ARCHIVED - Canada Communicable Disease Report
November 2011
An Advisory 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
Table 10: Summary of Evidence for NACI Recommendation(s)
- Evidence related to efficacy of FluMist®
- Evidence related to effectiveness of FluMist®
- Evidence related to immunogenicity of FluMist®
- Evidence related to safety of FluMist®
STUDY DETAILS | SUMMARY | |||||
---|---|---|---|---|---|---|
Study | Vaccine | Study Design |
Participants | Summary of Key Findings Using Text or Data |
Level of Evidence | Quality |
Children | ||||||
Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. N Engl J Med. 1998;338(20):1405-12.5 |
LAIV 0.25mL per nostril (106.7 TCID) Vaccine and circulating strains well-matched |
RCT, AV006 Year 1 1996/97 USA |
N=1602 (pp) Both groups received 1 (n=288) or 2 doses (n=1314); second dose 60d ± 14d apart Healthy children |
Primary endpoint: Incidence of CCI (≥28 days after receipt of first dose or any time after second dose) caused by matched strains. Vaccine Efficacy: Efficacy in reducing febrile illness: 21% (11, 30) |
Level I |
Fair Participants |
Belshe RB, Gruber WC, Mendelman PM, et al. Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine. J Pediatr. 2000;136(2):168-75.6 |
LAIV 0.25mL per nostril (107.0 TCID50 per strain) Single dose Vaccine and circulating strains not well-matched (A/H3N2/Sydney not contained in vaccine) |
RCT, AV006 Year 2 1997/98 |
N=1358 Both groups received 1 dose of vaccine or placebo, based on assignment in year 1 Healthy children |
Primary endpoint: First episode of CCI after receipt of revaccination (Year 2 of multi-year study by Belshe et al) Vaccine Efficacy (Year 2): Efficacy against A/H3N2 (Sydney/5/97-like) not contained in vaccine: 86% (75, 92) Vaccine Efficacy (Years 1 and 2 combined): |
Level I |
Good |
Tam JS, Capeding MR, Lum LC, et al. Efficacy and safety of a live attenuated, cold-adapted influenza vaccine, trivalent against culture-confirmed influenza in young children in Asia. Pediatr Infect Dis J. 2007;26(7):619-28.7 |
CAIV-T 0.1mL per nostril Year 1: B-component of vaccine was not well matched in either year. |
RCT, double-blind, placebo controlled, multicentre 2000/01 & 2001/02 16 sites, Asia NCT00192244 |
Year 1 Both groups received 2 doses Year 2 (re-randomized) Healthy children aged 12 to <36 months |
Primary endpoint: CCI caused by matched strains after 2nd dose Year 1 Year 2 Vaccine Efficacy (any strains): Revaccination in second year has greater efficacy than only vaccinating in first year |
Level I |
Good |
Vesikari T, Fleming DM, Aristegui JF, et al. Safety, efficacy, and effectiveness of cold-adapted influenza vaccine-trivalent against community-acquired, culture-confirmed influenza in young children attending day care. Pediatrics. 2006;118(6):2298-312.8 |
CAIV-T 0.1mL per nostril (107 TCID) Vaccine and circulating strains well-matched (H3N2/A substituted in Year 2) |
RCT, 2000-01 & 2001/02 Belgium, Finland, Israel, Spain, UK NCT00192283 |
Year 1 2 doses with second dose 35d ± 7d apart Year 2 (one dose) 1 dose based on assignment in year 1 Healthy children aged 6 to <36 months attending day care ≥12hours/week |
Primary endpoint: CCI caused by matched strains (year 1) Year 1 Year 2 Efficacy against AOM associated with CCI |
Level I |
Good |
Bracco Neto H, Farhat CK, Tregnaghi MW, et al. Efficacy and safety of 1 and 2 doses of live attenuated influenza vaccine in vaccine-naive children. Pediatr Infect Dis J. 2009;28(5):365-71.11 |
LAIV 0.1mL per nostril 2 doses in Year 1, single dose in Year 2 Vaccine and circulating strains well-matched |
RCT, double-blind, placebo controlled, 2001 and 2002 influenza seasons South Africa, Brazil, Argentina NCT00192283 |
Year 1 Year 2 (one dose) Healthy influenza vaccine-naïve children aged 6 to <36 months |
Primary endpoint: CCI caused by subtype antigenically similar to vaccine (year 1) Secondary endpoints: CCI caused by subtype antigenically similar to vaccine (year 2) and CCI caused by any subtype (both years); efficacy against AOM Year 1 vaccine efficacy (similar subtype): LAIV-LAIV vs LAIV/Placebo:37.3% (9.5, 56.9) Year 1 efficacy against any subtype: Year 2 vaccine efficacy (similar subtype): Efficacy against AOM associated with CCI |
Level I |
Good Error in treatment allocation coding and labelling in |
