Projected Cost-effectiveness of Pneumococcal Conjugate Vaccination ...

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Projected Cost-effectiveness of Pneumococcal Conjugate Vaccination of Healthy Infants and Young Children Tracy A. Lieu, MD, MPH G. Thomas Ray, MBA

Context Pneumococcal conjugate vaccine for infants has recently been found effective against meningitis, bacteremia, pneumonia, and otitis media.

Steven B. Black, MD Jay C. Butler, MD

Objective To evaluate the projected health and economic impact of pneumococcal conjugate vaccination of healthy US infants and young children.

Jerome O. Klein, MD Robert F. Breiman, MD Mark A. Miller, MD

Setting and Patients A hypothetical US birth cohort of 3.8 million infants.

Design Cost-effectiveness analysis based on data from the Northern California Kaiser Permanente randomized trial and other published and unpublished sources.

Henry R. Shinefield, MD

S

TREPTOCOCCUS PNEUMONIAE IS

the leading bacterial cause of meningitis, sepsis, pneumonia, and otitis media (OM) among US children.1,2 Emergence of drug-resistant pneumococci has substantially complicated therapy of these infections and has focused attention on the need for effective prevention strategies.3 New pneumococcal conjugate vaccines designed to stimulate immunity in infants and young children who respond poorly to pneumococcal polysaccharide vaccine could prevent much of this disease.4,5 The first such vaccine was licensed by the Food and Drug Administration on February 17, 2000. National recommendations about new preventive health interventions ideally should be based on clinical effectiveness. For many health care policymakers, cost-effectiveness is another important consideration. Our aim was to evaluate the projected health benefits, costs, and cost-effectiveness of routine pneumococcal conjugate vaccination of healthy infants, who are currently being considered as the primary target 1460 JAMA, March 15, 2000—Vol 283, No. 11

Interventions Hypothetical comparisons of routine vaccination of healthy infants, requiring 4 doses of pneumococcal conjugate vaccine (at 2, 4, 6, and 12-15 months), and catch-up vaccination of children aged 2 to 4.9 years requiring 1 dose, with children receiving no intervention. Main Outcome Measures Cost per life-year saved and cost per episode of meningitis, bacteremia, pneumonia, and otitis media prevented. Results Vaccination of healthy infants would prevent more than 12 000 cases of meningitis and bacteremia, 53 000 cases of pneumonia, 1 million episodes of otitis media, and 116 deaths due to pneumococcal infection. Before accounting for vaccine costs, the vaccination program would save $342 million in medical and $415 million in workloss and other costs from averted pneumococcal disease. Vaccination of healthy infants would result in net savings for society if the vaccine cost less than $46 per dose, and net savings for the health care payer if the vaccine cost less than $18 per dose. At the manufacturer’s list price of $58 per dose, infant vaccination would cost society $80 000 per life-year saved or $160 per otitis media episode prevented (other estimated costs would be $3200 per pneumonia case prevented, $15 000 for bacteremia, and $280 000 for meningitis). The cost-effectiveness of an additional program to administer 1 dose of vaccine to children aged 2 to 4.9 years would vary depending on the children’s ages, relative risks of pneumococcal disease, and vaccine cost. Conclusions Pneumococcal conjugate vaccination of healthy US infants has the potential to be cost-effective. To achieve cost savings, its cost would need to be lower than the manufacturer’s list price. In addition to tangible costs, the vaccine should be appraised based on the less tangible value of preventing mortality and morbidity from pneumococcal disease. www.jama.com

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group for vaccination in the United States. We also analyzed the potential cost-effectiveness of catch-up vaccination of children during the transitional years of vaccine implementation.

Author Affiliations and Financial Disclosures are listed at the end of this article. Corresponding Author and Reprints: Tracy A. Lieu, MD, MPH, Department of Ambulatory Care and Prevention, Harvard Pilgrim Health Care and Harvard Medical School, 126 Brookline Ave, Suite 200, Boston, MA 02215 (e-mail: [email protected]).

©2000 American Medical Association. All rights reserved.

