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October 2, 2014

Influenza Vaccines for Healthy Children aged 2 through 8 Years—Review of Comparative 

Studies of Live Attenuated Influenza Vaccine (LAIV) and Inactivated Influenza Vaccine (IIV)

METHODS

Background: An adaptation of Grading of Recommendations Assessment, Development, and 

Evaluation (GRADE) methods [1] was used to evaluate relative benefits and harms of live 

attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) for healthy children 

aged 2 through 8 years. As of the 2013-14 influenza season, the Advisory Committee on 

Immunization Practices (ACIP) recommendations stated that healthy children in this age group 

may receive either vaccine, with no preferential recommendation for one over the other. 

Outcome values and evidence of benefits and harms were reviewed in accordance with GRADE 

methods as adopted by the ACIP [1]. The primary policy question was “Should LAIV be 

recommended preferentially over IIV for healthy children aged 2 through 8 years?” 

While several individual studies noted greater relative efficacy of LAIV relative to TIV among 

children [2-4], most studies conducted among adults have generally noted either similar 

efficacy or greater relative efficacy of IIV [5-11]. Because it is unclear at what age the greater 

relative efficacy of LAIV begins to decline, and given considerations to the feasibility of 

implementation of a potential change in program, this assessment focused on younger children. 

The rationale for the selected age range included the following considerations: 1) LAIV is not 

licensed in the U.S. for children under 2 years of age [12], and 2) 8 years is the current upper 

age limit for consideration of whether a child needs one or two doses of influenza vaccine [13], 

and was selected for programmatic consistency. 

Identification and valuation of outcome measures: Efficacy and safety outcomes were 

discussed within the ACIP Influenza Work Group. Outcomes valued as “critical” or “important” 

[1] to policy decisions are summarized in Table 1. One initially selected outcome, “medically 

attended wheezing”, was replaced with “medically significant wheezing” after literature review 

revealed data were available for this similar outcome. Three initially selected safety outcomes 

“febrile seizure”, “immediate hypersensitivity/anaphylaxis”, and “Guillain-Barré syndrome” 

were noted to be sufficiently rare that it would not be possible to draw meaningful 

comparisons between the two vaccines. As a proxy outcome intended to enumerate very rare 

but severe events, these outcomes were replaced with “any related serious adverse event

(SAE)”. Two additional outcomes, “respiratory symptoms” and “other neurologic outcomes” 

were not sufficiently specific to permit data collection. 

Evidence retrieval: Prior to literature retrieval, study inclusion/exclusion criteria were defined.

Included studies pertained to healthy children (i.e., did not specifically seek to enroll children 

with medical conditions conferring higher risk of complications due to influenza), evaluated 

https://www.cdc.gov/vaccines/acip/recs/grade/laiv-child.pdf
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vaccines that were U.S.-licensed or were similar to U.S.-licensed products, and included both 

LAIV and IIV arms (so as to permit comparison within the same population and influenza 

season). Excluded studies included those assessing vaccines dissimilar from U.S.-licensed

products (e.g., virosomal, whole-virus, and adjuvanted vaccines and Russian-manufactured 

LAIV), those exclusively of monovalent influenza A(H1N1)pdm 2009 vaccines, those for which 

inactivated vaccine antigen content was characterized in units other than micrograms of 

hemagglutinin (HA), those for which all participants were outside the indicated age range for 

either vaccine, and those for which outcomes were based upon ICD-9 codes (without clinical or 

laboratory evaluation). For efficacy outcomes, a total of five randomized trials [2-4, 14, 15] and 

six observational studies [16-21] were identified. Among the five randomized trials, three were 

excluded from the analysis: one in which not all influenza cases were laboratory confirmed [14], 

one of children 1 through 15 years of age for which age-stratified data were not available [15], 

and one of children 6 through 17 years of age for which-age stratified data were not available 

and for which having a diagnosis of asthma was an inclusion criterion [3]. Among the six

observational studies, one study of children 5 through 18 years of age for which age stratified 

data were not available for the outcome of interest was excluded [21]. The efficacy assessment 

thus included two randomized trials [2, 4] and five observational studies [16-20]. For safety 

outcomes, observational studies were not included in GRADE analyses because of concerns that 

differences in the health status of the populations receiving LAIV and IIV might affect safety 

endpoints. Of the 5 randomized trials identified during the efficacy outcome search, 2 included 

safety outcomes in the appropriate age group [2, 4]. 

