Table 10. Summary of Evidence for NACI Recommendation(s).
| Evidence related to efficacy 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, Mendel-man 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 0.25mL per nostril (106.7 TCID) Vaccine and circulating strains well-matched |
RCT, double-blind, placebo controlled, multicentre AV006 Year 1 1996/97 season USA | N=1602 (pp) nLAIV= 1070 nplacebo= 532 Both groups received 1 (n=288) or 2 doses (n=1314); second dose 60d ±14d apart Healthy children ≥ 15-71 months |
Primary endpoint: Incidence of CCI (≥28 days after receipt of first dose or any time after second dose) caused by matched strains. Secondary endpoint: Efficacy of one or two dose regimen Vaccine Efficacy: Overall efficacy: 93% (88, 96) (One dose: 89% (65, 96) / Two doses: 94% (88, 97)) Strain-specific efficacy A/H1N1 – No cases in vaccine group A/H3N2: 95% (88, 97) B: 91% (79, 96) Efficacy in reducing febrile illness: 21% (11, 30) Efficacy in reducing AOM:30% (18, 45) Breakthrough illness in vaccinated recipients was milder than illnesses in placebo recipients. |
Level I | Fair Participants not randomized into 1 or 2 dose groups, and equivalency between 1 and 2 dose was not established |
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| 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 1997/98 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) |
Primary endpoint: First episode of CCI after receipt of revaccination (Year 2 of multi-year study by Belshe et al) Vaccine Efficacy (Year 2): Overall efficacy: 87% (78, 93) Strain-specific efficacy (Year 2): A/H1N1 – No cases in study group A/H3N2 (Wuhan/359/95-like): 100% (54, 100) B: 100% (79, 100) Efficacy against A/H3N2 (Sydney/5/97-like) not contained in vaccine: 86% (75, 92) Vaccine Efficacy (Years 1 and 2 combined): Overall efficacy: 92% (88, 94) Efficacy of LAIV to reduce AOM: 94% Efficacy of LAIV to reduce LRTD: 95% |
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 TCID 50 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=2784 CAIV-T =1653 nplacebo =1111 Both groups received 2 doses Year 2 (re-randomized) N=2527 nCAIV-T/CAIV-T = 771 nCAIV-T/placebo = 759 nplacebo/CAIV-T= 503 nplacebo/placebo = 494 Healthy children aged 12 to <36 months |
Primary endpoint: CCI caused by matched strains after 2nd dose Secondary endpoints: CCI caused by any subtype after 2nd dose in year 1 and single dose in year 2 Year 1 Vaccine Efficacy (matched strains): Overall efficacy – 72.9% (62.8, 80.5) Strain-specific efficacy: A/H1N1: 80.9% (69.4, 88.5) A/H3N2: 90.0% (71.4, 97.5) B: 44.3% (6.2, 67.2) (vaccine mismatch) Efficacy against any subtype was 70.1% (60.9, 77.3) Year 2 Vaccine Efficacy (matched strains): Overall efficacy (Year 1 / Year 2 group comparisons) CAIV/CAIVT vs. plac./plac.: 84.3% (70.1, 92.4) CAIVT/plac. vs. plac./plac.: 56.2% (30.5, 72.7) CAIVT/CAIVT vs. CAIVT/plac: 64.2% (28.9, 83.2) CAIVT/CAIVT vs. plac./CAIVT:60.9% (15.9, 82.6) Plac./CAIVT vs. plac./plac: 59.9% (31.1, 77.4) Vaccine Efficacy (any strains): Overall efficacy (Year 1 / Year 2 group comparisons) CAIVT/CAIVT vs. plac./plac.: 64.2% (44.2, 77.3) CAIVT/plac. vs. plac/plac.: 44.8% (18.2, 62.9) CAIVT/CAIVT vs. CAIVT/plac.: 35.0% (-2.9, 59.5) CAIVT/CAIVT vs. plac./CAIVT: 17.2% (-4.2, 52.0) Plac./CAIVT vs. plac./plac.: 56.7% (30.3, 73.8) 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-rivalent against community-acquired, culture-confirmed influenza in young children attending day care. Pediatrics. 2006;118(6):2298-312 (8). | CAIV-T Wyeth Vaccines Research 0.1mL per nostril (107TCID) Vaccine and circulating strains well-matched (H3N2/A substituted in Year 2) |
RCT, prospective, double-blind, placebo controlled, multicenter 2000-01 & 2001/02 seasons Belgium, Finland, Israel, Spain, UK NCT00192283 D153-P502 |
Year 1 N=1616 nCAIV-T = 951 nplacebo = 665 2 doses with second dose 35d ±7d apart Year 2 (one dose) N=1090 nCAIV-T = 640 nplacebo = 450 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 Vaccine efficacy after 2 doses (matched strains): Overall efficacy: 85.4% (74.3, 92.2) Strain-specific efficacy: A/H1N1:91.8% (80.8, 97.1) B:72.6% (38.6, 88.9) NCT0019228383.8% (74.2, 90.2) Year 2 Vaccine efficacy (matched strains): Overall efficacy: 88.7% (82.0, 93.2) Strain-specific efficacy: A/H1N1: 90.0% (56.3, 98.9) A/H3N2: 90.3% (82.9, 94.9) (predominant circulating strain) B: 81.7% (53.7, 93.9) (lower attack rate this year) Efficacy against any subtype 85.3% (78.3, 90.4) Efficacy against AOM associated with CCI Year 1: 90.6% (68.7, 97.2) Year 2: 97% (77.6, 99.6) |
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 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 nLAIV-LAIV=944 nLAIV-placebo=935 nplacebo-placebo=942 Year 2 (one dose) N = 2202 nLAIV = 1467 nplacebo = 735 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: 73. 5% (63.6, 81.0) LAIV-Placebo: 57.7% (44.7, 67.9) LAIV-LAIV vs LAIV/Placebo:37.3% (9.5, 56.9) Year 1 efficacy against any subtype: LAIV-LAIV: 72.0% (61.9, 79.8) LAIV-Placebo: 56.3% (43.1, 66.7) Year 2 vaccine efficacy (similar subtype): LAIV-LAIV/LAIV: 73.6% (33.3, 91.2) LAIV-Placebo/LAIV: 65.2% (31.2, 82.8) LAIV-LAIV/Placebo: 57% (6.1, 81.7) Year 2 efficacy against any subtype: LAIV-LAIV/LAIV: 46.6%% (14.9, 67.2) LAIV-Placebo/LAIV: 46.4% (21.1, 63.5) Efficacy against AOM associated with CCI Year 1: LAIV-LAIV: 73.5% (52.4, 85.3) Year 1: LAIV-Placebo: 69.6% (46.9, 82.6) Year 2: LAIV-LAIV/LAIV: 59.8% (-106.7, 92.2) – small sample size due to study error) Year 2: LAIV-Placebo/LAIV: 90.1% (15.0, 98.8) |