Downloaded from www.jama.com at National Institute of Hlth, on February 15, 2007

PNEUMOCOCCAL VACCINATION FOR INFANTS AND CHILDREN

METHODS Decision Analysis Model

We constructed a decision tree (FIGURE 1) to compare 2 major options. Under “no vaccination,” infection with S pneumoniae could cause meningitis, bacteremia, pneumonia, simple or complex OM, or OM with tympanostomy tube placement. Meningitis could lead to death, disability, deafness, or no sequelae. Bacteremia was defined as all other bacteremic infections, including bacteremic pneumonia, and could result in death or no sequelae. Under “vaccination,” the incidence of each infection was reduced in proportion to the demonstrated efficacy of the vaccine against that infection.6 We assumed that routine vaccination of healthy infants required 4 doses (at 2, 4, 6, and 12-15 months), and that catch-up vaccination of children aged 2 to 4.9 years required only 1 dose. Our model took into account the fact that the pneumococcal conjugate vaccine currently under consideration includes 7 serotypes, but other pneumococcal serotypes may also cause disease. In addition, pneumonia and OM may be caused by organisms other than pneumococci and children with these conditions do not typically have bacterial cultures performed to confirm origin. For pneumonia and OM, we designed our model to maximize consistency with the best available data on disease incidence and vaccine efficacy from the Northern California Kaiser Permanente (NCKP) randomized trial and from published sources on disease epidemiology.6-8 The model did not include sinusitis because there are no data to suggest that vaccination prevents sinusitis. We conducted the analysis from both the societal perspective (medical and nonmedical costs) and the health care payer’s perspective (medical costs primarily borne by health plans). We projected pneumococcal disease outcomes from birth to death for a hypothetical US birth cohort of 3.8 million infants. The model used a microsimulation (semi-Markov) approach in which disease incidence was calcu-

lated on a monthly basis, and was programmed using statistical software (Data [version 3.5], TreeAge Software Inc, Williamstown, Mass).

ness, and disability after invasive pneumococcal disease were based on Active Bacterial Core Surveillance/ Emerging Infections Program data and published sources.1,11,12

Probabilities of Health Outcomes

The probabilities of events in the decision model (TABLE 1) were derived from published studies, unpublished data from local and national sources, and expert panel consensus. We convened 9 experts for a 1-day meeting and used a modified Delphi process to derive estimates for selected questions on which the data were sparse or lacking. When estimates or assumptions were equivocal, we chose the one that would bias the results against vaccination. Age-specific incidence rates of pneumococcal meningitis and bacteremia (Table 1) were from recent data from the Centers for Disease Control and Prevention’s Active Bacterial Core Surveillance/Emerging Infections Program Network (Chris Van Beneden, MD, MPH, written communication, September 1999).1,9 Rates of pneumonia and OM were from analyses of the NCKP population and from other published sources.8,10 Probabilities of death, deaf-

Vaccine Efficacy

Estimates of vaccine efficacy were based on the findings of the NCKP trial. Because bacteriologic cultures are not routinely ordered for pneumonia and OM, we used estimates contributed by the expert panel to infer efficacy against pneumococcal vaccine serotypes for these conditions. When making inferences, we always maintained consistency with the trial’s intention-totreat efficacy results for each disease. For example, the trial’s intention-totreat analysis observed 73% efficacy against pneumonia defined as pneumococcal based on chest radiograph findings that met World Health Organization guidelines for this definition. Extrapolating from studies of invasive disease, we estimated that 80% of pneumococcal pneumonia was due to vaccine serotypes. Thus, we inferred that the vaccine was 90% efficacious against pneumococcal pneumonia due to vaccine serotypes.

Figure 1. Policy Options and Clinical Outcomes After No Vaccination or Vaccination of All Healthy Infants With Pneumococcal Conjugate Vaccine No Sequelae Deafness Meningitis Disability Invasive Pneumococcal Disease

Death No Sequelae Bacteremia

Pneumococcal Pneumonia

No Vaccination

1

Pneumococcal Conjugate Vaccine Policy

Death

Simple Otitis Media

Complex With Tympanostomy Tube Placement

No Infection Vaccination of All Healthy Infants

2

Dashed lines denote outcomes for which incidence estimates are used; these outcomes are not mutually exclusive. Node 2 is identical in structure to node 1, but disease incidence is reduced due to vaccination.


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Table 1. Pneumococcal-Associated Disease Probabilities and Vaccine Efficacy Estimates* Base Case Estimate

Variable Annual incidence rates Invasive pneumococcal disease cases per 100 000 population†

185.6

Clinically diagnosed pneumonia cases per 100 population

2.8

Clinically diagnosed otitis media episodes, per person†

1.18

Tympanostomy tube placement, per 1000 population† Pneumococcal-associated disease outcomes Proportion of invasive disease cases that are meningitis†

16.8

Estimates in Sensitivity Analysis 50%-200% of base case ...

Source ABCs/EIP 8, 49

125% and 200% 10, 20, 21, of base case‡ 50 200% of base case

10, 20, 21

0.03

0.14

ABCs/EIP,18, 19

Proportion of clinically diagnosed otitis media episodes that are complex†§

0.07

...

6

Proportion of simple otitis media episodes that are due to pneumococci†\

0.19

...

