Vaccinating children earlier (ie, September or October) can provide net economic benefit to society and to third-party payers. Vaccination of children remained cost-effective through December.
To determine how much should be invested each year to encourage and operationalize the administration of influenza vaccine to children before November and how late the vaccine should be offered each year.
Monte Carlo decision analytic computer simulation models.
The children’s influenza vaccination timing model quantified the incremental economic value of vaccinating a child earlier in the influenza season and the incremental cost of delaying vaccination. The children’s monthly influenza vaccination decision model evaluated the cost-effectiveness of vaccinating versus not vaccinating for every month of the influenza season.
Getting children vaccinated by the end of October rather than when they are currently getting vaccinated could save society between $6.4 million and $9.2 million plus 653 and 926 quality-adjusted life-years (QALYs) and third-party payers between $4.1 million and $6.1 million plus 647 to 942 QALYs each year. Decision makers may want to continue offering influenza vaccination to children at least through the end of December. Vaccinating with trivalent inactivated virus vaccine was more cost-effective than vaccinating with live attenuated influenza vaccine for every month.
Policymakers could invest up to $6 million to $9 million a year to get children vaccinated in September or October without expending any net costs.
(Am J Manag Care. 2010;16(3):e75-e85)
The 2009 influenza A(H1N1) pandemic, as well as past influenza seasons, demonstrated the feasibility of administering seasonal influenza vaccine to children by September or October.
The Advisory Committee on Immunization Practices (ACIP) has identified children as a high-risk group for influenza and recommends that children (aged 6 months to 18 years) receive influenza vaccine each year.1,2 The 2009 influenza A(H1N1) (H1N1) pandemic highlights the importance of the timing of influenza vaccination as decision makers have endeavored to get vaccines to priority groups as soon as possible. While the presumption is that earlier vaccination is better so that a child is protected for a greater proportion of the influenza season, studies to date have not quantified how the economic value of vaccination may change with the timing of vaccine administration. Moreover, it is unclear how late in the influenza season vaccination still should be offered. Quantifying how the vaccine’s economic value changes with the timing of vaccination may be important for vaccine production, distribution, and administration planning.
The 2009 H1N1 pandemic demonstrated the feasibility of manufacturing, delivering, and administering seasonal influenza vaccine by September or October.3 Manufacturers and the supply chain were able to expeditiously produce and distribute seasonal influenza vaccine, despite manufacturing H1N1 influenza vaccine concurrently.4-6 In fact, studies6,7 have shown that in past years more than 70% of seasonal influenza vaccines have been available for administration by October. With evidence suggesting that earlier vaccination is possible, the next question is how much should be invested to ensure timely vaccination? The answer to this question depends in large part on the economic effect of delaying vaccination. Investment could occur all along the supply chain, from the very beginning (eg, investing to expand vaccine production capacity or to use antigen-sparing technology) to the very end (eg, investing to improve access to immunization clinics, school-based programs, health fairs, and healthcare provider visits). To address these issues, we constructed the following 2 sets of computer simulation models for children aged 2 to 18 years: (1) the children’s influenza vaccination timing model, to quantify the incremental economic value of vaccinating a child earlier in the influenza season and the incremental cost of delaying vaccination, and (2) the children’s monthly influenza vaccination decision model, to determine the cost-effectiveness of vaccinating versus not vaccinating a child for every month of the influenza season.
We used TreeAge Pro 2009 (TreeAge Software, Williamstown, MA) to develop 2 models (the children’s influenza vaccination timing model and the children’s monthly influenza vaccination decision model) that each fed into a pediatric influenza outcomes subtree. The models depicted 1 full influenza season, with the baseline scenario assuming a societal perspective (accounting for direct and indirect illness costs), and an additional scenario assuming the third-party payer perspective (direct illness costs only). Details of the models are as follows.
Children’s Influenza Vaccination Timing Model
The children’s influenza vaccination timing model Monte Carlo decision analytic computer simulation model determined the incremental cost-effectiveness of administering influenza vaccine to a child at different months of the influenza season (September to June) (Figure 1). Each vaccinated patient has a probability of experiencing local adverse effects (requiring 1 day of ibuprofen treatment) or systemic adverse effects (requiring 3 days of ibuprofen treatment). Vaccination confers immunity 2 weeks after administration. Vaccinated patients have a decreased probability of contracting influenza if exposed. Exposure to influenza is a function of the time left in the influenza season. Patients who contract influenza then proceed through the pediatric influenza outcomes subtree.