Level I | Good Error in treatment allocation coding and labelling in Year 2 resulted in 2 additional treatment protocols |
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| 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) 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 13 countries (Europe/Asia) NCT:00192166 D153-P522 |
N=1150 nLAIV+MMR = 765 nplacebo+MMR=385 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): 78.4% (50.9, 91.3) Vaccine efficacy against any subtype: 63.8%% (36.2, 79.8) Strain-specific efficacy (similar subtype): A/H1N1: insufficient cases A/H3N2: insufficient cases B: 81.7% (38.2, 95.8) 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, open-label, active controlled, multi-centre Control vaccine: TIV, 0.25mL/dose or 0.50mL/dose based on participant age 2002/03 influenza season Europe, Israel NCT00192205 D153-P514 |
N = 2085 nTIV= 1035 nCAIV-T= 1050 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): 52.7% (21.6, 72.2) – similar ITT value Strain-specific efficacy (similar subtype) A/H1N1: 100% (42.3, 100.0) A/H3N2: -97.1% (-540, 2:31.5) B: 68% (37.3, 84.8) Similar results seen for efficacy against any subtype. Relative to TIV, CAIV-T reduced the number of RTI health-care 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 FluMist® 0.1mL per nostril (107TCID50 per strain) Single dose |
RCT, open-label, active controlled, multicentre Control vaccine: TIV Aventis Pasteur 002/03 season Europe NCT:00192257 D153-P515 |
N = 2220 nTIV=1109 nCAIV-T=1111 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): 34.7% (3.9, 56.0) – similar ITT value Strain-specific efficacy A/H1N1: 100% (-8.4, 100) A/H3N2: 0.6% (141.8, 59.2) B: 36.3% (0.1, 59.8) Overall relative efficacy for CAIV-T (any subtype): 31.9% (1.1, 53.5) Strain-specific efficacy A/H1N1: 100% (15.6, 100) A/H3N2: -29.9% (-190.9, 40.6) B: 36.8% (1.6, 59.8) |
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) Vaccine and circulating A/H3N2 not well matched |
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=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) (data in Supplementary Appendix 23) - antigenically similar strains: 0.4% (-146, 59.6) - antigenically dissimilar strains: 61.4% (32.2, 78.8) Reductions in LRI regardless of match: 45.9% (4.4, 70.2) (data in Supplementary Appendix 23) - antigenically similar strains: 24.5% (-89.8, 71.0) - antigenically dissimilar strains: 63.4% (18.9, 84.7) |
Level I | Good | ||
| Adults | ||||||||
| Nichol KL, Mendel-man 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 nLAIV= 3041 nplacebo=1520 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 Secondary endpoints: severe febrile illness (SFI), febrile upper respiratory illness (FURI) work loss, use of health care facilities Outcomes during peak outbreak periods (LAIV vs placebo) Reduction of AFI: 10% (95%CI: -2.1, 20.7) Reduction of SFI: 18.8% (95%CI, 7.4, 28.8) Reduction in FURI: 23.6% (95%CI, 12.7, 33.2) Efficacy (reported in % reduction) for all illnesses combined: Total days ill (22.9% to 27.3%, p<0.001) Work-loss days (13.1% to 28.4%, p=.07 for AFI, p≤.01 for SFI, FURI) Prescription antibiotic use (42.9% to 47%, p<.001) Use of OTC medications (23.3% to 28%, p<.001) |
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, double-blind, active and placebo controlled, multi-centre Control vaccine: TIV (15μg HA per strain), Year 1 vaccine (bivalent A), trivalent thereafter 1985/86 to 1988-89 seasons 7 sites, Nashville, Tennessee. USA |
N=5210 GroupTIV 1 (n=1739) GroupLAIV 2 (n=1733) Groupplacebo 3 (n=1738) Persons aged 1-65 years (n<15 years=809) |
Primary endpoint: culture-positive illness and seroconversion. Retrospective reports of ILI (only 48-64% of those reporting ILI post-season had presented for culture during acute illness) Strain-specific efficacy (1986/1988 combined): A/H1N1: LAIV (85%, 70-92) vs TIV (76%, 58-87) Strain-specific efficacy (1987/1989 combined): A/H3N2: LAIV (58%, 29-75) vs TIV (74%, 52-86) 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 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=92 nCAIV-T=29 nTIV=32 nplacebo=31 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 |
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 sample size, low rates of infection/illness in placebo recipients |
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| 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 |
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: CAIV-T: 51% (19,70). 36% (0, 59), 36% (0, 59) TIV: 73% (51, 85) 68% (46,81). 68% (46,81) Relative efficacy of TIV compared to LAIV: 45% (3,69), 50% (20,69), 50% (20,69) Absolute efficacy for A/H3N2 strain: CAIV-T: 29% (-14, 55) TIV: 72% (49,84) Relative efficacy of TIV compared to LAIV: 60% (33,77) |
