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 Aviron, Mountain View, CA, USA 0.25mL per nostril (106.7 TCID50 per strain) 2 dose, 60±14 days apart Vaccine and circulating strains well-matched	RCT, double-blind, placebo controlled, multicentre, AV006 Year 1 1996/97 Influenza season	N=1602 nLAIV= 1070 nplacebo= 532 Both groups received 1 or 2 doses; second dose 60d ±14d apart Healthy children ≥ 15-71 months	After 1st dose (LAIV vs placebo): Rhinorrhea (Days 2,3,8,9) (27% vs 18%, p=0.001) (30% vs 20%, p<0.001) (30% vs 22%, p=0.01) (29% vs 21%, p=0.02) respectively Fever (Day 2) (mean duration 1.4 days, low grade)(6.5% vs 1.6%, p<0.001) Decreased activity (Day 2) (6.0% vs 2.1%, p=0.008) No significant differences in other symptoms (cough, headache, sore throat, irritability, chills, vomiting, muscle aches). No significant differences in any variable after 2nd dose in year 1. No SAE attributed to vaccine	Level I	Fair Participants not randomized into 1 or 2 dose groups, and equivalency between 1 and 2 dose was not established
Belshe RB, Gruber WC, Mendelman PM, et al. Correlates of immune protection induced by live, attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine. J Infect Dis. 2000;181(3):1133-7 (39).	Intranasal trivalent live, attenuate, cold-adapted influenza vaccine Dosage not reported (107 TCID50 per strain) Single dose	RCT, double-blind, placebo controlled, multicentre Year 2 Challenge study (A/H1N1) 1997/98 influenza season	N=222 nLAIV=144 nplacebo=78 5-71 months old Children from year 1 of trial, (healthy and 34-91 months at Year 1 recruitment)	Primary endpoint: shedding of vaccine virus in respiratory secretions on days 1-4, ORP (overall rate of protection) Shedding of vaccine vs. placebo: 4.2% vs. 24.4% ORP 83% (95%CI, 60% to 93%) No serious adverse events occurred No significant differences in occurrence of runny nose, nasal congestion or fever between vaccine and placebo groups	Level I	Good
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 Aviron, Mountain View, CA, USA 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, double-blind, placebo controlled, multicentre AV006 Year 2 997/98 influenza season	N=1358 nLAIV = 917 nplacebo =441 Both groups received 1 dose of vaccine or placebo, based on assignment in year 1 Healthy children 26-85 months from year 1 of trial (85% return rate)	No significant differences in rhinorrhea (LAIV 19% vs placebo 14%), fever (LAIV: 2.0% vs placebo:1.8%) or decreased activity were present in year 2 revaccination.	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 FluMist® 0.1mL per nostril (107 TCID50)	RCT, prospective, double-blind, active controlled, multi-centre Control vaccine: TIV Fluzone® (US/Asia) Vaxigrip® (Europe/Middle East), 0.25mL or 0.5mL/dose based on age 2004/05 season 249 sites in 16 countries (US, Europe/Middle East, Asia) NCT00128167 MI-CPIII	N=8352 nTIV=4173 nCAIV-T=4179 1 or 2 doses for both groups. Second dose given to vaccine-naive children 28-42 days after first dose Placebo saline injection or intranasal mist given concurrently with active intervention 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%)	Significant reactogenicity events (LAIV vs TIV) Fever on day 2 after 1st dose: 5.4% vs 2.0%, (p<0.001) Significant increases in MSW ≤42 days after Dose 1 (LAIV vs TIV, 95% CI) Vaccine-naïve children (6-59 mos) (2.3% vs 1.5%) (adjusted difference of 0.77%, 0.12, 1.46). Seen after weeks 2, 3, 4 Vaccine-naïve children (6-24 mos) (3.2% vs 2.0%) (adjusted difference of 1.18%, 0.13, 2.29) Vaccine-naïve children (6-12 mos) (3.8% vs 2.1%) (p=.08) Beyond 42 days, rates of MSW did not differ between groups. Rates of hospitalization for any cause within 180 days after vaccination (LAIV vs TIV): 6-59 mos: 3.1% vs 2.9% 12-59 mos: 2.5% vs 2.9% 6-11 mos: 6.1% vs 2.6% (95% CI, 1.4, 5.8) Trends were higher hospitalization for any cause among LAIV children aged 6 to 46 mos with hx of wheezing compared to same age TIV recipients with hx of wheezing (not significant). Children aged 12-59 mos with no hx wheezing, hospitalization for any cause lower in LAIV than TIV (p=0.07) SAEs: similar incidence between groups (136: LAIV & 128 TIV) 6 SAEs in LAIV (n=2 bronchiolitis, n=1 asthma exacerbation, n=1 wheezing, n=1 acute gastroenteritis, n=1 RAD) 5 SAEs in TIV (1 of each of pneumonia, wheezing, febrile convulsion, febrile convulsion and pneumonia, viral gastroenteritis). Two deaths in each group not related to study.	Level I	Good
