Effects of Adverse Events on the Projected Population Benefits and Cost-effectiveness of Using Live Attenuated Influenza Vaccine in Children Aged 6 Months to 4 Years | Infectious Diseases | JAMA Pediatrics | JAMA Network
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February 7, 2011

Effects of Adverse Events on the Projected Population Benefits and Cost-effectiveness of Using Live Attenuated Influenza Vaccine in Children Aged 6 Months to 4 Years

Author Affiliations

Author Affiliations: Child Health Evaluation and Research Unit, Division of Pediatrics, University of Michigan Health System, Ann Arbor (Dr Prosser); Center for Child Health Care Studies, Department of Population Medicine (Drs Prosser and Lieu and Ms Hinrichsen), Harvard Medical School and Harvard Pilgrim Health Care, Boston, Massachusetts; and Division of Emerging Infections and Surveillance Services, National Center for Preparedness Detection and Control of Infectious Diseases, and Coordinating Center for Infectious Diseases (Dr Meltzer), and Influenza Division (Drs Fiore and Bridges and Mr Epperson), Centers for Disease Control and Prevention, Atlanta, Georgia.

Arch Pediatr Adolesc Med. 2011;165(2):112-118. doi:10.1001/archpediatrics.2010.182

Live attenuated influenza vaccine (LAIV) is approved for children 2 years or older without a history of wheezing or asthma.1-3 A recent randomized controlled trial among children younger than 5 years of age found that intranasal LAIV was more effective in preventing laboratory-confirmed influenza compared with inactivated influenza vaccine (IIV), yet these data also suggested an increase in adverse events, such as wheezing, in children younger than 5 years of age who receive LAIV compared with IIV.1 Given that a possible increase in adverse events was of potential concern to providers and parents, we sought to evaluate the effect of these events on cost-effectiveness results. The objective of this study was to evaluate the cost-effectiveness of LAIV using new data on adverse events.


We used a previously validated simulation model, built using standard software (TreeAge Pro 2007 Software, release 1.2; TreeAge Software, Williamstown, Massachusetts), to estimate the effect of influenza vaccination on influenza-related health outcomes and costs among children.4 The decision tree evaluates 3 options: (1) no vaccination; (2) IIV; and (3) LAIV. A simplified schematic of the decision tree is shown in the Figure. Healthy children were divided into subgroups by age: 6 to 23 months, 2 years (24-35 months), and 3 to 4 years. We used a time frame of 1 year but also included the long-term effects of influenza and influenza vaccines (eg, death, long-term sequelae of influenza-related illness, and vaccine-related adverse effects). All effects lasting more than 1 year were discounted at 3% per year. We used a societal perspective. Event probabilities, by age and risk group, were derived from the published literature and were supplemented by expert opinion where data were limited or unavailable (Table 1 and eTable 1 and eTable 2). Additional details of the model structure are available in the eAppendix and have been published previously.4 Modifications to the model specific to this analysis are described later.

Simplified schematic of influenza cost-effectiveness simulation model. *Injection site reaction for inactivated influenza vaccine only.

Simplified schematic of influenza cost-effectiveness simulation model. *Injection site reaction for inactivated influenza vaccine only.

Table 1. 
Modeling Assumptions and Simulation Inputsa
Modeling Assumptions and Simulation Inputsa

Vaccination-related adverse events

This analysis incorporated medically attended wheezing episodes and hospitalization following wheezing, in addition to 4 adverse events included in previous analyses (eAppendix)1,5,22,23,35 Trial data1 included a slight increase in all-cause hospitalization for LAIV compared with IIV, although these increases were not statistically significant; therefore, these probabilities were included in the current analysis as a parameter range that included zero.