Expert panel

Proportion of complex otitis media/tympanostomy tube placement episodes that are due to pneumococci†\

0.50

...

Expert panel

Death after meningitis

0.05

...

ABCs/EIP

Death after bacteremia

0.007

...

ABCs/EIP

Deafness after meningitis

0.13

...

11

Disability after meningitis

0.07

...

12

Proportion of pneumococcal disease due to vaccine serotypes Invasive disease

0.80

...

ABCs/EIP

Pneumonia

0.80

...

Expert panel¶

Simple otitis media

0.60

...

Expert panel

Complex otitis media

0.60

...

Expert panel

Otitis media with tympanostomy tube placement

0.60

...

Expert panel

Vaccine efficacy estimates\ Invasive disease (meningitis or bacteremia) due to pneumococcal vaccine serotypes

1.00

75% of base case

6

Pneumonia due to pneumococcal vaccine serotypes†

0.90

50% of base case

6

Pneumonia, clinically diagnosed

0.11

50% of base case

6

Otitis media, clinically diagnosed† Simple

0.07

50%-140% of base case

6

Complex

0.19


6

With tympanostomy tube placement

0.20


6

0.64


6

Otitis media due to vaccine serotypes (simple or complex)†

*Ellipses indicate estimates were not used in sensitivity analysis. ABCs/EIP indicates Active Bacterial Core Surveillance/ Emerging Infections Program Network. Data indicated with ABCs/EIP are unpublished from the Centers for Disease Control and Prevention, 1997-1998. The expert panel is listed in the acknowledgement. Numbers in the “Source” column correspond to references. †Estimate shown is for infants at 12 months to children at 23 months. Incidence estimates used in the analysis varied by age. ‡Outpatient visit rates were increased to 125% and tympanostomy tube placement rates to 200% of base case estimates. §Vaccine efficacy estimates are based on intention-to-treat analysis and include disease episodes in partially vaccinated infants. These estimates may differ from those in other reports due to differences in the definitions of the study group and the outcomes included. \Estimates are for clinically diagnosed otitis media episodes. These were classified as simple or complex based on definitions described in “Methods.” ¶Inferences were made based on the initial estimates from the expert panel.

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The expert panel recommended making the conservative assumption that a vaccinated infant would experience reductions in pneumococcal diseases only until his/her fifth birthday. Based on expert panel consensus, in vaccinated infants, vaccine efficacy against invasive disease was assumed to decrease from 100% during ages 0 to 23 months to 93% during 2 to 4.9 years. Vaccine efficacy against pneumonia and simple or complex OM was similarly assumed to wane during ages 2 to 4.9 years. Costs

Medical Care for PneumococcalAssociated Diseases. The mean medical costs of pneumococcal diseases (TABLE 2) were derived by analyzing the costs of disease episodes using NCKP’s Cost Management Information System. This accounting system uses a step-down method of allocating all fixed and variable costs, including administrative overhead, to units of service (eg, a 10-minute visit to a pediatrician). The cost analysis included all hospital, emergency department, outpatient, and prescription medication use. We determined the costs of pneumococcal meningitis and bacteremia (including bacteremic pneumonia) by studying invasive pneumococcal disease cases identified by NCKP’s active surveillance program.5 To determine the cost of pneumonia, we identified an initial set of hospitalized and outpatient cases using International Classification of Diseases, Ninth Revision (ICD-9) codes for pneumonia (486, 481, and 482.9). From this initial set, we followed recent World Health Organization guidelines and defined pneumococcal pneumonia cases as those with chest radiographs read by the original radiologist as having consolidation, air bronchograms, or pleural effusion without other known causes. Because this analysis focuses on routine vaccination of low-risk infants, we used the conservative approach of excluding children with immunodeficiency, cancer, and congenital cardiac or respiratory diseases when making cost estimates.




To determine the cost of OM, we conducted an analysis of approximately 120 000 children who were members of NCKP during 1997; details are reported elsewhere.10 We defined an OM visit as one with an appropriate ICD-9 code (382.XX and related codes) and an OM-related antibiotic prescription filled. Consistent with a previous study,7 we defined a new OM visit as one that was not preceded by another OM visit during the prior 21 days. An OM episode was defined as the period beginning with a new visit and ending with the last OMrelated physician visit or medication before the next new OM visit. The costs of follow-up visits (ie, those coded as OM but without antibiotics), audiometry, otorhinolaryngologist visits, antibiotics, surgical procedures (eg, tympanostomy tube placement), and hospitalizations related to OM were counted as associated with the episode during which they occurred. We divided OM episodes into those that included tympanostomy tube placement and those that did not; the latter group were further classified as simple (1 or 2 OM visits during the episode) or complex ($3 OM visits during the episode). The costs of long-term medical care and special education for neurologically disabled survivors of meningitis were assumed to be similar to the costs for cerebral palsy.13 We assumed that patients with deafness after meningitis would be candidates for a cochlear implant, whose cost was estimated from published sources.14 Vaccination Program Costs. The manufacturer’s list price for the recently licensed version of this vaccine is $58 per dose. We generated estimates of cost-effectiveness for vaccine costs ranging from $1 to $100 per dose, consistent with the price ranges of recently licensed vaccines. The cost of vaccine administration at a routine infant visit was estimated at $10 based on a previous study and on consultation with NCKP administrators.15 In this analysis, we prorated the cost of vaccine administration to $5 per dose because at least 1 other vaccination would be given at each visit during which