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) |
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 TIV vs placebo: Cell culture +ve: 77% (37, 92) Culture +ve or PCR+: 75% (42, 90) Culture or serologic +: 67% (16,87) % relative reduction of LAIV vs placebo: Cell culture +ve: 57% (-3, 82) Culture +ve or PCR+: 48% (-7, 74) Culture or serologic +: 30% (-57, 67) % relative reduction of LAIV vs TIV: Cell culture +ve: 46% (-44, 82) Culture +ve or PCR+: 53% (-5, 80) Culture or serologic +: 53% (-4, 80) 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 FluMist® 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: TIV, Fluzone®, 0.5mL (15μg HA per strain) 2005/06 season NCT:00133523 6 sites, Michigan, USA Year 2 of 2 |
N=2058 nLAIV= 853 nTIV= 867 nplacebo=338 (IN spray or IM injection) (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 TIV vs placebo: Cell culture +ve: 23% (-153, 73) Culture +ve and/or PCR+: 16% (-171, 70) Culture or serologic +: 54% (4,77) % relative reduction of LAIV vs placebo: Cell culture +ve: 61% (-48, 89) Culture +ve and/or PCR+: 8% (-194, 67) Culture or serologic +: 43% (-15, 71) % relative reduction of LAIV vs TIV: Cell culture +ve: -95% (-539, 32) Culture +ve and/or PCR+: 9% (-110, 60) Culture or serologic +: 19% (-56, 58) 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 |
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| 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: TIV 2004/05 to 2006/07 seasons |
2004/05 N=1,061,728 nTIV=366,201 nLAIV=184,707 Nunimmunized=510,820 2005/06 N=1,041,264 nTIV=626,478 nLAIV=143,054 Nunimmunized=271,732* 2006/07 N=1,067,959 nTIV=436,600 nLAIV=400,630 Nunimmunized=230,729* *includes personnel unimmunized in current & previous years Military personnel Aged 17-49 years over three influenza seasons Exclusions: pregnant women, >1 dose of flu vaccine in current season (vaccine-naïve=no immunization in prior 1 or 2 seasons) |
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) (TIV vs unimmunized) (LAIV vs unimmunized) (TIV vs LAIV) 2004/05 (53.7%: 49.8, 57.3) (7.3%, -9.21, 21.3) (31.6%: 21.6, 40.8) 2005/06 (33.5%: 26.3, 39.9) (5.9%: -9.25, 18.9) (15.9%: 4.77, 25.6) 2006/07 (33.1%: 25.6, 40.0) (11.8%, 0.85, 21.5) (13.3%: 5.78, 20.1) Effect of vaccination in vaccine-naïve cohorts (propensity-matched) (unimmunized in last year or last 2 years) (95% CI) 2005/06 (34.6%: 23.8, 43.9) (31.9%, 10.0, 48.3) (-6.7%: -44.1, 21.0) 2006/07 (39.3%: 19.9, 54.0) (38.2%, 12.8, 56.2) (-1.8%: -53.1, 32.3) Incidence rates of pneumonia and ILI similar between unimmunized and vaccine-naïve cohorts. Correlation between years of being vaccine-naïve and effect of vaccination was statistically significant for LAIV (P=0.04) but not for TIV (p=.63) 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 ICD-9 codes, different uptake of LAIV during the observation period |
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| 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 FluMist® 0.2mL (107TCID50 per strain) B strains not well matched to vaccine (production issues) Low incidence of influenza this season |
Randomized, prospective, double-blind, placebo controlled, multicentre NCT00217230 D153-P507 2001 31 sites in South Africa |
N=3,136 nLAIV= 1567 nplacebo= 1569 Healthy adults ≥60 years (median age 69) Many with chronic underlying medical conditions 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): Overall: 42.3% (21.6, 57.8) A/H1N1: not determined A/H3N2: 52.5% (32.1, 67.2) B: -10.1% (-113, 42.7) (could be due to low # cases, antigenic differences in vaccine, lack of protective immune response) Efficacy against CCI to all strains (95% CI): Overall: 41.6% (20.9, 57.1) A/H1N1: not determined A/H3N2: 52.5% (32.1, 67.2) B: -9.7% (-108.0, 42.0) Protective efficacy of LAIV (95% CI): All ILI: 4.3% (-4.8, 12.7) Hospitalizations: 8.2% (-127, 63.3) Pneumonia: -0.1% (-155, 60.6) Death: 66.6%, (-316, 99.4) Post-hoc analysis: Efficacy in subjects 60-<70 years of age A/H3N2: 41.8% B: -22.7% Efficacy in subjects ≥70 years A/H3N2: 65.7% B: 9.9% |
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, multicentre Control vaccine: TIV, 0.5mL (15μg HA per strain) 1987-88, 1988-89 seasons 3 large nursing homes in NY |
N=523 TIV + placebo TIV+intranasal monovalent LAIV 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 Primary endpoint: Laboratory-documented influenza A (CCI plus culture isolation + serology) Protective Efficacy (95% CI) Lab-documented Influenza A Overall = 60.6%, 18-82) TIV + LAIV (9/162) TIV + placebo (24/169) Respiratory Illness (outbreak-associated) Overall = 56.8%, 95% CI: 23,76) TIV + LAIV (13/162) TIV + placebo (34/169) ILI (outbreak-associated) Overall = 65.0%, 95% CI: 17, 86) TIV + LAIV (6/162) TIV + placebo (18/169) |
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 Wyeth Vaccines Research 0.1mL per nostril (107TCID) Vaccine and circulating strains well-matched (H3N2/A substituted in Year 2) |
RCT, prospective, double-blind, placebo controlled, multicentre 2000-01 & 2001/02 seasons Belgium, Finland, Israel, Spain, UK NCT00192283 D153-P502 |
