OBJECTIVE. In February 2006, a safe, efficacious, orally administered pentavalent human-bovine reassortant rotavirus vaccine was licensed and recommended for routine immunization of all children in the United States. We assessed the health and economic impacts of a national rotavirus immunization program in the United States.
METHODS. Monte Carlo cost-effectiveness analyses, from health care and societal perspectives, of vaccination of a hypothetical US birth cohort of 4010000 children monitored from birth to 59 months of age were performed. We compared the disease and economic burden of rotavirus infection in an unvaccinated cohort of children with one vaccinated at 2, 4, and 6 months with pentavalent human-bovine reassortant rotavirus vaccine.
RESULTS. A routine rotavirus immunization program would prevent 13 deaths, 44000 hospitalizations, 137000 emergency department visits, 256000 office visits, and 1100000 episodes requiring only home care for children <5 years of age in the United States. Assuming costs of administration of $10, the break-even price per dose of vaccine was $42 from the societal perspective and $12 from the health care perspective. From the societal perspective, at the manufacturer's price of $62.50 per dose, vaccination would cost $138 per case averted, $3024 per serious case averted, and $197190 per life-year saved, at a total cost of $515 million to the health care system and $216 million to society. Key variables influencing the results were parental workdays lost, costs of hospitalization, emergency department visits, and child care.
CONCLUSIONS. Despite a higher burden of serious rotavirus disease than estimated previously, routine rotavirus vaccination would unlikely be cost-saving in the United States at present. Nonetheless, rotavirus vaccination may still be considered a cost-effective intervention.
Rotavirus is the most common cause of severe gastroenteritis among children <5 years of age in the United States. In 1998, a tetravalent rhesus-human reassortant rotavirus vaccine (RRV-TV) (RotaShield; Wyeth Laboratories, Collegeville, PA) was licensed and recommended for inclusion in the US schedule for routine childhood immunizations. In October 1999, after >500000 children had received ≥1 dose,1 the vaccine was withdrawn after reports of cases of intussusception among recent vaccinees.2
Since 1999, 2 new oral rotavirus vaccines with different biological properties have been developed. Large clinical trials with 60000 to 70000 children have demonstrated these vaccines to be highly efficacious and without evidence of vaccine-associated intussusception or other serious adverse events.3,4 In February 2006, the US Food and Drug Administration licensed a pentavalent human-bovine reassortant rotavirus vaccine (PRV) (RotaTeq; Merck, Whitehouse Station, NJ)3 and the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention (CDC) recommended this vaccine for routine immunization of infants in the United States.
The Advisory Committee on Immunization Practices requires cost-effectiveness analyses to make recommendations for new vaccines. Our previous cost-effectiveness study of vaccination with the discontinued RRV-TV demonstrated that, each year, a rotavirus vaccination program would prevent 39% of all episodes of rotavirus gastroenteritis, including 67% of hospitalizations, 59% of emergency department visits, and 55% of physician visits. In 1996 US dollars and at $20 per dose, the program was projected to cost $107 million to the health care system but overall would result in savings of $296 million to society.5 That study is now outdated in several key aspects. First, it was based on vaccine efficacy data for the discontinued RRV-TV vaccine, and newer vaccines have different biological properties. Second, modern modeling techniques allow for better assessment of data uncertainty, such as the natural variation of disease incidence from year to year. Third, many data elements, such as vaccine coverage, likely vaccine price, and the burden and cost of rotavirus disease, have changed in the past 10 years, as have health care utilization patterns.6 Finally, no calculation of the costs of possible adverse effects of rotavirus, such as intussusception, was included previously. We present updated estimates of the disease burden of rotavirus in the United States, estimate the impact of vaccination, and perform a cost-effectiveness analysis by using recent data on the newly licensed and recommended PRV.