pneumococcal vaccine was recommended. Work-Loss and Other Nonmedical Costs. Lost time from work, valued at the parent’s wage rate, was used as a proxy for the value of the time spent tending a child with pneumococcal disease. Wage rates and lost work time were derived from interviews with parents whose children had experienced bacteremia (n = 17), pneumonia (n = 307), and OM (n = 300). There were no cases of meningitis available during the survey period. We assumed that meningitis work-loss costs would equal bacteremia work-loss costs multiplied by the ratio of meningitis medical costs to bacteremia medical costs. Lost productivity for individuals who died or had longterm disability due to meningitis was assigned a monetary value based on the present value of expected future lifetime earnings forgone.13,16

sumed that 100% of infants would receive 4 doses of vaccine). Consistent with therecommendationsofanationalpanel, costs and benefits were discounted at a rate of 3% per year.17 Cost-effectiveness ratios were calculated as dollars invested in the vaccination program minus dollars saved due to disease episodes averted divided by health benefits, in which the health benefits were life-years saved or episodesofmeningitis,bacteremia,pneumonia, or OM averted. Based on the national panel’s recommendations, to avoid double counting benefits, productivity losses due to death were not included in calculating dollars per life-year saved. However, when calculating dollars per invasive disease case prevented, productivity losses due to disability were included in the numerator. Likewise, productivity losses were included in calculations of break-even points. Sensitivity Analyses

Cost-effectiveness Calculations

The base case analysis was conducted from the societal perspective for a hypothetical birth cohort of 3.8 million US infants. The base case analysis made projections for a fully implemented vaccination program at steady state (ie, it as-

We evaluated how the model’s results changed as we varied key assumptions over plausible ranges. Sensitivity analyses included: (1) the incidence of invasive disease was varied from 50% to 200% of baseline; (2) the proportion of invasive disease that was men-

Table 2. Costs of Pneumococcal-Associated Disease Events* Event Meningitis, pneumococcal

Medical Work-Loss Cost† Cost 9208 1492

Other Costs† 381

Source Ray, Kaiser Permanente‡ Ray, Kaiser Permanente‡ Capra, Kaiser Permanente‡ 10 10 10 14 13

Bacteremia, pneumococcal§

1922

312

79

Pneumonia with consolidation on chest radiograph Simple otitis media episode Complex otitis media episode Tympanostomy tube placement Cochlear implant for deafness Disability\

1167

263

34

134 389 1869 71 158 367 164

141 589 443 NA

19 67 78 NA 881 866 (productivity)

NA NA NA NA

201 603 (special education) 13 869 299 (productivity) 16 NA NA NA 15, Ray, Kaiser Permanente†

Death\ Vaccine dose Vaccine administration

NA NA 1-80 5

*Costs in 1997 US dollars. NA indicates data not available. Numbers in the “Source” column correspond to references. †Medical costs include health care payer costs alone. Other costs include costs borne by families (eg, nonprescription medications), productivity losses due to premature death or disability, and special education. ‡Analyses of Kaiser Permanente data (G.T.R. and Angela Capra, MA, unpublished data, April 1999). §Discounted by 3% per year throughout the potential lifetime of the affected person. \Includes all nonmeningitis bacteremic infections, eg, bacteremic pneumonia.