Year 1 N=1616 nCAIV-T = 951 nplacebo = 665 2 doses with second dose 35d ±7d apart Year 2 (one dose) N=1090 nCAIV-T = 640 nplacebo = 450 1 dose based on assignment in year 1 Healthy children aged 6 to <36 months attending day care ≥12hours/week |
Effectiveness endpoints: CCI caused by any strain (both years); efficacy against AOM, effectiveness measures (parent/guardian time off to care for sick child; missed paid work days; days child missed from daycare; incidence of ≥1outpatient/emergency visit from acute febrile and/or respiratory illness; incidence of related antibiotic prescriptions; days of antibiotic use) Effectiveness Impact of CAIV-T most visible in year 2 45.1% reduction in parent/guardian time off work 47.5% reduction in days of work lost 36.3% reduction in missed day care 24.0% reduction in days of antibiotic use |
Level I | Good | ||
| Gaglani MJ, Piedra PA, Herschler GB, et al. Direct and total effectiveness of the intranasal, live-attenuated, trivalent cold-adapted influenza virus vaccine against the 2000-2001 influenza A(H1N1) and B epidemic in healthy children. Arch Pediatr Adolesc Med. 2004;158(1):65-73 (9). | CAIV-T MedImmune, Mountain View, CA, USA 0.25mL per nostril (106-7 TCID50 per strain) Single dose In 2000, A/H1N1 strain A/Beijing/262/95 was replaced by A/New Caledonia/20/99 |
Community-based non-randomized open-label trial 1998/99 to 2000/01 (3 seasons) Texas, USA |
Nintervention=3212 NComparison =25,589 (20-25% coverage) Healthy vaccine-naïve children aged 18 months to 18 years (Children <5 had no natural infection with A/H1N1) |
Study designed to measure herd immunity (indirect effectiveness) Primary endpoint: direct effectiveness of CAIV-T by comparing medically attended acute respiratory illness (MAARI) for CAIV-T recipients with that in age-eligible non-recipients in intervention communities Secondary endpoint: total effectiveness of CAIV-T by comparing MAARI for CAIV-T recipients with that in non-recipients in comparison communities where CAIV-T was not offered. Direct effectiveness Year 3 cumulative group (n=2281) During H1N1/B epidemic: 20% (95% CI: 14,25) During H1N1 epidemic: 17% (95% CI: 9,27) Year 2 cumulative vs. Year 2 only During H1N1/B epidemic: 18% (95% CI: 9,27) During H1N1 epidemic: 22% (95% CI: 11,32) Total effectiveness Year 3 cumulative group (n=2281) During H1N1/B epidemic: 18% (95% CI: 13,24) During H1N1 epidemic: 26% (95% CI: 18,33 Year 2 cumulative vs. Year 2 only During H1N1/B epidemic: 18% (95% CI: 13,24) During H1N1 epidemic: 26% (95% CI: 18,33) Reductions in MAARI were observed among children who received 1 dose of CAIV-T during the 1990-00 and 2000-01 influenza seasons even though antigenically drifted influenza A/H1N1 and B viruses were circulating during that season. |
Level II-1 | Good | ||
| Glezen WP, Gaglani MJ, Kozinetz CA, et al. Direct and indirect effectiveness of influenza vaccination delivered to children at school preceding an epidemic caused by 3 new influenza virus variants. J Infect Dis. 2010;202(11):1626-33 (14). | LAIV 0.1mL per nostril Single dose |
Nonrandomized, open label, active controlled community-based trial Control vaccine: TIV, 0.5mL 2007 Bell County, TX NCT00138294 |
N = 6191 Intervention Site: 6191 of 10,418 students (48% coverage) LAIV 84.8% TIV 15.2% Healthy children aged 4 to 11 years |
Primary endpoint: rates of medically attended acute respiratory illness (assessing direct and indirect protection) Risk ratio (MAARI rates in intervention vs. comparison communities): Vaccination period: 0.89 (0.86, 0.91) During epidemic: 0.90 (0.88, 0.92) Post-epidemic: 0.91 (0.88, 0.93) LAIV protection more evident in children 5-11 Indirect protection detected for all age groups, except 12-17 year olds (were not offered free vaccine) |
Level II-2 | 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 FluMist® 0.1mL per nostril (107TCID50 per strain) Single dose |
RCT, open-label, active-controlled, multicentre Control vaccine: TIV Aventis Pasteur 2002/03 season Europe NCT:00192257 D153-P515 |
N = 2220 nTIV=1109 nCAIV-T=1111 Children with asthma (not all influenza vaccine-naïve children) ≥6 years to ≤17 years of age |
Effectiveness endpoints: Use of prescribed medication/antibiotics, incidence of healthcare provider visits, incidence of hospitalizations, # days missed from school/work No significant difference between CAIV-T and TIV groups in incidence of asthma exacerbations post-vaccination or any of the identified endpoints. |
Level I | Good | ||
| Halloran ME, Piedra PA, Longini IM, Jr., et al. Efficacy of trivalent, cold-adapted, influenza virus vaccine against influenza A (Fujian), a drift variant, during 2003-2004. Vaccine. 2007;25(20):4038-45 (10). | LAIV 0.1mL per nostril (107FFU per strain) Circulating H3N2 strains were poorly matched with strains in the vaccine |
Open-label, prospective, nonrandomized community-based trial Comparator vaccine: TIV (0.5mL) 2003-2004 influenza season Within the county of Temple-Belton, TX |
N=6403 nLAIV 1706 nTIV 548 nPREV (previously vaccinated in 1998-2001) n=983 nunimmunized=3166 Healthy children aged 5-18 years |