Bergen R, Black S, Shinefield H, et al. Safety of cold-adapted live attenuated influenza vaccine in a large cohort of children and adolescents. Pediatr Infect Dis J. 2004;23(2):138-44 (60).	CAIV-T FluMist® 0.25mL per nostril (107TCID50 per strain) 1 or 2 doses, depending on age	Randomized, double-blind, placebo controlled AV019 2000 Excluded those who received TIV in 2000 or any live virus within 1 month of study or inactivated vaccine within 2 weeks.	N = 9,689 Children aged 1-8 years nTCAIV-T=3,769 nplacebo=1,868 Children aged 9-17 years nTCAIV-T=2,704 nplacebo=1,348 Healthy children aged 12 months to 17 years (2nd dose given 28 to 42 days after 1st dose)	None of the 4 prespecified diagnostic categories (acute respiratory tract events, systemic bacterial infections, acute gastrointestinal tract events, rare events) associated with vaccine. Healthcare utilization rates similar between groups. Signal detected in children 18 to 35 months within 42 days of vaccination Asthma/Reactive Airway Disease incidence: FluMist: 2.2% Placebo: 0.54% Relative Risk: 4.06 (90% CI: 1.29, 17.86) • 8.8% of CAIV participants in this age group had prior hx of asthma/RAD. No increased asthma risk found with CAIV-T. Statistically significant AEs URI (18-35 mos) (Relative Risk 1.30, 90%CI: 1.01, 1.67) Musculoskeletal pain, Otitis media with effusion, Adenitis/adenopathy potentially related but low incidence. No SAE deemed related to study in either group.	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-naïve children. Pediatr Infect Dis J. 2009;28(5):365-71 (11).	LAIV Wyeth Vaccines, Marietta, PA, USA 0.1mL per nostril (107±0.5FFU per strain) 2 doses in Year 1, single dose in Year 2 Vaccine and circulating strains well-matched	RCT, double-blind, placebo controlled, multi-centre 2001 and 2002 influenza seasons South Africa, Brazil, Argentina NCT00192283 D153-P502	Year 1 N=2821 Year 2 N = 2054 Healthy influenza vaccine-naïve children aged 6 to <36 months	Significant reactogenicity events within 11 days were cough and rhinorrhea. No statistically significant differences among treatment and placebo groups for AE (fever, upper respiratory tract infections, rhinitis, coughing) Year 2 only significant AE was bronchitis (3.1% LAIV and 1.6% placebo; p=0.046) SAEs in year 1 related to study (n=29), including pneumonia, bronchopneumonia, bronchiolitis and bronchitis. 3 deaths, not related to study.	Level I	Good Error in treatment allocation coding and labelling in Year 2 resulted in 2 additional treatment protocols
Nolan T, Lee MS, Cordova JM, et al. Safety and immunogenicity of a live-attenuated influenza vaccine blended and filled at two manufacturing facilities. Vaccine. 2003;21(11-12):1224-31 (42).	CAIV-T 0.25mL per nostril (107TCID50 per strain) Vaccine from different facilities (Medeva vs. Aviron-PA)	RCT, CAIV-T (Medeva) control, double-blind AV018 1997, off-season Australia	N=225 nMedeva=135 nAviron=90 Healthy children aged 12-42 months 2 doses given 4-6 weeks apart.	Only significant adverse event: Vomiting after dose 1: (3% (Aviron) vs 13% (Medeva), p=0.01)	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 Wyeth, Marietta, PA, USA 0.1mL per nostril (107 TCID50 per strain) Year 1: 2 doses ≥28 days apart Year 2: Single dose B-component of vaccine was not well matched in either year. (29.2% distinct in year 1, 77% in year 2)	RCT, double-blind, placebo controlled, multicentre 2000/01 & 2001/02 seasons 16 sites, Asia NCT00192244 D153-P501	Year 1 N=3174 nCAIV-T =1900 nplacebo =1274 Both groups received 2 doses Year 2 (re-randomized) N=2527 nCAIV-T/CAIV-T= 881 nCAIV-T/placebo = 876 nplacebo/CAIV-T= 596 nplacebo/placebo = 594 Healthy children aged 12 to <36 months	Significant reactogenicity events within 11 days (Year 1) 1st Dose (CAIV-T vs placebo) Fever ≥37.5ºC (22.0% vs 17.6%; p=0.004) Rhinorrhea (62.0% vs 52.0%; p<0.001) Decreased activity (13.4% vs 10.7%; p=0.026) Decreased appetite (24.2% vs 19.7%; p=0.003) Use of fever medication (21.3% vs 18.4%; p=0.044) (Year 1) 2nd dose: Rhinorrhea/Nasal congestion (49.8% vs 45.6%; p=0.030) Year 2: Rhinorrhea (62.0% vs 55.4%; p=0.019) AEs (year 1, dose 1) Fever (15.4% vs 11.7%; p=0.003) AEs (year 2) Fever (12.7% vs 9.8%; p=0.017) Year 1 cases of SAE Bronchospasm (7 vs 3) Bronchitis (3 vs 2) Rhinitis (3 vs 0) Fever x 3 days in 20 month old (1 vs 0) – withdrew 2 deaths, both unrelated Year 2 cases of SAE Pneumonia 6 days after vaccine (1 in CAIV-T group)	Level I	Good