Children’s Monthly Influenza Vaccination Decision Model
The children’s monthly influenza vaccination decision model characterized the decision of whether to vaccinate a patient in a specific given month (Figure 2). For example, if a patient is seen in February, is it still cost-effective to vaccinate the patient? Separate models were created for each month of the year from September to June, encompassing the influenza season. Similar to the children’s influenza vaccination timing model, patients who are vaccinated have chances of developing local or systemic adverse effects. Vaccination confers immunity after 2 weeks and reduces the probability of contracting influenza if exposed. Exposure to influenza is a function of the time left in the influenza season. Patients who contract influenza then proceed through the pediatric influenza outcomes subtree.
Pediatric Influenza Outcomes Subtree
For both sets of models, patients who develop influenza have probabilities of self-medicating with over-the-counter medications, visiting an outpatient clinic, or being hospitalized. Hospitalized patients have a probability of not surviving. Vaccination status affects these probabilities.
Trivalent Inactivated (Killed) and Live Attenuated Influenza Virus Vaccines
Different scenarios looked at trivalent inactivated virus vaccine (TIV) and live attenuated influenza vaccine (LAIV). This involved changing the costs and the efficacy variable values to match each vaccine, as summarized in Table 1.
The following equation computed the incremental costeffectiveness ratio (ICER) of vaccine administration in a given month versus another comparison month: (Cost of Vaccinating in Baseline Month − Cost of Vaccinating in Comparison Month)/(Effectiveness of Vaccinating in Baseline Month − Effectiveness of Vaccinating in Comparison Month).
To assess if vaccinating is cost-effective, the threshold used in our model was $50,000/quality-adjusted life-year (QALY), which is a frequently cited criterion for cost-effectiveness analysis in the United States.21 Based on nonparametric estimates by Shiroiwa et al,22 this US cost-effectiveness threshold was similar to previously reported thresholds.
National Investment Using the Children’s Influenza Vaccination Timing Model
Using the children’s influenza vaccination timing model, we then constructed a model to project the potential economic value (from the societal and third-party payer perspectives) of moving the current timing of pediatric vaccination to October throughout the United States. The US Census data (http://www.census.gov/) from 2008 provided the sizes of the different age groups as follows: 2 to 4 years (21,005,852 children), 5 to 9 years (20,065,249 children), 10 to 14 years (20,054,627 children), and 15 to 18 years (21,514,358 children). Vaccination coverage among children was obtained from previous studies23,24 by the Centers for Disease Control and Prevention (CDC).
Table 1 lists the models’ data inputs, their respective distributions, and their sources. The cost of vaccine was the average wholesale price of TIV and LAIV, respectively.8 The cost of over-the-counter medications comprised the average wholesale price of acetaminophen (triangular distribution).8 The cost of hospitalization for influenza was obtained from the National Inpatient Survey of the Healthcare Cost and Utilization Project (HCUP).9 The cost of death was derived from differences in invasive pneumococcal disease costs in adults discharged alive versus those not surviving, which varied from $3700 to $14,000 based on HCUP data.10,25 The cost of an outpatient visit was obtained from a systemic review article11 regarding the effectiveness of vaccinating healthy children. The cost of vaccine adverse effects consisted of the average wholesale price of ibuprofen, assuming 1 to 3 days of ibuprofen treatment.8 Productivity losses from an outpatient visit comprised 4 hours of lost median wages (incurred by a parent missing 4 hours of work to bring a child to the clinic).12
Durations of clinic visits (in hours) and influenza (in days) were obtained from previous studies.10,13,14 Cochrane15,16 systematic reviews provided probabilities of influenza and vaccine efficacy (in preventing influenza, hospitalization, and death). Probabilities of various influenza outcomes were obtained from a CDC study.17 Probabilities of vaccine adverse effects were obtained from a 2007 study.18
All utility variables drew from triangular distributions and are expressed in QALYs; all other variables drew from normal and beta distributions.19,20,26 When possible, data inputs were obtained from published meta-analyses. The CDC27 monthly influenza surveillance data from 2000 to 2008 were used to generate the distribution of monthly influenza risk. Each simulation run randomly drew from 1 of 9 influenza seasons from 2000 to 2008.