Examined direct protective effects of LAIV against drift variant Primary endpoint: incidence of MAARI during 10 week outbreak period Overall effectiveness against MAARI Received LAIV in 2003: 0.26 (0.11, 0.39) Previous vaccinated but not in 2002 or 2003: -0.13 (-0.30, 0.03) Overall effectiveness in culture confirmed children Received LAIV in 2003: 0.56 (0.32, 0.75) Previous vaccinated but not in 2002 or 2003: -0.11 (-0.19, 0.37) LAIV was cross-protective against a drift variant |
Level II-1 | Good | ||
| Children | ||||||||
| Belshe RB, Swierkosz EM, Anderson EL, et al. Immunization of infants and young children with live attenuated trivalent cold-recombinant influenza A H1N1, H3N2, and B vaccine. J Infect Dis. 1992;165(4):727-32 (47). | Cold-adapted trivalent influenza vaccine 0.5mL (H1N1 104.5 TCID50, H3N2 104.4, B 105.0) by nasal droplet delivery Single dose |
RCT, double blind, vaccine diluent (placebo) controlled | N = 49 nvaccine=32 nplacebo=17 Healthy children 6 months-13 years |
Serum collected at baseline and 28-31 days post-vaccination First clinical trial of trivalent vaccine in infants and young children Seroconversion 8/17 (47%) triply baseline seronegative participants developed an antibody response to all three strains ELISA more sensitive in detecting antibody increase in baseline seropositive children than HAI compared to baseline seronegatives |
Level I | Good | ||
| 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 season |
N=203 nLAIV=136 nplacebo=67 Healthy children 15-71 months |
Serum collected at baseline and 4 weeks after dose 2 Primary endpoint was strain-specific GMT factor of ≥4 after dose 2 Baseline seronegative (LAIV) A(H1N1): 89/136 A(H3N2): 66/136 B: 93/136 Baseline seronegative (Placebo) A(H1N1): 47/67 A (H3N2): 30/67 B: 42/67 LAIV highly immunogenic for H3N2 and B after first dose 2 dose required to induce serum antibodies to H1N1 in most children In baseline seronegative children receiving LAIV, 61% had antibodies to H1N1 and 96% had antibodies to H3N2 and B after 2 doses |
Level I | Good | ||
| 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 season |
N=199 5-71 months old Children from year 1 of trial, (healthy and 34-91 months at Year 1 recruitment) |
Specimens collected pre- and post-challenge 6 months after vaccination Significant difference in serum HAI antibody and nasal wash IgA antibody levels between vaccine and placebo groups Presence of IgA antibody in pre-challenge nasal wash specimens significantly correlated with protection from vaccine virus challenge |
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 1997/98 season |
N=159 Groups based on assignment in year 1 Healthy children 26-85 months from immunogenicity substudy in Year 1 |
Serum collected at baseline and 4 weeks post-vaccination Immunogenicity in LAIV vs. placebo: H1N2: 82% vs 20% H3N2 100% vs 65% B: 100% vs 46% GMT of HAI antibodies LAIV vs. placebo: A/Sydney: 68 vs 12 (p<0.01) |
Level I | Good | ||
| Boyce TG, Gruber WC, Coleman-Dockery SD, et al. Mucosal immune response to trivalent live attenuated intranasal influenza vaccine in children. Vaccine. 1999;18(1-2):82-8 (38). | Trivalent, cold-adapted influenza vaccine Aviron, Mountain View, CA, USA 0.25mL per nostril (106.5 TCID50 per strain) 2 doses 54 days (48-74d) apart |
RCT, double-blind, placebo controlled, multicentre 1996/97 season |
N=19 nvaccine=13 nplacebo=6 Healthy children 15-71 months |
Specimens collected at baseline, 4 weeks after dose 1 and 4 weeks after dose 2 Mucosal antibody response Vaccine generated higher IgA values than placebo for all three antigens Percentage of subjects with response was statistically significant for A/H3N2 and B Seroconversion (≥ 4 fold) A/H3N2 (p=0.01) B (p=0.01) A/H1N1 (p = 0.09) Patients seropositive at baseline were 4.5 times more likely to develop a mucosal response than an HAI response (p = 0.015) |
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 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 seasons South Africa, Brazil, Argentina NCT00192283 D153-P502 |
Year 1 N=334 Year 2 N=524 Healthy influenza vaccine-naïve children 6 to <36 months |
Serum collected at baseline and 35±7 days after final dose in each year Year 1 Seroconversion rates (p>0.03), GMTs, GMFRs, GMFR ratios higher in LAIV-LAIV and LAIV-placebo than placebo only Seroconversion rates (p≤0.037) and GMFRs (p<0.001) after 2 LAIV doses were higher than after one dose compared to LAIV-LAIV and LAIV-placebo Year 2 Seroconversion rates and GMTs increased in each LAIV group postvaccination Overall Baseline seronegative patients had higher seroconversion rates than all subjects in both years |
Level I | Good | ||
| Forrest BD, Pride MW, Dunning AJ, et al. Correlation of cellular immune responses with protection against culture-confirmed influenza virus in young children. Clin Vaccine Immunol 2008;15 (7):1042-53 (57). | CAIV-T Wyeth, Marietta, PA, USA 0.1 mL per nostril (107.0±0.5, 105.0±0.5FFU per strain) A strains antigenically identical, B strains differ: TIV B: Sichuan/379/99 LAIV B: Victoria/504/2000 |
Active and placebo controlled, dose-ranging, exploratory study (immunogenicity) Control vaccine: TIV: FluShield™ 0.25mL (15 µg HA per strain in adult dose of 0.5mL) 2001/02 season NCT00192374 D153-P513 |