Costs included direct medical and opportunity costs (parent travel, waiting, and visit time)4 (Table 1 and eTable 1) The costing year of the analysis was 2006; all costs were adjusted to 2006 US dollars.36 Costs of influenza-related hospitalizations were updated to reflect new data available for costs of influenza-related hospitalizations in children.25

Health outcomes

The model projected 4 different outcomes that were averted through vaccination: influenza episodes, hospitalizations, deaths, and loss of quality-adjusted life-years (QALYs). A QALY attempts to measure a patient's physical health and well-being, including the ability to engage in “normal,” everyday activities. The QALYs lost to a disease or condition, therefore, measure the overall reduction in a patient's well-being, or health-related quality of life, due to an episode of disease and its consequences. We obtained QALY valuations for influenza-related and vaccination-related events from published studies conducted by us and from published data25,27,37,38 (Table 1). A value for the QALYs lost because of an episode of wheezing in a child was not available. We, therefore, used a published estimate of the QALYs lost because of wheezing in an adult experiencing an episode of acute asthma.34


The primary outcome measure was the incremental cost-effectiveness ratio in dollars per QALY saved for vaccination compared with no vaccination (eAppendix). Secondary measures included costs of vaccination and clinical influenza-related events averted per 1000 vaccinated children, dollars per influenza-related event avoided, dollars per hospitalization avoided, and dollars per death averted. One-way sensitivity analyses were conducted on all variables, in which the impact on the cost-effectiveness ratio was examined by altering each variable within the range of given values (Table 1). We also conducted a sensitivity analysis that examined the effect of increasing all-cause hospitalization following vaccination with LAIV (ie, a possible vaccine-related adverse effect). A probabilistic sensitivity analysis was also conducted (ie, a Monte Carlo analysis was conducted).


Health benefits, risks, and costs

For lower-risk children aged 2 to 4 years, LAIV was projected to avert more episodes of influenza, influenza-related hospitalizations, and deaths than IIV per 1000 children vaccinated. However, adverse events were projected to be higher for LAIV than for IIV. All vaccination strategies had a net health benefit compared with no vaccination, as measured by QALYs gained. Costs of vaccination were projected to be higher for LAIV compared with IIV, reflecting both higher costs of the vaccine dose and higher probabilities of adverse events and associated costs for LAIV (Table 2).

Table 2. 
Health Benefits, Risks, and Costs of Influenza Vaccination for Lower-Risk Children Aged 6 Months to 4 Yearsa,b
Health Benefits, Risks, and Costs of Influenza Vaccination for Lower-Risk Children Aged 6 Months to 4 Yearsa,b


For lower-risk children aged 2 and 3 to 4 years, vaccination with either IIV or LAIV resulted in a net cost both in terms of cost per influenza episode averted and cost per QALY saved (Table 2 and Table 3 and eTable 3). In 1-way sensitivity analyses, results were not sensitive to variables representing incidence, cost, or quality adjustment for wheezing following vaccination with LAIV (eFigure 1). Cost-effectiveness ratios were most sensitive to changes in the probability of influenza illness, probability of influenza-related hospitalizations, and total vaccination costs (eFigure 1). For a possible increase in the probability of all-cause hospitalization following vaccination with LAIV greater than 0.006, IIV would become the preferred strategy because LAIV would become more costly and save fewer QALYs (ie, LAIV is dominated by IIV) as this probability increased (eFigure 2 and eTable 4).

Table 3. 
Cost-effectiveness Ratios for Vaccination Using IIV and LAIV Compared With No Vaccination for Lower-Risk Children Aged 6 Months to 4 Years
Cost-effectiveness Ratios for Vaccination Using IIV and LAIV Compared With No Vaccination for Lower-Risk Children Aged 6 Months to 4 Years


Major findings

Vaccinating lower-risk children using either LAIV or IIV did not generate cost savings but yielded cost-effectiveness ratios less than $40 000 per QALY gained for children aged 6 months to 4 years. For children in this age group, vaccination with LAIV yielded slightly more favorable mean cost-effectiveness ratios than IIV under a wide range of assumptions about the incidence of adverse events but confidence intervals for cost-effectiveness ratios were overlapping for the 2 vaccination strategies. We found the addition of wheezing-related adverse events had little impact on the cost-effectiveness of vaccination with LAIV (Table 3). Even after the inclusion of wheezing-related adverse events, vaccination with LAIV resulted in health benefits that outweighed vaccine adverse events as measured by QALYs.