Vesikari T, Karvonen A, Korhonen T, et al. A randomized, double-blind study of the safety, transmissibility and phenotypic and genotypic stability of cold-adapted influenza virus vaccine. Pediatr.Infect. Dis.J. 2006 July 2006; 25(7):590-595 (80).	LAIV 0.25 mL per nostril (107TCID50 per strain)	Prospective, randomized, double-blind, placebo controlled study NCT00192322 D153-P002 1999 Finland	N=197 NCAIV-T=98 nplacebo=99 Healthy children in daycare aged 9-36 months Second dose was offered 42 days after 1st	Nasal swab specimens collected on day 0, and on days 1,3 alternating weeks for 21 days. SAE (42 days after vaccination) Placebo: acute laryngitis CAIV-T: pyelonephritis, acute gastroenteritis. All unrelated to vaccine. Other (not statistically significant) adverse events among CAIV-T/placebo groups: Otitis media (12.2% vs 16.2%, p=0.54) Cough (8.2% vs 8.1%, p>0.99) Fever (7.1% vs 3.0%, p-0.21) Rhinitis (6.1% vs 8.1%, p-0.78) Viral shedding: 80% of vaccine recipients shed at least one virus strain.	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 (107TCID50 per strain) Vaccine and circulating strains well-matched (H3N2/A substituted in Year 2)	RCT, prospective, double-blind, placebo controlled, multicentre NCT00192283 D153-P502 2000-2001 & 2001-2002 influenza seasons Belgium, Finland, Israel, Spain, UK	Year 1 Dose 1 N=1784 Year 1 Dose 2 N=1784 2 doses with second dose 35d ±7d apart Year 2 N=1119 1 dose based on assignment in year 1 Healthy children aged 6 to <36 months attending day care ≥12hours/week	The only significant reactogenicity events within 11 days occurred in Year 1 after first dose: rhinorrhea (82.3% vs 75.4%, p=0.001)	Level I	Good
Adults
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 FluMist® 0.1mL per nostril (107TCID50 per strain) B strains not well matched to vaccine (production issues)	Randomized, prospective, double-blind, placebo controlled, multicentre NCT:00217230 D153-P507 2001 31 sites in South Africa	N=3242 nLAIV= 1620 nplacebo= 1622 Healthy adults ≥60 years (median age 69) Sera obtained pre-vaccination, 35±7 days post-vaccination, at study completion	Significant reactogenicity events (within 11 days post-vaccination): (LAIV vs placebo) Cough (20.3% vs 14.7%) (p<0.001) Sore throat (14.9% vs 10.1%) (p<0.001) Runny nose/nasal congestion (41.3% vs 22.7%) (p<0.001) (greatest on days 2-4) Headache (28.8% vs 24.1%) (p=0.003) (greatest on days 2-4) Muscle ache (16.6% vs 11.8%) (p<0.001) Tiredness (19.0% vs 15.6%) (p=0.12) Decreased appetite (7.7% vs 5.2%) (p=0.003) No fever ≥40.0ºC SAEs during first 28 days post-vaccination LAIV (n=16) Placebo (n=24) SAEs reported during 8 months study period: LAIV (351 SAEs in 163 LAIV recipients and 139 placebo) 7 events possibly related (4 cases of pneumonia, 1 case GBS in placebo and 1 case bronchopneumonia and 1 asthma in LAIV)	Level I	Good
Forrest BD, Steele AD, Hiemstra L, et al. A prospective, randomized, open-label trial comparing the safety and efficacy of trivalent live attenuated and inactivated influenza vaccines in adults 60 years of age and older. Vaccine. 2011;29(20):3633-9 (66).	LAIV 0.1mL per nostril (107TCID50 per strain)	Randomized, prospective, open-label, active controlled, multicentre Control vaccine: TIV, 0.5mL (15μg HA per strain) NCT00192413 D153-P516 2002 30 sites in South Africa	N=3009 nTIV=1501 nLAIV=1508 ≥60-95 years (median age 68)	Significant reactogenicity events (within 11 days post-vaccination): (LAIV vs TIV) Cough (17.5% vs 12.3%) (p<0.000) Sore throat (15.3% vs 10.2%) (p<0.000) Runny nose/nasal congestion (36.7% vs 24.0%) (p=0.000) Decreased activity (lethargy) (18.7% vs 15.5%) (p=0.023) Decreased appetite (7.2% vs 5.3%) (p=0.031) Fever similar in both groups (none above 40ºC) AEs Rhinitis (3.7% LAIV and 1.5% TIV) (p<0.001) SAEs: LAIV (1 case of bronchopneumonia possibly related to study) 29 deaths not related to study.	Level I	Good Insufficient number of endpoints collected to demonstrate non-inferiority as a result of low incidence of influenza
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 FluMist® 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: TIV, Fluzone®, 0.5mL (15μg HA per strain) 2007/08 season NCT 00538512 Michigan, USA	N=1952 nLAIV= 814 nTIV= 813 nplacebo=325 Healthy adults aged 18-49 years	Runny Nose/congestion (52.3% LAIV vs 37.7% placebo, p=0.001) Arm soreness (52.6% TIV vs 21.3% placebo, p<0.001) SAE within 30 days: Placebo: Hospitalization for depression/anxiety (unrelated to study) SAE within 6 months: TIV (n=8) LAIV (n=4) Placebo (n=2) None related to study.	Level I	Good