We built a probabilistic (Monte Carlo) model by using spreadsheet-based software (@Risk 4.5.4; Palisade, Newfield, NY) to calculate the cost-effectiveness of fully vaccinating a cohort of 4010000 children against rotavirus. We used cumulative probability distributions to describe the total annual number of cases of rotavirus disease for children 0 to 59 months of age. To estimate the risk of rotavirus gastroenteritis requiring medical care (hospitalization, emergency department visit, hospital outpatient visit, or physician office visit), we used the following general formula: number of rotavirus-related gastroenteritis episodes for each out come = annual number of episodes of gastroenteritis (all causes) for that outcome × probability that episode is attributable to rotavirus.We also used probability distributions to describe the medical and nonmedical costs of each episode of rotavirus gastroenteritis and to estimate vaccine efficacy.
We used the following formula for cost-effectiveness: (cost of vaccination program − costs saved because of outcomes averted)/number outcomes prevented by vaccination program.We calculated the cost-effectiveness ratio per life-year saved, per case (any disease) averted, and per serious case (hospitalization, emergency department visit, or death) averted, from both a health care payer perspective (medical costs borne primarily by health plans) and a societal perspective (medical and nonmedical costs). We discounted costs at 3% per year. All costs were inflated to 2004 equivalent values, by using the medical component of the consumer price index.7
To estimate the actual impact of a mature vaccine program on disease burden, we calculated the total national reduction in cost and number of episodes in any 1 year by using current national vaccine coverage estimates. With the assumption of a static population, the annual number of any one outcome among all children <59 months of age equals the cumulative number of that outcome a birth cohort experiences from 0 to 59 months.
Estimates of Disease Burden of Rotavirus
Rotavirus Gastroenteritis Requiring Medical Care
To obtain annual national weighted estimates of the mean total number of gastroenteritis episodes requiring care among children up to 59 months of age, we applied International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for gastroenteritis of determined cause (bacterial: codes 001-005.9, excluding code 003.2, and codes 008-008.5; parasitic: codes 006-007.9, excluding codes 006.3-006.6; viral: codes 008.6-008.8) and of undetermined cause (infectious: codes 009.0-009.3; noninfectious: codes 558.9 and 787.91) to data from the National Health Care Survey (National Center for Health Statistics, CDC)8 for each year from 1993 to 2002. A SE was calculated from the survey data by using methods described elsewhere,9 allowing each annual estimate to be described as a normal distribution. Our source for data on hospitalizations was the National Hospital Discharge Survey, that for emergency department and hospital outpatient visits was the National Hospital Ambulatory Medical Care Survey, and that for physician office visits was the National Ambulatory Medical Care Survey (Appendix 1). We extracted the records with the relevant codes in the first 15 positions for hospitalizations and the first 5 positions for outpatient visits.
To estimate the number of rotavirus events requiring medical care, we multiplied each distribution of diarrhea outcomes (hospitalization, emergency department visit, hospital outpatient visit, or physician office visit) in any 1 year by a second likelihood distribution that the outcome was attributable to rotavirus. For hospitalizations, we built a probability distribution by using rotavirus-related data from the largest prospective study of gastroenteritis-related hospitalizations conducted over 8 years (Table 1 and Appendices 1 and 2).10 No data exist on the proportion of emergency department visits attributable to rotavirus in the United States, although data from Canada suggest a proportion of >40%.11 Evidence from vaccine trials indicated that that the reduction in emergency department visits for all gastroenteritis in a population vaccinated against rotavirus was more than the reduction in outpatient settings but less than that in hospitalizations (P. Heaton, MD, written communication, 2005). Therefore, we assumed that a median of 28% of gastroenteritis-associated emergency department visits would be attributable to rotavirus. For outpatient and physician office visits for gastroenteritis, no longitudinal data on the rotavirus proportion were available; therefore, we determined a distribution by using averages from published studies in the United States and abroad (Table 1 and Appendices 1 and 2).11–16
The resulting estimated numbers of rotavirus-related outcomes were then standardized to the population <5 years of age in that year, to give the number of outcomes in the birth cohort of 4010000 over a period of 5 years. Analyses of the age distributions of rotavirus illness requiring hospitalization, outpatient visit, or no medical care were similar in several studies10,15,17–21; therefore, we applied an age distribution for rotavirus hospitalizations20 to estimate the number of outcomes requiring medical care that this birth cohort would experience at each of the following ages: <3 months, 3 to 5 months, 6 to 23 months, 24 to 35 months, 36 to 47 months, and 48 to 59 months (Fig 1).