Lum LC, Borja-Tabora CF, Breiman RF, et al. Influenza vaccine concurrently administered with a combination measles, mumps, and rubella vaccine to young children. Vaccine. 2010;28(6):1566-74.12 |
LAIV 0.1mL per nostril (107 TCID50 ) 2 doses 35±7 days apart Vaccine and circulating A/H3N2 not well matched |
Phase III RCT, Non-inferiority trial Co-vaccine: MMR (Priorix®) 2002/03 season 13 countries (Europe/Asia) |
N=1150 Both groups received MMR with dose 1 Healthy vaccine-naïve children aged 11-<24 months |
Primary endpoint: CCI caused by subtype antigenically similar to vaccine ≥15 days after receipt of dose 2 of vaccine/placebo Secondary endpoints: CCI caused by any subtype ≥15 days after receipt of dose 2 of vaccine or placebo, efficacy against AOM Overall vaccine efficacy (similar subtype): Strain-specific efficacy LAIV efficacy was not adversely affected by the concomitant administration with MMR Protection against AOM could not be measured due to low incidence of influenza-associated AOM. |
Level I |
Good |
Relative Efficacy (Children) | ||||||
Ashkenazi S, Vertruyen A, Aristegui J, et al. Superior relative efficacy of live attenuated influenza vaccine compared with inactivated influenza vaccine in young children with recurrent respiratory tract infections. Pediatr Infect Dis J. 2006;25(10):870-9.20 |
CAIV-T 0.1mL per nostril (107 TCID50 ) |
RCT, Control vaccine: TIV, 0.25mL/dose or 0.50mL/dose based on participant age 2002/03 Europe, Israel NCT00192205 |
N = 2085 2 doses: 35d ± 7d apart Vaccine naïve children 6 to 71 months, 45% of sample had history of recurrent respiratory tract infections (≥2 RTIs in past 12 months or since birth) |
Primary endpoint: CCI caused by subtype antigenically similar to vaccines Secondary endpoints: CCI caused by any subtype, incidence of AOM, incidence of RTI Overall relative efficacy for CAIV-T (similar subtype): Similar results seen for efficacy against any subtype. Relative to TIV, CAIV-T reduced the number of RTI healthcare visits by 8.9% (90% CI: 1.5, 15.8); missed days of school by 16.2% (90% CI: 10.4, 21.6) Few reports of influenza-associated AOM reported; no significant difference between groups for all AOM episodes |
Level I |
Good |
Fleming DM, Crovari P, Wahn U, et al. Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma. Pediatr Infect Dis J. 2006;25(10):860-9.21 |
CAIV-T 0.1mL per nostril (107 TCID50 per strain) Single dose |
RCT, Control vaccine: 2002/03 season Europe NCT:00192257 |
N = 2220 Children with asthma (not all influenza vaccine-naïve children) ≥6 years to ≤17 years of age |
Primary endpoint: CCI >14 days after vaccination caused by matched strains Overall relative efficacy for CAIV-T (matched): Overall relative efficacy for CAIV-T (any subtype): |
Level I |
Good |
Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med. 2007;356(7):685-96.19 |
CAIV-T 0.1mL per nostril (107 TCID50 ) Vaccine and circulating A/H3N2 not well matched |
RCT, Control vaccine: 2004/05 season 249 sites in 16 countries (US, Europe/Middle East, Asia) NCT00128167 |
N=7852 1 or 2 doses for both groups. Second dose given to vaccine-naive children 28-42 days after first dose Children aged ≥6-≤59 months, both groups included some children with underlying medical conditions (5.7% of total) mild/moderate asthma (4%) or a history of recurrent (6%) or any wheezing(21%). Exclusions: wheezing within 42 days of study |
Primary endpoint: efficacy of CAIV-T versus TIV in preventing CCI illness (oral temperature of 37.8°C or higher or equivalent in presence of cough, sore throat, running nose/nasal congestion occurring on the same or consecutive days) caused by well-matched strains. Secondary endpoints: efficacy of CAIV-T versus TIV in preventing CCI by mismatched and all flu viruses; any CCI symptom due to matched or mismatched strains, AOM, LRI Relative efficacy for CAIV-T (well-matched): Relative efficacy for CAIV-T (not well matched): Overall relative efficacy for CAIV-T (regardless of match): Reductions in AOM regardless of match: 50.6% (21.5, 69.5) (data in Supplementary Appendix23) |
Level I |
Good |
Adults | ||||||
Nichol KL, Mendelman PM, Mallon KP, et al. Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial. JAMA. 1999;282(2):137-44.26 |
LAIV 0.25mL per nostril 1 dose A/H3N2 strains not well matched to vaccine. (A/Sydney/H3N2 predominantly circulating strain) |