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 Dosage unreported A/H3N2 strains not well matched to vaccine.	Randomized double-blind placebo controlled trial, multi-centre AV009 1997-1998 influenza season, 13 centres in USA	N=4,561 NLAIV= 3041 nplacebo=1520 healthy working (≥30 hrs/week) adults aged 18-64	75% vaccine and 69% placebo recipients self administered without difficulty. Reactogenicity Data (7 days following vaccination)(LAIV vs placebo) Runny Nose (44.3% vs 26.6%, CI 95%: 14.7, 20.7) Sore throat (26.6% vs 16.3%, 95% CI: 7.2, 12.9) Equivalent rates of other symptoms # SAE 28 days post-immunization: 9 (LAIV: 5, placebo: 4) (0.18% vs 0.27%, p=0.50). None related to study. #SAE 14 weeks post-immunization 49 (LAIV: 30, placebo: 19) (1.0% vs 1.3%, p=0.50). No hospitalizations related to study.	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 FluMist® 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: TIV, Fluzone®, 0.5mL (15μg HA per strain) 2004/05 season NCT: 00133523 4 sites, Michigan, USA Year 1 of 2	N=1247 nLAIV= 519 nplacebo=103 (IN spray) nTIV= 522 nplacebo=103 (IM injection) Healthy adults aged 18-46 years (mean age 24.9)	Significant reactogenicity events: Runny Nose/congestion (48.8% LAIV vs 30.3% IN placebo, p=0.001) Cough (18.2% LAIV vs 8.1% IN placebo, p=0.01) Headache (37.9% LAIV vs 25.3% IN placebo, p=0.02) Muscle aches (13.2% LAIV vs 5.1% IN placebo, p=0.02) Arm soreness (53.9%TIV vs 20.2% IM placebo, p<0.001) SAE within 30 days (n=4): LAIV: hospitalization for acute pericarditis (possibly related to study) Other 3 not related	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 FluMist® 0.25mL per nostril (106.5-107.6 TCID50 per strain) Single dose A/H3N2 similar to vaccine	RCT, double-blind, placebo controlled, community-based Control vaccine: TIV, Fluzone®, 0.5mL (15μg HA per strain) 2005/06 season NCT:00133523 6 sites, Michigan, USA Year 2 of 2	N=1917 nLAIV= 787 nTIV= 818 nplacebo (IN)=157 nplacebo (IM)=155 (participants assigned to same group as in year 1, additional subjects enrolled) Healthy adults aged 18-48 years (mean age 24.9)	Significant reactogenicity events: LAIV Runny Nose/congestion (42.7% LAIV vs 31.2% IN placebo, p=0.008) Sore throat (26.9% LAIV vs 16.6% IN placebo, p=0.006) TIV Arm soreness (50.4%TIV vs 14.2% IM placebo, p<0.001) Arm redness (7.1%TIV vs 0.7% IM placebo, p=0.002) Muscle Aches (13.5%TIV vs 20.2% IM placebo, p=0.008) SAE within 30 days (n=3) SAE within 6 months (n=18) Only one hospitalization for viral meningitis was considered possibly related to study. Others were not.	Level I	Good Lower than expected attack rate, low power
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 Flu Mist® 0.25mL per nostril (107 TCID50 per strain)	RCT, active and placebo controlled double-blind wild type challenge study Control vaccine: TIV: Fluvirin® 0.5mL (15μg HA per strain) 1995/96 season AV003 NCT: 2 sites, USA	N=103 nCAIV-T=36 nTIV=33 nplacebo=34 Groups challenged with 1 strain of virus 28 days after vaccination (then placed in group isolation x7 days) Healthy adult volunteers aged 18-40 years who were serosusceptible (HAI ≤1:8) to at least 1 of 3 strains	Reactogenicity within 7 days post-vaccination (fever, systemic symptoms, respiratory symptoms) CAIV-T (3%, 25%, 61%) Any symptom: 67% TIV-(0%, 12%, 48%) Any symptom: 52% Placebo-(9%, 21%, 53%) Any symptom: 62%	Level I	Good
Concurrent administration with other live vaccines
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 Wyeth Vaccines Research, Marietta, PA, USA 0.1mL per nostril (107 TCID50 per strain) 2 doses 35±7 days apart Vaccine and circulating A/H3N2 not well matched	Phase III RCT, double-blind, placebo controlled, multicentre Non-inferiority trial (lower bound -10.0%) Co-vaccine: MMR (Priorix®) 2002/03 season NCT:00192166 D153-P522 13 countries (Europe/Asia)	N=1233 Dose 1: nLAIV+MMR =753-806 nplacebo+MMR=378-406 Dose 1: nLAIV+MMR =733-765 nplacebo+MMR=357-383 Both groups received MMR with dose 1 Healthy vaccine-naïve children 11 to <24 months	Receipt of LAIV/Priorix did not increase injection site reactions Significant reactogenicity events (within 11 days post-dose 1): (LAIV/Priorix vs Placebo/Priorix) Fever ≥37.5°C (49.9% vs 41.7%) (p<0.009) Use of medication to treat fever (37.7% vs 29.2%) (p=0.004) Runny nose/nasal congestion (70.1% vs 51.6%) (p=<0.001) Decreased appetite (33.6% vs 27.7%) (p=0.036) Significant reactogenicity events after dose 2 (LAIV/Priorix vs Placebo/Priorix) Fever ≥40°C (0.0% vs 0.8%)(p=0.035) Unsolicited AEs (LAIV vs placebo) Fever (24.3% vs 18.4%, p=0.020) Rhinitis (9.6% vs 6.0%, p=0.039) SAEs across both treatment groups (no statistical difference): Gastroenteritis, convulsion, bronchospasm, pneumonia, pharyngitis, bronchitis, fever. 2 deaths, not attributed to study.	Level I	Good