N = 162 nCAIV-T 107= 40 nCAIV-T <105= 40 nTIV= 42 nplacebo= 40 Young children |
Serum collected at baseline and 28 days post-vaccination GMFR among all subjects Higher among subjects receiving CAIV-T (107 FFU) for H3N2 and B compared to CAIV-T (105 FFU), TIV and placebo TIV had highest GMFR for H1N1 strain only GMFR among baseline sereonegative subjects Higher among subjects receiving CAIV-T (107 FFU) for all strains Seroconversion CAIV-T (107 FFU) conversation rates higher for H3N2 and B compared to all groups (p<0.042) TIV conversion rates higher for H1N1 (not significant) |
Level III | Poor Study protocol and population unclear |
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| King JC,Jr, Lagos R, Bernstein DI, et al. Safety and immunogenicity of low and high doses of trivalent live cold-adapted influenza vaccine administered intranasally as drops or spray to healthy children. J Infect Dis. 1998 May;177(5):1394-1397 (40). | CAIV-T Aviron, Mountain View, CA, USA 0.25mL per nostril (104, 105, 106, 107 TCID50 per strain) Single dose Dropper or spray delivery |
RCT, placebo controlled, double-blind, multicentre 3 stages: Stage 1: March 1995 Stage 2 & 3: March – May 1996 USA (dropper or spray), Chile (spray only) |
N= 356 Stage 1 n104=57 n105=53 Stage 2 n106=54 Stage 3 n107=60 nplacebo=118 Healthy children 18-71 months |
Serum collected at baseline and 42±7 days post-vaccination Seroconversion Seroconversion for H3N2 and B significantly higher compared to placebo at all doses except H3N2 at 104 TCID Seroconversion for H1N1 occurred only at 107 TCID No significant difference in HAI response at any dose between drop and spray methods |
Level I | Good US participants removed from H1N1 analysis as wild type began circulating before post-vaccination serum collection occurred |
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| 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 Aug; 26(33):4210-4217 (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 |
Serum collected at baseline, 28 days and 6 months post-vaccination; Nasal swab days 3, 14, and 28 post-vaccination No significant increases in median/mean plasma HIV viral load from baseline in any group Median CD4% did not change significantly at any point as a result of vaccination HAI GMT at 4 weeks post-vaccination correlated with HAI GMT prior to vaccination for all strains in both interventions (p<0.0001) LAIV: Inverse relationship between entry HIV RNA plasma levels and HAI GMT for H3N2 TIV: Inverse relationship between entry HIV RNA plasma levels and HAI GMT for all strains TIV induced higher serum HAI titers for H3N2 and B strains, and greater increases in antibody titer compared to LAIV in baseline seropositive children |
Level I | Good | ||
| 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=1120 nLAIV+MMR=747 nplacebo+MMR=373 Both groups received MMR with dose 1 Healthy vaccine-naïve children 11-<24 months |
Serum collected before dose 1 and dose 2 Rubella Per-protocol study definition failed to show non-inferiority: Seroconversion rate for LAIV (78%) vs. placebo (83.9%) had difference in rates with 95% confidence interval (-10.5, -1.0) Post-hoc analysis using ELISA threshold: Seroconversion rate for LAIV (89.8%) vs. placebo (93.4%) had difference in rates with 95% confidence interval (-6.9, -0.1) Mumps Seroconversion rate for LAIV (86.6%) vs. placebo (84.5%) had difference in rates with 95% confidence interval (-2.1, 6.8) Measles Seroconversion rate for LAIV (90.8%) vs. placebo (85.3%) had difference in rates with 95% confidence interval (1.5, 9.9) |
Level I | Good | ||
| Rudenko LG, Lonskaya NI, Klimov AI, et al. Clinical and epidemiological evaluation of a live, cold-adapted influenza vaccine for 3-14-year-olds. Bull World Health Organ. 1996;74(1):77-84 (46). | LAIV (Master donor virus A/Lenin-grad/134/47/57) Institute of Experimental Medicine, St. Petersburg, Russia 0.25mL per dose 2 doses 21-28 days apart Monovalentbivalent, trivalent |
RCT, placebo controlled, multicentre | N=131,930 School children 3-15 years 2 doses given 21-28 days apart Serum and urine sample taken 3 days and 1 month after each dose |
Specimens collected at baseline, 3 days and 1 month after dose 1, 3 days and 1 month after dose 2 Protective levels of antibody induced in mono, bi and trivalent participants Seroconversion Among baseline seronegative individuals: H1N1: 61.0-63.6% seroconverted H3N2: 69.8-73.7% B: 43.7-54.5% |
Level I | Good | ||
| Schiff GM, Linnemann CC, Jr., shea L, et al. Evaluation of a live, attenuated recombinant influenza vaccine in high school children. Infect Immun. 1975;11(4):754-7 (45). | LAIV Experimental lot (Derived from A/England/42/72 and A/PR8/34) 5 drops per nostril (107.5 TCID) |
Active and placebo controlled trial, open label Control vaccine: Bivalent inactivated vaccine (BIV): Fluogen® 0.5mL Wyoming High School, Wyoming, Ohio |
N=126 nLAIV=74 nBIV=24 nplacebo =28 High school students (Gr. 9-12) |