A 3% discount rate converted costs and effectiveness measures into 2009 values. Effectiveness was expressed in QALYs. Each patient who experienced neither vaccine adverse effects nor influenza accrued 1.00 QALY.26 The occurrence of vaccine adverse effects, influenza, or hospitalization each caused relative QALY reductions.19,20 Death resulted in a QALY loss based on the QALY-adjusted life expectancy of that patient’s age.28
Sensitivity analyses varied variable values across the ranges listed in Table 1. We also looked specifically at how the age of the vaccine recipient (2-18 years) affected our results. This involved cohorts of the following age groups: 2 to 4, 5 to 9, 10 to 14, and 15 to 18 years. In addition, specific scenarios examined how much could be invested per child to encourage earlier vaccination with vaccination still remaining cost-effective.
Probabilistic (Monte Carlo) sensitivity analyses examined the effects of varying all variables simultaneously using all distributions in Table 1.
Children’s Influenza Vaccination Timing Model
Each simulation run comprised sending 5000 simulated patients 1000 times through the model, for a total of 5 million trials. Simulations found September and October to be the optimal months for vaccination, dominating other months (ie, yielding lower costs and greater effectiveness than other months).
For TIV, delaying vaccination until November cost society an additional $0.13 to $0.26 and 0.000016 to 0.000018 QALY per patient and cost third-party payers an additional $0.08 to $0.16 and up to 0.000017 QALY per patient. For LAIV, delays were even more costly for society (an additional $0.18-$0.37 and 0.000024-0.000025 QALY per patient) and for third-party payers (an additional $0.10-$0.27 and 0.000024-0.000026 QALY per patient).
Various scenarios explored the effects of investing different amounts of money per child to facilitate October vaccination. For TIV, October vaccination remained cost-effective up to and including a $0.75 per child investment (the ICER from the societal perspective ranged from $27,901-$36,413 per QALY and from the third-party payer perspective ranged from $33,191-$39,490 per QALY). For LAIV, October vaccination remained cost-effective up to and including a $1.25 per child investment (the ICER from the societal perspective ranged from $36,538-$46,266 per QALY and from the third-party payer perspective ranged from $41,431-$48,282 per QALY). This reinforced that delaying vaccination for LAIV was worse than delaying vaccination for TIV.
National Investment Using the Children’s Influenza Vaccination Timing ModelTable 2 and Table 3 summarize the national investment results from the societal and third-party payer perspectives, respectively. The tables give the number of children who are currently being vaccinated in each month after October and then the potential value of moving all these vaccinations to before November. As summarized in Table 2, the potential total savings is between $6.4 million and $9.2 million from the societal perspective, suggesting that society could invest this much money into vaccinating children before November. In addition, this could save between 653 and 926 QALYs. As summarized in Table 3, the potential total savings for third-party payers is between $4.1 million and $6.1 million, with an accompanying 647 to 942 QALYs saved.
Children’s Monthly Influenza Vaccination Decision Model
Each simulation run comprised sending 1000 simulated patients 1000 times through the model, for a total of 1 million trials. Table 4 summarizes the results from these simulation runs for each month. Using the $50,000 per QALY threshold, TIV remained cost-effective through December for society ($33,639-$44,511 per QALY) and for third-party payers ($32,823-$48,847 per QALY). After December, the ICER of vaccination exceeded $50,000 per QALY (the shaded area in Table 4). Results changed with LAIV. Vaccinating patients with LAIV remained cost-effective only through November for society ($28,988-$38,350 per QALY) and for third-party payers ($33,497-$41,038 per QALY). The ICER for LAIV vaccination quickly exceeds $50,000 per QALY in December and onward. By March, no vaccination dominates vaccination for TIV and for LAIV. In other words, vaccination not only costs more but also resulted in decreased effectiveness.