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ingitis was varied up to 14%18,19; (3) rates of OM-related use were increased (outpatient visit rates were increased to 125% and tympanostomy tube placement rates were increased to 200% of baseline) based on estimates and inferences from alternative data sources20,21; (4) vaccine efficacy was varied as shown in Table 1, based on the 95% confidence intervals from the NCKP randomized trial; (5) the cost of vaccine administration was increased to $1315,22; (6) the costs of clinic visits and hospitalizations were changed to those from national sources, mainly the Medicare fee schedule23-25; (7) the discount rate was changed to 5% for both costs and benefits; (8) the coverage rate was decreased to 90%26; and (9) poten-

tial costs of medical use and work loss due to vaccine adverse reactions were incorporated. The base case did not include costs for vaccine adverse reactions because 1 study found that fever and irritability among pneumococcal conjugate vaccine recipients were no higher than among controls, although it must be recognized that controls received a different conjugate vaccine.27 To accommodate this in the sensitivity analysis, we estimated the cost of adverse reactions after pneumococcal vaccination at $5 per dose, consistent with our findings on other vaccines (T.A.L., unpublished data, 1998). Best-case (most favorable to vaccine using assumptions 1, 2, 3, and 4 above) and worst-case (least favorable to vac-

Table 3. Projected Annual Pneumococcal Disease Outcomes With and Without a Routine Pneumococcal Conjugate Vaccination Program for Healthy US Infants

Disease Outcomes Simple otitis media episodes* Complex otitis media episodes* Otitis media episodes with tympanostomy tube placement Pneumococcal pneumonia cases† Pneumococcal bacteremia cases Pneumococcal meningitis cases Total Episodes, All Diseases‡

Outcomes Prevented by Vaccination 875 000

No Vaccination

Vaccination

12 630 000

11 755 000

1 045 000 149 000

893 000 119 000

152 000 30 000

77 000

24 000

53 000

15 000 790 13 917 000

3300 180 12 795 000

11 700 610 1 122 000

150 4300

34 970

116 3300

Deaths Life-years lost§

*Otitis media episodes were clinically diagnosed and classified as simple or complex according to definitions in “Methods.” †Diagnosed using a chest radiograph and consistent with pneumococcal etiology. ‡Values are rounded. §Discounted by 3% per year.

Table 4. Projected Annual Costs With and Without a Routine Pneumococcal Conjugate Vaccination Program for Healthy US Infants* Costs Pneumococcal-associated disease costs Medical costs Parent work-loss and other costs

No Vaccination

Vaccination

Cost (Savings) From Vaccination

2529 2825

2186 2540

(342) (285)

167 5521

37 4764

(130) (757)

NA NA

295 589

295 589

NA

855

855

NA

74

74

Future productivity costs Total Disease Costs Vaccination program costs† Vaccine per dose, $ 20 40 58 Vaccine administration

*Costs are discounted by 3% per year, are in millions, and are in 1997 US dollars. NA indicates not applicable. Totals may not add up exactly; the difference is due to rounding. †Assumes 4 doses of vaccine for each infant.

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cine using assumptions 1, 4, and 5 above) scenarios also were modeled. Unless otherwise noted, sensitivity analysis results were from the societal perspective at a vaccine cost, based on the manufacturer’s anticipated list price, of $58 per dose. Catch-up Vaccination for Children

When any new infant immunization program is introduced, policymakers must decide whether those persons older than the recommended age should be vaccinated in a supplementary catch-up program. 28 We modeled the costeffectiveness of catch-up pneumococcal vaccination of children aged 2 to 4.9 years. Immunogenicity data suggest that this may require only 1 dose of vaccine for this age group.29 For children, we used vaccine efficacy estimates that the expert panel derived by extrapolation from the infant efficacy data. We assumed that catch-up vaccination would not generate additional clinic visits, but would be offered during routine preventive or urgent clinic visits that already occurred in practice. We made the conservative assumption that a child who received catch-up vaccination would experience reduced pneumococcal disease for 3 years. Based on a recent study of risk factors for invasive pneumococcal disease, children in day care were assumed to have a 2.4-fold elevated risk of all pneumococcal diseases.30 In accord with this study, we defined day care as care of 2 or more unrelated children outside the home for 4 or more hours per week. National statistics suggest that 25% to 30% of all children are in this type of day care.31,32 This study was an academic-public health collaboration in which the vaccine manufacturer contributed a grant to support the work of the nongovernmental investigators. Representatives of the manufacturer reviewed an interim analysis and a draft of the manuscript, but did not have authority for scientific or editorial decisions. RESULTS TABLE 3 and TABLE 4 show projected disease outcomes and costs with and




FIGURE 2 shows how the cost per lifeyear saved and the cost per OM episode prevented varied depending on vaccine cost. From the societal perspective, pneumococcal vaccination of healthy infants would result in savings if the vaccine cost $46 or less per dose. From the health care payer perspective, the vaccination program would result in net savings if the vaccine cost $18 or less per dose, and would result in $25 000 per life-year saved if the vaccine cost $25 per dose. Preliminary information suggests the vaccine’s nondiscounted list price will be $58. At this price, the costs per lifeyear saved would be $80 000 (societal) and $176 000 (health care payer). Using alternative measures of health benefit, vaccination at $58 per dose would cost society (or the health care payer) $160 ($550) per OM, $3200 ($11 000) per pneumonia, $15 000 ($50 000) per bacteremia, or $280 000 ($970 000) per meningitis episode prevented. These ratios reflect the net cost of vaccination after accounting for medical costs, work loss, and other costs averted from disease episodes prevented. Sensitivity Analyses