We used estimates of 20 to 40 rotavirus-related deaths among children <5 years of age in the United States from 2 studies.22,23 In those studies, risk of death was higher at earlier ages than risk of milder outcomes; therefore, we divided the risk of death between age groups according a distribution derived from one of those studies (Fig 1 and Table 1).22
Rotavirus Gastroenteritis Not Requiring Medical Care
We assumed a uniform distribution of the overall incidence of rotavirus gastroenteritis in children <5 years of age, by using data from 2 longitudinal studies on the risk of a rotavirus gastroenteritis episode in the first 5 years of life.18,21 We distributed the risk in each age group as for episodes requiring health care (Fig 1).20 We applied these age-specific risks to the US birth cohort, to give us the total number of rotavirus episodes experienced each year by children <5 years of age. To calculate the number of children in each age group who experienced rotavirus-related gastroenteritis that did not require medical care, we subtracted the estimated numbers of deaths and episodes requiring health care from the total number of rotavirus gastroenteritis episodes (Table 1).
Costs of Disease
Direct Medical Costs
The MarketScan database (Thomson Medstat, Ann Arbor, MI) includes >500 million claim records on inpatient and outpatient health care services from 45 large employers, health plans, and public organizations and from almost 100 different payers. We extracted gross payments (reimbursements) to providers for patient visits in the 4 years of 2000 to 2003 and fitted probability distributions to each sample of costs. To extract costs of hospitalization, we applied the specific rotavirus ICD-9-CM code (code 008.61) in any of the first 15 discharge diagnoses for inpatient services, because this code is highly specific for rotavirus-confirmed infection24 and >25% of all gastroenteritis hospitalizations in the database listed this code, which suggests that these were representative of all rotavirus hospitalizations. For costs of outpatient services (ie, emergency department visit, hospital outpatient visit, or physician office visit), we used the same diarrhea-specific ICD-9-CM codes as applied to extract data from the National Health Care Survey. We chose outpatient visits for gastroenteritis attributable to any cause because the few rotavirus-coded outpatient events might have represented a bias toward more severely ill patients. We added the cost of drugs to the cost of outpatient hospital and office visits, because these were recorded separately (Table 2 and Appendix 3). Median costs of hospitalization and outpatient visits were consistent with previously published data.5,25–27
Loss of earnings per day of missed work for parents of children with gastroenteritis and lifetime productivity loss attributable to death were calculated from published tables with Bureau of Labor statistics adjusted for weekends and holidays.28 Published estimates for workdays lost for gastroenteritis seen in a physician office vary from 0.71 days to 2 days.27,29–31 We chose a midpoint of 1.3 days of missed work for rotavirus disease seen in an outpatient clinic, 10 days for every child death, 2 days for hospitalization and emergency department visits, and 1 day for episodes not requiring medical care. Our estimate of work lost for episodes requiring home care is consistent with one study of gastroenteritis in day care29 and with data for simple otitis media, which would require a comparable level and duration of home care.32 For additional costs to a family for special foods, diapers, travel, and child care, we used the average costs and SDs of these items (adjusted to 2004 dollars) reported in an outpatient study,27 and we created normal distributions for these costs (Table 2). These were consistent with costs incurred at home for the same items in 2 studies of hospitalized children.33,34
Cost of Program
The current manufacturer's list price for PRV is $62.50 per dose (excluding tax). We calculated the cost-effectiveness ratios for a range of costs associated with a complete vaccination course ($0 to $300). The cost of a full vaccination course included the cost of 3 doses of vaccine and an assumed cost of administration of $10 per dose.32,35 Although the large clinical trial of PRV did not demonstrate any association with intussusception,3 a very low risk of intussusception attributable to the vaccine remains possible. Moreover, in the early phase of vaccine introduction, anxiety regarding possible intussusception might result in more-aggressive diagnostic evaluations among vaccinees with adverse reactions. Lastly, administration of the first dose of PRV was associated with mild gastroenteritis and vomiting in some recipients (P. Heaton, MD, written communication, 2005), which could result in an extra outpatient visit. We used inpatient records to estimate that diagnosis and treatment of intussusception with the specific ICD9-CM code (code 560.0) cost $4263 (Appendix 3). At a hypothetical rate of 1 vaccine-associated intussusception case per 50000 vaccinees, this added $0.10 to the total cost of vaccination per child. By using outpatient costs for diagnosis of true intussusception as a proxy, we estimated $227 for evaluation of an adverse reaction to rule out intussusception (Appendix 3). To cover the cost of 1 extra outpatient diagnostic evaluation per 1500 vaccinees, $0.15 was added to the total cost per vaccinee. This rate of postvaccine adverse reactions is consistent with the rate of reports of nonserious gastrointestinal adverse events associated with administration of the withdrawn RRV-TV vaccine.36 No costs associated with parent travel or workdays lost were included, because we assumed that the vaccine would be administered with scheduled vaccinations (diphtheria-tetanus-acellular pertussis [DTaP] vaccine) at 2, 4, and 6 months of age.