For every month, TIV is more cost-effective than LAIV. For example, in October from the societal perspective, TIV’s ICER ranged from $21,005 to $29,355 per QALY, while LAIV’s ICER ranged from $27,055 to $34,074 per QALY (Table 4). From the third-party payer perspective, this trend held as well: TIV’s ICER in October ranged from $26,507 to $32,327 per QALY, while LAIV’s ICER ranged from $31,387 to $38,337 per QALY.
Advantages of Earlier Vaccination
Our results demonstrate how the economic value of influenza vaccine for children can vary substantially with the timing of vaccine administration and can rapidly decay with delays in vaccination. Earlier vaccination has the following potential advantages:
Preventing November and December Cases. A substantial number of influenza cases occur in November and December and can only be prevented if influenza vaccine is administered at least 2 weeks before this time (because influenza vaccine typically takes 2 weeks to achieve seroprotection).
Protecting Against Early Peaking Influenza Seasons. Some influenza seasons over the past decade have arrived earlier than usual. This makes earlier protection even more valuable.
Achieving Early Local Herd Immunity. Our study may in some ways underestimate the value of earlier vaccination because it could achieve earlier local herd immunity and reduce local influenza risk, as suggested by findings of previous studies.29 In other words, immunizing a large proportion of children in a school before influenza enters the population may impede the spread of influenza and confer protection to unvaccinated children. Our model did not explicitly model herd immunity because effects may vary significantly among populations.
Decreasing Inventory Holding Costs. Another potential benefit of earlier vaccination is decreasing the length of time different locations (including clinics) must store influenza vaccine. Inventory costs are not insignificant, especially in places with limited refrigerator space, and they vary significantly among locations.
Therefore, while efforts have focused on increasing vaccine coverage among children, focusing on earlier vaccination may be worthwhile as well. Although some recent studies30-32 have focused on the importance of administering vaccine early during a pandemic, the literature to date is sparse on the issue of seasonal influenza vaccine timing. A study33 in Israel demonstrated that the effectiveness of influenza vaccine decreases with later administration during the influenza season. A multistate case-cohort study34 examined but did not focus on pediatric vaccination timing. The ACIP1,2 has advocated influenza vaccination in October or November. However, little is known about whether parents understand the effect of seasonal influenza vaccination timing or the extent to which clinics, local health departments, workplaces, and other vaccination locations are encouraging earlier vaccination.
Evidence suggests that earlier vaccination is feasible and would not result in decreased vaccine efficacy.35,36 Manufacturing, supply chain, and vaccine administration capacity did not prevent the expeditious rollout of seasonal influenza vaccine in August and September 2009. In addition, strain selection ypically occurs in January or February before the influenza season, leaving more than the typical 4 to 6 months required for traditional egg-based vaccine production, which suggests that promoting October vaccination will not adversely affect vaccine efficacy.35,36 The fact that historically more than 70% of seasonal influenza vaccines are available to be administered by October but more than 50% of children are vaccinated after October implies that the vaccination delays have not been due to inherent production timeline constraints.37 In other words, promoting earlier vaccination may not require earlier development or substantially strain distribution systems.
Decision makers (eg, policymakers, manufacturers, distributors, third-party payers, administrators, clinicians, and school officials) can take various steps to get vaccines to children earlier. They can increase access (eg, making hours and locations more convenient) to vaccination locations (eg, clinics or alternative locations), order vaccines further in advance, and initiate vaccination campaigns sooner. Educational and awareness programs may convince parents to bring their children to vaccination locations more promptly. Parents and schools may be important targets. Parental availability can affect when their children are vaccinated. Working parents may struggle to find time to bring their children to physician offices. School-based vaccination campaigns could help vaccinate children who would otherwise wait until their next scheduled physician visits.
Investment can come in many forms such as supporting facilities and personnel to expand vaccination availability during off-hours and weekends, increasing refrigerator capacity, and conducting educational campaigns. Another possibility is financial incentives to patients or physicians to vaccinate earlier. However, results of prior studies38-40 have been equivocal about the potential effectiveness of such incentives.