DiseaseIncidence. Theresultsweresensitive to variation in the incidence of invasive disease. As incidence estimates

the relative risk of pneumococcal disease as well as vaccine cost. The breakeven vaccine cost also varied depending on children’s ages. From the societal perspective, the break-even vaccine cost for children in day care ranged from $85 (for 4- to 4.9-year-olds) to $135 (for 2to 2.9-year-olds), compared with $32 to $53 for those not in day care. From the health care payer perspective, the break-even vaccine costs for children were $41 to $66 for those in day care and $14 to $25 for those not in day care. COMMENT Major Findings

This study found that routine pneumococcal conjugate vaccination of healthy infants is potentially costeffective, although its projected savings for society are more than double those for health care payers. From the

Figure 2. Projected Cost per Life-Year Saved and Cost per Otitis Media Episode Prevented by Routine Pneumococcal Conjugate Vaccination of Healthy US Infants, at Varying Vaccine Cost per Dose 200 000

$ per Life-Year Saved

Cost-effectiveness Ratios

were varied from 50% to 200% of base case assumptions and the vaccine cost was held constant at $58 per dose, the societal cost per life-year saved decreased from $188 000 to $25 000. When the proportion of invasive disease due to meningitis was increased to 14%, the societal break-even vaccine cost increased from $46 to $58 per dose. When health care services use due to OM was increased from base case assumptions (by 125% for outpatient visits and 200% for tympanostomy tube placement), the break-evenvaccinecostsincreasedto$58 per dose (societal) and $25 per dose (health care payer). Other Sensitivity Analyses. As vaccineefficacyassumptionswerevariedfrom optimistic to pessimistic over the ranges showninTable1,thesocietalcostperlifeyear saved increased from $20 000 to $235 000 (as vaccine cost was held constant at $58 per dose) and the break-even costdecreasedfrom$60to$23.Whenthe cost of vaccine administration was increased to $13, the societal cost per lifeyear saved increased to $113 000. When alternativecostsfromnationaldatasources were used, there were negligible changes in the cost per life-year saved ($80 000) and the break-even vaccine cost ($46). At a discount rate of 5%, the societal cost per life-year saved was $144 000. Decreasing the vaccine coverage rate to 90% reduced projected costs and savings by a similar proportion but did not change costeffectiveness results. When we incorporated a cost for potential vaccine adverse reactions of $5 per dose, the break-even cost decreased by $5. Best- and Worst-Case Scenarios. From a societal perspective, the best-case scenario resulted in savings and a breakevenvaccinecostof$112,whiletheworstcase scenario resulted in a cost per lifeyear saved of $593 000 and a break-even vaccine cost of $10.

150 000 100 000 50 000 0 Perspective Health Care Payer (Medical Costs) Societal (Medical and Nonmedical Costs) 1000

$ per Otitis Media Episode Prevented

without a routine pneumococcal vaccination program for infants. Vaccination would prevent approximately 1 million episodes of OM, 53 000 cases of pneumonia, 12 000 cases of invasive disease, and 116 deaths due to pneumococcal infection for each US birth cohort. Pneumococcal-associated diseases (including OM due to all causes) were estimated to cause $2.5 billion in direct medical costs, and $3 billion in work-loss and productivity costs for each US birth cohort. A fully implemented infant vaccination program was estimated to reduce direct medical costs by $342 million and other costs by $415 million, before accounting for the costs of vaccine doses and administration.

750 500 250 0

Catch-Up Vaccination for Children

One dose of catch-up vaccine for all 2to 4.9-year-old children would result in savings from the societal perspective if vaccine costs were in the $60 range or less. As F I G U R E 3 shows, costeffectiveness results were sensitive to


0

20

40

60

80

Vaccine Cost per Dose, $

Four doses would be recommended for infant vaccination. Cost-effectiveness analysis from the societal perspective includes medical and nonmedical costs; cost-effectiveness analysis from the health care payer perspective includes medical costs primarily borne by health plans. JAMA, March 15, 2000—Vol 283, No. 11


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societal perspective, vaccination is projected to reduce pneumococcal disease costs by almost $760 million for each cohort of infants born in the United States each year. However, more than half of the projected savings are from reduced work loss by parents who care for ill children or averted produc-