Nolan T, Bernstein DI, Block SL, et al. Safety and immunogenicity of concurrent administration of live attenuated influenza vaccine with measles-mumps-rubella and varicella vaccines to infants 12 to 15 months of age. Pediatrics. 2008;121(3):508-16 (49).	LAIV MedImmune 0.25mL per nostril (107TCID50 per strain)	RCT, prospective, placebo controlled, multicentre 2 influenza seasons (2001/2002) Co-vaccines: MMR: M-M-RII, Merck Varicella: Varivax, Merck NCT00192491 AV-018 US/Australia	N=1245 MMR/varicella group (n=411) (Day 0) MMR/Varicella/placebo (Day 42) LAIV (Day 72) LAIV MMR/varicella/LAIV group (n=422) (Day 0) MMR/Varicella/LAIV (Day 42) LAIV (Day 72) placebo LAIV group (n=412) (Day 0) LAIV (Day 42) LAIV (Day 72) MMR/Varicella Healthy children aged 12 to 15 months	Significant reactogenicity events 42 days after 1st dose LAIV or placebo concurrent with MMR and varicella vaccines: Runny Nose/Nasal congestion (84% MMR/varicella/LAIV vs 77.6% MMR/Varicella) Incidence of ≥1 AE MMR/varicella/LAIV (overall: 47%) Diarrhea (17%) Otitis media (8%) Wheezing (1.2%) MMR/varicella/placebo (overall: 49%) Diarrhea (15%) Otitis media (11%) Wheezing (2.5%) SAEs (n=9) possibly related to study include: MMR/varicella: 2 cases croup, 1 case pneumonia, 1 bronchiolitis MMR/varicella/LAIV: 1 case croup, 1 case bronchiolitis LAIV: 1 case viral chest infection, bronchiolitis, bronchospasm 9 children experienced 9 significant new medical conditions MMR/varicella: asthma, excessive language delay MMR/varicella/LAIV: cerebral palsy LAIV: 3 cases asthma, 2 cases speech delay, seizure No deaths	Level I	Good
Breiman RF, Brooks WA, Goswami D, et al. A multinational, randomized, placebo-controlled trial to assess the immunogenicity, safety, and tolerability of live attenuated influenza vaccine coadministered with oral poliovirus vaccine in healthy young children. Vaccine. 2009;27(40):5472-9 (50).	LAIV 0.1mL per nostril (107±5FFU per strain)	RCT, LAIV blinded, placebo controlled, multicentre Co-vaccine: OPV (various sources) open label NCT00192491 D153-P511 2002 Asia, South America (OPV still used)	N=2503 Dose 1 nLAIV+OPV=787-818 nPlacebo + OPV=794-826 (blinded) nLAIV=777-814 Dose 2 nLAIV+OPV=725-753 nPlacebo + OPV=748-769 (blinded) nLAIV=740-760 2nd dose LAIV (or placebo) given 28-42 days after 1st dose Healthy influenza vaccine-naïve children aged 6 to <36 months receiving routine OPV Exclusions included administration of any live vaccine within 1 month and no other live vaccine during study	Reactogenicity (≥1 solicited systemic event within 11 days of any vaccination) Runny nose/nasal congestion (68.6% LAIV vs 62.7% placebo) (p=0.003) after dose 1 only Fever ≥40C and decreased activity more frequent with placebo and OPV than with LAIV recipients combined (p=0.037 and p=0.017) after dose 1 AEs (majority mild to moderate) LAIV + OPV = 38.3% Placebo + OPV = 36.0% LAIV = 35.9% Most common: upper respiratory tract infections, rhinitis. Dose 1 conjunctivitis significant: LAIV: 0.7%; LAIV+OPV: 0.1%; placebo+OPV: 0.1% (p=0.04). Onset between days 0 and 38, duration 3-19 days. SAEs (p=0.552) LAIV+OPV: 1.8% Placebo+OPV: 2.5% LAIV: 1.9% 17 SAEs included pneumonia (n=4), acute gastroenteritis (n=8), bronchospasm (n=2), acute tonsillitis (n=1), febrile seizure (n=1), and acute gastritis (n=1). Receipt of LAIV not associated with disproportionate incidence of SAE	Level I	Good
Safety in Populations with Respiratory Conditions (including asthma)
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 FluMist® 0.1mL per nostril (107 TCID50)	RCT, prospective, double-blind, active controlled, multicentre Control vaccine: TIV Fluzone® (US/Asia) Vaxigrip® (Europe/Middle East), 0.25mL or 0.5mL/dose based on age 2004/05 season 249 sites in 16 countries (US, Europe/Middle East, Asia) NCT00128167 MI-CPIII	N=7852 nTIV=3936 nCAIV-T=3916 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): 44.5% (22.4, 60.6) Strain-specific efficacy (similar subtype): A/H1N1: 89.2% (67.7, 97.4) A/H3N2: no cases B: 27.3% (-4.8, 49.9) Relative efficacy for CAIV-T (not well matched): 58.2% (47.4, 67.0) Strain-specific efficacy (similar subtype): A/H1N1: no cases A/H3N2: 79.2% (70.6, 85.7) B: 6.3% (-31.6, 33.3) Overall relative efficacy for CAIV-T (regardless of match): 54.9% (45.4, 62.9) Strain-specific efficacy: A/H1N1: 89.2% (67.7, 97.4) A/H3N2: 79.2% (70.6, 85.7) B: 16.1% (-7.7, 34.7) Reductions in AOM regardless of match: 50.6% (21.5, 69.5) Reductions in LRI regardless of match: 45.9% (4.4, 70.2)	Level I	Good
