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Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for Use of Live Attenuated Influenza Vaccine (LAIV) and Inactivated Influenza Vaccine (IIV) in Children

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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 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

Outcomes valued as critical
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 wheezing[1] Critical Yes
Immediate hypersensitivity/anaphylaxis[2] Critical No
Febrile seizure[2] Critical No
Guillain-Barre syndrome[2] Critical No
Respiratory symptoms[4] Important
Other neurologic outcomes[4] Important
Fever Important Yes
Any related SAE[3] Yes

Table 1 Footnotes

  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

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 months[1] (1609 aged ≥2 years) x x
Belshe, 2007 [4] Randomized, blinded, placebo-controlled 8352 6 through 59 months[1] (4166 aged ≥2 years) x x
Treanor, 2012 [16] Observational, Test-negative case-control 49 2 through 8 years[2] x
Ohmit, 2013 [17] Observational, Test-negative case-control 358 2 through 8 years[2] x
Fry, 2013 [18] Observational, Test-negative case-control 559 2 through 8 years[2] x
Macintosh, 2013 [19] Observational, Test-negative case-control 66 2 through 8 years[2] x
Eick-Cost, 2013 [20] Observational, Test-negative case-control 195 2 through 8 years[2] x

Table 2 Footnotes

  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

LAIV vs. IIV for healthy children aged 2-8 years
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
Laboratory-confirmed influenza (2)
Critical
Not serious[1] Not serious Not serious Not serious 182/4966 398/4971 0.46 [0.39-0.54] 43 fewer [37-49 fewer] 1 High
Laboratory-confirmed influenza–24-71 month olds[2] (2)
Critical
Not serious[1] Not serious Not serious Not serious 117/2873 251/2902 0.47 [0.38-0.58] 46 fewer [36-54 fewer] 1 High
Influenza-associated hospitalization (1)
Critical
Not serious[1] Not serious Serious[3] Serious[4] 12/1048 11/1034 1.08 [0.48-2.43] 1 more [6 fewer-15 more] 3 Low
Influenza-associated acute otitis media (2)
Important
Not serious[1] 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 Quality
With LAIV[5] With IIV Adj. OR [95% CI]
MAARI (1)
Critical
Not serious[1] Not serious Serious Not serious 878/72476 949/71337 0.91[0.77-1.08] 2 Moderate

Table 3 Footnotes

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

LAIV vs. IIV for healthy children aged 2-8 years
Outcome (Studies, n) Value Risk of Bias Inconsistency Indirectness Imprecision Outcome events Effect Quality
With LAIV With IIV Adj. OR [95% CI]
Laboratory-confirmed influenza[1] (5)
Critical
Not serious Not serious Not serious Serious[2] 83/288 257/939

0.74 [0.50-1.08]

4 [Very Low]

Table 4 Footnotes

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

LAIV vs. IIV for healthy children aged 2-8 years: Harms
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-naïve[1] (1)
Critical
Not serious Not serious Not serious Serious[2] 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 vaccinated[1] (1)
Critical
Not serious Not serious Not serious Serious[2] 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 vaccinated[1] (1)
Critical
Not serious Not serious Not serious Serious[3] 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°C[4] (2)
Critical

Not serious[5] Not serious Not serious Serious[3] 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 serious[5] Not serious Not serious Serious[2] 8/5280 9/5289 0.90 [0.34-2.37] 0 fewer [1 fewer-2 more] 2 Moderate

Table 5 Footnotes

  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

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]
Laboratory-confirmed influenza
Critical
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)

Table 6 Footnotes

  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.

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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.

Table 7: Considerations for Formulating Recommendations

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 influenza-associated 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 laboratory-confirmed 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

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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.

 

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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References

  1. Ahmed, F., U.S. Advisory Committee on Immunization Practices (ACIP) Handbook for Developing Evidence-based Recommendations: Version 1.2 [November 1, 2013]. 2013, Centers for Disease Control and Prevention: Atlanta, GA.
  2. Ashkenazi, S., 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): p. 870-9.
  3. Fleming, D.M., 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): p. 860-9.
  4. Belshe, R.B., et al., Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med, 2007. 356(7): p. 685-96.
  5. Monto, A.S., et al., Comparative efficacy of inactivated and live attenuated influenza vaccines. N Engl J Med, 2009. 361(13): p. 1260-7.
  6. Ohmit, S.E., et al., Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. N Engl J Med, 2006. 355(24): p. 2513-22.
  7. Ohmit, S.E., et al., Prevention of symptomatic seasonal influenza in 2005-2006 by inactivated and live attenuated vaccines. J Infect Dis, 2008. 198(3): p. 312-7.
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  9. Eick, A.A., et al., Comparison of the trivalent live attenuated vs. inactivated influenza vaccines among U.S. military service members. Vaccine, 2009. 27(27): p. 3568-75.
  10. Treanor, J.J., 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): p. 899-906.
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  12. MedImmune Vaccines, I., Package Insert for FluMist Quadrivalent Intranasal Spray. 2013. p. 25.
  13. Prevention and control of seasonal influenza with vaccines. Recommendations of the Advisory Committee on Immunization Practices–United States, 2013-2014, in MMWR Recomm Rep. 2013, Centers for Disease Control and Prevention. p. 1-43.
  14. Clover, R.D., et al., Comparison of heterotypic protection against influenza A/Taiwan/86 (H1N1) by attenuated and inactivated vaccines to A/Chile/83-like viruses. J Infect Dis, 1991. 163(2): p. 300-4.
  15. Neuzil, K.M., et al., Efficacy of inactivated and cold-adapted vaccines against influenza A infection, 1985 to 1990: the pediatric experience. Pediatr Infect Dis J, 2001. 20(8): p. 733-40.
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  17. Ohmit, S.E., et al., Influenza Vaccine Effectiveness in the 2011-2012 Season: Protection Against Each Circulating Virus and the Effect of Prior Vaccination on Estimates. Clin Infect Dis, 2013.
  18. Centers for Disease, C. and Prevention, Interim adjusted estimates of seasonal influenza vaccine effectiveness – United States, February 2013. MMWR Morb Mortal Wkly Rep, 2013. 62(7): p. 119-23.
  19. MacIntosh, V.H., K.J. Tastad, and A.A. Eick-Cost, Mid-season influenza vaccine effectiveness 2011-2012: a Department of Defense Global, Laboratory-based, Influenza Surveillance System case-control study estimate. Vaccine, 2013. 31(13): p. 1651-5.
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  23. Luce, B.R., et al., Cost-effectiveness of live attenuated influenza vaccine versus inactivated influenza vaccine among children aged 24-59 months in the United States. Vaccine, 2008. 26(23): p. 2841-8.

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