Figure 3. Two-Way Sensitivity Analysis That Illustrates How the Break-Even Vaccine Cost for Children Aged 2 to 4.9 Years Varies Depending on the Relative Risk of Disease Perspective Societal (Medical and Nonmedical Costs) Health Care Payer (Medical Costs)

Vaccine Cost per Dose, $

100 80 60 40 20 0 0.5

0.8

1.0

1.3

1.5

Relative Risk of Pneumococcal Disease Among Children Aged 2 to 4.9 Years

The lines represent the break-even vaccine costs at varying relative risks of disease from the societal perspective (medical and nonmedical costs) and health care payer perspective (medical costs). For costs and relative risks below each line, vaccination would result in net savings. Above each line, vaccination would result in net costs. Children in day care have a relative risk of 2.4 compared with those not in day care.

tivity loss due to disability or death caused by pneumococcal disease. Comparisons With Other Studies

From the health care payer perspective, pneumococcal conjugate vaccination—like varicella, hepatitis B, and other recently recommended vaccines—may not result in net savings but could be relatively cost-effective compared with other health interventions.33-36 TABLE 5 illustrates how pneumococcal conjugate vaccination at varying vaccine costs would compare with other health interventions in cost per life-year saved. At its anticipated list price, infant pneumococcal vaccination would have a cost-effectiveness ratio at the high end of the range for current preventive measures. However, the average cost of vaccine will likely be lower because government agencies, which buy approximately 60% of vaccine doses, typically receive discounted prices under negotiated contracts. If our assumptions on the vaccine’s efficacy for children hold true, catch-up vaccination of children would be cost-effective compared with infant vaccination, especially when directed toward high-risk groups such as those in day care. In sensitivity analyses, we found that results changed as key assumptions were

Table 5. Cost-effectiveness of a Routine Pneumococcal Conjugate Vaccination Program Compared With Other Preventive Health Interventions* $ per Life-Year Saved, by Perspective† Intervention Varicella vaccination Pneumococcal infant vaccination at $20 per dose‡ Hepatitis B vaccination Pneumococcal infant vaccination at $40 per dose‡ Respiratory syncytial virus immune globulin for high-risk premature infants§ Mammography of 40- to 50-year-old women Pneumococcal infant vaccination at $58 per dose‡

Societal Saving Saving Saving 16 000 51 000 Not available 144 000

Health Care Payer Source 16 000 51 20 000 Current analysis 21 000 34 156 000 Current analysis 51 000 52 105 000 278 000

53 Current analysis

*Costs from original articles were updated to 1997 dollars using the medical care component of the Consumer Price

Index.54 †Per national recommendations, calculations of dollar per life-year saved did not include productivity losses. Calculations of the break-even price of $46 (societal) and $18 (health care payer) did include productivity losses. ‡To achieve comparability between the current analysis and older studies, costs and benefits were discounted at 5% per year. Thus, estimates in this table differ from those elsewhere in the article, in which they are presented at a discount rate of 3% per year in accord with current standards. §For infants with gestational age of 23 to 32 weeks who received 28 or more days of supplemental oxygen during the birth hospitalization and were discharged home during respiratory syncytial virus season.

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varied over plausible ranges. For example, under assumptions unfavorable to vaccination, including low incidence of invasive disease, low vaccine efficacy, orhighvaccineadministrationcosts,routine infant vaccination at a cost of $40 per dose would not result in societal cost savings. Conversely, under favorable assumptions about invasive disease incidence, OM use, or vaccine efficacy, the societal break-even vaccine cost increased from $46 to approximately $60. These findings underscore the importance of gathering more robust empiricaldataonvaccineeffectivenessandcosts in postlicensure studies. Limitations

The current analysis made conservative assumptions that likely biased against a vaccination program. Pneumococcal conjugate vaccination will reduce not only mortality due to invasive disease, but also morbidity due to OM and pneumonia, which account for more than 90% of the disease episodes prevented. We have presented results in terms of cost per life-year saved to enable comparisons with other health interventions. However, this ratio underrepresents the vaccine’s value because it gives credit only for reducing mortality, but not morbidity. We have also not attempted to place a value on the psychological costs of pain for the child, and anxiety for the child and parent, due to OM, pneumonia, and invasive pneumococcal diseases. As yet, these psychological costs have not been standardized as utilities (the formal measure of preferences recommended for calculating quality-adjusted life-years) in population-based studies.37-39 Ideally, however, policymakers evaluating these costeffectiveness ratios should take into account the benefits of preventing morbidity and suffering due to OM and pneumonia as well as mortality due to invasive pneumococcal disease. Based on the recommendations of our expert panel, vaccine efficacy was assumed to last only 5 years for infants and 3 years for children. Based on the panel’s recommendations, the vaccine was not assumed to have any efficacy against