Redding G, Walker R, Hessel C, et al. Safety and tolerability of cold-adapted influenza virus vaccine in children and adolescents with asthma. Pediatr Infect Dis J. 2002;21(1):44-8 (63).	CAIV-T 0.25mL per nostril (107 TCID)	Randomized, double-blind, placebo controlled 1997 2 pediatric allergy practices in Seattle, WA	N=48 nCAIV-T=24 nplacebo=24 Children 9-17 years of age with stable moderate to severe asthma.	Safety endpoints: percent change in predicted FEV1 7 days before and 28 days after vaccination. Secondary measures: morning PEFR; asthma rescue medication; asthma exacerbations; daily clinical asthma sx scores; nighttime awakening scores; changes in FVC. % change in percent predicted FEV1 scores (CAIV-T vs placebo) 0.2% vs 0.4%, (p=0.78) Other endpoints were not significant between 2 groups. Post-vaccination symptoms were similar between groups. No serious adverse event. 2 LAIV recipients had mild asthma exacerbations within 28 days after vaccination that required increased bronchodilator or oral steroid usage but did not require emergency department visits or hospitalizations. Concluded CAIV-T is safe for administration to children with stable asthma.	Fair Small sample size	Fair Small sample size
Piedra PA, Gaglani MJ, Riggs M, et al. Live attenuated influenza vaccine, trivalent, is safe in healthy children 18 months to 4 years, 5 to 9 years, and 10 to 18 years of age in a community-based, nonrandomized, open-label trial. Pediatrics. 2005;116(3):e397-407 (61).	LAIV Aviron 0.25mL per nostril (1076-TCID50 per strain)	Prospective, multi-year open label, non-randomized trial 4 years (1998 to 2002) Templeton-Belton	N= 18,780 doses to 11,096 children 18mos-4 years (4529 doses) 5-9 years (7036 doses) 10-18 years (7215 doses) Healthy children aged 1.5-18 years. Children with a history of intermittent wheezing, medically attended acute-respiratory illness, including asthma exacerbation, not excluded.	Assessed medical records for 6 weeks post-vaccination No significant increase in healthcare utilization for MAARI in 0-14 or 15-42 days post-vaccination in any age group in any year. 18 mos-4 years - no significant increase in health care utilization for MAARI, MAARI subcategories, asthma on days 0-14 or days 15-42, except: Asthma events in year 1: RR 2.85 (95% CI, 1.01-8.03) days 15 to 42 post-vaccination. No statistically significant increase in subsequent years. This is most likely due to chance. No SAE attributed to study	Good	Good
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 Wyeth Vaccines Research (Marietta, PA) 0.1mL per nostril (107TCID50 per strain)	RCT, open-label, active controlled, multi-centre Control vaccine: TIV, Aventis Pasteur, 0.25mL/dose or 0.50mL/dose based on participant age NCT00192205 D153-P514 2002-2003 influenza season Europe, Israel	N = 2187 nTIV= 1086 nCAIV-T= 1101 2 doses: 35d ±7d apart Vaccine naïve children 6 to 71 months, with history of recurrent respiratory tract infections (≥2 RTIs in past 12 months of since birth if under 12 months) 23% had prior diagnosis of asthma	Reactogenicity events 11 days after dose 1 (CAIV vs TIV) Overall: (87.2% vs 83.7%) (p=0.033) Runny nose/nasal congestion (68.3% vs 55.1%) (p<0.001) Reactogenicity events after dose 2 (CAIV vs TIV) Overall: (76.2% vs 73.6%) (p=210) Runny nose/nasal congestion (52.1% vs 44.4%) (p=0.0001) Decreased appetite (23.9% vs 19.8%) (p=0.031) AEs within 11 days (dose 1) Overall: 33.8% vs 29.6%) (p=0.039) • Rhinitis (8.7% vs 5.3%, p=0.002) AEs within 11 days (dose 2) Overall: 32.4% vs 28.6%) (p=0.059) • Rhinitis (6.1% vs 3.8%, p=0.021) • Otitis media (3.7% vs 1.8%, p=0.011) Incidence of wheezing similar in both groups. SAEs reported in CAIV-T (n=104 in 64 subjects) and TIV (n=76 in 51 subjects) 2 CAIV-T and 4 TIV recipient SAEs possibly related to vaccine. No deaths.		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 Wyeth Vaccines Research (Marietta, PA) 0.1mL per nostril (107TCID)	RCT, Open-label, active-controlled, multicentre Control vaccine: TIV, Aventis Pasteur, 0.5mL (15μg HA per strain) NCT00192257 D153-P515 2002/2003 influenza season Europe	N = 2229 nTIV=1114 nCAIV-T=11115 Children with asthma (not all influenza vaccine-naïve children) ≥6 years to ≤17 years of age	Primary endpoint: incidence of asthma exacerbation (acute wheezing associated with hospitalization, unscheduled clinic visit or new prescription) within 15 days post-vaccination. Secondary end-points: recurrent wheezing during entire study (until May); first asthma exacerbation within 42 days; PEFR scores; nighttime awakenings; asthma symptoms. Reactogenicity events 15 days after dose 1 (CAIV vs TIV) Overall: (84.2% vs 78.9%) (p=0.002) Runny nose/nasal