We derived our estimates of vaccine efficacy from data from a large clinical trial of PRV (Table 3). 3 The few data available from the vaccine trial on the efficacy of an incomplete rotavirus vaccination course suggested that 1 or 2 doses might have ≥1 half the efficacy of 3 doses (P. Heaton, MD, written communication, 2005). We assumed that children 0 to 2 months of age (unvaccinated) would have no protection, those 3 to 5 months of age (1 or 2 doses) would have one half the protection, and children ≥6 months of age (3 doses) would benefit from the full vaccine efficacy.
We used “tornado graphs,” which the software constructed through stepwise regression procedures, to investigate the relative importance of the input distributions (Appendix 4). Because caregivers' loss of earnings accounts for >40% of all costs of rotavirus disease and published data on workdays lost are sparse, we examined the impact on our final results of increasing and decreasing the workdays lost by 50%, rather than including a range in the model.
Estimate of Burden Reduction During Program
In 2003, the US National Immunization Survey found that, by 3 months of age, >89% of children had received ≥1 dose of DTaP vaccine; by 6 months, 98% had received ≥1 dose of DTaP vaccine, whereas 71% had received all 3 doses.37 We calculated the reduction of disease burden and cost in the US birth cohort with 95% of children having received ≥1 dose by 3 months of age, with 70% of children >6 months of age with receipt of 3 doses of rotavirus vaccine and the remaining 25% of children >6 months of age with receipt of only 1 or 2 doses.
Rotavirus vaccination of every child in the US birth cohort would prevent 63% of all cases and 79% of all serious cases (hospitalizations, emergency department visits, and deaths) of rotavirus disease. These estimates are of reduction in all rotavirus episodes from birth and therefore are lower than clinical trial efficacy estimates that measure effects only after vaccination. From the health care perspective, the break-even total cost of rotavirus vaccination (where net savings are as likely as net costs) is $66 per vaccinee (∼$12 per dose, assuming an administration cost of $10 per dose). Rotavirus vaccination likely would be cost-saving from the health care perspective at less than $12 per dose and very probably (ie, >95% likely) would be cost-saving at less than $33 per vaccinee ($1 per dose). Vaccination would be unlikely to be cost-saving at more than $12 per dose and would incur net costs at more than $143 per vaccinee (∼$38 per dose). Similarly, from the societal perspective, rotavirus vaccination very probably would be cost-saving at a total cost of less than $107 per vaccinee (ie, 5th percentile, ∼$26 per dose) and likely would be cost-saving at up to $156 per vaccinee (ie, break-even point, ∼$42 per dose). The vaccine would be decreasingly likely to be cost-saving with prices increasing from $156, and a vaccination program would incur a net cost from the societal perspective at more than $238 per vaccinee (ie, 95th percentile, $69 per dose) (Fig 2).
At the current manufacturer's price of $62.50 per dose ($217.50 per child, including administration costs of $10 per dose), vaccination would result in a net overall cost to the health care system, with a median cost-effectiveness ratio of $336 per case prevented (5th to 95th percentile: $165 to $436), $3024 per serious case prevented (5th to 95th percentile: $1498 to $4460), and $470729 per life-year saved (5th to 95th percentile: $218710 to $738949). Vaccination would also likely incur net costs from the societal perspective, with a median cost-effectiveness ratio of $138 per case prevented (5th to 95th percentile: $44 to $247), $2636 per serious case prevented (5th to 95th percentile: $1108 to $4043), and $197190 per life-year saved (5th to 95th percentile: $67298 to $406933) (Figs 2 and 3).