Evidence assessment: Quality of available evidence was graded in terms of risk of bias, 

indirectness, imprecision, and inconsistency and was assessed as “High”, “Moderate”, “Low”, of 

“Very Low” for each outcome [1]. For randomized studies, when summarizing results for 

outcomes in which denominators reported individual participants, pooled weighted risk ratios 

were calculated using a random-effects model. For outcomes for which the denominator was 

expressed as person-time, risk ratios were calculated using the inverse variance method. For 

observational studies, odds ratios (ORs) were transformed by taking the natural logarithm and 

pooling log(OR)s and standard errors using the inverse variance method.

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RESULTS

Assessment of Benefits and Harms

Table 1: Outcomes valued as “Critical” or “Important” to policymaking by the ACIP Influenza 

Work Group

Outcome Importance Data

Available

Benefits (Efficacy)

Laboratory-confirmed influenza Critical Yes

Influenza-associated mortality Critical No

Influenza-associated hospitalization Critical Yes

Medically attended acute respiratory illness Critical Yes

Influenza-like illness Important No

Influenza-associated acute otitis media Important Yes

Harms (Safety)

Medically significant wheezing1 Critical Yes

Immediate hypersensitivity/anaphylaxis2 Critical No

Febrile seizure2 Critical No

Guillain-Barre syndrome2 Critical No

Respiratory symptoms4 Important --

Other neurologic outcomes4 Important --

Fever Important Yes

Any related SAE3 -- Yes

1

Replaced medically attended wheezing. 2

Rare events; insufficient frequency to permit comparison. 3

Added as a means to potentially capture rare but serious events. 

4

Not sufficiently specific to permit assessment.

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Table 2: Characteristics of included studies

Studies Design Number of 

participants

Age group 

evaluated

Efficacy/

Effectiveness Safety

Ashkenazi, 

2006 [2] 

Randomized, 

open-label 

2187 6 through 71 

months1 

(1609 aged ≥2 years)

X X 

Belshe, 

2007 [4] 

Randomized, 

blinded, placebocontrolled

8352 6 through 59 

months1 

(4166 aged ≥2 years)

X X 

Treanor, 

2012 [16]

Observational,

Test-negative case-control

49 2 through 8 years2 X 

Ohmit, 

2013 [17]

Observational,

Test-negative case-control

358 2 through 8 years2 X 

Fry, 

2013 [18]

Observational,

Test-negative case-control

559 2 through 8 years2 X 

Macintosh, 

2013 [19]

Observational,

Test-negative case-control

66 2 through 8 years2 X 

Eick-Cost, 

2013 [20]

Observational,

Test-negative case-control

195 2 through 8 years2 X 

1

Data available for children aged 24 through 71 months for one outcome, laboratory-confirmed 

influenza, from a post-hoc meta-analysis of data from these two studies [22]. 

2

Authors provided data specific to this age group

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Table 3: LAIV vs. IIV for healthy children aged 2-8 years: Benefits—Randomized studies

Outcome

(Studies, n)

Value

Risk of

Bias Inconsistency Indirectness Imprecision

Outcome events Effect

Quality With LAIV With IIV RR

[95% CI]

Risk Difference 

per 1000

with LAIV

Laboratoryconfirmed influenza

(2)

Critical

Not

serious1 

Not

serious

Not

serious

Not

serious 182/4966 398/4971 0.46[0.39-0.54]

43 fewer

[37-49 fewer]

1 

High

Laboratoryconfirmed 

influenza--24-71 

month olds2 

(2)

Critical

Not 

serious1 

Not 

serious

Not 

serious

Not 

serious 117/2873 251/2902 0.47[0.38-0.58]

46 fewer

[36-54 fewer]

1 

High

Influenzaassociated 

hospitalization 

(1)

Critical

Not 

serious1

Not

serious Serious3 Serious4 12/1048 11/1034 1.08

[0.48-2.43]

1 more

[6 fewer-15 more]

3 

Low

Influenzaassociated acute 

otitis media

(2)