congestion (66.2% vs 52.5%) (p<0.001) Wheeze (19.5% vs 23.8%, p=0.020) Pharmacoeconomic Events: No difference between CAIV-T vs TIV in use of medications; unscheduled visits; hospitalizations or days off school/work. Asthma Events: Entire Study: no difference in asthma exacerbations between CAIV-T (31.2%, 90% CI: -1.6, 4.8) vs TIV (29.6%, 95% CI: -2.2, 5.4). No difference noted from days 0-42. PEFR findings, asthma symptoms, nighttime awakening scores similar. AE’s (day 15 to 28 post-vaccination) Rhinitis (7.4% vs 3.9%, p=0.000) and headache (6.5% vs 4.2%, p=0.023) only significant events SAEs Respiratory (0.9% in both groups) 4 SAES (nCAIV-T=3, pneumonia with severe asthma attack, acute pansinusitis, painful gland behind L ear) (nTIV=1, hypergylcemia with nausea) possibly related to study		Good
Gorse GJ, O’Connor TZ, Young SL, et al. Efficacy trial of live, cold-adapted and inactivated influenza virus vaccines in older adults with chronic obstructive pulmonary disease: a VA cooperative study. Vaccine. 2003;21(17-18):2133-44 (65).	CAIV-T 0.25mL per nostril (107TCID50 per strain)	RCT, placebo controlled, double blinded, stratified by site Co-vaccine: TIV, Fluvirin™ 0.5mL (15μg HA per strain) 1998-1999 20 VA Medical Center sites	N=2215 nCAIV-T=1107 nplacebo=1108 Adults ≥50 years meeting the spirometric criteria for COPD Excluded if received TVV in previous 6 months	Mean number of days for signs and symptoms higher for CAIV-T vs. placebo: Stuffy or runny nose: 1.9±2.6 vs. 1.5±2.4; p=0.0001 Increased shortness of breath: 1.0±2.0 vs. 0.75±1.7; p=0.0001 Chills: 0.35±1.1 vs. 0.29±1.0 p<0.05 Headache: 0.86±1.8 vs. 0.69±1.6; p<0.05 Itchiness at TVV injection site: 0.13±0.65 vs. 0.08±0.54; p<0.05 Statistically significantly higher recorded signs and symptoms for CAIV-T vs. placebo: Increase in sputum production, stuffy or runny nose, increased shortness of breath, chills, itchiness at TVV injection site No significant difference between adverse events possibly attributed to vaccination when comparing CAIV-T and placebo groups 64 subject deaths during trial (34 received LAIV-T, 30 received placebo); 1/6 deaths within 28 days post-vaccination was potentially attributed to placebo immunization No difference in estimate of survival from immunization to end of study participation between treatment groups No significant differences in spirometry post-immunization between groups		Good
Immune compromised
Halasa N, Englund JA, Nachman S, et al. Safety of live attenuated influenza vaccine in mild to moderately immuno-compromised children with cancer. Vaccine. 2011;29(24):4110-5 (75).	LAIV 0.5mL (106.5-7.5 TCID50) 2 formulations: 2004/05 (n=2) in first year 2005/06 (n=8) in subsequent years	Phase 1 RCT, double-blind, placebo controlled, multicentre, multi-year Off-season (conducted during summers of 2005-07) NCT: 00112112	N=19 nLAIV=9 nplacebo=10 Mild to moderately immunocompromised children with cancer aged 5-17 years with life expectancy >1 year on chemotherapy and/or radiation therapy for treatment of cancer (or received within the past 12 weeks)	Runny nose/nasal congestion occurred more frequently in LAIV recipients between Days 0-10 (p<0.02) Placebo group reported more adverse events overall than LAIV group (24 events in 10 subjects vs. 10 events in 6 subjects) Shedding Influenza positive nasal swabs detected in 4 LAIV recipients No viral shedding detected after day 10		Good
King JC, Jr., Fast PE, Zangwill KM, et al. Safety, vaccine virus shedding and immunogenicity of trivalent, cold-adapted, live attenuated influenza vaccine administered to human immunodeficiency virus-infected and noninfected children. Pediatr Infect Dis J. 2001;20(12):1124-31 (73).	LAIV Aviron, Mountain View, CA, USA 0.25mL per nostril (107 TCID50 per strain) Three doses administered 28-35 days apart Two protocols: LAIV-placebo-LAIV and placebo-LAIV-LAIV	RCT, double-blind, placebo controlled, cross-over	N=49 nHIV=24 nnon-HIV=25 HIV-infected and non-infected children aged 1-7 years in good general health	No fevers >38.9°C observed Rates of fever, reactogenicity events or ILI not significantly different between non-HIV-infected and HIV-infected children after administration of LAIV 3 serious adverse events occurred in 2 HIV-infected children (wheezing requiring 2 hospitalizations in a known asthmatic and hospitalization for abdominal pain, vomiting and fever) determined unrelated to LAIV and resolved without sequelae Shedding 7 (28%) of non-HIV infected children shed type A or B LAIV virus 3 (13%) of HIV-infected children shed type A or B virus		Good