In the United States, rotavirus infections result in 30 deaths, 67000 hospitalizations, 213000 emergency department visits, 37000 hospital outpatient visits, 387000 physician visits, and 2281000 cases of gastroenteritis not requiring medical care in children <5 years of age, at a total cost of $319 million to the health care system and $893 million to society. Assuming current vaccine coverage for DTaP vaccine, rotavirus vaccination would prevent 1530000 cases (51%) of any rotavirus gastroenteritis, 13 deaths (44%), 44000 rotavirus-related hospitalizations (66%), 137000 emergency department visits (64%), 22000 hospital outpatient visits (60%), and 233000 office visits (60%). At a vaccine price of $62.50 per dose, a vaccination program would incur more medical costs than savings and would have a net cost of $515 million from the health care perspective. However, a program would save $299 million in nonmedical costs and overall, from the societal perspective, would incur a net cost of $216 million (Table 4).
At a total cost of $217.50 per vaccinee, the costs of hospitalizations, emergency department visits, and extra child care were the most important variables in our model (Appendix 4). Varying the number of parental days lost also had a strong influence on the results; a 50% increase in the number of workdays lost increased the best-estimate, break-even, total cost per vaccinee from the societal perspective from $156 to $187, whereas a 50% decrease in days decreased this cost to $123 per child vaccinated (Fig 4).
We estimate that, in the United States every year, 3 million children <5 years of age develop rotavirus disease, of whom ∼700000 seek health care; 280000 of those become seriously ill (emergency department visit, hospitalization, or death). The total cost to society is $893 million, of which $319 million are to the health care system. At current coverage for the DTaP vaccine, a rotavirus vaccine program would prevent 51% of all cases of rotavirus disease and 64% of serious cases but would not be cost-saving from the health care perspective and would be unlikely to be cost-saving from the societal perspective unless the price of the vaccine were $42 or less (assuming administration costs of $10 per dose). At $217.50 per vaccinee ($62.50 per dose), a vaccine program would incur a net cost of $336 per case averted from the health care perspective and $138 per case from the societal perspective. If the vaccine was associated with low rates of adverse events, including intussusception (undetected in the prelicensure trials), then such events would have a negligible effect on the cost-effectiveness of vaccination.
Our results differ from previous cost-effectiveness analyses for rotavirus in several respects. First, and consistent with several recent studies,9,38 our updated disease burden estimates suggest that rates of hospitalizations and emergency department visits for rotavirus are not declining and, even corrected for a smaller birth cohort, might have been underestimated in the previous cost-effectiveness analysis. Because these serious events account for 90% of rotavirus health care costs, our analysis suggests that the impact of a rotavirus vaccine on health care systems may be larger than estimated previously. Second, our calculated overall costs of rotavirus disease to society are lower than the previous estimate of approximately $1 billion in 1996 dollars. This is in large part attributable to our more-conservative estimates of workdays lost, which is biased away from the case for vaccination. In particular, we used 1 workday lost for a case requiring only home care, whereas the previous analysis assumed 3.4 workdays lost whether medical care was required or not. Our results are consequently less favorable from the societal perspective, with a break-even cost of approximately $42 per vaccine dose, compared with $65 extrapolated from the previous analysis ($51 per dose in 1996 dollars, converted to 2004 dollars by using the medical care consumer price index7). However, with an extra 50% of workdays lost included in our model, the break-even cost moved to $52 per dose, below the current list price of $62.50. The CDC Vaccines for Children Fund provides free vaccines for eligible children and recently negotiated a price of $52 per dose of rotavirus vaccine.39 If the Vaccines for Children Fund purchased ∼50% of the rotavirus vaccine supply, then this would lower the cost of vaccination of $217 per vaccinee by approximately $15, although this would have little effect on the overall conclusions (Figs 2 and 3).