Blood samples collected at beginning and after 30 days; also collected at the end of the study if influenza-like illness reported LAIV 62.2% experienced fourfold or greater rise in antibody titer GMT rose from 30.2 to 189.6 Nine participants lacked pre-existing antibody and developed GMT of 276.2 BIV 79.2% developed increase in antibody titer from GMT 32.9 to 361.8 Placebo No significant seroconversion (GMT 38.1 to 42.0 post-placebo) |
Level II-1 | Poor Relevant inclusion/exclusion criteria not considered; comparability of groups unclear; Randomization feasible but not used |
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| 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 (107TCID) 2 doses in Year 1 ≥28d apart 1 dose in Year 2 Vaccine and circulating B strain not well matched in either year (29.2% distinct in year 1, 77% in year 2) |
RCT, double-blind, placebo controlled, multicentre, crossover 2000/01 and 2001/02 seasons Asia NCT00192244 D153-P501 |
nCAIV-T=111 nplacebo = 52-75 Groups were re-randomized in Year 2 Healthy children 12-<36 months |
Specimens collected pre- and post-vaccination after dose 2 in Year 1 and dose 1 in Year 2 Year 1 GMFR – All (CAIV-T vs placebo) H1N1: 5.0 (3.9, 6.5) vs. 1.2 (1.0, 1.5) H3N2: 17.0 (11.0, 26.4) vs. 1.1 (1.0, 1.4) B: 6.8 (4.9, 9.4) vs. 1.0 (0.9, 1.2) GMFR – Baseline Seronegative (CAIV-T vs. placebo) H1N1: 9.6 (7.2, 12.8) vs. 1.4 (1.1, 1.8) H3N2: 91.0 (64.0, 129.6) vs. 1.2 (0.9, 1.5) B: 11.7 (8.1, 16.8) vs. 1.1 (0.9, 1.3) Seroconversion Seroconversion rates higher in baseline seronegative subjects compared to all subjects with CAIV-T Rate of seroconversion higher in CAIV-T (56.8-95.1%) than placebo (2.1-13.5%) Year 2 Rate of seroconversion and fold-increases statistically significant only in treatments groups receiving CAIV-T in year 2, regardless of serostatus and year 1 treatment |
Level I | 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 |
Level I | Good | ||
| Children and Adults | ||||||||
| Block SL, Yogev R, Hayden FG, et al. Shedding and immunogenicity of live attenuated influenza vaccine virus in subjects 5-49 years of age. Vaccine. 2008;26(38):4940-6 (78). | LAIV FluMist® 0.25mL per nostril (107 TCID50) Single dose |
Phase IV, open-label clinical trial, multi-centre 2004/05 season 1 sites, USA |
N=343 n5-8=102 n9-17=126 n18-49=115 3 age cohorts (5-8, 9-17, 18-49 years) |
Serum collected at baseline and day 28 post vaccination Study endpoints: Strain-specific HAI titers at 28 days immunization and seroresponse (≥4 fold rise in HAI compared to baseline) Seroresponse to any strain in all subjects Age 5-8: 67.7% (57.4, 76.9) Age 9-17: 63.7% (54.6, 72.2) Age 18-49: 47.0% (37.6, 56.5) Seroresponse in baseline seronegative subjects H1N1: 81.1% H3N2: 70.3% B: 29.8% Seroresponse higher in 5-8 and 9-17 groups than 18-49 |
Level II-2 | Good | ||
| 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, double-blind, active and placebo controlled, multicentre Control vaccine: TIV (15μg HA per strain), Year 1 vaccine (bivalent A), trivalent thereafter 1985/86 to 1988-89 seasons 7 sites, Nashville, Tennessee. USA |
N=5210 GroupTIV 1 (n=1739) GroupLAIV 2 (n=1733) Groupplacebo 3 (n=1738) Healthy persons aged 1-65 years (n<15 years=809) |
Serum collected pre-immunization, ~1 month post vaccination, spring after end of influenza season Postimmunization titers increased significantly for TIV and LAIV groups each year, but were higher for TIV than LAIV in all years except 1985 Control group more likely to seroconvert and have confirmed or retrospectively reported illness for all years LAIV group more likely to seroconvert and have confirmed or retrospectively reported illness than TIV group, when H3N2 was circulating, but not when H1N1 was circulating First vaccination: % of participants ≥4-fold increase in HAI; Post-vaccination titer ≥32 H1N1 Control: 5.5 (4.0, 7.3); 60.0 (57.0, 63.0) LAIV: 24.4 (31.0, 38.0); 84.4 (82.0, 87.0) TIV: 69.4 (66.0, 73.0); 91.9 (90.0, 94.0) H3N2 Control: 10.0 (7.5, 13.0); 35.8 (32.0, 40.0) LAIV: 14.2 (11.0, 18.0); 42.2 (38.0, 47.0) TIV: 72.7 (68.9, 77.0); 82.4 (79.0, 86.0) Subsequent vaccination: % of participants ≥4-fold increase in HAI; Post-vaccination titer ≥32 H1N1 Control: 5.21 (3.8, 7.0); 47.1 (44.0, 51.0) LAIV: 17.8 (15.0, 21.0); 82.8 (80.0, 85.0) TIV: 19.4 (17.0, 22.0); 96.8 (95.0, 98.0) H3N2 Control: 5.3 (4.2, 6.6); 23.0 (21.0, 25.0) LAIV: 6.8 (5.5, 8.1); 31.9 (29.0, 34.0) TIV: 16.8 (15.0, 19.0); 73.5 (71.0, 76.0) |
Level I | Good | ||
| Mallory RM, Malkin E, Ambrose CS, et al. Safety and immunogenicity following administration of a live, attenuated monovalent 2009 H1N1 influenza vaccine to children and adults in two randomized controlled trials. PLoS ONE. 2010;5(10):e13755. (48) | LAIV MedImmune 0.25mL per nostril (107 FFU) Monovalent (H1N1) |
RCT, double-blind, placebo controlled, multicentre 2 trials: children (NCT00946101) and adults (NCT00945893) Randomization stratified by site in adults and by age groups (2-8y, 9-17y) in children 2009 season |
Child trial N=326 nLAIV=261 nplacebo=65 Adult trial N=300 nLAIV=240 nplacebo=60 |