These findings are similar to results from a previous analysis using an earlier version of this simulation model.4 The current analysis revised the previous model to incorporate newly identified potential adverse events for LAIV, revised assumptions regarding the relative incidence of previously identified adverse events for LAIV and IIV, and new data on the costs of influenza-related hospitalizations for children. The key findings remain robust to the inclusion of new data on adverse events and hospitalization costs: cost-effectiveness ratios for vaccination of healthy children younger than 5 years are favorable compared with other well-accepted pediatric interventions. These results are also consistent with other published analyses of influenza vaccination in children that also demonstrated cost savings or cost-effective results for vaccination in similar age groups but that did not consider new adverse events.39

One potential limitation of this analysis is the exclusion of herd immunity effects. If these effects were considered, they would likely result in more favorable cost-effectiveness ratios for vaccination options. In addition, published data were not available for some key variables, such as quality adjustments for a wheezing episode and hospitalizations following vaccination, and our analysis used values from similar health states not associated with vaccination. The current analysis assumes that hospitalizations following vaccination have the same loss in quality of life associated with an influenza-related hospitalization. However, parents may place a greater value for the loss in quality of life due to a vaccination-related adverse event and that loss would not be fully captured herein.32

We used data on the loss in QALYs associated with wheezing events in adults because values for children were not available. This approach may underestimate the loss in quality of life associated with wheezing in children, because we have shown that respondents valued influenza health states in children as associated with a greater loss in quality of life (L.A.P., K. Payne, PhD, D. Rusinak, BA, P. Shi, MA, T. Uyeki, MD, MPH, M. Messonnier, PhD, “Value in Health,” unpublished data, December 2007); however, sensitivity analysis for this parameter did not demonstrate a substantial effect on results.

This analysis assumes that vaccine effectiveness does not vary by age whereas recent data have suggested that the relative effectiveness of LAIV compared with IIV may be greater in very young children.1 This would have some effect on cost-effectiveness ratios as demonstrated by 1-way sensitivity analyses that indicate that cost-effectiveness ratios could vary as much as 25% to 50% when using the upper and lower bounds of plausible ranges for vaccine effectiveness. However, given the substantial uncertainty associated with the base case estimates (Table 2 and Table 3), the main conclusion that the cost-effectiveness ratios for LAIV and IIV are not significantly different would likely hold even for the younger age groups. Future research should explore the variation of vaccine effectiveness by age on cost-effectiveness.


The cost-effectiveness of influenza vaccination for children remains favorable when considering new data for vaccine adverse effects. Cost-effectiveness ratios were comparable for LAIV and IIV for low-risk children aged 6 months to 4 years. Postlicensing safety studies of both LAIV and IIV in children should continue to monitor wheezing-related adverse advents, including all-cause hospitalization.

Correspondence: Lisa A. Prosser, PhD, Division of General Pediatrics, University of Michigan Health System, 300 N Ingalls St, Room 6E14, SPC 5456, Ann Arbor, MI 48109 (lisapros@med.umich.edu).

Accepted for Publication: August 3, 2010.

Author Contributions:Study concept and design: Prosser, Meltzer, Fiore, Bridges, and Lieu. Acquisition of data: Prosser, Meltzer, Epperson, Bridges, and Hinrichsen. Analysis and interpretation of data: Prosser, Meltzer, Fiore and Bridges. Drafting of the manuscript: Prosser, Meltzer, and Fiore. Critical revision of the manuscript for important intellectual content: Prosser, Meltzer, Fiore, Epperson, Bridges, Hinrichsen, and Lieu. Statistical analysis: Prosser and Meltzer. Obtained funding: Prosser, Fiore, Bridges, and Lieu. Administrative, technical, and material support: Epperson, Bridges, Hinrichsen, and Lieu. Study supervision: Prosser and Fiore.