Our study has several limitations in the estimation of disease burden and costs. Data from clinical trials indicated a 63% reduction in all diarrhea hospitalizations among children vaccinated against rotavirus3; although the decrease was measured only among children <18 months of age, who have a relatively high incidence of rotavirus, this suggests that the true impact of a rotavirus vaccine could be substantially greater from the health care perspective than we report. Our model does not account specifically for nosocomially acquired rotavirus gastroenteritis, because no reliable data exist on the rate and cost of either treatment of these episodes or outbreak control. An unknown number of cases of nosocomial rotavirus diarrhea would have been included in the analysis, because they would have been coded as gastroenteritis at discharge.
We did not account for rotavirus disease in adults40 or for any effect of herd immunity. We might have overestimated the average value of a lost workday, because women are more often care providers but in general have lower salaries than men. Also, some evidence suggests that costs of hospitalization for rotavirus disease among vaccinated children may be lower than those among unvaccinated children.41,42 We did not use quality-adjusted life-years in our analysis because no data exist on the psychological costs of gastroenteritis of relatively short duration among young infants and parents. Future willingness-to-pay studies may better estimate the true value that parents attach to the prevention of rotavirus disease and to a risk-free vaccine. Extra costs may be incurred if pediatricians administer the vaccine in a separate visit and not concomitantly with DTaP vaccine. Program vaccine effectiveness may be lower than trial efficacy because of suboptimal vaccine storage and administration and any shift in circulating rotavirus strains to those not included in the vaccine. However, vaccine effectiveness may be higher if 1 or 2 doses provide strong protection. Although data are sparse from recent clinical trials of PRV, 1 dose of RotaShield was shown to be 89% effective against severe disease.43 The MarketScan database may under-represent poorer segments of society that are more at risk of severe, and therefore costly, rotavirus disease44 but also may be less likely to seek care for less severe episodes.
A mature rotavirus immunization program would prevent almost two thirds of all serious rotavirus disease but, at the current manufacturer's list price, would almost certainly result in net costs to the health care system and would be unlikely to be cost-saving from the societal perspective. Newer vaccines have been introduced without being considered cost-saving initially, either from the health care perspective (eg, varicella32 and hepatitis B45 vaccines) or from the societal perspective (eg, pneumococcal conjugate vaccine46). Because few children die as a result of rotavirus disease in the United States, the vaccine is currently a very expensive childhood vaccine for preventing death, even in comparison with recently introduced vaccines ($197000 per life-year saved from the societal perspective, compared with $80000 per life-year saved for pneumococcal conjugate vaccine46 and $121000 per life-year saved for meningococcal vaccine47). However, rotavirus vaccination may still be a cost-effective intervention. Although comparison of cases of different disease should be performed with care, the costs per case of rotavirus averted ($138) and per serious case averted ($2636) are comparable to the cost-effectiveness of pneumococcal conjugate vaccine in preventing otitis media ($160 per case averted) and pneumonia ($3200 per case averted).46 Future competition with other rotavirus vaccines and negotiated contracts with private organizations may result in a lower cost per dose than used in this analysis. Postlicensure surveillance data on adverse reactions and the impact of vaccination on disease burden will be needed to assess more accurately the impact and cost-effectiveness of rotavirus vaccination.
APPENDIX 1. ESTIMATION OF PROPORTION OF GASTROENTERITIS EVENTS ATTRIBUTABLE TO ROTAVIRUS FOR EACH HEALTH CARE OUTCOME
APPENDIX 2. DISTRIBUTIONS OF PERCENT OF GASTROENTERITIS-RELATED MEDICAL VISITS ATTRIBUTABLE TO ROTAVIRUS
APPENDIX 3. COSTS OF GASTROENTERITIS AND INTUSSUSCEPTION
This research was supported by intramural funds of the CDC.
We thank Robert Holman, MS, for technical assistance.
- Accepted December 12, 2006.
- Address correspondence to Marc-Alain Widdowson, VetMB, MSc, Respiratory and Enteric Virus Branch, Mailstop A34, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA 30333. E-mail:
The authors have indicated they have no financial relationships relevant to this article to disclose.
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
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- Copyright © 2007 by the American Academy of Pediatrics