cross-reactive serotypes, which account foratleast5%ofpneumococcalinfections in young children,40 because reliable data on this topic are not yet available. In the current analysis, we did not evaluate the potential cost-effectiveness of using 23-valent pneumococcal polysaccharide vaccine in 2- to 4.9year-olds. There is some evidence that this vaccine may be effective at preventing invasive disease in this age group.41 The polysaccharide vaccine costs $5 to $13 per dose. However, limited evidence exists about its impact on OM,42,43 which drives the pneumococcal vaccination’s cost-effectiveness. Some potentially important indirect effects of a nationwide pneumococcal vaccination program are unknown. For example, reduced pneumococcal carriage in vaccinated children could lead to reduced transmission to unvaccinated persons. Thus, vaccine effectiveness in a population may be greater than initially observed in randomized trials.44 Because Pneumococcus is the leading cause of occult bacteremia, vaccination might also result in a more limited set of clinical circumstances in which blood cultures and empirical antimicrobials are indicated. In addition, the emergence of drugresistant S pneumoniae has made treatment of pneumococcal infections more difficult and expensive.3 Pneumococcal conjugate vaccination could reduce the proportion of infections caused by drug-resistant strains and allow clinicians to reduce empiric, broadspectrum antibiotic prescribing for young children. The end result could be less disease caused by drug-resistant strains and reduced antimicrobial pressure causing selection of new drug-resistant strains. Our analysis might have underestimated the vaccination’s health benefits and cost savings because we did not attempt to model these indirect effects. We did not evaluate the costeffectiveness of vaccinating of infants and children in developing countries in which pneumococcal disease has higher incidence and impact. For example, the mortality rate due to bacteremic pneu-

mococcal pneumonia is less than 5% in US children but is likely much higher in developing countries.45 Although the theoretical model in our analysis is generalizable, alternative assumptions on disease epidemiology and costs would be needed for these settings. Some experts have raised concerns that although vaccination may lead to a reduction in vaccine serotypes, other disease-causing serotypes may replace them in the nasopharynx of vaccinated children.46-48 To date, no data indicate increasing rates of disease with nonvaccine serotypes in vaccinated children. Postimplementation research should evaluate the effects of vaccination on disease incidence in unvaccinated persons, use of antimicrobial drugs, and carriage and disease due to nonvaccine serotypes. CONCLUSIONS We conclude that routine pneumococcal conjugate vaccination of healthy US infants has the potential to be costeffective relative to other preventive health interventions. Decisions about implementation should rest not only on cost considerations but also on qualitative judgments about the value of preventing mortality due to invasive disease and morbidity due to invasive disease, OM, and pneumonia. Author Affiliations: Department of Ambulatory Care and Prevention, Harvard Pilgrim Health Care and Harvard Medical School, Boston, Mass (Dr Lieu); Division of Research (Dr Lieu and Mr Ray), Vaccine Study Center (Drs Black and Shinefield), Kaiser Permanente, Oakland, Calif; Department of Pediatrics, Boston City Hospital, Boston University Medical Center, Boston, Mass (Dr Klein); Artic Investigations Program, National Center for Infectious Diseases, Anchorage, Alaska (Dr Butler) and National Vaccine Program Office (Dr Breiman), Centers for Disease Control and Prevention, Atlanta, Ga; and Children’s Vaccine Initiative, Geneva, Switzerland (Dr Miller). Financial Disclosures: The work of Dr Lieu, Mr Ray, and Drs Black, Klein, and Shinefield on this study was supported by a grant from Wyeth-Lederle Vaccines and Pediatrics to the Kaiser Foundation Research Institute. Dr Black is a consultant to and on the speaker’s bureau for Wyeth-Lederle. Acknowledgment: We are grateful to our colleagues at the Kaiser Division of Research, especially Bruce Fireman, MA, Angela Capra, MA, and Ned Lewis, MPH, who contributed cogent advice and data for this work. We thank Laura Elvin for sharing information about cases of invasive pneumococcal infection for our cost analyses. We appreciate the contributions of Chris Van Beneden, MD, Donna Ambrosino, MD, Mathuram Santosham, MD, Robert Austrian, MD, and Kathryn Edwards, MD, who joined 4 of the coinvestigators as


expert panelists for the assumptions on disease incidence and vaccine efficacy. We also thank Vincent Ciuryla, PhD, Marcia Coleman, MD, Jill Hackell, MD, Bill Hausdorff, PhD, Lois Privor-Dumm, and Peter Tobar, who gave thoughtful comments on a previous version of this analysis.

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