King JC, Jr., Treanor J, Fast PE, et al. Comparison of the safety, vaccine virus shedding, and immunogenicity of influenza virus vaccine, trivalent, types A and B, live cold-adapted, administered to human immunodeficiency virus (HIV)-infected and non-HIV-infected adults. J Infect Dis. 2000;181(2):725-8 (72).	LAIV Aviron, Mountain View, CA, USA 0.25mL per nostril (107 TCID50 per strain) Single dose	RCT, double-blind, placebo controlled	N=111 nHIV=57 ncontrol=54 Adults in good general health 18-58 years; HIV participants with CDC class of A1-2 and plasma HIV RNA PCR measurement of <10,000 copies/mL and >200 CD4 cells/mm3 within 4 months, and on stable antiretroviral regimen if ≤500 CD4 cells/mm3	Similar rates of reactogenicity events LAIV and placebo groups regardless of HIV status Occurrence of runny nose/nasal congestion higher in LAIV (p<0.05) No significant difference between events in HIV infected and non-infected receiving LAIV Adverse events No serious adverse events 4 adverse events reported potentially related to vaccine • 2 in HIV-infected LAIV (clinical sinusitis, wheezing) • 1 in HIV-infected placebo (wheezing) • 1 non-HIV-infected placebo (bronchitis) 1 case of vaccine virus shedding in HIV-infected LAIV		Good
Levin MJ, Song LY, Fenton T, et al. Shedding of live vaccine virus, comparative safety, and influenza-specific antibody responses after administration of live attenuated and inactivated trivalent influenza vaccines to HIV-infected children. Vaccine. 2008;26(33):4210-7 (74).	LAIV FluMist® 0.25mL per nostril Single dose	Randomized, active controlled, open label clinical trial, stratified by CD4% Active vaccine: TIV: Fluzone® 0.5mL 2004/05 season Note: Stratification into 3 groups (CD4%<15 at nadir and ≥15 at screening; CD4% ≥15 at nadir and <25 at screening; CD4%≥25 at nadir and screening)	N=243 nLAIV=122 nTIV=121 Children ≥5 to <18 years old on a stable highly active antiretroviral therapy for ≥16 weeks; HIV-1 plasma <60,000 copies/mL within 60 days prior to screening; and received at least one TIV within previous 2 years	Similar adverse events reported within 28 days post-vaccination abdominal, constitutional, ear or eye, and pulmonary signs and symptoms, skin abnormality and other reactions TIV had most injection reactions (23% overall) LAIV had most nasopharyngeal reactions compared to TIV (52% vs. 31%, p=0.002) No statistically significant differences between stratified groups for either LAIV or TIV in toxicity grades (from DAIDS Toxicity Manual) of adverse events 3 LAIV subjects had Grade 3 events (1 considered vaccine-related) 2 TIV subjects had Grade 3 events (both considered vaccine-related) 2 cases of radiographically confirmed pneumonia (1 in TIV subject and 1 in LAVI subject) No significant increase from baseline in median/mean plasma HIV viral load or CD4% resulting from vaccination Shedding Did not correlate with age, CD4 count or CD4% or HIV viral load at any time during vaccination, or subsequent boost in any specific antibody measured at 4 weeks post-vaccination		Good
Weinberg A, Song LY, Walker R, et al. Anti-influenza serum and mucosal antibody responses after administration of live attenuated or inactivated influenza vaccines to HIV-infected children. J Acquir Immune Defic Syndr. 2010;55(2):189-96 (44).	LAIV FluMist® 0.25mL per nostril	RCT, active controlled, open label Control vaccine: TIV: Fluzone® 0.5mL 2004-05 season Note: Stratification into 3 groups by nadir: CD4<15; CD4 ≥15 at and <25; CD4 ≥25)	N=243 nLAIV=122 nTIV=121 Children and adolescents 5-18 years, HIV-infected on a stable highly active antiretroviral therapy for ≥16 weeks; plasma viral load <60,000 copies/mL, CD4 ≥15% within 60 days prior to enrollment; and received at least one TIV within previous 2 years	Specimens collected at baseline, week 4 and week 24 post-vaccination; nasal shedding monitored on days 3, 14, and 28 post-vaccination Magnitude of response to TIV and LAIV most correlated with baseline microneutralization titers (p<0.0001) and baseline viral load Significant increases in microneutralization titers at 4 and 24 weeks for TIV and LAIV (p≤0.02) Week 4 titers higher in TIV recipients than LAIV (p≤0.002) No significant associations between salivary influenza-IgA concentrations with baseline plasma viral load, CD4%, CD8% or CD19% Week 4 salivary anti-influenza-IgG response were associated with baseline concentrations and baseline plasma HIV viral load LAIV and TIV both demonstrated heterotypic HAI responses, with TIV inducing significantly higher HAI titers than LAIV at 4 and 24 weeks post-vaccination		Good