Making such operational changes to ensure timely vaccination may require some investment.41-43 Our results suggest that October remains cost-effective even when investing up to $0.75 to $1.25 per child. In other words, there may be some room for investment to ensure that children are vaccinated earlier. Decision makers may consider committing resources to enhance vaccine production, shipping, and distribution. Other possibilities are increasing the number of vaccination locations (eg, schools or health fairs) and the hours of availability. They also may want to include the timing concept in vaccine education and awareness campaigns. Another possibility is direct financial incentives to parents who normally would not get their children vaccinated in a timely manner.
While the effect of vaccination timing holds for TIV and LAIV, TIV is more cost-effective than LAIV for every given month (ie, LAIV’s potential efficacy advantages do not outweigh its higher cost).44-47 As an intranasal formulation that does not require needles, LAIV has potential administration advantages that are hard to capture in economic models. However, the higher cost of LAIV has hindered its adoption and continues to make TIV the more cost-effective choice for children when both are available.
Advocating earlier vaccination in no way suggests that vaccination should not be continuously offered for a large portion of the influenza season. The savings presented herein are only from getting children vaccinated earlier and not from shutting down vaccination operations and capabilities after October. In fact, results from the children’s monthly influenza vaccination decision model suggest that influenza vaccination remains cost-effective through the end of December. This may help decision makers (eg, clinicians, policymakers, healthcare administrators, vaccine logicians, vaccine purchasers) justify maintaining influenza vaccination operations (eg, maintaining refrigerator space for vaccines, retaining staff to administer vaccines, ordering vaccines, offering vaccine to patients) at least into January. Clinicians must know what to do when parents and children may arrive at vaccination locations late in the influenza season. Monthly results in Table 4 also suggest differences in the cost-effectiveness of TIV and LAIV: TIV vaccination remains cost-effective through the end of December, but LAIV remains cost-effective only through the end of November.
Models by definition are simplifications of clinical and public health situations and decision making and cannot completely represent every possible influenza and vaccination event and outcome. Models also cannot fully incorporate the sociodemographic and clinical diversity of the pediatric population. Comorbidities may alter the benefits of influenza vaccination. Moreover, our model did not account for the potential effects of vaccination on influenza transmission (eg, earlier vaccination generating herd immunity sooner and conferring greater protection to the entire population).
Quantifying how the economic value of vaccinating children may change with the timing of vaccine administration may help decision makers understand how early and late the vaccine should be available and how much to invest to get children vaccinated earlier. Our study found that policymakers could invest up to $6 million to $9 million a year to get children vaccinated in September or October without expending any net costs. For every month, TIV was more cost-effective than LAIV. Administration of TIV remained cost-effective through December, and administration of LAIV remained cost-effective through November. Clinicians, policymakers, manufacturers, administrators, school officials, and other decision makers should consider strategies, programs, policies, and practices that will ensure children are vaccinated earlier.
Author Affiliations: From the Public Health Computation and Operations Research (PHICOR) Group (BYL, JHYT, RRB), the Section of Decision Sciences and Clinical Systems Modeling (BYL, JHYT, RRB, KJS), the Department of Biomedical Informatics (BYL, JHYT, RRB), the Department of Epidemiology (BYL, JHYT, RRB), and the Division of Infectious Diseases (AJN), University of Pittsburgh, Pittsburgh, PA.
Funding Source: National Institute General Medical Sciences Models of Infectious Agent Study (MIDAS) grant (1U54GM088491-0109) and the National Library of Medicine (NLM) grant (SR01LM-009132-02).
Author Disclosure: The authors (BYL, JHYT, RRB, KJS, AJN) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.
Authorship Information: Concept and design (BYL, RRB, KJS, AJN); acquisition of data (BYL, JHYT, RRB); analysis and interpretation of data (BYL, JHYT, RRB, KJS, AJN); drafting of the manuscript (BYL, JHYT, RRB, AJN); critical revision of the manuscript for important intellectual content (BYL, RRB, KJS); statistical analysis (BYL, JHYT, RRB); provision of study materials or patients (BYL); obtaining funding (BYL); administrative, technical, or logistic support (BYL, KJS); and supervision (BYL).
Address correspondence to: Bruce Y. Lee, MD, MBA, Public Health Computational and Operations Research (PHICOR), University of Pittsburgh, 200 Meyran Ave, Ste 200, Pittsburgh, PA 15213. E-mail: email@example.com.
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