Important

Not 

serious1

Not

serious

Not 

serious

Not

serious 28/4964 60/4970 0.47

[0.30-0.73]

6 fewer

[3-8 fewer]

1 

High

Outcome

(Studies, n)

Value

Risk of

Bias Inconsistency Indirectness Imprecision

Outcome events Effect

With LAIV Quality 5 With IIV Adj. OR

[95% CI]

MAARI

(1)

Critical

Not 

serious1

Not

serious Serious Notserious 878/72476 949/71337 0.91

[0.77-1.08]

2 

Moderate

ABBREVIATIONS: adj. OR, adjusted odds ratio; CI, confidence interval; MAARI, Medically attended acute respiratory illness. 1 One trial was open-label [2]. 2 Meta-analysis including these two trials contained data restricted to those children aged 2 years and older. 3 Hospitalizations were for influenza-like respiratory illness that prompted culture, rather than laboratory-confirmed influenza

4 Wide confidence interval; includes 1.0 and exceeds 0.75 in lower bound and 1.25 in upper bound. 5 Denominator was surveillance-days

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Table 4: LAIV vs. IIV for healthy children aged 2-8 years: Benefits—Observational studies

Outcome

(Studies, n)

Value

Risk of

Bias Inconsistency Indirectness Imprecision

Outcome events Effect

With LAIV With IIV Adj. OR Quality

[95% CI]

Laboratory-confirmed 

influenza1

(5) 

Critical

Not

serious

Not

serious

Not

serious Serious2 83/288 257/939 0.74[0.50-1.08]

4 

[Very Low]

1

Authors provided data for subgroup of children aged 2 through 8 years.

2

Wide confidence interval includes 1.0 and exceeds 0.75 in lower bound.

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Table 5: LAIV vs. IIV for healthy children aged 2-8 years: Harms—Randomized studies

Outcome

(Studies, n)

Value

Risk of

Bias Inconsistency Indirectness Imprecision

Outcome events Effect

Quality With LAIV With IIV RR

[95% CI]

Risk Difference 

per 1000 with 

LAIV

Medically

significant wheezing, 42 days--

Following dose 1, vaccine-naïve1

(1)

Critical

Not

serious

Not 

serious

Not

serious Serious2 19/1521 14/1520 1.36[0.68-2.69]

3 more

[3 fewer-16 more]

2 

Moderate

Medically

significant wheezing, 42 days--

Following dose 1, previously 

vaccinated1

(1)

Critical

Not

serious

Not 

serious

Not

serious Serious2 12/666 14/678 0.87[0.41-1.87]

3 fewer

[12 fewer-18 

more]

2 

Moderate

Medically

significant wheezing, 42 days— 

Following dose 2, not previously 

vaccinated1

(1)

Critical

Not

serious

Not 

serious

Not

serious Serious3 16/1424 28/1439 0.58[0.31-1.06]

8 fewer

[13 fewer-1 more]

2 

Moderate

Fever, days 0-10--

≥38.6°C or ≥38.9°C4

(2) 

Critical

Not

Serious5 

Not 

serious

Not 

serious Serious3 189/5095 211/5068 0.89[0.73-1.08]

5 fewer

[11 fewer-3 more]

2 

Moderate

Any related serious adverse 

event (SAE) 

(2)

(Not valued)

Not 

Serious5

Not 

serious

Not 

serious Serious2 8/5280 9/5289 0.90

[0.34-2.37]

0 fewer

[1 fewer-2 more]

2 

Moderate 

1

Data limited to children aged 24 through 59 months.

2

Wide confidence interval; includes 1.0 and exceeds 0.75 in lower bound and 1.25 in upper bound. 3

Wide confidence interval; includes 1.0 and exceeds 0.75 in lower bound.

4

Fever reported differently in the two studies. 5

One trial was open-label.

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Table 6: Evidence summary. 

