals with immune compromising conditions since data supporting the safety and efficacy of LAIV in people who are immune compromised are limited. The available data in individuals with immune compromising conditions are detailed below. Studies include evaluation in patients with HIV and a small cohort of children with cancer.

Safety of LAIV was first evaluated in 57 HIV+ and 54 HIV- adults 18 to 58 years of age in a randomized, double-blind, placebo controlled study.72 HIV infected participants were to have a CDC class of A1-2 and a plasma HIV RNA polymerase chain reaction (PCR) measurement of <10,000 copies/mL and 1200 CD4 cells/mm3 within 3 months prior to vaccination and were to be on a stable antiretroviral regimen if they had <500 CD4 cells/mm3. In this study, there were no serious adverse events attributable to LAIV, and vaccine shedding in HIV+ individuals was comparable to that seen in healthy populations. No adverse effects on HIV viral load or CD4 counts were identified following LAIV administration. King et al also assessed the safety of LAIV to 59 relatively asymptomatic or mildly symptomatic HIV+ children and HIV- children.73 There were no significant differences found in rates of reactogenicity and vaccine-related adverse events after placebo or LAIV within each group. There were no significant changes in geometric mean HIV RNA concentrations, CD4 counts or CD4% or prolonged or increased quantity of LAIV virus shedding.

Subsequently Levin et al 74 assessed the comparative safety and antibody responses in 243 HIV+ children ≥5 to <18 years of age receiving stable antiretroviral therapy. Participants were stratified by immunologic status and randomly assigned to receive LAIV or TIV. The safety profile after LAIV or TIV closely resembled the previously reported tolerability to these vaccines in children without HIV infection. Post-vaccination HAI antibody responses and shedding of LAIV virus were also similar, regardless of immunological stratum, to children without HIV infection.

The effectiveness of LAIV in preventing influenza-like illness in HIV+ individuals has not been evaluated.2

Halasa et al conducted a multicentre, randomized, double-blind study of LAIV versus placebo in children 5 to 17 years of age with cancer to assess reactogenicity, adverse events, immunogenicity, and shedding in 20 subjects (n=10 LAIV, 10 placebo).75 Ten of these subjects had hematologic malignancy (LAIV, n=4, placebo n=6); ten had solid tumors (LAIV, n=6; placebo, n=4). LAIV resulted in an increased incidence of runny nose/nasal congestion occurring in all LAIV recipients; no related SAEs were observed. Four of ten LAIV recipients shed vaccine virus, with none exceeding 7-10 days duration. LAIV demonstrated modest immunogenicity by HAI (≥4 fold rise for any strain, 33%) and microneutralization assays ((≥4 fold rise for any strain, 44%).

IV.12.2 Precautions

Egg Allergy/hypersensitivity
Given the lack of data around egg allergy and the intranasal vaccine LAIV, TIV is the currently recommended product for egg-allergic individuals. Ovalbumin concentrations in LAIV are documented to be very low and a study is currently underway to assess the use of LAIV in egg-allergic individuals. The use of LAIV in egg-allergic individuals will be reevaluated when further data becomes available. If LAIV is the only option that will be considered by an egg-allergic individual, consultation with a specialist with expertise in allergies should be sought.

Neurologic
It is not known whether influenza vaccination is causally associated with increased risk of recurrent Guillain-Barré Syndrome (GBS) in persons with a previous history of GBS due to any cause. Avoiding subsequent influenza vaccination of persons known to have had GBS within eight weeks of a previous influenza vaccination appears prudent at this time.

Drug Interactions
Although no data exists on Reye's syndrome and LAIV, because of a theoretical risk, it is recommended that aspirin-containing medications given to children younger than 18 years be delayed for four weeks after vaccination with LAIV. For children or adolescents <18 years of age who are receiving ongoing aspirin therapy or aspirin-containing therapy, vaccination with TIV should be considered instead of using LAIV.

It is also recommended that LAIV not be administered until 48 hours after antiviral agents active against influenza (e.g. oseltamivir and zanamivir) are stopped, and that antiviral agents not be administered until two weeks after receipt of LAIV unless medically indicated. If antiviral agents are administered within this time frame (from 48 hours before to two weeks after LAIV) revaccination should take place at least 48 hours after the antivirals are stopped.76

Nasal congestion & Illness
Persons with serious acute febrile illness should usually not be vaccinated until their symptoms have abated. Those with non-serious febrile illness (such as mild upper respiratory tract infections) may be given influenza vaccine. However, if nasal congestion is present that might impede delivery of the vaccine to the nasopharyngeal mucosa, deferral of administration should be considered until resolution of the illness, or TIV should be considered instead.

No data exist about concomitant use of nasal corticosteroids or other intranasal medications.

Health Care Workers or others providing care to persons with severe immune compromising conditions
TIV should be used for health care workers providing care to those with immune compromising conditions, unless LAIV is the only product the health care worker will accept. If a health care worker, or another caregiver, receives LAIV and is providing care to individuals with severe immune compromising conditions (hospitalized and receiving care in a protected environment), they should wait two weeks following receipt of LAIV before continuing to provide care to such individuals.

IV.12.3 Other considerations

Shedding/transmission
There is an inversely proportional relationship observed between age and incidence of shedding vaccine virus. 77-79 Although both children and adults may shed vaccine virus when vaccinated with LAIV,72-74 78-81 younger individuals are more likely to shed and shed higher titers than older individuals. The frequency of shedding decreases with age, with 69%, 44%, 27%, and 17% of individuals 2-4 years, 5-8 years, 9-17 years, and 18-49 years of age shedding virus following vaccination.77,78 Shedding is rare after day 11 following vaccination, although children may shed for a mean duration of 7.6 days. 80

Peak titers of viral shedding occur around the second day post-vaccination, but in lower amounts than would occur with infection by wild-type influenza virus. Talbot et al showed that viral titers ranged from 0.4 to 3.0 TCID/mL (tissue culture infective dose) in adults in the respiratory tract, while the mean titers of virus needed for infectivity range from 4.9 to 6.4 TCID/mL in adults.79

Shedding is not synonymous with transmission; however in rare instances, shed vaccine viruses can be transmitted from vaccine recipients to unvaccinated persons. A study conducted in a Finnish daycare of 197 children 8 to 36 months of age resulted in one instance of transmission of a vaccine strain to a placebo recipient.80 Symptoms reported for this child were similar to those reported in the treatment group and included runny nose/nasal congestion, irritability, and cough. Statistical modeling estimated the probability of transmission to a subject in a contact group containing a single subject vaccinated with LAIV to be 0.58% (95% CI: 0,1.7). For subjects in contact with two, three, four, or five subjects vaccinated with LAIV, the probability of transmission was estimated to be 1.16%, 1.73%, 2.30% or 2.87% respectively. Serious illness has not been reported among unvaccinated persons who have been infected inadvertently with vaccine viruses.

Although no transmission of LAIV in a health care setting has ever been reported, vaccine recipients should be informed that LAIV is an attenuated live virus vaccine and has the theoretical potential for transmission to immune compromised contacts. Because the vaccine is cold-adapted, cannot replicate at normal body temperature, and fairly low viral titers are shed, the risk of transmitting the vaccine virus to a severely immune compromised person and causing severe infection appears to be extremely low. However, due to the theoretical risk of transmission, health care providers and other close contacts of severely immune compromised hospitalized patients requiring care in a protected environment should avoid contact with these patients for at least two weeks following vaccination.