ARCHIVED - Canada Communicable Disease Report

 

Volume 37 • ACS-7
November 2011

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

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

Table 10: Summary of Evidence for NACI Recommendation(s)



Evidence related to efficacy of FluMist®
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

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

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 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=2784
nCAIV-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-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 (107 TCID)

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

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)
Vaccine efficacy against any subtype
83.8% (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±0.5 FFU 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

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, multicentre

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 healthcare visits by 8.9% (90% CI: 1.5, 15.8); missed days of school by 16.2% (90% CI: 10.4, 21.6) Few reports of influenza-associated AOM reported; no significant difference between groups for all AOM episodes

Level I

Good

Fleming DM, Crovari P, Wahn U, et al. Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma. Pediatr Infect Dis J. 2006;25(10):860-9.21

CAIV-T
FluMist®

0.1mL per nostril (107 TCID50 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

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, multicentre

Control vaccine:
TIVFluzone®
(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 Appendix23)
- 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
Appendix23)
- antigenically similar strains: 24.5% (-89.8, 71.0)
- antigenically dissimilar strains: 63.4% (18.9, 84.7)

Level I

Good

Adults

Nichol KL, Mendelman PM, Mallon KP, et al. Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial. JAMA. 1999;282(2):137-44.26

LAIV

0.25mL per nostril

1 dose

A/H3N2 strains not well matched to vaccine. (A/Sydney/H3N2 predominantly circulating strain)

Randomized double-blind placebo controlled trial, multi-centre

AV009

1997-1998 influenza season,

13 centres in USA

N=4,561
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, 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)

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

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

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

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
(107 TCID50 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, 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

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

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