Focus Outcome (Importance) Design 

(n) 

Findings (difference 

between LAIV and IIV)

Evidence

Quality by 

Outcome

Overall 

Evidence 

Quality

Benefits

Laboratory-confirmed influenza

CRITICAL

RCT (2) Lower risk with LAIV 1

(High)

2 

(Moderate)1 

OBS (5) No difference 4

(Very low)

Influenza-associated 

hospitalization 

CRITICAL

RCT (1) No difference 3 

(Low)

Medically attended acute 

respiratory illness

CRITICAL

RCT (1) No difference 2 

(Moderate)

Acute otitis media

IMPORTANT RCT (2) Lower risk with LAIV 1(High)

Harms 

Medically significant wheezing

CRITICAL RCT (1) No difference 2(Moderate)

2 

(Moderate)

Fever 

IMPORTANT RCT (2) No difference 1(High)

Any related severe adverse event 

IMPORTANT RCT (2) No difference 2(Moderate) 1

For Benefits, quality is taken to be “moderate” rather than “low” because available hospitalization data was 

downgraded for indirectness (respiratory illness-associated hospitalizations rather than influenza-associated 

hospitalizations), and because data were available for two other critical outcomes.

Cost considerations: 

A formal cost analysis was not performed. Such analysis would be complex given the current 

spectrum of available influenza vaccine products available in the United States, and their widely 

variable costs. As of 2013-14, LAIV is available in the U.S. only as a quadrivalent vaccine, while

IIV is available in both quadrivalent and trivalent formulations of highly differing cost. A cost 

effectiveness model compared LAIV3 and IIV3 for younger children and estimated a cost savings 

of USD$45.80 for each child vaccinated with LAIV as compared with IIV [23]. It is unclear how 

applicable such an analysis is at present, given the recent availability of quadrivalent vaccines. 

Private sector process listed in the 2014-15 Vaccines for Children (VFC) price list for trivalent 

IIVs range from $7.65 to $14.81/dose; those for quadrivalent IIV from $14.90 to $21.09/dose. 

The most highly priced quadrivalent IIV4 is similar in cost to LAIV at $22.70 per dose (available 

at: http://www.cdc.gov/vaccines/programs/vfc/awardees/vaccine-management/pricelist/index.html).

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Table 7: Considerations for Formulating Recommendations

Key factor Comments

Evidence type for 

benefits and 

harms

• Overall evidence quality 2 (MODERATE) for efficacy and safety.

• Evidence lacking for some critical outcomes, such as influenzaassociated mortality, febrile seizure, Guillain-Barré syndrome, 

immediate hypersensitivity 

• Available studies not powered to detect rare but serious events

Balance between 

benefits and 

harms

• Benefits outweigh harms

• Modestly better efficacy of LAIV (~46 fewer cases of laboratoryconfirmed influenza per 1000)

• No significant differences in rates of wheezing or fever

Value • ACIP Influenza Work Group placed high value on prevention of 

laboratory-confirmed influenza

Cost-effectiveness • Uncertainty regarding cost benefit given current available range of 

vaccines

LIMITATIONS

• All data reviewed pertain to trivalent influenza vaccines. As of the 2013-14 season, all 

LAIV available in the United States is quadrivalent, and IIV is available in both trivalent 

and quadrivalent formulations. Quadrivalent vaccines met criteria for immunogenic 

non-inferiority compared to trivalent vaccines prior to licensure, and pre-licensure 

studies demonstrated similar safety profiles. 

• It is as yet unknown whether greater relative efficacy is sustained with repeated 

vaccination/increasing age. Comparative studies of LAIV and IIV in adults generally have 

noted either that the two vaccines are similar in efficacy, or that IIV is somewhat more 

effective. The age or degree of previous seasonal vaccine exposure at which relative 

benefits of LAIV decline, or are no longer apparent, is not known. Available RCT data 

include children under 2 years of age; data excluding these children was only available 

for one outcome (laboratory-confirmed influenza). Moreover, available RCT data does 

not include children over 71 months of age. While the age or degree of previous 

seasonal vaccine exposure at which relative benefits of LAIV begins to decline is 

unknown, one additional comparative RCT of older children (aged 6 through 17 years) 

with asthma has also noted greater relative efficacy of LAIV [3]. 

Given these limitations, ongoing evaluation of the relative efficacy of current formulations 

of LAIV and IIV will be important. 

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SUMMARY

Benefits outweigh harms. High value was placed on the prevention of laboratory-confirmed 

influenza. The Work Group recommended that when LAIV is available, it should be used for 

children aged 2 through 8 years (Category A). 

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