Financial Disclosure: None reported.

Funding/Support: Funding for this study was provided by the Centers for Disease Control and Prevention (CDC) through the Harvard/CDC Joint Initiative in Vaccine Economics.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the CDC. This project was conceived and conducted primarily at the Department of Population Medicine (formerly the Department of Ambulatory Care & Prevention) at Harvard Medical School and Harvard Pilgrim Health Care.

Online-Only Material: The eAppendix, eFigures, and eTables are available at http://www.archpediatrics.com.

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    1 Comment for this article
    Live Attenuated Influenza Vaccine and the Incidence of Wheezing Postvaccination
    Christopher S. Ambrose, MD | MedImmune, LLC,
    In their recent article, Prosser et al. examined the impact of vaccine-associated adverse events, particularly postvaccination wheezing, on the cost-effectiveness of vaccinating young children with live attenuated influenza vaccine (LAIV).1 The authors included LAIV- associated wheezing risks of 1.21, 0.37, and 0.16 per 100 vaccinated children aged 6-23 months, 24-35 months, and 36-59 months, respectively. LAIV is not approved for use in children 6-23 months of age because a small increase in postvaccination wheezing was observed between days 7 and 28 following the first vaccination in a large, randomized, controlled trial.2 However, the rationale for the authors' inclusion of LAIV- associated wheezing risks for children 24-35 and 36-59 months of age is not clearly addressed in the article. Although not explicitly stated, we believe that the LAIV-associated wheezing rates for recipients 24-35 and 36-59 months of age were included as hypothetical scenarios; if so, we agree that inclusion of these rates is appropriate to address the public health question raised. However, for the benefit of readers, the available data do not support an association between LAIV and an increased risk of wheezing postvaccination among children 24 months of age and older. In fact, in the overall cohort of children 24-59 months of age in the study by Belshe et al., 2.1% of LAIV recipients versus 2.5% of trivalent inactivated virus (TIV) recipients experienced medically significant wheezing through 42 days following vaccination.1, 3, 4 We realize that the authors demonstrated that the presence of a small increased risk of wheezing has little impact on LAIV cost-effectiveness. However, the presence or absence of a wheezing risk is relevant for parents and pediatric healthcare providers when evaluating influenza vaccine options.
    Additionally, it is worth noting that Luce et al also evaluated the cost-effectiveness of LAIV and TIV among children 24-59 months of age using data from the randomized trial by Belshe et al. and identified net cost savings with LAIV compared with TIV.5
    1. Prosser LA, Meltzer MI, Fiore A, et al. Effects of Adverse Events on the Projected Population Benefits and Cost-effectiveness of Using Live Attenuated Influenza Vaccine in Children Aged 6 Months to 4 Years. Arch Pediatr Adolesc Med. October 4 2010:archpediatrics.2010.2182.
    2. Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med. Feb 15 2007;356(7):685-696.
    3. Belshe RB, Ambrose C, Yi T. Safety and efficacy of live attenuated influenza vaccine in children 2-7 years of age. Vaccine. 2008;26S:D10-16.
    4. FluMist®. Influenza Virus Vaccine Live, Intranasal, Full prescribing information. 2010.
    5. Luce BR, Nichol KL, Belshe RB, et al. Cost-effectiveness of live attenuated influenza vaccine versus inactivated influenza vaccine among children aged 24-59 months in the United States. Vaccine. Jun 2 2008;26(23):2841-2848.

    Conflict of Interest: Dr. Ambrose is an employee of MedImmune, LLC. Dr. Belshe has served as a consultant and/or member of a speaker's bureau for MedImmune, GlaxoSmithKline, and Novartis.