Randomized double-blind placebo controlled trial, multi-centre AV009 1997-1998 influenza season, 13 centres in USA |
N=4,561 healthy working (≥30 hrs/week) adults aged 18-65 |
Primary endpoint: any febrile illness (AFI) during 14-wk outbreak period. Culture confirmation of influenza was not performed Outcomes during peak outbreak periods (LAIV vs placebo) Efficacy (reported in % reduction) for all illnesses combined: |
Level I |
Good |
Relative Efficacy (Adults) | ||||||
Edwards KM, Dupont WD, Westrich MK, et al. A randomized controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease. J Infect Dis. 1994;169(1):68-76.27 |
LAIV 0.5mL per nostril (0.25mL per strain; 107 -107.6 pfu/mL) Children <3 received same volume with 1/10 dilution Bivalent for A strains only throughout study Single dose per strain Nasal drops delivery |
RCT, Control vaccine: TIV (15μg HA per strain), Year 1 vaccine 1985/86 to 1988-89 seasons 7 sites, Nashville, Tennessee. USA |
N=5210 GroupTIV 1 Persons aged 1-65 years (n<15 years =809) |
Primary endpoint: culture-positive illness and seroconversion. Strain-specific efficacy (1986/1988 combined): Strain-specific efficacy (1987/1989 combined): LAIV demonstrated protection against natural influenza A infection among children and adults that was approximately equivalent to that of TIV. |
Level I |
Good |
Treanor JJ, Kotloff K, Betts RF, et al. Evaluation of trivalent, live, cold-adapted (CAIV-T) and inactivated (TIV) influenza vaccines in prevention of virus infection and illness following challenge of adults with wild-type influenza A (H1N1), A (H3N2), and B viruses. Vaccine. 1999;18(9-10):899-906.30 |
CAIV-T 0.25mL per nostril (107 TCID50 per strain) |
RCT, active and placebo controlled double-blind wild type challenge study Control vaccine: 1995/96 season AV003 2 sites, USA |
N=92 Groups challenged with 1 strain of virus 28 days after vaccination Healthy adult volunteers aged 18-40 years who were serosusceptible (HAI ≤1:8) to at least 1 of 3 strains |
Primary endpoint: lab documented influenza Secondary endpoints: viral shedding on 1+ days following challenge and/or 4-fold+ increase in serum HAI antibody titer between pre/post challenge; 1+ respiratory symptoms %response (Serum)(CAIV-T;TIV;placebo) A/H1N1 (23%; 91%; 16%) A/H3N2 (33%; 76%; 6%) B (3%, 76%, 0%) % response (Nasal) (CAIV-T;TIV;placebo) A/H1N1 (14.3%; 23.3%; 12.9) A/H3N2 (32.1%; 16.7%; 9.7%) B (17.9%; 16.7%; 3.2%) Both FluMist and TIV demonstrated statistically significant efficacy against lab-documented illness compared to placebo TIV vs CAIV-T ; 71% ((p=0.006) vs 85% (P=0.001). No comparison of efficacy between TIV/CAIV-T conducted. |
Level I |
Good Limited |
Monto AS, Ohmit SE, Petrie JG, et al. Comparative efficacy of inactivated and live attenuated influenza vaccines. N Engl J Med. 2009;361(13):1260-7.28 |
LAIV 0.1mL per nostril (106.5 -107.6 FFU per strain) Single dose H3N2 predominant strain (90%) |
RCT, double-blind, active and placebo controlled, community-based Control vaccine: 2007/08 season NCT 00538512 Michigan, USA |
N=1952 Healthy adults aged 18-49 years |
Primary endpoint: a case of symptomatic illness that was confirmed as influenza A or B by either isolation by cell culture or PCR assay. Absolute efficacy for both strains (A/H3N2 and B) by positive culture, PCR, or both: Relative efficacy of TIV compared to LAIV: Absolute efficacy for A/H3N2 strain: Relative efficacy of TIV compared to LAIV: |
Level I |
Good |
Ohmit S, Victor J, Rotthoff J, et al. Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. N Engl J Med. 2006;355(24):2513-22.31 |
LAIV 0.25mL per nostril (106.5 -107.6 TCID50 per strain) Single dose A/H3N2 strains not well matched to vaccine, two lineages of type B were circulating (one in vaccine) |
RCT, double-blind, active and placebo controlled, community-based Control vaccine: 2004/05 season NCT: 00133523 4 sites, Michigan, USA Year 1 of 2 |
N=1247 nTIV = 522 Healthy adults aged 18-46 years (mean age 24.9) |
Primary endpoint: a case of symptomatic illness that was confirmed as influenza A or B by either isolation by cell culture or rise in antibody titer ≥4 times against circulating strain or HI serology Efficacy for all strains (95% CI): % relative reduction of LAIV vs placebo: % relative reduction of LAIV vs TIV: Difference in efficacy of LAIV not statistically significant and attributable primarily to a difference in efficacy against influenza B. |