Serum collected at days 0 and 57, and participants were randomized for collection for day 15 or 29 Primary endpoint: Proportion of subjects experiencing postvaccination seroresponse in baseline seronegative and in all subjects Secondary endpoint: proportion of subjects with HAI titer ≥32 and HAI GMTs Seroconversion rate (%) in baseline seronegative LAIV (placebo): Children at day 57 – 34.8 (16.1) Children GM ≥32: 19.0% (7.1%) Adults at day 57 – 16.9 (7.1) Adults GM ≥32: 7.4% (2.4%) Seroconversion rate (%) in all LAIV (placebo): Children (all) at day 57 – 32.0 (14.5) GM ≥32: 26.4% (9.7%) Children (2-9y) at day 57 – 28.0 (6.7) GM ≥32: 23.1% (6.7%) Adults at day 57 – 14.9 (5.6) Adults GM ≥32: 13.5% (11.1%) |
Level I | Good | ||
| Sasaki S, Jaimes MC, Holmes TH, et al. Comparison of the influenza virus-specific effector and memory B-cell responses to immunization of children and adults with live attenuated or inactivated influenza virus vaccines. J Virol. 2007;81(1):215 (43). | LAIV FluMist® Single dose (2 dose for vaccine naïve children) |
RCT, active controlled serology Control vaccine: TIV: Fluzone® 2003/04 and 2004/05 seasons |
N=108 nadult=44 nolder children=39 nyounger children=25 Adults: 21-49 years Older children: 5-9 years Younger children: 6 months-4 years Influenza vaccine naive children given 2nd dose 28 days (TIV) or 42 days (LAIV) after first dose Younger children only immunized with TIV (LAIV not licensed for this group) |
Specimens collected for adults and older children at baseline, days 9 (7-12 in adults, 9-11 in older children, 30 (27-42); specimens collected in younger children at baseline and at random on day 9 (9-11) No detectable difference in effector IgA B-cell response in adults or older children after LAIV (p=.125) Adults had higher effector IgA B-cell response than older children after TIV (p=.024) IgG antibody secreting cell (ASC) responses in adults higher after TIV (IgG ASC/million PBMC 41±11) than LAIV (12±4) (p=.005); no significant difference in older children between TIV and LAIV (p=.152) IgG ASC response in adults and older children not significantly different after TIV (p=.287), but children had higher IgG response on average than adults after LAIV (p=.028) IgG B-cell response numerically greater than IgA ASC (p≤.011) after TIV in adults and older children, and after LAIV in children (p=.004) IgA and IgG ASC not detectably different in adults after LAIV (p=.109) No statistical difference in B-cell response, effector IgA, IgG B-cell response, IgA ASC or IgG ASC in younger children after first vs. second dose of TIV IgG ASC response lower in younger children than older children and adults Serum antibody response with ≥4 fold rise in HAI/neutralization (LAIV vs. TIV) Adults: 15.8/21.1% vs. 43.5/52.2%; p≤.048 Children: 26.7/37.5% vs. 78.9/78.9%l; p≤.012 |
Level I | Good | ||
| Adults | ||||||||
| 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 |
Plasma HIV RNA PCR levels stable in LAIV and placebo HIV-infected individuals Slight decline in CD4 cells post-vaccination in HIV-infected, but magnitude of difference was not significant between placebo and LAIV groups Few participants had seroresponse to LAIV (≥4-fold rise in HAI titer) |
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 controlled, community-based Control vaccine: TIV: Fluzone® 0.5mL (15μg HA per strain) 2004/05 season CT: 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) |
Specimens collected at baseline, 3-5 weeks post-vaccination and end of influenza season (April-May 2005) Participants (%) showing ≥4-fold increase in HAI (TIV vs. LAIV) A/H3: 348 (66.7) vs. 110 (21.2), p<.001 B: 445 (85.2) vs. 70 (13.5), p<.001 A/H1: 367 (70.3) vs. 44 (8.5), p<.001 |
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 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) 995/96 season AV003 NCT: 2 sites, USA |
N=92 nCAIV-T=29 nTIV=32 nplacebo=31 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 |
Serum collected at baseline and on day 28 post-vaccination Serum HAI response in placebo significantly different from TIV but not CAIV-T Nasal secretion antibody response (sIgA) more frequent in CAIV-T and TIV compared to placebo, but were not significantly different from each other Serum antibody response in all subjects (pre GMT, post GMT; % response with ≥4-fold increase in HAI) H1N1 CAIV-T – 4.8, 9.8; 23 TIV – 4.9, 199.0; 91 Placebo – 5.8, 11.8; 16 H3N2 CAIV-T – 6.1, 14.3; 33 TIV – 11.0, 99.5; 76 Placebo – 9.3, 11.9; 6 B CAIV-T – 18.8, 19.4; 3 TIV – 17.4, 133.5; 76 Placebo – 15.3, 15.3; 0 |
Level I | Good Limited sample size, low rates of infection/illness in placebo recipients |
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| 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: TIV, 0.5mL (15μg HA per strain) 1987-88, 1988-89 seasons 3 large nursing homes in NY |
N=523 TIV + placebo TIV+ intranasal monovalent LAIV Participants received TIV and were re-randomized for placebo or LAIV each year Elderly - 95% >65 years, 75% female |
Serum collected at baseline, day 28 after vaccination and 1 month after end of influenza season in years 2 and 3 No difference observed in frequency of serum HAI or IgG EIA titers in TIV + placebo vs. TIV+ LAIV groups No correlation found between pre-vaccine HA titers and HAI response post-vaccination |
Level I | Fair Nasal secretory antibody titers not determined |
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