Level I |
Good |
Ohmit S, Victor J, Teich E, et al. Prevention of symptomatic seasonal influenza in 2005-2006 by inactivated and live attenuated vaccines. J Infect Dis. 2008;198(3):312-7.32 |
LAIV 0.25mL per nostril (106.5 -107.6 TCID50 per strain) Single dose A/H3N2 similar to vaccine |
RCT, double-blind, active and placebo controlled, community-based Control vaccine: 2005/06 season NCT:00133523 6 sites, Michigan, USA Year 2 of 2 |
N=2058 (participants assigned to same group as in year 1, additional subjects enrolled) Healthy adults aged 18-48 years |
Primary endpoint: a case of symptomatic illness that was confirmed as influenza A or B by either isolation by cell culture or rise in antibody titer ≥4 times against circulating strain or HI serology. Secondary endpoints: illness confirmed by virus identification on PCR Efficacy for all strains (95% CI): % relative reduction of LAIV vs placebo: % relative reduction of LAIV vs TIV: Efficacy of live attenuated vaccine was slightly less than that of TIV but not statistically greater than that of placebo. Identified no significant difference in vaccine efficacy |
Level I |
Good Lower than expected attack rate, low power |
Wang Z, Tobler S, Roayaei J, et al. Live attenuated or inactivated influenza vaccines and medical encounters for respiratory illnesses among US military personnel. JAMA. 2009;301(9):945-53.29 |
LAIV Single dose |
Population-based, active control, retrospective, observational Control vaccine: 2004/05 to 2006/07 seasons |
2004/05 2005/06 2006/07 *includes personnel unimmunized in current & previous years Military personnel |
Primary endpoint: Incidence of health care encounters for pneumonia or influenza illness. Incidence (IR/1000 person-years) (TIV; LAIV; unimmunized): Health care encounters 2004/05 (8.6%; 18.3%; 19.4%) 2005/06 (7.8%; 10.6%; 10.9%) 2006/07 (8.0%; 11.1%; 11.7%) Pneumonia/hospitalization: 2004/05 (.38%; .90%; .46%) 2005/06 (.28%; .56%; .38%) 2006/07 (.29%; .48%; .38%) In all 3 seasons, TIV was associated with lower rates of health care encounters for pneumonia and influenza when compared to no immunization Effect of vaccination in vaccine groups (propensity matched) (95% CI) Effect of vaccination in vaccine-naïve cohorts (propensity-matched) (unimmunized in last year or last 2 years) (95% CI) Pre-existing vaccine immunity may play a role in determining effectiveness of LAIV (also see Bernstein, Lee, Block) |
Level II-2 |
Fair Could not control for some confounding variables, use of |
Adults aged 60+ | ||||||
De Villiers PJ, Steele AD, Hiemstra LA, et al. Efficacy and safety of a live attenuated influenza vaccine in adults 60 years of age and older. Vaccine. 2009;28(1):228-34.67 |
LAIV 0.2mL B strains not well matched to vaccine (production issues) Low incidence of influenza this season |
Randomized, prospective, double-blind, placebo controlled, multicentre NCT00217230 2001 31 sites in South Africa |
N=3,136 Healthy adults ≥60 years (median age 69) Sera obtained pre-vaccination, 35±7 days post-vaccination, at study completion |
Primary endpoint: efficacy of LAIV against CCI (≥15 days post-vaccination) caused by subtypes antigenically matched to vaccine. Secondary endpoint: efficacy against CCI caused by all subtypes; efficacy against ILI/pneumonia/mortality without culture confirmation. Efficacy against CCI to matched strains (95% CI): Efficacy against CCI to all strains (95% CI): Protective efficacy of LAIV (95% CI): Post-hoc analysis: Efficacy in subjects 60-<70 years of age |
Level I |
Good |
Treanor JJ, Mattison HR, Dumyati G, et al. Protective efficacy of combined live intranasal and inactivated influenza A virus vaccines in the elderly. Ann Intern Med. 1992;117(8):625-33.68 |
LAIV 0.25mL per nostril (107.2 TCID50 per strain) A/H3N2 strains only Intranasal drops |
RCT, double-blind, active and placebo controlled, multi-centre Control vaccine: 1987-88, 1988-89 seasons 3 large nursing homes in NY |
N=523 TIV + placebo Participants received TIV and were re-randomized for placebo or LAIV each year Elderly - 95% >65 years, 75% female |
Participants were given monovalent intranasal influenza A/H3N2 vaccine + TIV vs placebo + TIV Protective Efficacy (95% CI) Respiratory Illness (outbreak-associated) ILI (outbreak-associated) |
Level I |
Good |
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